RU2816208C2 - Antigenic polypeptides based on ospa sequence - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to vaccinology. Disclosed are antigenic polypeptides based on the sequence of OspA and ferritin protein and use thereof to induce an immune response to Borrelia or to protect a subject from Lyme disease. Also disclosed is a nucleic acid coding an antigenic polypeptide, a ferritin particle, a composition and a method for inducing an immune response to Borrelia or protecting a subject from Lyme disease.

EFFECT: inventions provide self-adjuvant antigenic polypeptides for protection against Borrelia infection with reduced risk of autoimmune response stimulation, allow reducing the total dose required for protection.

19 cl, 25 dwg, 3 tbl, 7 ex

Description

[0001] This application claims priority to U.S. Provisional Patent Application No. 62/652210, filed April 3, 2018, the entire contents of which are incorporated herein by reference.

[0002] This application contains a sequence listing that was filed electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy of the file in question, created on March 18, 2019, is named 2019-03-18_01121-0033-00PCT_SL.txt and is 370862 bytes in size.

[0003] Even with numerous advances in the field of vaccinology, new discoveries are needed to protect people from many life-threatening infectious diseases. Many currently licensed vaccines rely on decades-old technologies to produce live attenuated or inactivated killed pathogens, which carry safety concerns and in many cases stimulate only short-term, weak immune responses that require multiple doses. Although advances in genetic and biochemical engineering have made it possible to develop therapeutics for intractable diseases, these avenues of application in the field of vaccinology have not been fully realized. Recombinant protein technologies now enable the development of optimal antigens. In addition, nanoparticles are increasingly showing potential for optimal antigen presentation and targeted drug delivery. Nanoparticles with multiple attached antigens have been shown to have increased binding avidity provided by the multivalent display of their molecular cargo and the ability to more effectively cross biological barriers due to their nanoscopic size. Ferritin nanoparticlesHelicobacter pylori (H. pylori) fused to the influenza virus hemagglutinin (HA) protein has improved antigen stability and immunogenicity in mouse models of influenza (see Kanekiyo et al., Nature 499:102-106 (2013)). This fusion protein self-assembled into an octahedrally symmetrical nanoparticle with 8 trimeric HA spikes to produce robust immune responses in various preclinical models when administered with an adjuvant.

[0004] Lyme borreliosis is a zoonotic disease caused by certain species of bacteria of the genus Borrelia and is transmitted to humans and dogs by the bite of an infected Ixodes spp. tick. Lyme disease is a global public health problem, with cases reported in temperate climates of Europe, North America and Asia. Borrelia outer surface protein A (OspA) is the main antigen that triggers the immune response. There are at least seven different serotypes (serotypes 1–7) of OspA that are found in Borrelia worldwide. There are different Borrelia genospecies around the world, so immunity to one genospecies may not provide immunity to other bacteria that can also cause Lyme borreliosis. Additionally, the localized distributions of ticks carrying Borrelia mean that an OspA serotype associated with Lyme disease in patients in one geographic region may not be associated with Lyme disease in patients in another geographic region.

[0005] Presented herein is a set of novel polypeptides, nanoparticles, compositions, methods and routes of application including OspA polypeptides. The modified OspA polypeptide was developed to provide protection against Borrelia infection with a reduced risk of stimulating an autoimmune response. In addition, self-adjuvant antigenic polypeptides have been developed, including OspA polypeptide and ferritin, where immunostimulatory moieties, such as adjuvants, have been directly chemically attached to the antigenic polypeptide. Direct conjugation of the immunostimulatory moiety to an antigenic polypeptide allows for targeted co-delivery of the immunostimulatory moiety and the OspA polypeptide as a single macromolecular entity, which can significantly reduce the potential for systemic toxicity that is a concern with traditional vaccines that contain antigens and immunostimulatory molecules, such as adjuvants, in the form of individual molecules. Co-delivery of immunostimulatory moieties along with OspA polypeptides as a macromolecular entity and their multivalent presentation may also reduce the total dose required to provide protection, reducing manufacturing costs and costs.

SHORT DESCRIPTION

[0006] The purpose of the present disclosure is to provide compositions, kits, methods and uses that are capable of providing one or more of the benefits discussed above, or at least providing the public with a useful choice. Accordingly, the following embodiments are disclosed herein.

[0007] Embodiment 1 is an OspA sequence-based antigenic polypeptide comprising a serotype 1 OspA polypeptide from Borrelia , wherein the polypeptide does not contain the sequence of SEQ ID NO: 77.

[0008] Embodiment 2 is an antigenic polypeptide based on the OspA sequence of Embodiment 1, where the polypeptide does not have a transmembrane domain or part of a transmembrane domain.

[0009] Embodiment 3 is an antigenic polypeptide based on the OspA sequence of any of the previous embodiments, wherein the polypeptide is non-lipidated.

[0010] Embodiment 4 is an antigenic polypeptide based on the OspA sequence of any of the previous embodiments, wherein there is at least one amino acid substitution relative to the sequence of SEQ ID NO: 77, wherein the substitution reduces identity to SEQ ID NO: 78 or is non-conservative and does not result in higher identity to SEQ ID NO: 78.

[0011] Embodiment 5 is an antigenic polypeptide based on the OspA sequence of Embodiment 4, where the substitution reduces identity to SEQ ID NO: 78.

[0012] Embodiment 6 is an antigenic polypeptide based on the OspA sequence of any of the previous embodiments, wherein one or more amino acids from SEQ ID NO: 77 are replaced with the corresponding amino acid(s) from OspA of a serotype other than serotype 1.

[0013] Embodiment 7 is an antigenic polypeptide based on the OspA sequence of embodiment 6, wherein OspA of a serotype other than serotype 1 is OspA of serotype 2, 3, 4, 5, 6, or 7.

[0014] Embodiment 8 is an antigenic polypeptide based on the OspA sequence of embodiment 6, wherein each of the amino acids from SEQ ID NO: 77 is replaced by the corresponding amino acids from OspA serotype 2, 3, 4, 5, 6, or 7.

[0015] Embodiment 9 is an antigenic polypeptide based on the OspA sequence of any of the previous embodiments, wherein the polypeptide further comprises a modification to reduce or eliminate glycosylation.

[0016] Embodiment 10 is an antigenic polypeptide based on the OspA sequence of Embodiment 9, where the modification includes replacing at least one asparagine.

[0017] Embodiment 11 is an antigenic polypeptide based on the OspA sequence of embodiment 10, wherein the at least one asparagine includes any one, two, three, or more of N71, N190, N202, and N251 of OspA serotype 1.

[0018] Embodiment 12 is an antigenic polypeptide based on the OspA sequence of embodiment 11, wherein the at least one asparagine includes N71, N190, N202, and N251 from OspA serotype 1.

[0019] Embodiment 13 is an antigenic polypeptide based on the OspA sequence of any one of embodiments 10-12, wherein one or more asparagines are replaced with glutamine.

[0020] Embodiment 14 is an antigenic polypeptide based on the OspA sequence of any one of embodiments 10-13, wherein the polypeptide does not have an N-glycosylation site.

[0021] Embodiment 15 is an antigenic polypeptide based on the OspA sequence of any of the previous embodiments, wherein OspA is derived from Borrelia burgdorferi, Borrelia mayonii, Borrelia afzelii, Borrelia garinii or Borrelia bavariensis .

[0022] Embodiment 16 is an antigenic polypeptide based on the OspA sequence of any of the previous embodiments, comprising a sequence with at least 85%, 90%, 95%, 97%, 98%, 99%, 99.5%, or 100% identical to the sequence under any of SEQ ID NO: 1, 3, 4 or 53.

[0023] Embodiment 17 is an antigenic polypeptide based on the OspA sequence of any of the previous embodiments, comprising the sequence of any of SEQ ID NO: 1-10 or 12-76.

[0024] Embodiment 18 is an antigenic polypeptide based on the OspA sequence of any of the previous embodiments, including an OspA ectodomain.

[0025] Embodiment 19 is an antigenic polypeptide based on the OspA sequence of any of the previous embodiments, comprising a sequence with at least 85%, 90%, 95%, 97%, 98%, 99%, 99.5%, or 100% identical to the sequence under any of SEQ ID NO: 94-102.

[0026] Embodiment 20 is an antigenic polypeptide based on the OspA sequence of any of the previous embodiments, further comprising a ferritin protein.

[0027] Embodiment 21 is an antigenic polypeptide based on the OspA sequence of Embodiment 20, wherein ferritin contains a mutation replacing the surface exposed amino acid with cysteine.

[0028] Embodiment 22 is an antigenic polypeptide based on the OspA sequence comprising an OspA polypeptide and ferritin, wherein the ferritin contains a mutation replacing the surface exposed amino acid with cysteine.

[0029] Embodiment 23 is an antigenic polypeptide based on the OspA sequence of any one of embodiments 20-22, wherein the ferritin contains one or more of the E12C, S26C, S72C, A75C, K79C, S100C, and S111C ferritin mutations from H. pylori or one or more relevant mutations in a ferritin other than ferritin from H. pylori , as determined by pairwise or structural alignment.

[0030] Embodiment 24 is an antigenic polypeptide based on the OspA sequence of any one of embodiments 20-22, wherein the ferritin comprises the E12C mutation of H. pylori ferritin or a corresponding mutation in ferritin other than H. pylori ferritin, as defined by pairwise or structural alignment.

[0031] Embodiment 25 is an antigenic polypeptide based on the OspA sequence of any one of embodiments 20-22, wherein the ferritin comprises the S26C mutation of H. pylori ferritin or a corresponding mutation in a ferritin other than H. pylori ferritin, as defined by pairwise or structural alignment.

[0032] Embodiment 26 is an antigenic polypeptide based on the OspA sequence of any of embodiments 20-22, wherein the ferritin comprises the S72C mutation of H. pylori ferritin or a corresponding mutation in a ferritin other than H. pylori ferritin, as defined by pairwise or structural alignment.

[0033] Embodiment 27 is an antigenic polypeptide based on the OspA sequence of any one of embodiments 20-22, wherein the ferritin comprises the A75C mutation of H. pylori ferritin or a corresponding mutation in a ferritin other than H. pylori ferritin, as defined by pairwise or structural alignment.

[0034] Embodiment 28 is an antigenic polypeptide based on the OspA sequence of any one of embodiments 20-22, wherein the ferritin comprises the K79C mutation of H. pylori ferritin or a corresponding mutation in ferritin other than H. pylori ferritin, as defined by pairwise or structural alignment.

[0035] Embodiment 29 is an antigenic polypeptide based on the OspA sequence of any one of embodiments 20-22, wherein the ferritin comprises the S100C mutation of H. pylori ferritin or a corresponding mutation in ferritin other than H. pylori ferritin, as defined by pairwise or structural alignment.

[0036] Embodiment 30 is an antigenic polypeptide based on the OspA sequence of any one of embodiments 20-22, wherein the ferritin comprises the S111C mutation of H. pylori ferritin or a corresponding mutation in ferritin other than H. pylori ferritin, as defined by pairwise or structural alignment.

[0037] Embodiment 31 is an antigenic polypeptide based on the OspA sequence of any one of embodiments 20-30, comprising one or more immunostimulatory moieties linked to ferritin via a surface exposed amino acid, wherein optionally the surface exposed amino acid is a cysteine derived as a result of mutation.

[0038] Embodiment 31a is an antigenic polypeptide based on the OspA sequence of embodiment 31, wherein the immunostimulatory moiety is a TLR2 agonist, where optionally the agonist is PAM2CSK4, FSL-1, or PAM3CSK4.

[0039] Embodiment 31b is an antigenic polypeptide based on the OspA sequence of embodiment 31, wherein the immunostimulatory moiety is a TLR7/8 agonist, wherein the agonist is optionally a single-stranded RNA, an imidazoquinoline, a nucleoside analog, 3M-012, or SM7/8a.

[0040] Embodiment 31c is an antigenic polypeptide based on the OspA sequence of embodiment 31, wherein the immunostimulatory moiety is a TLR9 agonist, wherein optionally the agonist is an oligodeoxynucleotide (ODN) CpH, an ODN containing one or more 6-mer CpG motifs containing 5'-purine (Pu)-pyrimidine (Py)-C-G-Py-Pu 3', ODN containing the sequence of SEQ ID NO: 210, or ISS-1018.

[0041] Embodiment 31d is the ferritin protein of Embodiment 31c, wherein the TLR9 agonist includes a backbone containing phosphorothioate linkages.

[0042] Embodiment 31e is an antigenic polypeptide based on the OspA sequence of embodiment 31, wherein the immunostimulatory moiety is a STING agonist, wherein the agonist is optionally a cyclic dinucleotide (CDN), cdA, cdG, cAMP-cGMP, and 2'-5' ,3'-5' cGAMP or DMXAA.

[0043] Embodiment 32 is an antigenic polypeptide based on the OspA sequence of any one of embodiments 20-31e, wherein the ferritin contains a mutation replacing the surface exposed asparagine with a non-asparagine amino acid, wherein optionally the asparagine is at position 19 of the ferritin from H. pylori or at a similar position in ferritin other than ferritin from H. pylori , as determined by pairwise or structural alignment.

[0044] Embodiment 33 is an antigenic polypeptide based on the OspA sequence of any one of embodiments 20-32, wherein the ferritin contains a mutation replacing the internal cysteine with a non-cysteine amino acid, wherein optionally the internal cysteine is at position 31 of ferritin from H. pylori or at a position that corresponds to position 31 of ferritin from H. pylori , as determined by pairwise or structural alignment.

[0045] Embodiment 34 is the OspA sequence-based antigenic polypeptide of any one of embodiments 20-33, wherein the OspA sequence-based antigenic polypeptide comprises a peptide linker between the OspA polypeptide and ferritin.

[0046] Embodiment 35 is an antigenic polypeptide based on the OspA sequence of embodiment 34, wherein the peptide linker is N-terminal to ferritin.

[0047] Embodiment 35a is an antigenic polypeptide based on the OspA sequence of embodiment 34, wherein the peptide linker is C-terminal to ferritin.

[0048] Embodiment 36 is an antigenic polypeptide based on the OspA sequence of any of the previous embodiments, wherein ferritin comprises an amino acid sequence with 80%, 85%, 90%, 95%, 98%, or 99% identity to any of the SEQ IDs NO: 201-207 or 211-215.

[0049] Embodiment 36a is an antigenic polypeptide based on the OspA sequence of embodiment 36, comprising an amino acid sequence with 80%, 85%, 90%, 95%, 98%, or 99% identity to any of SEQ ID NO: 201.

[0050] Embodiment 36b is an antigenic polypeptide based on the OspA sequence of embodiment 36, comprising an amino acid sequence with 80%, 85%, 90%, 95%, 98%, or 99% identity to any of SEQ ID NO: 202.

[0051] Embodiment 36c is an antigenic polypeptide based on the OspA sequence of embodiment 36, comprising an amino acid sequence with 80%, 85%, 90%, 95%, 98%, or 99% identity to any of SEQ ID NO: 203.

[0052] Embodiment 36d is an antigenic polypeptide based on the OspA sequence of embodiment 36, comprising an amino acid sequence with 80%, 85%, 90%, 95%, 98%, or 99% identity to SEQ ID NO: 215.

[0053] Embodiment 36e is an antigenic polypeptide based on the OspA sequence of embodiment 36, comprising an amino acid sequence with 80%, 85%, 90%, 95%, 98%, or 99% identity to SEQ ID NO: 204.

[0054] Embodiment 36f is an antigenic polypeptide based on the OspA sequence of embodiment 36, comprising an amino acid sequence with 80%, 85%, 90%, 95%, 98%, or 99% identity to SEQ ID NO: 205.

[0055] Embodiment 36g is an antigenic polypeptide based on the OspA sequence of embodiment 36, comprising an amino acid sequence with 80%, 85%, 90%, 95%, 98%, or 99% identity to SEQ ID NO: 206.

[0056] Embodiment 36h is an antigenic polypeptide based on the OspA sequence of embodiment 36, comprising an amino acid sequence with 80%, 85%, 90%, 95%, 98%, or 99% identity to SEQ ID NO: 207.

[0057] Embodiment 36i is an antigenic polypeptide based on the OspA sequence of embodiment 36, comprising an amino acid sequence with 80%, 85%, 90%, 95%, 98%, or 99% identity to SEQ ID NO: 211.

[0058] Embodiment 36j is an antigenic polypeptide based on the OspA sequence of embodiment 36, comprising an amino acid sequence with 80%, 85%, 90%, 95%, 98%, or 99% identity to SEQ ID NO: 212.

[0059] Embodiment 36k is an antigenic polypeptide based on the OspA sequence of embodiment 36, comprising an amino acid sequence with 80%, 85%, 90%, 95%, 98%, or 99% identity to SEQ ID NO: 213.

[0060] Embodiment 36l is an antigenic polypeptide based on the OspA sequence of embodiment 36, comprising an amino acid sequence with 80%, 85%, 90%, 95%, 98%, or 99% identity to SEQ ID NO: 214.

[0061] Embodiment 37 is a ferritin particle containing an antigenic polypeptide based on the OspA sequence of any of embodiments 20-36l.

[0062] Embodiment 38 is an antigenic polypeptide based on the OspA sequence of any one of embodiments 1-19, further comprising a lumazine synthase protein.

[0063] Embodiment 39 is a lumazine synthase particle containing an antigenic polypeptide based on the OspA sequence of embodiment 38.

[0064] Embodiment 40 is a composition comprising an antigenic polypeptide based on the OspA sequence, a ferritin particle, or a lumazine synthase particle according to any of the previous embodiments, further comprising a pharmaceutically acceptable carrier.

[0065] Embodiment 41 is the composition of Embodiment 40 further comprising an adjuvant, where optionally the adjuvant is AF03.

[0066] Embodiment 42 is the composition of Embodiment 40 or 41, which comprises a first and second OspA sequence-based antigenic polypeptide, wherein the first and second OspA sequence-based antigenic polypeptides include OspA polypeptides of different serotypes.

[0067] Embodiment 43 is the composition of Embodiment 42 comprising one, two, three, four, five, six, or seven OspA sequence-based antigenic polypeptides selected from an OspA sequence-based antigenic polypeptide comprising an OspA serotype 1 polypeptide; an antigenic polypeptide based on the OspA sequence containing a serotype 2 OspA polypeptide; an antigenic polypeptide based on the OspA sequence containing a serotype 3 OspA polypeptide; an antigenic polypeptide based on the OspA sequence containing a serotype 4 OspA polypeptide; an antigenic polypeptide based on the OspA sequence containing an OspA serotype 5 polypeptide; an antigenic polypeptide based on the OspA sequence containing a serotype 6 OspA polypeptide; and an antigenic polypeptide based on the OspA sequence containing a serotype 7 OspA polypeptide.

[0068] Embodiment 44 is the composition of Embodiment 43 comprising an OspA sequence-based antigenic polypeptide comprising a serotype 1 OspA polypeptide; an antigenic polypeptide based on the OspA sequence containing a serotype 2 OspA polypeptide; an antigenic polypeptide based on the OspA sequence containing a serotype 3 OspA polypeptide; an antigenic polypeptide based on the OspA sequence containing a serotype 4 OspA polypeptide; an antigenic polypeptide based on the OspA sequence containing an OspA serotype 5 polypeptide; and an OspA sequence-based antigenic polypeptide comprising a serotype 7 OspA polypeptide.

[0069] Embodiment 45 is an antigenic polypeptide based on the OspA sequence, a ferritin particle, a lumazine synthase particle, or the composition of any of embodiments 1-44 for use in a method of inducing an immune response against Borrelia or for protecting a subject against Lyme disease.

[0070] Embodiment 46 is a method of inducing an immune response against Borrelia or protecting a subject from Lyme disease, comprising administering to the subject any one or more of an OspA sequence-based antigenic polypeptide, a ferritin particle, a lumazine synthase particle, or the composition of any one of Embodiment 1 -44.

[0071] Embodiment 47 is an OspA sequence-based antigenic polypeptide, ferritin particle, lumazine synthase particle, composition or method of any of embodiments 45-46, wherein the subject is a human.

[0072] Embodiment 47a is an OspA sequence-based antigenic polypeptide, ferritin particle, lumazine synthase particle, composition or method of any of embodiments 45-46, wherein the subject is a mammal, wherein optionally the mammal is a primate or domesticated mammal, wherein further optionally the primate is a non-human primate, monkey, macaque, rhesus or cynomolgus macaque, or an ape, or the domesticated mammal is a dog, rabbit, cat, horse, sheep, cow, goat, camel or donkey.

[0073] Embodiment 48 is a kit containing any one or more of an OspA sequence-based antigenic polypeptide, a ferritin particle, a lumazine synthase particle, and the compositions of embodiments 1-44, optionally with instructions for use for immunizing subjects against Lyme disease.

[0074] Embodiment 49 is a nucleic acid encoding an antigenic polypeptide based on the OspA sequence of any one of embodiments 1-36l, wherein optionally the nucleic acid is RNA.

[0075] Additional objects and advantages will be set forth in part in the description that follows, and in part will be apparent from the description, or may be ascertainable from practice. The objects and advantages will be realized and achieved through the elements and combinations specifically set forth in the appended claims.

[0076] It should be understood that both the foregoing general description and the following detailed description are illustrative and explanatory only and do not limit the claims.

[0077] The accompanying drawings, which are included in and constitute a part of this specification, illustrate several embodiments and, together with the description, serve to explain the principles described herein.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS

[0078] In FIG. 1A-1D show exemplary schematics of OspA-ferritin nanoparticles. Fig. 1A . OspA is genetically fused to ferritin to form a fusion protein. The OspA and ferritin sequences are separated by a glycine-serine linker (-GS-). Fig. 1B . The structure of the OspA ectodomain is shown. The C terminus where OspA binds to ferritin is indicated by an asterisk. Fig. 1C . An illustrative ferritin nanoparticle consisting of 24 ferritin monomers from H. pylori . Fig. 1D. Exemplary OspA-ferritin fusion protein nanoparticle. Ferritin (light gray), glycine-serine linker (GS) location, and OspA (dark gray and black) are shown ( n : number of subunits).

[0079] In FIG. 2A-2D show the expression and purification of exemplary OspA-ferritin nanoparticles. Fig. 2A . Size exclusion chromatography (SEC) profile of an exemplary OspA-ferritin nanoparticle purified on a Superose 6 column . FIG. 2B . SDS-PAGE gel of purified exemplary OspA-ferritin nanoparticles from Expi293 cells. Fig. 2C . Dynamic light scattering (DLS) profile of illustrative OspA-ferritin nanoparticles. The radius is 13 nm, the %Pd (a measure of normalized polydispersity) is 7.4, and the mass is 100%. Fig. 2D . A composite image of an illustrative OspA-ferritin nanoparticle constructed from a class-averaging of 318 particle micrographs obtained using a transmission electron microscope at 67,000x magnification. Ferritin nanoparticles appear under a transmission electron microscope as a concentrated ring-shaped seal with a hollow center. Each nanoparticle is surrounded by many short shapes corresponding to OspA, which appear round or slightly oblong.

[0080]In fig. 3A-3Bshows the formation of OspA nanoparticles of an alternative serotype inE. coli. Fig. 3A. Biochemical analysis by SDS-PAGE of OspA-ferritin serotypes 1-5 and 7 nanoparticles purified by size exclusion chromatography.Fig. 3B. Transmission electron microscopy of OspA-ferritin nanoparticles serotypes 1-5 and 7 (98000x).

[0081]In fig. 4 shows a comparison of the immunogenicity and stability of an illustrative OspA-ferritin serotype 1 nanoparticle with RECOMBITEK® Lyme (a liquid suspension of purified outer surface protein A (OspA)Borrelia burgdorferi). C3H mice (n=5) were immunized intramuscularly with 1 μg OspA-ferritin nanoparticles + Ribi adjuvant (Sigma adjuvant system, cat. no. S6322-1vl) or RECOMBITEK® Lyme at week 0 and week 4. Antibody response was assessed by endpoint titer measurements by ELISA 2 weeks after the 2nd immunization (week 6) and 21 weeks after the 2nd immunization (week 25) with each composition.

[0082]In fig. 5A-5C Provides information related to exemplary OspA-ferritin nanoparticles, wherein the OspA polypeptide is modified with an OspA serotype 1 epitope that has homology to a fragment of the human leukocyte function-associated antigen-1 (hLFA-1) sequence.Fig 5A. Structure showing the location of the homology site with LFA-1 (amino acids 165-173 of SEQ ID NO: 83) within the OspA ectodomain.Fig. 5B. Dendrogram showing the relationship of amino acids OspA 165-173 from SEQ ID NO: 83 (OspAB. burgdorferi serotype 1) with corresponding sequences in hLFA-1 and other species and serotypesBorrelia.Fig. 5C. The nine amino acid (nonapeptide) segment at amino acids 165-173 from SEQ ID NO: 83 (labeled "OspA") is compared to the corresponding nonapeptides from OspA serotype 2 and serotype 3 ("S2" (SEQ ID NO: 79) and "S3 " (SEQ ID NO: 80), respectively), a rationally designed replacement nonapeptide ("RD2"; SEQ ID NO: 81) and the corresponding nonapeptide from hLFA-1 (SEQ ID NO: 78). In fig. 5C disclosed are SEQ ID NOs 77, 79-81 and 78, respectively, in order of occurrence.Fig. 5D. C3H mice (n=5) were immunized intramuscularly (IM) at week 0 and week 4 with 1 μg doses of OspA serotype 1-ferritin nanoparticles adjuvanted with AddaVax^TM (squalene-based oil-in-water nanoemulsion; available from InvivoGen, part no. vac-adx-10). The OspA sequence included a site of homology to wild-type hLFA-1 (ie, amino acids 165-173 of SEQ ID NO: 83; "Sero1") or a replacement sequence as follows: SEQ ID NO: 81 ("RD"); SEQ ID NO: 80 ("Sero 3 replacement"); SEQ ID NO: 79 ("Sero 2 replacement"). Antibody response was assessed by endpoint titer measured by ELISA 2 weeks after the 2nd immunization with the indicated constructs.

[0083] In FIG. 6A-6B provide information relating to exemplary OspA-ferritin nanoparticles conjugated to an exemplary immunostimulatory moiety: TLR 7/8 agonist (3M-012). Fig. 6A . A 2-step click chemistry strategy was used to couple 3M-012 to ferritin. The DBCO-PEG4-maleimide linker was first attached to the surface exposed cysteine on ferritin. After removing excess linker, azide-3M-012 was added. Fig. 6B. C3H mice (n=5) were immunized intramuscularly with 1 μg of the indicated composition at weeks 0 and 4 and analyzed after 2 weeks. "Conjugate" means OspA-ferritin-3M-012 conjugated nanoparticle. “Supplement” means an unconjugated mixture of the same OspA-ferritin nanoparticles administered with 29 ng or 20 μg of 3M-012 or aluminum alum. 29 ng of the “spiked” mixture of OspA-ferritin and 3M-012 nanoparticles represents the molar equivalent of the amount of 3M-012 on the conjugated nanoparticle.

[0084] In FIG. 7A-7C show information relating to exemplary OspA-ferritin nanoparticles conjugated to an exemplary immunostimulatory moiety: ISS-1018 CpG (SEQ ID NO: 210). Fig. 7A . A 2-step click chemistry strategy was used to attach CPG to ferritin. The DBCO-PEG4-maleimide linker was first attached to the surface exposed cysteine on ferritin. After removing excess linker, azide-CpG was added. In fig. 7A discloses SEQ ID NO: 228. FIG. 7B. Biochemical analysis of CpG conjugation by SDS-PAGE in gel demonstrates the change in molecular weight after CpG conjugation with 92% of the CpG-conjugated OspA-ferritin nanoparticles. Fig. 7C. C3H mice (n=5) were immunized intramuscularly with 1 μg of the indicated composition at weeks 0 and 4 and analyzed after 2 weeks. "Conjugate" means an OspA-ferritin-CPG conjugated nanoparticle. “Supplement” means an unconjugated mixture of the same OspA-ferritin nanoparticles administered with 339 ng or 50 μg of CpG or alum. The 339 ng of “spiked” mixture of OspA-ferritin and CPG nanoparticles represents the molar equivalent of the amount of CpG on the conjugated nanoparticle.

[0085] In FIG. 8A-8F compare antibody responses to serotype 1 ( Fig. 8A ), serotype 2 ( Fig. 8B ), serotype 3 ( Fig. 8C ), serotype 4 ( Fig. 8D ), serotype 5 ( Fig. 8E ), and serotype 7 ( Fig. 8F ) following administration of monovalent serotype-matched OspA-ferritin nanoparticles (1 μg per dose) (“monovalent”) adjuvanted with aluminum alum, or a hexavalent composition containing each of the OspA serotype 1-containing particle types. ferritin, OspA serotype 2-ferritin, OspA serotype 3-ferritin, OspA serotype 4-ferritin, OspA serotype 5-ferritin, and OspA serotype 7-ferritin, 1 μg each per dose with Alum adjuvant (“hexavalent”). C3H mice (n=5) were immunized intramuscularly at weeks 0 and 4, and antibody responses were assessed by endpoint titer measured by ELISA at 2 weeks. ELISA plates were coated with the specific serotype OspA protein.

[0086]In fig. 9A-9Gshows antibody responses in mice to serotype 1 (fig. 9A), serotype 2 (fig. 9B), serotype 3 (fig. 9C), serotype 4 (fig. 9D), serotype 5 (fig. 9E), serotype 6 (fig. 9F) and serotype 7 (fig. 9G) observed in mice after administration of conjugated and unconjugated hexavalent compositions based on OspA-ferritin nanoparticles. The hexavalent compositions contained each type of nanoparticle containing OspA serotype 1-ferritin, OspA serotype 2-ferritin, OspA serotype 3-ferritin, OspA serotype 4-ferritin, OspA serotype 5-ferritin, and OspA serotype 7-ferritin, as described for FIG. 8A-F, except that “hexavalent nanoparticle-CPG” and “hexavalent nanoparticle-3M-012” mean that the nanoparticles have been chemically conjugated to CPG and 3M-012 (see fig. 7A and 6A and accompanying description). Antibody response was assessed by endpoint titer measured by ELISA after 2 weeks. ELISA plates were coated with the specific serotype OspA protein.

[0087] In FIG. 10A-10G show antibody responses to serotypes 1-7, respectively, in rhesus monkeys (n=3 per group) to the hexavalent OspA-ferritin nanoparticle compositions that were described for FIG. 9A-G, except that the doses were a total of 60 μg (10 μg of each serotype) and contained unconjugated AF03 adjuvant. Monkeys were immunized intramuscularly at week 0 and week 6. Antibody responses were analyzed 2 weeks after immunization by endpoint titer measured by ELISA. RECOMBITEK® Lyme was used as a reference standard at a dose of 10 μg. For all experiments, the ELISA plate was coated with OspA protein of the serotype indicated in each panel.

[0088]In fig. 10H-10N shows antibody responses to serotypes 1-7, respectively, in rhesus monkeys (n=3 per group) to the hexavalent OspA-ferritin nanoparticle formulations that were described for FIG. 10A-G, except that the AF03 adjuvant was not used and the nanoparticles were instead conjugated with 3M-012 or CpG (see Fig. fig. 6A and 7A and accompanying description). Doses totaled 60 μg (10 μg of each serotype). Monkeys were immunized intramuscularly at week 0 and week 6. Antibody responses were analyzed 2 weeks after immunization by endpoint titer measured by ELISA. For all experiments, the ELISA plate was coated with OspA protein of the serotype indicated in each panel.

[0089]In fig. eleven The results of testing compositions based on OspA-ferritin nanoparticles conjugated to 3M-012 during tick infection are shown. Mice were immunized with a 1 μg dose of the indicated compositions at week 0 and week 4. The monovalent composition contained 1 μg of OspA-ferritin serotype 1 nanoparticles conjugated to 3M-012. The "hexavalent nanoparticle-3M-012" composition was as described for FIG. 9A-G. The control particle did not contain the OspA polypeptide. Mice were infected with 5-6 ticks infected with the strain N40Borrelia burgdorferi(serotype 1), for 5 days two weeks after the second immunization and sacrificed two weeks later. Tissue samples from the heart, ankle and ear were cultured in BSK medium with antibiotics againstB. burgdorferiwithin 6 weeks. Specimens negative for infection were tested by PCR for the presence ofB. burgdorferi.A sample positive for infection was positive by either culture or PCR.

[0090] In FIG. 12 shows confirmation of the conjugation of OspA-ferritin nanoparticles with the TLR 7/8 agonist 3M-012 using mass spectrometry. The top panel shows unconjugated and the bottom panel shows conjugated constructs. The data shows a mass change of 586.69 Da, corresponding to the addition of 3M-012.

[0091] In FIG. 13 shows the antibody response in mice to non-glycosylated mutant OspA-ferritin (NG-RD) compared to its glycosylated counterpart (RD), measured by ELISA in a dilution series as shown. RD=SEQ ID NO: 52. NG-RD=SEQ ID NO: 53. Mice were vaccinated at 1 μg doses at week zero and week 4.

[0092] In FIG. 14 shows the antibody response in mice to OspA-ferritin (SEQ ID NO: 52). Glycosylation mutant OspA-ferritin N>Q (SEQ ID NO: 53) and glycosylation mutant OspA-ferritin S/T>A (SEQ ID NO: 63) were compared with RECOMBITEK® Lyme and negative (preimmune) controls as measured with using ELISA in a series of dilutions as shown.

[0093] In FIG. 15A-15E show the purification and characterization of OspA constructs containing various linkers (GS, Gly-Ser linker; GS1, Gly-Gly-Gly-Ser linker (SEQ ID NO: 226); GS2, linker under SEQ ID NO: 91; GS5 , linker under SEQ ID NO: 92; the sequences of the constructs were SEQ ID NO: 53 and 60-62, respectively). Fig. 15A. Coomassie staining of purified OspA constructs containing the indicated linkers. In fig. 15A disclosed are SEQ ID NOs 226 and 91-92, respectively, in order of occurrence. Fig. 15B. Dynamic light scattering (DLS) of OspA-ferritin nanoparticle containing GS1 (SEQ ID NO: 60). Fig. 15C. DLS of OspA-ferritin nanoparticle containing GS2 (SEQ ID NO: 61). Fig. 15D. Electron micrograph (EM) of OspA-ferritin nanoparticle containing GS5 (SEQ ID NO: 62). Fig. 15E. DLS of OspA-ferritin nanoparticle containing GS5 (SEQ ID NO: 62).

[0094] In FIG. 16 shows the antibody response in mice to OspA-ferritin constructs containing various linkers (1X GGGS linker construct (SEQ ID NO: 226), SEQ ID NO: 60; 2x GGGS linker construct (SEQ ID NO: 91), SEQ ID NO: 61; 5X GGGS linker construct (SEQ ID NO: 92), SEQ ID NO: 62), compared to RECOMBITEK® Lyme and negative (preimmune) controls, as measured by dilution series ELISA as shown .

[0095] In FIG. 17A-17C show characterization of the serotype 4 lumazine synthase-OspA construct (SEQ ID NO: 18). Fig. 17A. DLS data. Fig. 17B. Coomassie gel of the indicated fractions 22-64 by trace size exclusion chromatography (SEC). Fig. 17C. EM data.

[0096] In FIG. 18 shows the antibody response in mice to the OspA serotype 4-ferritin construct (SEQ ID NO: 4) and the OspA serotype 4-lumazine synthase construct (SEQ ID NO: 18) with or without aluminum alum.

[0097] In FIG. 19A-19C show characterization of the OspA serotype 1-lumazine synthase construct (SEQ ID NO: 12). Fig. 19A. EM data. Fig. 19B. Gel with Coomassie of the indicated fractions 20-40 with SEC trace amounts. Fig. 19C. DLS data.

[0098] In FIG. 20A-20C show characterization of the OspA serotype 2-lumazine synthase construct (SEQ ID NO: 16). Fig. 20A. EM data. Fig. 20B. Gel with Coomassie of the indicated fractions 27-56 with SEC trace amounts. Fig. 20C. DLS data.

[0099] In FIG. 21A-21B show characterization of the OspA serotype 3-lumazine synthase construct (SEQ ID NO: 17). Fig. 21A. Gel with Coomassie of the indicated fractions 23-39 with SEC trace amounts. Fig. 21B. DLS data.

[00100] In FIG. 22A-22C show characterization of the OspA serotype 5-lumazine synthase construct (SEQ ID NO: 19). Fig. 22A. EM data. Fig. 22B. Gel with Coomassie of the indicated fractions 22-38 with SEC trace amounts. Fig. 22C. DLS data.

[00101] In FIG. 23A-23C show characterization of the OspA serotype 7-lumazine synthase construct (SEQ ID NO: 21). Fig. 23A. EM data. Fig. 23B. Gel with Coomassie of the indicated fractions 20-38 with SEC trace amounts. Fig. 23C. DLS data.

[00102] In FIG. 24A-24G show antibody responses to serotypes 1-7, respectively, in C3H mice (n=5 per group) to heptavalent compositions based on OspA-ferritin nanoparticles, 1 μg of each type of OspA-ferritin nanoparticle corresponding to OspA serotypes 1-7 (total 7 μg) to which either alum, AF03, or RECOMBITEK® Lyme were added as an adjuvant. For all experiments, the ELISA plate was coated with OspA protein of the serotype indicated in each panel as “SX,” where X represents the serotype number.

[00103] In FIG. Figure 25 shows the dynamics of antibody titer at the end point in rhesus monkeys. Monkeys were immunized intramuscularly at week 0 and week 6 with either hexavalent OspA-ferritin vaccine (containing OspA serotypes 1, 2, 3, 4, 5 and 7 in individual nanoparticles) adjuvanted with AF03 or RECOMBITEK®. The ELISA plate was coated with OspA serotype 1 protein.

DETAILED DESCRIPTION

[00104] This document provides new antigens for vaccination against Lyme disease. Lyme disease is caused by bacteria belonging to the Borrelia burgdorferi sensu lato ( s.l. ) complex (herein referred to as " Borrelia "). The antigens described herein include antigenic polypeptides, fusion proteins, nanoparticles and compositions that can be used alone or with an unconjugated adjuvant to vaccinate subjects against Lyme disease. Fusion proteins may include antigenic polypeptides fused to ferritin. Ferritin may be wild-type ferritin or may include one or more mutations, for example, a mutation to replace a surface-exposed amino acid with a cysteine such that immunostimulatory moieties can be directly conjugated to the engineered surface-exposed cysteine. The cysteine resulting from such a mutation can eliminate or reduce the need for a separately administered adjuvant, and potentially reduce the amount of adjuvant/immunostimulatory moiety required to elicit an immune response to the antigen. Also provided are nucleic acids that encode the antigenic polypeptides described herein.

Definitions

[00105] As used herein, the term “adjuvant” refers to a substance or carrier medium that nonspecifically enhances the immune response to an antigen. Adjuvants may include, but are not limited to, a suspension of minerals (eg, aluminum alum, aluminum hydroxide, or phosphate) onto which the antigen is adsorbed; a water-in-oil or oil-in-water emulsion in which a solution of the antigen is emulsified in mineral oil or water (for example, Freund's incomplete adjuvant). Sometimes killed mycobacteria are included (eg, Freund's complete adjuvant) to further enhance antigenicity. Immunostimulatory oligonucleotides can also be used as adjuvants (for example, see US Patent Nos. 6194388, 6207646, 6214806, 6218371, 6239116, 6339068, 6406705 and 6429199). Adjuvants may also include biological molecules such as Toll-like receptor (TLR) agonists and costimulatory molecules. The adjuvant can be administered as a single molecule in the composition or covalently linked (conjugated) to a modified ferritin or antigenic polypeptide based on the ferritin sequence.

[00106] As used herein, the term “antigen” refers to an agent that elicits an immune response and/or an agent that is bound by a T cell receptor (eg, when presented by an MHC molecule) or an antibody (eg, produced by a B-cell receptor). cell) when exposed or introduced into the body. In some embodiments, the antigen induces a humoral response (eg, including the formation of antigen-specific antibodies) in the body. Alternatively or additionally, in some embodiments, the antigen elicits a cellular response (eg, involving T cells whose receptors specifically interact with the antigen) in the body. A particular antigen may elicit an immune response in one or more members of the target organism (eg, mice, rabbits, primates, humans), but not all members of the target organism's species. In some embodiments, the antigen elicits an immune response in at least about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85 %, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% representatives of the target organism species. In some embodiments, the antigen binds to an antibody and/or a T cell receptor and may or may not induce a specific physiological response in the body. In some embodiments, for example, an antigen can bind to an antibody and/or a T cell receptor in vitro, regardless of whether such interaction occurs in vivo. In some embodiments, the antigen reacts with specific humoral or cellular immune products, including inducible heterologous immunogens. Antigens include ferritin antigenic proteins, including a ferritin polypeptide (eg, including one or more mutations) and a non-ferritin polypeptide described herein.

[00107] As used herein, the terms “ferritin” or “ferritin protein” refer to a protein with detectable sequence identity to ferritin from H. pylori (SEQ ID NO: 208 or 209) or other ferritin discussed herein, such as ferritin P. furiosus , Trichoplusia ni ferritin or human ferritin, which serves to store iron, for example intracellularly or in tissues, or to transport iron in the bloodstream. Such exemplary ferritins, including those that occur as two polypeptide chains known as heavy and light chains (eg, T. ni ferritin and human ferritin), are discussed in detail below. In some embodiments, ferritin includes a sequence of at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or 99.5% identity to the ferritin sequence disclosed herein, for example, in Table 1 (sequence table). Ferritin may be a fragment of a full-length naturally occurring sequence. As used herein, the term “wild-type ferritin” refers to ferritin whose sequence consists of a naturally occurring sequence. Ferritins also include full-length ferritin or a fragment of ferritin with one or more differences in its amino acid sequence from wild-type ferritin.

[00108] As used herein, the term “ferritin monomer” refers to one ferritin molecule (or, if applicable, one ferritin heavy or light chain) that has not been assembled with other ferritin molecules. A "ferritin multimer" contains several associated ferritin monomers. "Ferritin protein" includes monomeric ferritin and multimeric ferritin.

[00109] As used herein, the term “ferritin particle” refers to ferritin that has self-assembled into a globular form. Ferritin particles are sometimes called "ferritin nanoparticles" or simply "nanoparticles". In some embodiments, the ferritin particle contains 24 ferritin monomers (or, if applicable, 24 total heavy and light chains).

[00110] As used herein, the term “hybrid ferritin” refers to a ferritin comprising ferritin from H. pylori with an amino terminal extension from bullfrog ferritin. An exemplary sequence used as an amino-terminal extension from bullfrog ferritin is provided as SEQ ID NO: 217. In a hybrid ferritin, the amino-terminal extension from bullfrog ferritin can be fused to ferritin from H. pylori such that the attachment sites of the immunostimulatory moieties are evenly distributed distributed on the surface of the ferritin particle. As used herein, the term “bullfrog linker” is a linker containing the sequence of SEQ ID NO: 217. Hybrid ferritin is also sometimes referred to as “bfpFerr” or “bfp-ferritin”. Any of the constructs comprising a bullfrog sequence may be provided without the bullfrog sequence, eg, without a linker or with an alternative linker. Exemplary bullfrog linker sequences are provided in Table 1. If a bullfrog linker is shown in Table 1, the same construct can be made without the linker or with an alternative linker.

[00111] As used herein, the term "glycosylation" refers to the addition of a saccharide unit to a protein.

[00112] As used herein, the term “immune response” refers to the response of an immune system cell, such as a B cell, T cell, dendritic cell, macrophage, or polymorphonuclear leukocyte, to a stimulus, such as an antigen or vaccine. The immune response may include any cell of the body involved in the host defense response, including, for example, an epithelial cell that secretes interferon or a cytokine. The immune response includes, but is not limited to, the innate and/or adaptive immune response. As used herein, the term “protective immune response” refers to an immune response that protects a subject from infection (eg, prevents infection or prevents the development of disease associated with infection). Methods for measuring immune responses are well known in the art and include, for example, measuring proliferation and/or activity of lymphocytes (such as B or T cells), secretion of cytokines or chemokines, inflammation, antibody formation, and the like. An “antibody response” is an immune response in which antibodies are produced.

[00113] As used herein, the term "immunostimulatory fragment" refers to a fragment that is covalently attached to ferritin or an antigenic polypeptide based on a ferritin sequence and that is capable of activating a component of the immune system (either alone or when attached to ferritin or an antigenic polypeptide based on a ferritin sequence ferritin). Exemplary immunostimulatory moieties include toll-like receptor (TLR) agonists, such as TLR 4, 7, 8, or 9. In some embodiments, the immunostimulatory moiety is an adjuvant.

[00114] As used herein, the term “kit” refers to a packaged collection of associated components, such as one or more compounds or compositions and one or more associated materials, such as solvents, solutions, buffers, instructions, or drying agents.

[00115] As used herein, the term “N-glycan” refers to a saccharide chain attached to a protein at the amide nitrogen of the N (asparagine) residue of the protein. Thus, N-glycan is formed through the process of N-glycosylation. This glycan may be a polysaccharide.

[00116] As used herein, the term “OspA ectodomain” refers to approximately amino acid residues 27-273 of B. burgdorferi OspA (UniProt, accession no. P0CL66) or the corresponding positions of its homologue identified by pairwise or structural alignment. Additional examples of OspA ectodomains include positions 27-X of any of SEQ ID NOs: 83-89, where X represents the C-terminal position of the relevant sequence, where optionally the C-terminal Lys is omitted. In some embodiments, the ectodomain further comprises at its N-terminus the 26th residue or the 25th and 26th residues of the corresponding full-length wild-type sequence; in SEQ ID NO: 83-89, the 25th and 26th residues are Asp and Glu. The following additional examples of OspA ectodomains include any of SEQ ID NOs: 94-102, wherein optionally the N-terminal 1, 2 or 3 residues (Met-Asp-Glu) are omitted, wherein additionally the optional C-terminal Lys is omitted.

[00117] As used herein, the term “transmembrane domain of OspA” refers to approximately amino acid residues 2-24 of B. burgdorferi OspA (UniProt, accession no. P0CL66) or the corresponding positions of its homologue identified by pairwise or structural alignment.

[00118] As used herein, the term “self-adjuvant” refers to a composition or polypeptide comprising ferritin and an immunostimulatory moiety directly conjugated to ferritin such that the ferritin and the immunostimulatory moiety are contained within a single molecular entity. An antigenic polypeptide based on the ferritin sequence, including a polypeptide other than ferritin, can be conjugated to an immunostimulatory moiety to form a self-adjuvant polypeptide.

[00119] As used herein, the term “OspA sequence-based antigenic polypeptide” refers to a polypeptide comprising all of OspA or a portion of OspA of sufficient length such that the polypeptide is antigenic to OspA. Full-length OspA includes a transmembrane domain and an ectodomain, defined below. Antigenicity may be a feature of the OspA sequence as part of a construct additionally containing a heterologous sequence such as ferritin or lumazine synthase protein. That is, if OspA is part of a construct additionally containing a heterologous sequence, then it is sufficient that the construct can serve as an antigen that generates antibodies to OspA regardless of whether the OspA sequence without the heterologous sequence is capable of doing so.

[00120] “Ferritin sequence-based antigenic polypeptide” and “ferritin antigenic protein” are used interchangeably herein to mean a polypeptide comprising ferritin and a non-ferritin polypeptide, such as OspA, of sufficient length such that the molecule is antigenic to the polypeptide , different from ferritin. The ferritin sequence-based antigenic polypeptide may further comprise an immunostimulatory moiety. The antigenicity may be a feature of a sequence other than the ferritin sequence as part of a larger construct. That is, it is sufficient that the construct can serve as an antigen against a non-ferritin polypeptide, regardless of whether the non-ferritin polypeptide can do so without ferritin (and the immunostimulatory moiety, if applicable). In some embodiments, the non-ferritin polypeptide is an OspA polypeptide, in which case the ferritin sequence-based antigenic polypeptide is also an "OspA sequence-based antigenic polypeptide." However, by way of clarification, an “antigenic polypeptide based on the OspA sequence” does not necessarily include ferritin. The term “antigenic polypeptide” is used herein to refer to a polypeptide that is a ferritin sequence-based antigenic polypeptide or an OspA sequence-based antigenic polypeptide, or both. The present invention describes nucleic acid sequences and amino acid sequences having a certain degree of identity with a given nucleic acid sequence or amino acid sequence, respectively (reference sequence).

[00121] "Sequence identity" of two nucleic acid sequences indicates the percentage of nucleotides that are identical in the two sequences. The "sequence identity" of two amino acid sequences indicates the percentage of amino acids that are identical in the two sequences.

[00122] The terms "% identical", "% identity" or similar terms are intended to indicate, in particular, the percentage of nucleotides or amino acids that are identical when optimally aligned in the compared sequences. The percentages stated are purely statistical and the differences between two sequences may, but need not, be randomly distributed over the entire length of the sequences being compared. Comparison of two sequences is typically accomplished by comparing said sequences after optimal alignment with respect to a segment or “window of comparison” to identify local regions of the corresponding sequences. Optimal alignment for comparison can be done manually or using the local homology search algorithm according to Smith and Waterman, 1981, Ads App. Math. 2, 482, using the local homology search algorithm according to Neddleman and Wunsch, 1970, J. Mol. Biol. 48, 443, using the matching algorithm of Pearson and Lipman, 1988, Proc. Natl Acad. Sci. USA 88, 2444, or by computer programs that use these algorithms (GAP, BESTFIT, FASTA, BLAST P, BLAST N and TFASTA in the Wisconsin Genetics software package, Genetics Computer Group, 575 Science Drive, Madison, WI).

[00123] Percent identity is obtained by determining the number of identical positions at which the compared sequences match, dividing this number by the number of positions being compared (e.g., the number of positions in the reference sequence), and multiplying this result by 100.

[00124] In some embodiments, the degree of identity is given for a region that is at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or approximately 100% of the full length of the reference sequence. For example, if the reference nucleic acid sequence consists of 200 nucleotides, then the degree of identity is given for at least about 100, at least about 120, at least about 140, at least about 160, at least about 180, or about 200 nucleotides , in some embodiments, for continuous nucleotides. In some embodiments, the degree of identity is given for the full length of the reference sequence.

[00125] Nucleic acid sequences or amino acid sequences that have a certain degree of identity to a given nucleic acid sequence or amino acid sequence, respectively, may have at least one functional property of that specified sequence, for example, and in some cases are functionally equivalent to that specified sequence. One important property includes the ability to act as a cytokine, particularly when administered to a subject. In some embodiments, a nucleic acid sequence or amino acid sequence having a certain degree of identity to a given nucleic acid sequence or amino acid sequence is functionally equivalent to the specified sequence.

[00126] As used herein, the term “subject” refers to any member of the animal kingdom. In some embodiments, “subject” refers to people. In some embodiments, “subject” refers to non-human animals. In some embodiments, subjects include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and/or worms. In certain embodiments, the non-human subject is a mammal (eg, rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cattle, primate, and/or pig). In some embodiments, the subject may be a transgenic animal, a genetically engineered animal, and/or a clone. In certain embodiments of the present invention, the subject is an adult, adolescent, or infant. In some embodiments, the terms “individual” or “patient” are used and are intended to be interchangeable with the term “subject.”

[00127] As used herein, the term "surface exposed" amino acid refers to an amino acid residue in a protein (eg, ferritin) with a side chain that is capable of contact with solvent molecules when the protein is in its native three-dimensional conformation after multimerization, if applicable. Thus, for example, in the case of ferritin that forms a 24-mer, the surface exposed amino acid residue is one whose side chain is capable of contacting a solvent when the ferritin is assembled as a 24-mer, eg, as a ferritin multimer or ferritin particle.

[00128] As used herein, the terms “vaccinate” or “vaccinate” refer to the administration of a composition intended to generate an immune response, for example, to a disease-causing factor. Vaccination can be administered before, during, and/or after exposure to a disease-causing agent and/or development of one or more symptoms, and, in some embodiments, before, during, and/or shortly after exposure to the agent. In some embodiments, vaccination includes repeated administration of the vaccination composition at appropriate intervals.

OspA polypeptides

[00129] OspA polypeptides are provided that can be antigenic when administered alone, adjuvanted as a single molecule, and/or as part of a nanoparticle (eg, ferritin particle or lumazine synthase particle) that can be self-adjuvant. In some embodiments, the OspA polypeptide includes a modified outer surface protein A (OspA) fromBorrelia. OspA exists in a number of serotypes, as determined by their reactivity with monoclonal antibodies to various OspA epitopes (see OspA). Wilske et al., J Clin Microbio 31(2):340-350 (1993)). These serotypes correlate with different bacterial gene speciesBorrelia. In some embodiments, OspA is any of serotypes 1-7. In some embodiments, OspA is derived fromBorrelia burgdorferi,Borrelia mayonii, Borrelia afzelii, Borrelia gariniiorBorrelia bavariensis. In some embodiments, OspA is OspABorrelia burgdorferi. In some embodimentsBorrelia can be carried by ticksIxodes. In some embodimentsBorrelia representsBorrelia burgdorferi,Borrelia mayonii, Borrelia afzelii, Borrelia gariniiorBorrelia bavariensis.

[00130] In some embodiments, the OspA polypeptide is a serotype 1 OspA polypeptide, such as the ectodomain of serotype 1 OspA. The serotype 1 OspA epitope at amino acids 165-173 of SEQ ID NO: 83 has been reported in the literature to have homology to a sequence fragment human leukocyte function-associated antigen-1 (hLFA-1), i.e. SEQ ID NO: 78 (see Gross, D.M., et al., Science 281(5377): p. 703-6 (1998)). Amino acids 165-173 of SEQ ID NO: 83 are shown as an isolated nonapeptide in SEQ ID NO: 77 and are referred to as the site of homology with hLFA-1. SEQ ID NO: 83 is an exemplary wild-type serotype 1 OspA sequence, which is used herein as a reference sequence when discussing amino acid positions in OspA. This site of homology may play a role in the development of Lyme arthritis, including antibiotic-resistant Lyme arthritis. Disclosed herein are antigenic polypeptides based on the OspA sequence, including a modified OspA serotype 1 polypeptide fromBorreliawherein the modified OspA does not include the sequence of SEQ ID NO: 77. Such polypeptides, when used to induce antibody formation, may have improved safety, such as a reduced risk of triggering an autoimmune response. In some embodiments, the serotype 1 OspA polypeptide has one or more modifications that reduce identity with hLFA-1. Any modification to reduce homology to SEQ ID NO: 78, to reduce identity to SEQ ID NO: 78, or to introduce one or more non-conservative substitutions relative to SEQ ID NO: 78 is covered. In some embodiments, an antigenic polypeptide is provided comprising an OspA serotype 1 polypeptide fromBorreliawherein the polypeptide does not include the sequence of SEQ ID NO: 77. In some embodiments, the antigenic polypeptide includes the ectodomain of OspA serotype 1, where the ectodomain does not include the sequence of SEQ ID NO: 77. In some embodiments, the antigenic polypeptide of OspA serotype 1 includes the sequence from at least 85%, 90%, 95%, 97%, 98%, 99%, 99.5%, or 100% sequence identity to any of SEQ ID NOs: 94-102.

[00131] “Reduced homology” includes reduction in sequence identity and/or reduction in sequence similarity, where each member of the series of amino acids listed as conservative substitutions in the table below is considered similar to the specified parent residue and other members of the series; for example, the first row of the table indicates that alanine, valine, leucine, and isoleucine are similar to each other, and the eighth row indicates that alanine and glycine are similar to each other. The similarity is not transitive, so, for example, isoleucine and glycine are not considered similar. In some embodiments, the modified OspA includes a serotype 1 OspA protein with reduced homology to hLFA-1 compared to wild-type serotype 1 OspA. In some embodiments, the modified OspA includes OspA serotype 1 including a modification of any one or more amino acids from SEQ ID NO: 77. In some embodiments, the modification in SEQ ID NO: 77 is a non-conservative amino acid substitution. A non-conservative substitution is a substitution other than the conservative substitutions shown in the following table.

Table 3. Conservative amino acid substitutions

Original
remainder Conservative
replacements Ala (A) Val; Leu; Ile Arg(R) Lys; Gln; Asn Asn(N) Gln; His; Asp, Lys; Arg Asp (D) Glu; Asn Cys(C) Ser; Ala Gln (Q) Asn; Glu Glu (E) Asp; Gln Gly (G) Ala His(H) Asn; Gln; Lys; Arg Ile (I) Leu; Val; Met; Ala;
Phe, norleucine Leu (L) Norleucine; Ile; Val;
Met; Ala; Phe Lys (K) Arg; Gln; Asn Met(M) Leu; Ph; Ile Phe (F) Trp; Leu; Val; Ile; Ala; Tyr Pro (P) Ala Ser (S) Thr Thr (T) Val; Ser Trp(W) Tyr; Phe Tyr (Y) Trp; Ph; Thr; Ser Val(V) Ile; Leu; Met; Ph;
Ala, norleucine

[00132] In some embodiments, one or more amino acids from SEQ ID NO: 77 are replaced with the corresponding amino acid(s) from an OspA serotype other than serotype 1, for example, from an OspA serotype 2, 3, 4, 5, 6, or 7. In some embodiments, each of the amino acids from SEQ ID NO: 77 is replaced with the corresponding amino acid(s) from OspA serotype 2, 3, 4, 5, 6, or 7. In some embodiments, the amino acids from SEQ ID NO: 77 replaced by the corresponding amino acids from serotype 2 (S2, SEQ ID NO: 79) or serotype 3 (S3, SEQ ID NO: 80).

[00133] In some embodiments, the modified OspA includes SEQ ID NO: 81. In some embodiments, the modified OspA includes SEQ ID NO: 82. SEQ ID NO: 81 and 82 are intended to replace SEQ ID NO: 77 and thereby reduce homology with SEQ ID NO: 78.

[00134] In some embodiments, the polypeptide is full-length OspA (eg, including a transmembrane domain and an ectodomain, which may or may not include modification to reduce homology with hLFA-1, as described herein).

[00135] In some embodiments, the polypeptide does not have a transmembrane domain. In some embodiments, the polypeptide lacks part of the transmembrane domain, for example, N-terminal 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 amino acids from the wild-type OspA sequence. In some embodiments, the polypeptide does not have a segment comprising amino acid 17 of OspA serotype 1 or the corresponding position of a homologue thereof, as identified through pairwise or structural alignment. In some embodiments, the polypeptide does not have at least amino acids 1-17 of OspA, such as OspA serotype 1, or similar amino acids in its homologue, as identified through pairwise or structural alignment. In some embodiments, the polypeptide lacks at least 18, 19, 20, 21, 22, 23, or 24 N-terminal amino acids of OspA, such as OspA serotype 1, or similar amino acids in its homologue, as identified through pairwise or structural alignment. In some embodiments, the polypeptide does not have amino acids 1-25 of OspA, such as OspA serotype 1, or similar amino acids in its homologue, as identified through pairwise or structural alignment. In some embodiments, the polypeptide does not have amino acids 1-26 of OspA serotype 1, or similar amino acids in its homolog, as identified through pairwise or structural alignment. For the avoidance of doubt, the absence of a transmembrane domain does not require the absence of an N-terminal methionine in the polypeptide; for example, a polypeptide in which the first residue is methionine and the second residue corresponds to residue 26 of wild-type OspA, followed by residues corresponding to 27, 28, etc. residues of wild-type OspA are considered to lack a transmembrane domain. In some embodiments, the polypeptide comprising OspA does not have a lipidation site, such as the lipidation site contained in the transmembrane domain of wild-type OspA serotype 1. In some embodiments, the polypeptide does not contain cysteine 17 of OspA serotype 1. In some embodiments, the polypeptide does not contain a cysteine that corresponds to any of positions 1-25 of wild-type OspA, such as any of SEQ ID NOs: 83-89. In some embodiments, the polypeptide lacks or has a cysteine 17 substitution of OspA serotype 1. In some embodiments, the polypeptide lacks at least a portion of the wild-type OspA transmembrane domain such that it does not have a lipidation site. In some embodiments, the polypeptide does not have amino acids that align with amino acids 1-17 of OspA serotype 1.

[00136] In some embodiments, the polypeptide does not contain a palmitoyl group. In some embodiments, the polypeptide does not contain a diacylglycerol group. In some embodiments, the polypeptide is non-lipidated. In some embodiments, the polypeptide does not have a lipidation site. In some embodiments, the lipidation site is contained within a transmembrane domain. In some embodiments, the lipidation site that is removed is cysteine 17 of OspA serotype 1. In some embodiments, the polypeptide does not have or has a substitution at cysteine 17 of OspA serotype 1.

[00137] In some embodiments, removal of the OspA lipidation site and/or transmembrane domain or portion thereof, and/or the absence of a palmitoyl and/or diacylglycerol group allows for easier protein purification, for example, by improving protein solubility, and/or makes the protein more useful for purification using techniques such as ion exchange and other forms of chromatography.

[00138] In some embodiments, the polypeptide includes a mammalian leader sequence (also known as a signal sequence). In some embodiments, the mammalian leader sequence results in secretion of the polypeptide when expressed in mammalian cells.

[00139] In some embodiments, the polypeptide does not have a glycosylation site. Modifications to remove glycosylation sites are described in detail herein. The OspA polypeptides of the present invention may include any such modification, which may be combined with any other modifications described herein, including modifications of the hLFA-1 homology site and/or deletion of part or all of the transmembrane domain. In some embodiments, the polypeptide does not include SEQ ID NO: 77 (eg, has reduced homology to hLFA-1a) and has modifications to reduce glycosylation, and/or lacks a transmembrane domain.

1. Modification of glycosylation

[00140] N-linked glycosylation is the addition of a glycan to the amide nitrogen of an asparagine (Asn;N) residue of a protein. The attachment process results in the formation of a glycosylated protein. Glycosylation can occur at any asparagine residue in a protein that is accessible and recognized by glycosylation enzymes after protein translation, and most commonly occurs in accessible asparagines that are part of the NXS/TX site, where the second amino acid residue after the asparagine is a serine or threonine. A non-human glycosylation pattern may render the polypeptide undesirably reactogenic when used to induce antibody formation. In addition, glycosylation of a polypeptide that is not normally glycosylated may alter its immunogenicity. For example, glycosylation can mask important immunogenic epitopes in a protein. Thus, to reduce or eliminate glycosylation, either the asparagine residues or the serine/threonine residues can be modified, for example by substitution with another amino acid.

[00141] In some embodiments, the polypeptide comprising OspA is modified to reduce or eliminate glycosylation. In some embodiments, one or more N-glycosylation sites in OspA are deleted. In some embodiments, removal of the N-glycosylation site reduces glycosylation of OspA. In some embodiments, the polypeptide has reduced glycosylation relative to wild-type OspA, such as wild-type OspA serotype 1. In some embodiments, removal of N-glycosylation sites eliminates glycosylation of OspA.

[00142] In some embodiments, one or more asparagines in OspA are replaced with a non-asparagine amino acid. In some embodiments, each asparagine in OspA is replaced with a non-asparagine amino acid. Any natural or unnatural amino acid found in proteins, such as glutamine, can be used to replace asparagine. In some embodiments, the modification to reduce or eliminate glycosylation modifies the NXS/TX glycosylation site (where the second residue after N is S or T). In some embodiments, the first X at the NXS/TX site is not proline, and/or the second X at the NXS/TX site is not proline. In some embodiments, the modification to reduce or eliminate glycosylation is a substitution of N for Q. In some embodiments, the modification to reduce or eliminate glycosylation is a substitution of S/T for A.

[00143] The following is a detailed discussion of provisions that can be modified to reduce or eliminate glycosylation. Position numbers refer to positions in the full-length OspA sequences provided as SEQ ID NO: 83-89. It should be understood that position numbers should be adjusted accordingly in the case of partial and modified OspA sequences (eg, if an N-terminal deletion results in a total truncation of 25 amino acid residues, then position numbers should be reduced by 25).

[00144] In some embodiments, the modification to reduce or eliminate glycosylation includes replacing any one or more of N20, N71, N190, N202, and N251 of OspA serotype 1 (SEQ ID NO: 83). In some embodiments, the modification includes modifications at each of N71, N190, N202, and N251 of OspA serotype 1. In some embodiments, the modification to reduce or eliminate glycosylation includes one or more of N20Q, N71Q, N190Q, N202Q, or N251Q of OspA serotype 1. The corresponding amino acids can be found in OspA of different serotypes through pairwise alignment. Thus, in some embodiments, the asparagine residues replaced in OspA serotypes 2-7 are amino acid residues that align with N20, N71, N190, N202, and N251 from OspA serotype 1. In some embodiments, the modification is to reduce or eliminate glycosylation includes replacing any one or more Ser or Thr residues at positions 22, 73, 192, 204, and 253 of OspA serotype 1. In some embodiments, the modification includes replacing one or more Ser or Thr residues at positions 22, 73, 192, 204, and 253 OspA serotype 1 to alanine.

[00145] In some embodiments, the modification to reduce or eliminate glycosylation includes substitutions of any one or more of N20, N71, N141, N164, N202, and N205 of OspA serotype 2 (SEQ ID NO: 84). In some embodiments, the modification includes modifications at each of N20, N71, N141, N164, N202, and N205 of OspA serotype 2. In some embodiments, the modification to reduce or eliminate glycosylation includes one or more of N20Q, N71Q, N141Q, N164Q, N202Q or N205Q OspA serotype 2. Similar amino acids can be found in OspA of different serotypes through pairwise alignment. Thus, in some embodiments, the asparagine residues replaced in OspA serotypes 1 or 3-7 are amino acid residues that align with N20, N71, N141, N164, N202, and N205 of OspA serotype 2. In some embodiments, the modification to reduce or eliminating glycosylation includes replacing any one or more Ser or Thr residues at positions 22, 73, 143, 166, 204, and 207 of OspA serotype 2. In some embodiments, the modification includes replacing one or more Ser or Thr residues at positions 22, 73, 143, 166, 204 and 207 OspA serotype 2 to alanine.

[00146] In some embodiments, the modification to reduce or eliminate glycosylation includes substitutions of any one or more of N20, N71, N95, N141, N191, and N203 of OspA serotype 3 (SEQ ID NO: 85). In some embodiments, the modification includes modifications at each of N20, N20, N71, N95, N141, N191, and N203 of OspA serotype 3. In some embodiments, the modification to reduce or eliminate glycosylation includes one or more of N20Q, N71Q, N95Q, N141Q , N191Q or N203Q OspA serotype 3. Similar amino acids can be found in OspA of different serotypes through pairwise alignment. Thus, in some embodiments, the asparagine residues replaced in OspA serotypes 1-2 or 4-7 are amino acid residues that align with N20, N20, N71, N95, N141, N191, and N203 from OspA serotype 3. In some embodiments, in embodiments, the modification to reduce or eliminate glycosylation includes replacing any one or more Ser or Thr residues at positions 22, 73, 97, 143, 193, and 205 of serotype 3 OspA. In some embodiments, the modification includes replacing one or more Ser or Thr residues at positions 22, 73, 97, 143, 193 and 205 of OspA serotype 3 to alanine.

[00147] In some embodiments, the modification to reduce or eliminate glycosylation includes substitutions of any one or more of N20, N71, N141, N202, N205, and N219 of OspA serotype 4 (SEQ ID NO: 86). In some embodiments, the modification includes modifications at each of N20, N71, N141, N202, N205, and N219 of OspA serotype 4. In some embodiments, the modification to reduce or eliminate glycosylation includes one or more of N20Q, N71Q, N141Q, N202Q, N205Q or N219Q OspA serotype 4. Similar amino acids can be found in OspA of different serotypes through pairwise alignment. Thus, in some embodiments, the asparagine residues replaced in OspA serotypes 1-3 or 5-7 are amino acid residues that align with N20, N71, N141, N202, N205, and N219 from OspA serotype 4. In some embodiments, the modification to reduce or eliminate glycosylation includes replacing any one or more Ser or Thr residues at positions 22, 73, 143, 204, 207, and 221 of serotype 4 OspA. In some embodiments, the modification includes replacing one or more Ser or Thr residues at position 22 , 73, 143, 204, 207 and 221 OspA serotype 4 to alanine.

[00148] In some embodiments, modification to reduce or eliminate glycosylation includes substitutions of any one or more of N20, N71, and N141 of OspA serotype 5. (Certain serotypes, including serotypes 5-7, contain fewer glycosylation sites than certain others OspA sequences, such as OspA serotype 1 sequences). In some embodiments, the modification includes modifications to each of N20, N71, and N141 of OspA serotype 5 (SEQ ID NO: 87). In some embodiments, the modification to reduce or eliminate glycosylation includes one or more of N20Q, N71Q, or N141Q of OspA serotype 5. Similar amino acids can be found in OspA of different serotypes through pairwise alignment. Thus, in some embodiments, the asparagine residues replaced in OspA serotypes 1-4 or 6-7 are amino acid residues that align with N20, N71, and N141 from OspA serotype 5. In some embodiments, the modification is to reduce or eliminate glycosylation includes replacing any one or more Ser or Thr residues at positions 22, 73, and 143 of OspA serotype 5. In some embodiments, the modification includes replacing one or more Ser or Thr residues at positions 22, 73, and 143 of OspA serotype 5 with an alanine.

[00149] In some embodiments, the modification to reduce or eliminate glycosylation includes substitutions of any one or more of N20, N71, and N141 of OspA serotype 6 (SEQ ID NO: 88). In some embodiments, the modification includes modifications at each of N20, N71, and N141 of OspA serotype 6. In some embodiments, the modification to reduce or eliminate glycosylation includes one or more of N20Q, N71Q, or N141Q of OspA serotype 6. Similar amino acids can be found in OspA different serotypes through pairwise alignment. Thus, in some embodiments, the asparagine residues replaced in OspA serotypes 1-5 or 7 are amino acid residues that align with N20, N71, and N141 from OspA serotype 6. In some embodiments, the modification to reduce or eliminate glycosylation includes the replacement any one or more Ser or Thr residues at positions 22, 73, and 143 of OspA serotype 6. In some embodiments, the modification includes replacing one or more Ser or Thr residues at positions 22, 73, and 143 of OspA serotype 6 with an alanine.

[00150] In some embodiments, the modification to reduce or eliminate glycosylation includes substitutions of any one or more of N20, N71, N141, and N191 of OspA serotype 7 (SEQ ID NO: 89). In some embodiments, the modification includes modifications at each of N20, N71, N141, and N191 of OspA serotype 7. In some embodiments, the modification to reduce or eliminate glycosylation includes one or more of N20Q, N71Q, N141Q, or N191Q of OspA serotype 7. Similar amino acids can be found in OspA of different serotypes through pairwise alignment. Thus, in some embodiments, the asparagine residues replaced in OspA serotypes 1-6 are amino acid residues that align with N20, N71, N141, and N191 from OspA serotype 7. In some embodiments, the modification to reduce or eliminate glycosylation includes the replacement any one or more Ser or Thr residues at positions 22, 73, 143, and 193 of OspA serotype 7. In some embodiments, the modification includes replacing one or more Ser or Thr residues at positions 22, 73, 143, and 193 of OspA serotype 7 with an alanine.

Antigenic polypeptides based on the OspA sequence, including the OspA polypeptide and ferritin or lumazine synthase

[00151] In some embodiments, an antigenic polypeptide is provided including an OspA polypeptide and ferritin or lumazine synthase. It should be understood that such antigenic polypeptides based on the OspA sequence disclosed herein are antigenic to the OspA component, for example, they can be administered to a mammal, such as a human, to induce the formation of antibodies to OspA. The ferritin component of the antigenic polypeptide may be wild-type ferritin from any species or ferritin from any species that includes one or more mutations as described herein. In some embodiments, the antigenic polypeptide comprises amino acids from any of SEQ ID NO: 1-76. In some embodiments, the antigenic polypeptide includes a sequence with at least 85%, 90%, 95%, 97%, 98%, 99%, 99.5%, or 100% sequence identity to any of SEQ ID NO: 1-76 . The lumazine synthase component of the antigenic polypeptide may be a lumazine synthase from any species.

[00152] In some embodiments, the antigenic polypeptide includes a mammalian leader sequence (also known as a signal sequence). In some embodiments, the mammalian leader sequence results in the secretion of an antigenic polypeptide when expressed in mammalian cells.

1. Component representing the OspA polypeptide

[00153] An antigenic polypeptide based on the OspA sequence may include any of the modified OspA polypeptides described herein.

[00154] For example, in some embodiments, the OspA component of an OspA sequence-based antigenic polypeptide includes an OspA ectodomain. In some embodiments, the OspA ectodomain is derived from any of serotypes 1, 2, 3, 4, 5, 6, or 7. Exemplary wild-type OspA sequences are provided as SEQ ID NOs: 83-89. Their 25 N-terminal amino acids may be removed, for example, to remove a lipidation site. Accession numbers for illustrative OspA sequences are also provided in the examples. In some embodiments, the ectodomain is derived from Borrelia burgdorferi , Borrelia mayonii, Borrelia afzelii, Borrelia garinii, or Borrelia bavariensis. In some embodiments, the ectodomain is derived from Borrelia burgdorferi .

[00155] In some embodiments, the ectodomain is a wild-type ectodomain.

[00156] In some embodiments, the ectodomain is a modified ectodomain, for example, an ectodomain modified to reduce glycosylation. An introductory discussion of glycosylation is provided in the previous section and for brevity is not repeated here. The OspA component of an antigenic polypeptide based on the OspA sequence may include any of the modifications described herein to reduce or eliminate glycosylation, including, without limitation, the removal of one or more N-glycosylation sites in the ectodomain, for example, through amino acid substitutions, as discussed in detail herein. document.

[00157] In some embodiments, the OspA ectodomain is present as part of a larger OspA sequence in an antigenic polypeptide, for example, including part of a transmembrane domain or the entire transmembrane domain. In some embodiments, the OspA ectodomain is present in the full-length OspA sequence in the antigenic polypeptide. In some embodiments, the full-length OspA sequence is the full-length wild-type OspA sequence. In some embodiments, the antigenic polypeptide does not include a transmembrane domain.

[00158] Any of the modifications discussed above can be combined in an antigenic polypeptide. In some embodiments, the antigenic polypeptide includes at least one modification to reduce glycosylation and at least one additional modification described herein.

[00159] In some embodiments, the OspA ectodomain of the antigenic polypeptide is any of the modified OspA ectodomains described in section B above.

[00160] Any of the OspA ectodomains (or a sequence comprising an OspA ectodomain, such as full-length OspA) described herein can be combined into an antigenic polypeptide with any of the ferritins described below.

2. Ferritin component

[00161] In some embodiments, a fusion protein comprising an antigenic polypeptide based on the OspA sequence described herein and ferritin is covered. Ferritin in an antigenic polypeptide may be wild type or include one or more mutations (see next section). In some embodiments, ferritin is derived from bacteria, insects, fungi, birds, or mammals. In some embodiments, the ferritin is human. In some embodiments, the ferritin is bacterial. In some embodiments, the ferritin is ferritinTrichoplusia ni (PDB: 1Z6O_X, SEQ ID NO: 211 and 212).

[00162] In some embodiments, the ferritin is a ferritin light chain and/or a ferritin heavy chain. In some embodiments, the ferritin is human ferritin heavy chain (FTH1, Gene ID No: 2495) or human ferritin light chain (FTL, Gene ID No: 2512). In some embodiments, ferritin is a multimeric protein, referred to herein as a “ferritin particle” or “ferritin nanoparticle,” containing a total of 24 ferritin heavy chain and ferritin light chain subunits.

[00163] In some embodiments, the OspA sequence-based antigenic polypeptide includes a ferritin light chain and an OspA polypeptide. In some embodiments, the antigenic polypeptide includes a ferritin heavy chain and an OspA polypeptide. In some embodiments, an antigenic polypeptide comprising a ferritin light chain and an OspA polypeptide may assemble with a ferritin heavy chain that is not associated with a non-ferritin polypeptide. In some embodiments, an antigenic polypeptide comprising a ferritin heavy chain and an OspA polypeptide may assemble with a ferritin light chain that is not associated with a non-ferritin polypeptide. Ferritin not associated with a polypeptide other than ferritin may be referred to as “naked ferritin.”

[00164] In some embodiments, an antigenic polypeptide comprising a ferritin heavy chain and an OspA polypeptide may be assembled with an antigenic polypeptide comprising a ferritin light chain and an OspA polypeptide to allow expression of 2 identical or different antigens on a single ferritin particle. In some embodiments, 2 different antigens are encoded by the same infectious agent. In some embodiments, 2 different antigens are encoded by 2 different infectious agents, such as Borrelia of other serotypes or species.

[00165] In some embodiments, an antigenic polypeptide comprising a ferritin heavy chain and an OspA polypeptide may be combined with an antigenic polypeptide comprising a ferritin light chain and an OspA polypeptide to form a bivalent composition. In some embodiments, the ferritin is H. pylori ferritin (see SEQ ID NO: 90 for an exemplary wild-type H. pylori ferritin sequence including an 8 amino acid extension from bullfrog ferritin at its N-terminus). In some embodiments, lower sequence homology between ferritin from H. pylori (or other bacterial ferritins) and human ferritin may reduce the potential for autoimmunity when used as a platform for the design of antigenic polypeptides (see Kanekiyo et al., Cell 162, 1090-1100 (2015)).

[00166] In some embodiments, the ferritin is Pyrococcus furiosus ferritin (NCBI seq WP_011011871.1), optionally with one or more mutations described herein.

[00167] In some embodiments, ferritin includes a sequence characterized by greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 97%, greater than 98 % or greater than 99% identity with wild-type ferritin.

[00168] In some embodiments, the ferritin is insect ferritin. In some embodiments, the ferritin is Trichoplusia Ni ferritin (PDB: 1Z6O_X, SEQ ID NOs: 211 and 212), optionally with one or more mutations described herein.

Ferritin mutations

[00169] In some embodiments, ferritin contains one or more mutations disclosed herein. In some embodiments, the one or more mutations include changes to the amino acid sequence of wild-type ferritin and/or an insertion, for example, at the N- or C-terminus. In some embodiments, one, two, three, four, five, or more different amino acids in the ferritin are mutated compared to wild-type ferritin (in some embodiments, in addition to any N-terminal insertion). One or more mutations are capable of altering the functional properties of ferritin, for example, as discussed in detail below. Typically, mutation simply refers to a difference in sequence (such as a substituted, added or deleted amino acid residue or residues) relative to the corresponding wild-type ferritin.

(1) Cysteine for conjugation

[00170] In some embodiments, ferritin is mutated to provide a chemical mechanism for conjugation of an immunostimulatory moiety and/or polypeptide other than ferritin. This can be achieved by mutation to replace a surface-exposed amino acid other than cysteine with cysteine. For the avoidance of doubt, language such as “replacing a surface-exposed amino acid with a cysteine” necessarily implies that the surface-exposed amino acid in the wild-type or premutation sequence is not a cysteine. Another approach to provide a chemical mechanism for conjugating an immunostimulatory fragment or polypeptide other than ferritin is to include an amino acid segment, such as a linker, N- or C-terminal to ferritin, where the amino acid segment contains a cysteine. In some embodiments, this cysteine (whether it replaces a surface-exposed amino acid or in an N- or C-terminal linker) is unpaired, meaning that it does not have a suitable cysteine partner to form a disulfide bond. In some embodiments, this cysteine does not alter the secondary structure of ferritin. In some embodiments, this cysteine does not alter the tertiary structure of ferritin.

[00171] In some embodiments, this cysteine can be used to conjugate agents, such as immunostimulatory moieties, to ferritin. In some embodiments, this cysteine provides a free thiol group that is reactive. In some embodiments, agents conjugated to this cysteine on ferritin are exposed on the surface of the assembled ferritin particle. In some embodiments, the cysteine is capable of interacting with molecules and cells of the subject after administration during ferritin particle assembly.

[00172] In some embodiments, the presence of this cysteine enables conjugation of one or more immunostimulatory moieties, such as adjuvants. In some embodiments, conjugation of the immunostimulatory moiety would not occur in the absence of this cysteine.

[00173] In some embodiments, the non-cysteine amino acid that is replaced with cysteine is selected from E12, S72, A75, K79, S100, and S111 from H. pylori ferritin. Thus, in some embodiments, the surface-exposed amino acid that is replaced by a cysteine is an amino acid residue that corresponds to E12, S26, S72, A75, K79, S100, or S111 from H. pylori ferritin. Similar amino acids can be found in ferritin other than ferritin from H. pylori , through pairwise or structural alignment. In some embodiments, the non-cysteine amino acid that is replaced with cysteine is selected from an amino acid that corresponds to S3, S19, S33, I82, A86, A102, and A120 of the human ferritin light chain. In some embodiments, the surface exposed amino acid to be replaced with cysteine is selected based on the understanding that if the native amino acid were replaced with cysteine, it would be reactive in the assembled ferritin multimer or ferritin particle, and/or that the cysteine does not disrupt stability of the ferritin multimer or ferritin particle, and/or that this cysteine does not reduce ferritin expression levels.

[00174] In some embodiments, ferritin includes the E12C mutation. In some embodiments, the E12C residue can be used to conjugate agents (eg, immunostimulatory moieties and/or polypeptides other than ferritin) to ferritin. In some embodiments, the E12C moiety provides a free thiol group that is reactive. In some embodiments, agents conjugated to the E12C residue on ferritin monomers are expressed on the surface of the assembled ferritin multimer or ferritin particle. In some embodiments, twenty-four E12C residues (one from each monomer) are present on the surface of the ferritin multimer or ferritin particle.

[00175] In some embodiments, ferritin includes the S26C mutation. In some embodiments, the S26C residue can be used to conjugate agents (eg, immunostimulatory moieties and/or polypeptides other than ferritin) to ferritin. In some embodiments, the S26C residue provides a free thiol group that is reactive. In some embodiments, agents conjugated to the S26C residue on ferritin monomers are expressed on the surface of the assembled ferritin multimer or ferritin particle. In some embodiments, twenty-four S26C residues (one from each monomer) are present on the surface of the ferritin multimer or ferritin particle.

[00176] In some embodiments, ferritin includes the S72C mutation. In some embodiments, the S72C residue can be used to conjugate agents (eg, immunostimulatory moieties and/or polypeptides other than ferritin) to ferritin. In some embodiments, the S72C residue provides a free thiol group that is reactive. In some embodiments, agents conjugated to the S72C residue on ferritin monomers are expressed on the surface of the assembled ferritin multimer or ferritin particle. In some embodiments, twenty-four S72C residues (one from each monomer) are present on the surface of the ferritin multimer or ferritin particle.

[00177] In some embodiments, ferritin includes the A75C mutation. In some embodiments, the A75C residue can be used to conjugate agents (eg, immunostimulatory moieties and/or polypeptides other than ferritin) to ferritin. In some embodiments, the A75C residue provides a free thiol group that is reactive. In some embodiments, agents conjugated to the A75C residue on ferritin monomers are expressed on the surface of the assembled ferritin multimer or ferritin particle. In some embodiments, twenty-four A75C residues (one from each monomer) are present on the surface of the ferritin multimer or ferritin particle.

[00178] In some embodiments, ferritin includes the K79C mutation. In some embodiments, the K79C residue can be used to conjugate agents (eg, immunostimulatory moieties and/or polypeptides other than ferritin) to ferritin. In some embodiments, the K79C residue provides a free thiol group that is reactive. In some embodiments, agents conjugated to the K79C residue on ferritin monomers are expressed on the surface of the assembled ferritin multimer or ferritin particle. In some embodiments, twenty-four K79C residues (one from each monomer) are present on the surface of the ferritin multimer or ferritin particle.

[00179] In some embodiments, ferritin includes the S100C mutation. In some embodiments, the S100C residue can be used to conjugate agents (eg, immunostimulatory moieties and/or polypeptides other than ferritin) to ferritin. In some embodiments, the S100C residue provides a free thiol group that is reactive. In some embodiments, agents conjugated to the S100C residue on ferritin monomers are expressed on the surface of the assembled ferritin multimer or ferritin particle. In some embodiments, twenty-four S100C residues (one from each monomer) are present on the surface of the ferritin multimer or ferritin particle.

[00180] In some embodiments, ferritin includes the S111C mutation. In some embodiments, the S111C residue can be used to conjugate agents (eg, immunostimulatory moieties and/or polypeptides other than ferritin) to ferritin. In some embodiments, the S111C residue provides a free thiol group that is reactive. In some embodiments, agents conjugated to the S111C residue on ferritin monomers are expressed on the surface of the assembled ferritin multimer or ferritin particle. In some embodiments, twenty-four S111C residues (one from each monomer) are present on the surface of the ferritin multimer or ferritin particle.

(2) Removal of internal cysteine

[00181] In some embodiments, ferritin contains a mutation that replaces the internal cysteine with an amino acid other than cysteine. Removal of the native internal cysteine residue can ensure that there is only one unpaired cysteine in the ferritin monomer, which avoids unwanted reactions such as disulfide bond formation and can lead to a more stable and effective outcome (e.g., adjuvant presentation). In some embodiments, C31 from H. pylori ferritin is replaced with an amino acid other than cysteine. In some embodiments, C31 from H. pylori ferritin is replaced by serine (C31S), although any residue other than cysteine, such as alanine, glycine, threonine, or asparagine, can be used. Similar amino acids can be found in ferritin other than H. pylori ferritin, through pairwise or structural alignment. Thus, in some embodiments, the internal cysteine that is replaced with a non-cysteine amino acid is an amino acid residue that aligns with C31 from H. pylori ferritin. Exemplary ferritin sequences demonstrating the C31S mutation are shown in SEQ ID NOs: 201-207. In some embodiments, when more than one internal cysteine is present in ferritin, two or more (eg, each) internal cysteines are replaced with a non-cysteine amino acid, such as serine, or an amino acid selected from serine, alanine, glycine, threonine, or asparagine.

(3) Glycosylation

[00182] Glycosylation compatible with human glycosylation may contribute to the safety and efficacy of recombinant drug products. Regulatory approval may be contingent on demonstration of appropriate glycosylation as a critical quality attribute (see Zhang et al., Drug Discovery Today 21(5):740–765 (2016)). N-glycans can be formed by glycosylation of asparagine side chains and can vary in structure between humans and other organisms such as bacteria and yeast. Thus, it may be desirable to reduce or eliminate non-human glycosylation and/or N-glycan formation in ferritin in accordance with the present invention. In some embodiments, control of ferritin glycosylation improves the efficacy and/or safety of the composition, particularly when used for human vaccination.

[00183] In some embodiments, ferritin is mutated to inhibit N-glycan formation. In some embodiments, the mutated ferritin has reduced glycosylation compared to its corresponding wild-type ferritin.

[00184] In some embodiments, ferritin contains a mutation that replaces the surface-exposed asparagine with a non-asparagine amino acid. In some embodiments, the surface exposed asparagine is N19 of H. pylori ferritin or is at a position that corresponds to position 31 of H. pylori ferritin as determined by pairwise or structural alignment. In some embodiments, mutating such an asparagine, such as N19 from H. pylori ferritin, reduces the glycosylation of ferritin. In some embodiments, the mutation replaces asparagine with glutamine. In some embodiments, the ferritin is ferritin from H. pylori including the N19Q mutation. SEQ ID NOs: 201-207 are exemplary ferritin sequences including N19Q mutations.

[00185] A mammal exposed to a glycosylated protein produced in bacteria or yeast may generate an immune response to the glycosylated protein because the glycosylation pattern of the protein in the bacteria or yeast may be different from the glycosylation pattern of the same protein in mammals. Thus, some glycosylated therapeutic proteins may not be suitable for production in bacteria or yeast.

[00186] In some embodiments, reducing ferritin glycosylation by amino acid mutation facilitates protein production in bacteria or yeast. In some embodiments, reducing the glycosylation of ferritin reduces the potential for adverse effects to occur in mammals when administered with mutant ferritin that is expressed in bacteria or yeast. In some embodiments, the reactogenicity of the mutant ferritin produced in bacteria or yeast is lower in a human subject because glycosylation is reduced. In some embodiments, the incidence of hypersensitivity responses in human subjects is lower following treatment with reduced glycosylation mutant ferritin compared to wild-type ferritin.

[00187] In some embodiments, in a subject, degradation of a composition comprising a reduced glycosylation mutant ferritin occurs more slowly compared to a composition containing wild-type ferritin or a composition containing a corresponding wild-type ferritin with glycosylation. In some embodiments, a composition comprising a reduced-glycosylation mutant ferritin has reduced clearance in a subject compared to a composition containing wild-type ferritin or a composition containing a corresponding wild-type ferritin. In some embodiments, a composition comprising a reduced glycosylation mutant ferritin has a longer serum half-life compared to wild-type ferritin or a composition containing a corresponding wild-type ferritin with glycosylation.

(4) Combinations of mutations

[00188] In some embodiments, ferritin includes more than one type of mutation described herein. In some embodiments, ferritin contains one or more mutations independently selected from a mutation to reduce glycosylation, a mutation to remove an internal cysteine, and a mutation to produce a surface-exposed cysteine. In some embodiments, ferritin contains a mutation to reduce glycosylation, a mutation to remove an internal cysteine, and a mutation to produce a surface-exposed cysteine.

[00189] In some embodiments, ferritin includes a N19Q mutation, a C31S mutation, and a surface-exposed cysteine mutation. In some embodiments, ferritin includes the N19Q mutation, the C31S mutation, and the E12C mutation. In some embodiments, ferritin includes the N19Q mutation, the C31S mutation, and the S72C mutation. In some embodiments, ferritin includes the N19Q mutation, the C31S mutation, and the A75C mutation. In some embodiments, ferritin includes the N19Q mutation, the C31S mutation, and the K79C mutation. In some embodiments, ferritin includes the N19Q mutation, the C31S mutation, and the S100C mutation. In some embodiments, ferritin includes the N19Q mutation, the C31S mutation, and the S111C mutation. In some embodiments, ferritin includes mutations corresponding to any of the above groups of mutations, wherein the corresponding mutations change N to Q, C to S, and a non-cysteine surface exposed amino acid to cysteine at positions determined by pairwise alignment of the ferritin amino acid sequence with the amino acid sequence ferritin from H. pylori (SEQ ID NO: 208 or 209).

[00190] Exemplary ferritins including more than one type of mutation are provided under SEQ ID NO: 201-207.

3. Structural alignment

[00191] As discussed herein, mutation positions corresponding to mutation positions described for a given polypeptide (eg, ferritin from H. pylori ) can be identified through pairwise or structural alignment. Structural alignment is relevant in the case of large families of proteins, such as ferritin, where the proteins are characterized by similar structure despite significant sequence variation, and many members of the family have been structurally characterized, and can also be used to identify corresponding positions in various variants of other polypeptides described in herein, such as Borrelia polypeptides (eg, OspA). The Protein Databank (PDB) contains 3D structures of many ferritins, including those listed below with their accession numbers.

[00192] 2jd6, 2jd7 - PfFR - Pyrococcus furiosus. 2jd8 - PfFR+Zn. 3a68 - soFR from the SferH4 gene - soybean. 3a9q - soFR from the SferH4 gene (mutant). 3egm, 3bvf, 3bvi, 3bvk, 3bvl - HpFR - Heliobacter pylori. 5c6f - HpFR (mutant) + Fe. 1z4a, 1vlg - FR - Thermotoga maritime. 1s3q, 1sq3, 3kx9 - FR - Archaeoglubus fulgidus. 1krq - FR - Campylobacter jejuni. 1eum - EcFR - Escherichia coli. 4reu - EcFR+Fe. 4xgs - EcFR (mutant) + Fe2O2. 4ztt - EcFR (mutant) + Fe2O+Fe2+Fe+O2. 1qgh - LiFR - Listeria innocua. 3qz3 - VcFR - Vibrio cholerae. 3vnx - FR - Ulva pertusa. 4ism, 4isp, 4itt, 4itw, 4iwj, 4iwk, 4ixk, 3e6s - PnmFR - mixed genus of Pseudo-nitschia. 4zkh, 4zkw, 4zkx, 4zl5, 4zl6, 4zlw, 4zmc - PnmFR (mutant) + Fe. 1z6o - FR - Trichoplusia ni. 4cmy - FR+Fe - Chlorobaculum tepidum. Ferritin light chain (FTL). 1lb3, 1h96 - mFTL - mouse. 1rcc, 1rcd, 1rci - bFTL+tartrate+Mg. 1rce, 1rcg - bFTL+tartrate+Mn. 3noz, 3np0, 3np2, 3o7r - hoFTL (mutant) - horse. 3o7s, 3u90 - hoFTL. 4v1w - hoFTL - cryo EM. 3rav, 3rd0 - hoFTL+barbiturate. Ferritin light chains+ferritin heavy chains: 5gn8 - hFTH+Ca.

[00193] Structural alignment involves identifying corresponding residues in two (or more) polypeptide sequences by (i) modeling the structure of the first sequence using the known structure of a second sequence, or (ii) comparing the structures of the first and second sequences, where both are known, and identifying the residue in the first sequence located most similar to the residue of interest in the second sequence. Relevant residues are identified using some algorithms based on minimizing the distance between alpha carbons in overlapping structures (e.g., which set of paired alpha carbons provides the minimized standard deviation for the alignment). When identifying positions in ferritin other than ferritin fromH. pylori, corresponding to the provisions described in relation to ferritin fromH. pylori, ferritin fromH. pylori may represent a "second" sequence. If the ferritin of interest is other than the ferritin fromH. pylori, has no known structure available, but is closely related to another ferritin other than ferritin fromH. pylori, which has a known structure compared to ferritin fromH. pylori, then it may be most effective to model the ferritin of interest other than the ferritin fromH. pylori, using the known structure of closely related ferritin, different from ferritin fromH. pylori, and then compare this model with the structure of ferritin fromH. pylori to identify the required corresponding residue in the ferritin of interest. There is an extensive literature on structural modeling and alignment; illustrative disclosures include US 6,859,736; US 8738343; and disclosures cited in Aslam et al., Electronic Journal of Biotechnology 20 (2016) 9-13. For a discussion of modeling a structure based on a known related structure or structures, seeFor example, Bordoli et al., Nature Protocols 4 (2009) 1-13, and references cited therein.

4. Lumazine synthase

[00194] In some embodiments, the antigenic polypeptide includes a lumazine synthase protein (see Ra et al., Clin Exp Vaccine Res 3:227-234 (2014)). In some embodiments, the protein is a lumazine synthase serotype 1, 2, 3, 4, 5, 6, or 7. Exemplary lumazine synthase sequences are provided as SEQ ID NOs: 216 and 219. In some embodiments, the lumazine synthase comprises 80%, 85% sequence , 90%, 95%, 98% or 99% identity with SEQ ID NO: 216 or 219. Lumazine synthases are capable of forming higher order structures, for example, a lumazine synthase particle of 60 subunits. Exemplary lumazine synthases are Aquifex aeolicus lumazine synthase and E. coli lumazine synthase. The lumazine synthase may be located C-terminal to OspA (eg, a sequence including the OspA ectodomain, such as full-length OspA) and may be separated from OspA by a linker, as discussed herein. Exemplary antigenic polypeptides comprising the lumazine synthase protein are SEQ ID NOs: 12-21. In some embodiments, the antigenic polypeptide includes a sequence with 80%, 85%, 90%, 95%, 98%, or 99% identity to any of SEQ ID NOs: 12-21.

5. Linker

[00195] In some embodiments, ferritin or lumazine synthase is combined (eg, fused) to OspA (eg, to a sequence comprising the OspA ectodomain, such as full-length OspA) via a linker.

[00196] In some embodiments, the linker separates the amino acid sequence of a non-ferritin polypeptide (eg, OspA) from the amino acid sequence of ferritin. Any linker can be used. In some embodiments, the linker is a peptide linker that can facilitate expression of an antigenic polypeptide based on a ferritin sequence as a fusion protein (eg, from a single open reading frame). In some embodiments, the linker is a glycine-serine linker. In some embodiments, the glycine-serine linker is GS, GGGS (SEQ ID NO: 226), 2XGGGS (SEQ ID NO: 91) (i.e., GGGSGGGS (SEQ ID NO: 91)), or 5XGGGS (SEQ ID NO: 91) 92). The linker may be N- or C-terminal to ferritin.

[00197] In some embodiments, the linker length is 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids. In some embodiments, the linker length is approximately 2-4, 2-6, 2-8, 2-10, 2-12, or 2-14 amino acids. In some embodiments, the linker length is at least 15 amino acids. In some embodiments, the linker length is at least 25 amino acids. In some embodiments, the linker length is at least 30 amino acids. In some embodiments, the linker length is at least 35 amino acids. In some embodiments, the linker length is at least 40 amino acids. In some embodiments, the linker length is less than 60 amino acids or equal to 60 amino acids. In some embodiments, the linker length is less than 50 amino acids or equal to 50 amino acids. In some embodiments, the linker length is approximately 16, 28, 40, 46, or 47 amino acids. In some embodiments, the linker is flexible. In some embodiments, the linker includes a cysteine, for example, for use as a site for conjugation of an immunostimulatory moiety (eg, an adjuvant); an exemplary linker including cysteine is provided as SEQ ID NO: 225. In some embodiments, the linker includes a sequence with at least 75%, 80%, 85%, 90%, or 95% identity to SEQ ID NO: 225 and further includes a cysteine , corresponding to cysteine in SEQ ID NO: 225. In some embodiments, the linker includes at least 25 amino acids (e.g., 25-60 amino acids), wherein the cysteine is located at a position ranging from the 8th amino acid from the N-terminus to the 8th amino acids from the C-terminus, or within 10 amino acids of the central residue or linker bond.

[00198] In some embodiments, the linker includes the amino acids glycine (G) and/or serine (S). In some embodiments, the linker includes or consists of the amino acids glycine (G), serine (S), asparagine (N), and/or alanine (A), and optionally cysteine, as discussed above. In some embodiments, the linker comprises an amino acid sequence with at least 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 222. In some embodiments, the linker is ggggsggggsggggsg (SEQ ID No: 220), ggsgsgsnssassgassggasggsggsg (SEQ ID No: 221), ggsgsassgasasgssngsgsgsgsnsnssassgassggasggsggsg (SEQ ID No: 222) or GS. In some embodiments, the linker is FR1 (SEQ ID NO: 223) or FR2 (SEQ ID NO: 224).

[00199] In some embodiments, the ferritin comprises ferritin from H. pylori with an amino-terminal extension from bullfrog ferritin (which will be referred to as hybrid ferritin). In some embodiments, this hybrid ferritin forms multimers with non-ferritin polypeptide attachment sites uniformly distributed over the surface (see Kanekiyo 2015). In some embodiments, N-terminal ferritin fusion proteins enable the presentation of a non-ferritin polypeptide on the surface of a ferritin nanoparticle. In some embodiments, the non-ferritin polypeptide is a viral or bacterial polypeptide. In some embodiments, ferritin includes glutamate at a position corresponding to position 13 of SEQ ID NO: 208 (a hybrid ferritin that includes this glutamate), or at position 6 in SEQ ID NO: 209 (ferritin from wild type H. pylori , in which position 6 contains isoleucine). In combination with the bullfrog linker, this glutamate is thought to retain the conserved salt bridge found in human and bullfrog ferritins (6R and 14E in both the human ferritin light chain and the bullfrog ferritins with fewer subunits). See Kanekiyo et al., Cell 162, 1090-1100 (2015)).

[00200] In some embodiments, an antigenic polypeptide based on the OspA sequence is linked to ferritin via a cysteine-thrombin-histidine linker. In some embodiments, this linker is used directly to conjugate a moiety (eg, an immunostimulatory moiety or non-ferritin polypeptide) to ferritin using click chemistry. An exemplary sequence including the cysteine-thrombin-histidine linker is SEQ ID NO: 218 . Click chemistry suitable for conjugation reactions involving a cysteine-thrombin-histidine linker is discussed above.

[00201] In some embodiments, a linker containing a cysteine as a conjugation site for an immunostimulatory moiety, such as an adjuvant, is used in a construct containing a ferritin molecule that does not have an unpaired surface exposed cysteine, or in a construct containing a ferritin molecule containing an unpaired exposed cysteine. cysteine on the surface.

[00202] In some embodiments, the design does not include a linker. In some embodiments, the design includes a single linker. In some embodiments, the design includes two linkers or more than two linkers.

6. Immunostimulating fragments; adjuvants; conjugated polypeptides

[00203] In some embodiments, a non-ferritin polypeptide (eg, an OspA polypeptide) and/or an immunostimulatory moiety, such as an adjuvant, is attached to a surface exposed amino acid in the ferritin or linker. In some embodiments, the surface exposed amino acid is a cysteine, for example, resulting from the mutation discussed above. In some embodiments, the surface exposed amino acid is lysine, aspartate, or glutamate. Conjugation procedures using glutaraldehyde (to conjugate a lysine to an amino group-bearing linker or moiety) or carbodiimide (e.g., 1-cyclohexyl-3-(2-morpholin-4-yl-ethyl)carbodiimide or 1-ethyl-3-(3 -dimethylaminopropyl)carbodiimide (EDC; EDAC) for conjugation of aspartate or glutamate to an amino group-bearing linker or moiety, or lysine to an amino group-bearing linker or moiety) are described, for example, in chapter 4 of Holtzhauer, M., Basic Methods for the Biochemical Lab, Springer 2006, ISBN 978-3-540-32785-1, available online at atspringer.com.

[00204] In some embodiments, an immunostimulatory moiety, such as an adjuvant, is attached to a surface exposed amino acid in ferritin. In some embodiments, more than one immunostimulatory moiety, such as an adjuvant, is attached to a surface exposed amino acid in ferritin. In some embodiments, twenty-four immunostimulatory moieties are attached to a ferritin multimer or ferritin particle (eg, one moiety for each monomer in a H. pylori ferritin particle). In some embodiments, with multiple immunostimulatory moieties attached to a ferritin nanoparticle, all immunostimulatory moieties are identical. In some embodiments, with multiple immunostimulatory moieties attached to a ferritin nanoparticle, all immunostimulatory moieties are not identical.

Types of immunostimulating fragments; adjuvants

[00205] Any immunostimulatory moiety that can be attached to a surface exposed amino acid (eg, cysteine) can be used in ferritins (or linkers) in accordance with the present invention. In some embodiments, the immunostimulatory moiety is a B cell agonist.

[00206] In some embodiments, the immunostimulatory moiety is not hydrophobic. In some embodiments, the immunostimulatory moiety is hydrophilic. In some embodiments, the immunostimulatory moiety is polar. In some embodiments, the immunostimulatory moiety is capable of forming a hydrogen bond or an ionic bond, for example, contains a hydrogen bond donor, a hydrogen bond acceptor, a cationic moiety, or an anionic moiety. A moiety is considered cationic or anionic if it will ionize in aqueous solution at a physiologically relevant pH, such as pH 6, 7, 7.4, or 8.

[00207] In some embodiments, the immunostimulatory moiety is an adjuvant. In some embodiments, the adjuvant includes a pathogen-associated molecular pattern (PAMP). In some embodiments, the adjuvant is a Toll-like receptor (TLR) agonist or a stimulatory interferon gene (STING) agonist. In some embodiments, the adjuvant activates TLR signaling in B and/or T cells. In some embodiments, the adjuvant regulates the adaptive immune response.

(1) TLR2 agonists

[00208] In some embodiments, the immunostimulatory moiety is a TLR2 agonist. In some embodiments, the immunostimulatory moiety stimulates TLR2 signaling. In some embodiments, the immunostimulatory fragment is a synthetic small molecule TLR2 ligand. In some embodiments, the immunostimulatory fragment is a synthetic small molecule agonist of TLR2 signaling.

[00209] In some embodiments, the TLR2 agonist is PAM2CSK4, FSL-1, or PAM3CSK4.

(2) TLR7/8 agonists

[00210] In some embodiments, the immunostimulatory moiety is a TLR7 and/or TLR8 agonist (ie, an agonist of at least one of TLR7 and TLR8). In some embodiments, the immunostimulatory moiety stimulates TLR7 and/or TLR8 signaling. In some embodiments, the immunostimulatory moiety is a synthetic small molecule TLR7 and/or TLR8 ligand. In some embodiments, the immunostimulatory fragment is a synthetic small molecule agonist of TLR7 and/or TLR8 signaling.

[00211] In some embodiments, the TLR7 and/or TLR8 agonist is single-stranded RNA (ssRNA). In some embodiments, the TLR7 and/or TLR8 agonist is an imidazoquinoline. In some embodiments, the TLR7 and/or TLR8 agonist is a nucleoside analog.

[00212] In some embodiments, the TLR7 and/or TLR8 agonist is an imidazoquinolinamine Toll-like receptor (TLR) agonist, such as 3M-012 (3M Pharmaceuticals). The structure of free 3M-012 is:

.

It should be understood that an immunostimulatory moiety, such as 3M-012 or any moiety discussed herein, can be conjugated to ferritin by replacing the corresponding peripheral atom of the moiety (e.g., hydrogen) with a bond to ferritin described herein, e.g. sulfur exposed on the surface of the cysteine or via a linker attached to such a sulfur atom. Thus, when conjugated with ferritin, the structure of the immunostimulating fragment will be slightly different from the structure of the free molecule.

[00213] In some embodiments, the TLR7 and/or TLR8 agonist is SM7/8a. The structure of free SM7/8a is:

.

[00214] See, for example, Lynn et al., Nat Biotechnol. 2015 Nov; 33(11):1201-10. doi: 10.1038/nbt.3371.

(3) TLR9 agonists

[00215] In some embodiments, the immunostimulatory moiety is a TLR9 agonist. In some embodiments, the immunostimulatory moiety stimulates TLR9 signaling. In some embodiments, the immunostimulatory moiety is a synthetic small molecule TLR9 ligand. In some embodiments, the immunostimulatory fragment is a synthetic small molecule agonist of TLR9 signaling.

[00216] In some embodiments, the TLR9 agonist is a CpG oligodeoxynucleotide (ODN). In some embodiments, the TLR9 agonist is an unmethylated ODN CpG. In some embodiments, the ODN CpG includes a partial or full phosphorothioate (PS) backbone instead of the natural phosphodiester (PO) backbone found in regular DNA.

[00217] In some embodiments, the CpG ODN is a class B ODN that includes one or more 6-mer CpG motifs containing 5'-purine (Pu)-pyrimidine (Py)-C-G-Py-Pu-3'; has an entirely phosphorothioate (i.e., PS-modified) backbone and is 18–28 nucleotides in length. In some embodiments, the ODN CpG includes the sequence of SEQ ID NO: 210, optionally containing phosphorothioate linkages in the backbone.

[00218] In some embodiments, the TLR9 agonist includes an immunostimulatory sequence (ISS). In some embodiments, the TLR9 agonist is ISS-1018 (Dynavax) (SEQ ID NO: 210).

(4) STING agonists

[00219] In some embodiments, the immunostimulatory moiety is a STING (stimulator of interferon gene protein, also known as endoplasmic reticulum stimulatory IFN) agonist. In some embodiments, the immunostimulatory moiety stimulates STING signaling. In some embodiments, the immunostimulatory moiety is a synthetic small molecule STING ligand. In some embodiments, the immunostimulatory moiety is a synthetic small molecule STING signaling agonist.

[00220] In some embodiments, the STING agonist is a cyclic dinucleotide (CDN). See, for example, Danilchanka et al., Cell 154:962–970 (2013). Exemplary CDNs include cdA, cdG, cAMP-cGMP, and 2'-5',3'-5'-cGAMP (for structures, see in Danilchanka et al.). STING agonists also include synthetic agonists such as DMXAA

.

Conjugated polypeptides other than ferritin

[00221] In some embodiments, an antigenic polypeptide based on the OspA sequence is conjugated to a surface exposed amino acid in ferritin. In some embodiments, an antigenic polypeptide based on the OspA sequence is antigenic per se, while in some embodiments, an antigenic polypeptide based on the OspA sequence is antigenic because it is associated with ferritin.

7. Conjugation

[00222] In some embodiments, a surface-exposed cysteine is used to conjugate an immunostimulatory moiety, such as an adjuvant or an antigenic polypeptide based on the OspA sequence, to ferritin. In some embodiments, a surface-exposed cysteine is used to conjugate a linker to ferritin, which linker may subsequently be conjugated to an immunostimulatory moiety, such as an adjuvant, or an antigenic polypeptide based on the OspA sequence. In some embodiments, the surface exposed cysteine provides a chemical mechanism for conjugation reactions to attach an adjuvant, linker, or antigenic polypeptide based on the OspA sequence.

[00223] In some embodiments, bioconjugates are prepared wherein an immunostimulatory moiety, such as an adjuvant, or an antigenic polypeptide based on the OspA sequence is bound to ferritin after reduction of the unpaired surface-exposed cysteine in ferritin. An unpaired surface exposed cysteine is a cysteine that does not have a cysteine partner at a suitable position to form a disulfide bond. In some embodiments, the unpaired cysteine includes a free thiol side chain.

Types of Conjugation Chemistry

[00224] Any type of chemistry can be used to conjugate an immunostimulatory moiety, such as an adjuvant, or an antigenic polypeptide based on the OspA sequence to ferritin, for example, by reacting with a surface exposed amino acid such as cysteine or another amino acid such as Lys , Glu or Asp.

[00225] In some embodiments, conjugation is performed using click chemistry. As used herein, the term “click chemistry” refers to a reaction between a pair of functional groups that react rapidly and selectively (ie, “click”) with each other. In some embodiments, click chemistry can be performed under mild aqueous conditions. In some embodiments, the click chemistry reaction takes advantage of a cysteine on the surface of ferritin, such as a cysteine resulting from mutation of a surface-exposed amino acid, to perform click chemistry using a functional group that is capable of reacting with the cysteine.

[00226] Various reactions that satisfy the criteria of click chemistry are known in the art, and one skilled in the art can employ any of a number of published techniques (see, for example, Hein et al., Pharm Res 25(10):2216-2230 (2008)). A wide range of commercially available click chemistry reagents can be used, such as those from Sigma Aldrich, Jena Bioscience or Lumiprobe. In some embodiments, conjugation is performed using click chemistry, as described in the examples below.

[00227] In some embodiments, the click chemistry reaction occurs after ferritin reduction.

[00228] In some embodiments, the click chemistry may be a 1-step click reaction. In some embodiments, the click chemistry may be a 2-step click reaction.

[00229] In some embodiments, the reaction(s) involve click chemistry without the participation of a metal. In some embodiments, the reaction(s) involve thiol-maleimide and/or disulfide exchange.

Click chemistry without metal

[00230] Metal-free click chemistry can be used for conjugation reactions to avoid potential protein oxidation. Metal-free click chemistry has been used to form antibody conjugates (see van Geel et al., Bioconjugate Chem. 2015, 26, 2233−2242).

[00231] In some embodiments, metal-free click chemistry is used in reactions to couple an adjuvant to ferritin. In some embodiments, copper-free conjugation is used in reactions to couple an adjuvant to ferritin. In some embodiments, metal-free click chemistry employs bicyclo[6.1.0]nonine (BCN). In some embodiments, metal-free click chemistry uses dibenzoazacyclooctine (DBCO). In some embodiments, BCN or DBCO is reacted with an azide group.

[00232] DBCO has high specificity for azide groups due to a voltage-stimulated click reaction in the absence of a catalyst, resulting in high yields of a stable triazole. In some embodiments, DBCO reacts with an azide in the absence of a copper catalyst.

[00233] In some embodiments, metal-free click chemistry is used in a 1-step click reaction. In some embodiments, metal-free click chemistry is used in a 2-step click reaction.

Thiol-maleimide and disulfide exchange

[00234] Ferritins described herein may include a cysteine containing thiol, also known as a sulfhydryl, which is available for reaction with sulfhydryl-reactive chemical groups (or which can be made available through reduction). Thus, cysteine provides a chemoselective modification with the addition of an immunostimulatory moiety, such as an adjuvant, to ferritin. Under basic conditions, the cysteine will be deprotonated to form a thiolate nucleophile, which is capable of reacting with soft electrophiles such as maleimides and iodoacetamides. The reaction of cysteine with maleimide or iodoacetamide results in the formation of a carbon-sulfur bond.

[00235] In some embodiments, the sulfhydryl-reactive chemical moiety reacts with a surface-exposed cysteine or cysteine in the ferritin linker. In some embodiments, the sulfhydryl-reactive chemical group is a haloacetyl, maleimide, aziridine, acryloyl, arylation agent, vinyl sulfone, pyridyl disulfide, or TNB-thiol.

[00236] In some embodiments, the sulfhydryl-reactive chemical group is conjugated to the cysteine sulfhydryl via alkylation (ie, formation of a thioether bond). In some embodiments, the sulfhydryl-reactive chemical moiety is conjugated to the cysteine sulfhydryl via disulfide exchange (ie, the formation of a disulfide bond).

[00237] In some embodiments, the reaction for conjugating an immunostimulatory moiety, such as an adjuvant, to ferritin is a thiol-maleimide reaction.

[00238] In some embodiments, the sulfhydryl-reactive chemical moiety is a maleimide. In some embodiments, the reaction of a maleimide with a cysteine results in the formation of a stable thioester bond, for example, which is irreversible. In some embodiments, maleimide does not react with tyrosines, histidines, or methionines in ferritin. In some embodiments, unreacted maleimides are quenched upon completion of the reaction by adding a free thiol, for example in excess.

[00239] In some embodiments, the reaction for conjugating an immunostimulatory moiety, such as an adjuvant, to ferritin is a thiol-disulfide exchange, also known as a disulfide exchange. In some embodiments, the reaction includes the formation of a mixed disulfide containing a portion of the original disulfide. In some embodiments, the parent disulfide is a cysteine incorporated into ferritin through mutation of a surface-exposed amino acid or the addition of an N-terminal linker.

[00240] In some embodiments, the sulfhydryl-reactive chemical moiety is pyridyldithiol. In some embodiments, the sulfhydryl-reactive chemical group is a TNB-thiol group.

Linkers

[00241] In some embodiments, an immunostimulatory moiety, such as an adjuvant, or an antigenic polypeptide based on the OspA sequence is attached to ferritin via a linker that is covalently linked to a surface exposed amino acid, such as cysteine. In some embodiments, the linker includes a polyethylene glycol, such as a PEG linker. In some embodiments, the polyethylene glycol (eg, PEG) linker enhances the aqueous solubility and ligation efficiency of ferritin bound to an immunostimulatory moiety, such as an adjuvant. The PEG linker is 2-18 PEG in length, for example PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, PEG11, PEG12, PEG13, PEG14, PEG15, PEG16, PEG17 and PEG18.

[00242] In some embodiments, the linker comprises a maleimide. In some embodiments, the linker contains components of an (ISM)-linker-maleimide immunostimulatory moiety. In some embodiments, the maleimide ISM linker is conjugated to ferritin in a 1-step click chemistry reaction by reacting the maleimide with the cysteine in the ferritin. In some embodiments, the ISM from the maleimide linker adjuvant is SM7/8a. In some embodiments, the ISM-linker-maleimide linker is PEG4. In some embodiments, the maleimide ISM linker is SM7/8a-PEG4 maleimide.

[00243] In some embodiments, a 2-step click chemistry protocol is used with a linker comprising a sulfhydryl-reactive chemical group at one end and an amine-reactive group at the other end. In such a 2-step click chemistry protocol, the sulfhydryl-reactive chemical group reacts with the cysteine in ferritin, while the amine-reactive group reacts with the reagent attached to the ISM. Thus, ISM is conjugated to ferritin using a set of 2 click chemistry reagents.

[00244] In some embodiments of the 2-step click chemistry protocol, the sulfhydryl-reactive chemical moiety is a maleimide. In some embodiments of the 2-step click chemistry protocol, maleimide reacts with a cysteine embedded in ferritin through mutation of a surface-exposed amino acid or addition of an N-terminal linker.

[00245] In some embodiments of the 2-step click chemistry protocol, the amine-reactive group is DBCO. In some embodiments of the 2-step click chemistry protocol, DBCO reacts with an azide group attached to the ISM.

[00246] In some embodiments, a maleimide linker-DBCO is used. In some embodiments, the maleimide linker-DBCO is conjugated to ferritin after ferritin has been reduced. In some embodiments, the maleimide linker reagent is conjugated to ferritin by reacting the maleimide with a cysteine in the ferritin in a first step. In some embodiments, DBCO is used to couple to an ISM attached to an azide. In some embodiments, the ISM bound to the azide is ISS-1018. In some embodiments, the azide-linked adjuvant is 3M-012 or CpG.

[00247] In some embodiments, a linker with a reactive group is added to the ISM. In some embodiments, the linker is a PEG4 azide linker or a PEG4 maleimide linker.

[00248] In some embodiments, the PEG4 azide linker is conjugated to 3M-012. An exemplary structure of 3M-012 conjugated to a PEG4 azide linker is:

[00249] In some embodiments, the PEG4 azide linker is conjugated to SM7/8a. An exemplary structure of SM7/8a conjugated to a PEG4 azide linker is:

[00250] In some embodiments, the PEG4 maleimide linker is conjugated to SM7/8a. An exemplary structure of SM7/8a conjugated to a PEG4-maleimide linker is:

[00251] In some embodiments, the azide group is conjugated to ISS-1018. An exemplary structure of ISS-1018 conjugated to an NHS ester azide linker is:

Exemplary Compositions, Kits, Nucleic Acids, Uses and Methods

[00252] In some embodiments, a composition is provided comprising any one or more of the antigenic polypeptides described herein and a pharmaceutically acceptable carrier vehicle, adjuvant, or excipient.

[00253] In some embodiments, an antigenic polypeptide or composition described herein is administered to a subject, such as a human, for immunization against a Borrelia infection, such as Lyme disease. In some embodiments, an antigenic polypeptide described herein is administered to a subject, such as a human, to induce a protective immune response to a future Borrelia infection. In some embodiments, a polypeptide comprising a modified OspA serotype 1 polypeptide is administered, as described herein. In some embodiments, an antigenic polypeptide comprising OspA and ferritin is administered, as described herein.

[00254] In some embodiments, a protective immune response reduces the incidence of hospitalization. In some embodiments, the protective immune response reduces the incidence of acute or chronic Lyme disease, including joint inflammation, neurological symptoms, cognitive deficits, or heart rhythm disturbances.

[00255] In some embodiments, the composition contains a serotype 1 OspA polypeptide. In some embodiments, the composition contains a serotype 2 OspA polypeptide. In some embodiments, the composition contains a serotype 3 OspA polypeptide. In some embodiments, the composition contains a serotype 4 OspA polypeptide. In some embodiments, the composition contains a serotype 4 OspA polypeptide. In some embodiments, the composition contains a serotype 5 OspA polypeptide. In some embodiments, the composition contains a serotype 7 OspA polypeptide. In some embodiments, the composition contains only one OspA polypeptide. In some embodiments, the composition contains one or more OspA serotypes 1, 2, 3, 4, 5, 6, and 7.

[00256] In some embodiments, the composition contains more than one OspA polypeptide, for example, more than one OspA serotype. In some embodiments, such a composition provides vaccination against multiple typesBorrelia, for example, one, two, three, four, five, six or seven of serotypes 1-7. Because OspA serotypes are associated with genotypesBorrelia(cm. Wilske 1993), vaccination with such a composition containing several serotypes of OspA can provide immunity to a number of bacteria that can cause Lyme disease.

[00257] In some embodiments, a composition comprising multiple OspA serotypes provides immunity against Borrelia that express multiple OspA serotypes. For example, as discussed in the Examples section, it has been observed that a composition comprising OspA serotypes 1-5 and 7 polypeptides is capable of inducing the formation of antibodies that recognize OspA serotype 6. In some embodiments, such a composition provides immunity against multiple Borrelia genospecies.

[00258] In some embodiments, the composition contains two different serotypes of OspA. In some embodiments, the multivalent composition contains three different OspA serotypes. In some embodiments, the multivalent composition contains four different OspA serotypes. In some embodiments, the multivalent composition contains five different OspA serotypes. In some embodiments, the multivalent composition contains six different OspA serotypes. In some embodiments, the multivalent composition contains seven different OspA serotypes.

[00259] In some embodiments, the composition comprises OspA serotype 1 and any one or more of OspA serotypes 2-7. In some embodiments, the composition comprises OspA serotype 2 and any one or more of OspA serotypes 1 and 3-7. In some embodiments, the composition comprises OspA serotype 3 and any one or more of OspA serotypes 1-2 and 4-7. In some embodiments, the composition comprises OspA serotype 4 and any one or more of OspA serotypes 1-3 and 5-7. In some embodiments, the composition comprises OspA serotype 5 and any one or more of OspA serotypes 1-4 and 6-7. In some embodiments, the composition contains OspA serotype 6 and any one or more of OspA serotypes 1-5 and 7. In some embodiments, the composition contains OspA serotype 7 and any one or more of OspA serotypes 1-6. In some embodiments, the composition contains at least 2, 3, 4, 5, or 6 OspA serotypes 1-5 and 7 polypeptides.

[00260] In some embodiments, any one or more of the antigenic polypeptides or compositions described herein are provided for use in immunization against a Borrelia infection, such as Lyme disease. In some embodiments, any one or more of the antigenic polypeptides or compositions described herein are provided for use in inducing a protective immune response to a future Borrelia infection. In some embodiments, any one or more of the antigenic polypeptides or compositions described herein are for use in a mammal, such as a primate (e.g., a non-human primate such as a monkey (e.g., a macaque such as a rhesus monkey or cynomolgus macaque) or ape), rodent (eg mouse or rat) or domesticated mammal (eg dog, rabbit, cat, horse, sheep, cow, goat, camel or donkey).

1. Adjuvants

[00261] An adjuvant can be administered to a subject along with the antigenic polypeptides described herein, where such administration results in a higher titer of anti-OspA antibodies in the subject compared to administration of OspA without an adjuvant. An adjuvant may promote an earlier, stronger, or more sustained immune response to OspA.

[00262] In some embodiments, the composition contains a single adjuvant. In some embodiments, the composition contains more than one adjuvant. In some embodiments, the composition does not contain an adjuvant.

[00263] In some embodiments, the adjuvant includes aluminum. In some embodiments, the adjuvant is aluminum phosphate. In some embodiments, the adjuvant is aluminum alum (Alyhydrogel '85 2%; Brenntag, catalog no. 21645-51-2).

[00264] In some embodiments, the adjuvant is an organic adjuvant. In some embodiments, the adjuvant is an oil-based adjuvant. In some embodiments, the adjuvant comprises an oil-in-water nanoemulsion.

[00265] In some embodiments, the adjuvant includes squalene. In some embodiments, the adjuvant comprising squalene is Ribi (Sigma adjuvant system, Cat. No. S6322-1vl), AddaVax^TM (squalene-based oil-in-water nanoemulsion), MF59, AS03 or AF03 (see US9703095). In some embodiments, the adjuvant comprising squalene is a nanoemulsion.

[00266] In some embodiments, the adjuvant includes a polyacrylic acid (PAA) polymer. In some embodiments, the adjuvant comprising the PAA is SPA09 (see WO 2017218819).

[00267] In some embodiments, the adjuvant includes non-metabolizable oils. In some embodiments, the adjuvant is Freund's incomplete adjuvant (IFA).

[00268] In some embodiments, the adjuvant includes non-metabolizable oils and killed Mycobacterium tuberculosis. In some embodiments, the adjuvant is Freund's complete adjuvant (CFA).

[00269] In some embodiments, the adjuvant is a lipopolysaccharide. In some embodiments, the adjuvant is monophosphoryl A (MPL or MPLA).

2. Subjects

[00270] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[00271] In some embodiments, the subject is an adult (18 years of age or older). In some embodiments, the subject is a child or adolescent (under 18 years of age). In some embodiments, the subject is an elderly person (over 60 years of age). In some embodiments, the subject is a non-elderly adult (aged 18 years or older to 60 years or older).

[00272] In some embodiments, the subject is given more than one administration of the composition. In some embodiments, booster administration improves the immune response.

[00273] In some embodiments, any one or more of the antigenic polypeptides or compositions described herein are for use in a mammal, such as a primate (e.g., a non-human primate such as a monkey (e.g., a macaque, such as a macaque - rhesus or cynomolgus macaque) or ape), rodent (for example, mouse or rat) or domesticated mammal (for example, dog, rabbit, cat, horse, sheep, cow, goat, camel or donkey).

[00274] In some embodiments, the composition is formulated appropriately for the intended route of administration. Examples of suitable routes of administration include intramuscular, intradermal, subcutaneous, intranasal, oral or transdermal.

[00275] In some embodiments, the subject is given more than one administration of the composition. In some embodiments, booster administration improves the immune response.

3. Pharmaceutical compositions

[00276] In various embodiments, a pharmaceutical composition is provided comprising a ferritin sequence-based antigenic polypeptide described herein and/or related entities. In some embodiments, the pharmaceutical composition is an immunogenic composition (eg, a vaccine) capable of inducing an immune response, such as a protective immune response against Borrelia .

[00277] For example, in some embodiments, the pharmaceutical compositions may contain one or more of the following: (1) an antigenic protein ferritin comprising (i) a mutation to replace a surface-exposed amino acid with cysteine, and (ii) an antigenic polypeptide based on the OspA sequence ; (2) an antigenic protein ferritin, including (i) a mutation replacing a surface-exposed amino acid with cysteine, and an immunostimulatory fragment associated with cysteine; and (ii) an antigenic polypeptide based on the OspA sequence; (3) an antigenic ferritin protein comprising (i) a surface-exposed cysteine, (ii) a peptide linker N-terminal to the ferritin protein, and (iii) an antigenic polypeptide based on the OspA sequence N-terminal to the peptide linker; (4) an antigenic protein ferritin, including (i) a mutation replacing a surface-exposed amino acid with a cysteine and an immunostimulatory fragment associated with cysteine, (ii) a mutation replacing an internal cysteine at position 31 of ferritin from H. pylori or a mutation replacing an internal cysteine at a position that is similar to the position of 31 ferritin other than ferritin from H. pylori , as determined by pairwise or structural alignment, to a non-cysteine amino acid, (iii) a mutation replacing surface-exposed asparagine with a non-asparagine amino acid, and ( iv) an antigenic polypeptide based on the OspA sequence; or (5) a ferritin particle containing any of the above ferritin proteins.

[00278] In some embodiments, the present invention provides pharmaceutical compositions containing antibodies or other agents related to the antigenic polypeptides described herein. In one embodiment, the pharmaceutical composition contains antibodies that bind to and/or compete with an antigenic polypeptide described herein. Alternatively, the antibodies are capable of recognizing viral particles or bacteria containing a component of the antigenic polypeptide described herein that is a polypeptide other than ferritin.

[00279] In some embodiments, the pharmaceutical compositions described herein are administered alone or in combination with one or more agents to enhance the immune response, such as an adjuvant described above. In some embodiments, the pharmaceutical composition further comprises an adjuvant as described above.

[00280] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient. As used herein, the term “carrier” refers to the diluent, adjuvant, excipient or carrier medium with which the pharmaceutical composition is administered. In illustrative embodiments, carriers may include sterile liquids, such as, for example, water and oils, including petroleum, animal, vegetable, or synthetic oils, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like. .P. In some embodiments, the carriers are or include one or more solid components. Pharmaceutically acceptable carriers may also include, but are not limited to, saline, buffered saline, dextrose, glycerol, ethanol, and combinations thereof. As used herein, the term excipient refers to any non-therapeutic agent that can be included in a pharmaceutical composition, for example, to provide or help achieve a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, but are not limited to, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerin, propylene, glycol, water, ethanol, etc. In various embodiments, the pharmaceutical composition is sterile.

[00281] In some embodiments, the pharmaceutical composition contains minor amounts of wetting or emulsifying agents or pH buffering agents. In some embodiments, the pharmaceutical compositions may contain any of a variety of additives, such as stabilizers, buffers, or preservatives. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents may be included.

[00282] In various embodiments, the pharmaceutical composition can be formulated to suit any desired route of administration. For example, the pharmaceutical composition may be in the form of solutions, suspensions, emulsions, drops, tablets, pills, pellets, capsules, liquid capsules, gelatin capsules, powders, sustained release formulations, suppositories, emulsions, aerosols, sprays, suspensions, lyophilized powder , frozen suspension, dried powder or any other form suitable for use. General considerations for the formulation and manufacture of pharmaceuticals can be found, for example, in Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Co., Easton, PA, 1995; incorporated herein by reference.

[00283] The pharmaceutical composition can be administered by any route of administration. Routes of administration include, for example, oral, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, transmucosal, epidural, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectal, intratracheal instillation, bronchial instillation, inhalation, or topical. Administration may be local or systemic. In some embodiments, administration is orally. In another embodiment, administration is via parenteral injection. In some cases, administration results in the release of an antigenic polypeptide based on the ferritin sequence described herein into the bloodstream. The route of administration may be left to the discretion of the practitioner.

[00284] In some embodiments, the pharmaceutical composition is suitable for parenteral administration (eg, intravenous, intramuscular, intraperitoneal, and subcutaneous). Such compositions may be formulated, for example, as solutions, suspensions, dispersions, emulsions, and the like. They can also be formulated as sterile solid compositions (eg, lyophilized compositions), which can be dissolved or suspended in a sterile injection medium immediately prior to use. For example, parenteral administration can be accomplished by injection. In such embodiments, the injectable preparations are prepared in conventional forms, i.e. either in the form of liquid solutions or suspensions, solid forms suitable for dissolution or suspension in liquid before injection, or in the form of emulsions. In some embodiments, injectable solutions and suspensions are prepared from sterile powders, lyophilized powders, or granules.

[00285] In a further embodiment, the pharmaceutical composition is formulated for delivery by inhalation (eg, for direct delivery to the lungs and respiratory system). For example, the composition may be in the form of a nasal spray or any other known aerosol formulation. In some embodiments, formulations for inhalation or aerosol delivery contain multiple particles. In some embodiments, such formulations may have an average particle size of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, or about 13 microns. In some embodiments, the formulations for inhalation or aerosol delivery are formulated as a dry powder. In some embodiments, formulations for inhalation or aerosol delivery are formulated as a wet powder, for example, by including a wetting agent. In some embodiments, the wetting agent is selected from the group consisting of water, saline, or other liquid having a physiological pH value.

[00286] In some embodiments, the pharmaceutical composition of the present invention is administered as drops into the nasal or oral cavity. In some embodiments, the dose may comprise multiple drops (eg, 1-100, 1-50, 1-20, 1-10, 1-5, etc.).

[00287] The pharmaceutical composition of the present invention can be administered in any dose suitable to achieve the desired result. In some embodiments, the desired result is the induction of a durable adaptive immune response against a pathogen, such as a source of a non-ferritin polypeptide present in a ferritin sequence-based antigenic polypeptide present in the composition. In some embodiments, the desired result is a reduction in the intensity, severity, frequency, and/or delay of onset of one or more symptoms of the infection. In some embodiments, the desired result is inhibition or prevention of infection. The required dosage will vary from subject to subject depending on the species, age, weight and general condition of the subject, the severity of the infection being prevented or treated, the particular composition used and the route of administration.

[00288] In some embodiments, the pharmaceutical compositions of the present invention are administered in one or more doses. In some embodiments, the pharmaceutical compositions are administered in multiple doses administered on different days (eg, prime-boost vaccination strategies). In some embodiments, the pharmaceutical composition is administered as part of a booster regimen.

[00289] In various embodiments, the pharmaceutical composition is administered in conjunction with one or more additional therapeutic agents. Coadministration does not require simultaneous administration of therapeutic agents if the timing of their administration is such that the pharmacological activities of the additional therapeutic agent and the active ingredient(s) in the pharmaceutical composition overlap in time, thereby producing a combined therapeutic effect. Typically, each agent will be administered at the dose and schedule established for that agent.

4. Nucleic acid/RNA

[00290] Also provided is a nucleic acid encoding an antigenic polypeptide based on the OspA sequence described herein. In some embodiments, the nucleic acid is mRNA. Any nucleic acid capable of undergoing translation to produce a polypeptide is considered to be mRNA for the purposes of the present invention.

5. Sets

[00291] Also provided herein are kits containing one or more of the antigenic polypeptides, nucleic acids, antigenic ferritin particles, antigenic lumazine synthase particles, compositions, or pharmaceutical compositions described herein. In some embodiments, the kit further contains one or more of a solvent, solution, buffer, instructions, or drying agent.

* * *

[00292] This description and illustrative embodiments are not to be construed as limiting. For purposes of this specification and the accompanying claims, unless otherwise indicated, all numbers expressing quantities, percentages or proportions and other numerical values used in the specification and claims are to be understood as being modified in all cases by the term "about" as used herein. the extent to which they have not already been modified. “Approximately” indicates a degree of variation that does not significantly affect the properties of the described claimed item, such as within 10%, 5%, 2% or 1%. Accordingly, unless otherwise indicated, the numerical parameters set forth in the following description and the accompanying claims are exemplary values that may vary depending on the desired properties to be obtained. As a last resort, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of significant figures reported and the application of normal rounding techniques.

[00293] It should be noted that, as used in this specification and the accompanying claims, the singular form, as well as any use of any word in the singular, includes entities in the plural unless expressly and unambiguously limited to a single entity. As used herein, the term “include” and its grammatical variations are not intended to be limiting, such that listing items in a list does not exclude other similar items that may be replaced or added to the listed items. The term "or" is used in an inclusive sense, i.e. is equivalent to "and/or" unless the context indicates otherwise.

Table 1 (sequence table): Description of sequences

Description
("Ferritin" refers to ferritin from H. pylori , optionally with one or more mutations, unless otherwise noted) Sequences
Key for sequences 1-102:
Leader sequences are sometimes underlined
Modified LFA-1 site is italicized and underlined (if present)
Mutations other than the modified LFA-1 site are in bold and underlined by a wavy line
The linker is underlined with a double line
The bullfrog sequence is in italics and underlined with a wavy line (if present)
Human ferritin heavy chain sequence is in bold (if present)
Transmembrane domain is italicized (if present)
Lipidation site is shown in bold, italics and underlined (if present) SEQ ID NO: OspA serotype 1-RD2-ferritin MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG YTLEGQLSD EKTTLVVKEGTVTLSKNISKSGEVSVELND TDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLTQIFQKAYEHEQHISESINNIVDHAIK C KDH ATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 1 OspA serotype 1-RD1-ferritin MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG YDLKGELSS EKTTLVVKEGTVTLSKNISKSGEVSVELND TDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLTQIFQKAYEHEQHISESINNIVDHAIK C KDH ATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 2 OspA serotype 1-ferritin; replacement of LFA-1 serotype 2 MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG FTLEGKVAN EKTTLVVKEGTVTLSKNISKSGEVSVELND TDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLTQIFQKAYEHEQHISESINNIVDHAIK C KDH ATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 3 OspA serotype 1-ferritin; replacement for LFA-1 serotype 3 MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG FALEGTLTD EKTTLVVKEGTVTLSKNISKSGEVSVELNDT DSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLTQIFQKAYEHEQHISESINNIVDHAIK C KDHAT FNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 4 OspA serotype 2-ferritin MDEKNSASVDLPGEMKVLVSKEKDKDGKYSLKATVDKIELKGTSDKDNGSGVLEGTKDDKSKAKLTIADDLSKTTFELFKEDGKTLVSRKVSSKDKTSTDEMFNEKGELSAKTMTRENGTKLEYTEMKSDGTGKAKEVLKNFTLEGKVANDKVTLEVKEGTVTLSKEIAKSGEVTVALNDTNTTQAT KKTGAWDSKTSTLTISVNSKKTTQLVFTKQDTITVQKYDSAGTNLEGTAVEIKTLDELKNALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLTQIFQKAYEHEQHISESINNIVDHAIK C KDHATFNFL QWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 5 OspA serotype 3-ferritin MDEKNSVSVDLPGGMKVLVSKEKDKDGKYSLMATVEKLELKGTSDKSNGSGVLEGEKADKSKAKLTISQDLNQTTFEIFKEDGKTLVSRKVNSKDKSSTEEKFNDKGKLSEKVVTRANGTRLEYTEIKNDGSGKAKEVLKGFALEGTLTDGGETKLTVTEGTVTLSKNISKSGEITVALNDTETTPADKK TGEWKSDTSTLTISKNSQKPKQLVFTKENTITVQNYNRAGNALEGSPAEIKDLAELKAALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLTQIFQKAYEHEQHISESINNIVDHAIK C KDHATFNFLQWYVA EQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 6 OspA serotype 4-ferritin MDEKNSVSVDLPGEMKVLVSKEKDKDGKYSLMATVDKLELKGTSDKSNGSGTLEGEKSDKSKAKLTISEDLSKTTFEIFKEDGKTLVSKKVNSKDKSSIEEKFNAKGELSEKTILRANGTRLEYTEIKSDGTGKAKEVLKDFALEGTLAADKTTLKVTEGTVVLSKHIPNSGEITVELNDSNSTQATKK TGKWDSNTSTLTISVNSKKTKNIVFTKEDTITVQKYDSAGTNLEGNAVEIKTLDELKNALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLTQIFQKAYEHEQHISESINNIVDHAIK C KDHATFNFLQW YVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 7 OspA serotype 5-ferritin MDEKNSVSVDLPGGMKVLVSKEKDKDGKYSLMATVEKLELKGTSDKNNGSGTLEGEKTDKSKVKLTIAEDLSKTTFEIFKEDGKTLVSKKVTLKDKSSTEEKFNEKGEISEKTIVRANGTRLEYTDIKSDGSGKAKEVLKDFTLEGTLAADGKTTLKVTEGTVVLSKNILKSGEITVALDDSDTTQ ATKKTGKWDSKTSTLTISVNSQKTKNLVFTKEDTITVQKYDSAGTNLEGKAVEITTLEKLKDALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLTQIFQKAYEHEQHISESINNIVDHAIK C KDHATF NFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 8 OspA serotype 6-ferritin MDEKNSVSVDLPGGMTVLVSKEKDKDGKYSLEATVDKLELKGTSDKNNGSGTLEGEKTDKSKVKSTIADDLSQTKFEIFKEDGKTLVSKKVTLKDKSSTEEKFNGKGETSEKTIVRANGTRLEYTDIKSDGSGKAKEVLKDFTLEGTLAADGKTTLKVTEGTVVLSKNILKSGEITAALDDSDTTRAT KKTGKWDSKTSTLTISVNSQKTKNLVFTKEDTITVQRYDSAGTNLEGKAVEITTLKELKNALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLTQIFQKAYEHEQHISESINNIVDHAIK C KDHATFNFLQ WYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 9 OspA serotype 7-ferritin MDEKNSVSVDLPGEMKVLVSKEKDKDGKYSLEATVDKLELKGTSDKNNGSGVLEGVKAAKSKAKLTIADDLSQTKFEIFKEDGKTLVSKKVTLKDKSSTEEKFNDKGKLSEKVVTRANGTRLEYTEIQNDGSGKAKEVLKSLTLEGTLTADGETKLTVEAGTVTLSKNISESGEITVELKDTET TPADKKSGTWDSKTSTLTISKNSQKTKQLVFTKENTITVQKYNTAGTKLEGSPAEIKDLEALKAALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLTQIFQKAYEHEQHISESINNIVDHAIK C KDHAT FNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 10 OspA serotype 4-cysteine-thrombin-His MDEKNSVSVDLPGEMKVLVSKEKDKDGKYSLMATVDKLELKGTSDKSNGSGTLEGEKSDKSKAKLTISEDLSKTTFEIFKEDGKTLVSKKVNSKDKSSIEEKFNAKGELSEKTILRANGTRLEYTEIKSDGTGKAKEVLKDFALEGTLAADKTTLKVTEGTVVLSKHIPNSGEITVELNDSNSTQATKK TGKWDSNTSTLTISVNSKKTKNIVFTKEDTITVQKYDSAGTNLEGNAVEIKTLDELKNALK C LVPRGSLEHHHHHH eleven OspA serotype 1-lumazine synthase; replacing LFA-1 with RD2 MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG YTLEGQLSD EKTTLVVKEGTVTLSKNISKSGEVSVELND TDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK GGGS MQIYEGKLTAEGLRFGIVASRFNHALVDRLVEGAIDCIVRHGGREEDITLVRVPGSWEIPVAAGELARKEDIDAVIAIGVLIRGATPHFDYIASEVSKGLANLSLELRKPITFGVITADTLEQAIERAGTKH GNKGWEAALSAIEMANLFKSLR 12 OspA serotype 1-lumazine synthase; replacing LFA-1 with RD1 MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG YDLKGELSS EKTTLVVKEGTVTLSKNISKSGEVSVELND TDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK GGGS MQIYEGKLTAEGLRFGIVASRFNHALVDRLVEGAIDCIVRHGGREEDITLVRVPGSWEIPVAAGELARKEDIDAVIAIGVLIRGATPHFDYIASEVSKGLANLSLELRKPITFGVITADTLEQAIERAGTKH GNKGWEAALSAIEMANLFKSLR 13 OspA serotype 1-lumazine synthase; replacing LFA-1 with Sero2 MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG FTLEGKVAN EKTTLVVKEGTVTLSKNISKSGEVSVELND TDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK GGGS MQIYEGKLTAEGLRFGIVASRFNHALVDRLVEGAIDCIVRHGGREEDITLVRVPGSWEIPVAAGELARKEDIDAVIAIGVLIRGATPHFDYIASEVSKGLANLSLELRKPITFGVITADTLEQAIERAGTKH GNKGWEAALSAIEMANLFKSLR 14 OspA serotype 1-lumazine synthase; replacing LFA-1 with Sero3 MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG FALEGTLTD EKTTLVVKEGTVTLSKNISKSGEVSVELNDT DSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK GGGS MQIYEGKLTAEGLRFGIVASRFNHALVDRLVEGAIDCIVRHGGREEDITLVRVPGSWEIPVAAGELARKEDIDAVIAIGVLIRGATPHFDYIASEVSKGLANLSLELRKPITFGVITADTLEQAIERAGTKHG NKGWEAALSAIEMANLFKSLR 15 OspA serotype 2-lumazine synthase MDEKNSASVDLPGEMKVLVSKEKDKDGKYSLKATVDKIELKGTSDKDNGSGVLEGTKDDKSKAKLTIADDLSKTTFELFKEDGKTLVSRKVSSKDKTSTDEMFNEKGELSAKTMTRENGTKLEYTEMKSDGTGKAKEVLKNFTLEGKVANDKVTLEVKEGTVTLSKEIAKSGEVTVALNDTNTTQAT KKTGAWDSKTSTLTISVNSKKTTQLVFTKQDTITVQKYDSAGTNLEGTAVEIKTLDELKNALK GGGS MQIYEGKLTAEGLRFGIVASRFNHALVDRLVEGAIDCIVRHGGREEDITLVRVPGSWEIPVAAGELARKEDIDAVIAIGVLIRGATPHFDYIASEVSKGLANLSLELRKPITFGVITADTLEQAIERAGTKHGNKGW EAALSAIEMANLFKSLR 16 OspA serotype 3-lumazine synthase MDEKNSVSVDLPGGMKVLVSKEKDKDGKYSLMATVEKLELKGTSDKSNGSGVLEGEKADKSKAKLTISQDLNQTTFEIFKEDGKTLVSRKVNSKDKSSTEEKFNDKGKLSEKVVTRANGTRLEYTEIKNDGSGKAKEVLKGFALEGTLTDGGETKLTVTEGTVTLSKNISKSGEITVALNDTETTPADKK TGEWKSDTSTLTISKNSQKPKQLVFTKENTITVQNYNRAGNALEGSPAEIKDLAELKAALK GGGS MQIYEGKLTAEGLRFGIVASRFNHALVDRLVEGAIDCIVRHGGREEDITLVRVPGSWEIPVAAGELARKEDIDAVIAIGVLIRGATPHFDYIASEVSKGLANLSLELRKPITFGVITADTLEQAIERAGTKHGNKGWEAALSAIE MANLFKSLR 17 OspA serotype 4-lumazine synthase MDEKNSVSVDLPGEMKVLVSKEKDKDGKYSLMATVDKLELKGTSDKSNGSGTLEGEKSDKSKAKLTISEDLSKTTFEIFKEDGKTLVSKKVNSKDKSSIEEKFNAKGELSEKTILRANGTRLEYTEIKSDGTGKAKEVLKDFALEGTLAADKTTLKVTEGTVVLSKHIPNSGEITVELNDSNSTQATKK TGKWDSNTSTLTISVNSKKTKNIVFTKEDTITVQKYDSAGTNLEGNAVEIKTLDELKNALK GGGS MQIYEGKLTAEGLRFGIVASRFNHALVDRLVEGAIDCIVRHGGREEDITLVRVPGSWEIPVAAGELARKEDIDAVIAIGVLIRGATPHFDYIASEVSKGLANLSLELRKPITFGVITADTLEQAIERAGTKHGNKGWEAAL SAIEMANLFKSLR 18 OspA serotype 5-lumazine synthase MDEKNSVSVDLPGGMKVLVSKEKDKDGKYSLMATVEKLELKGTSDKNNGSGTLEGEKTDKSKVKLTIAEDLSKTTFEIFKEDGKTLVSKKVTLKDKSSTEEKFNEKGEISEKTIVRANGTRLEYTDIKSDGSGKAKEVLKDFTLEGTLAADGKTTLKVTEGTVVLSKNILKSGEITVALDDSDTTQ ATKKTGKWDSKTSTLTISVNSQKTKNLVFTKEDTITVQKYDSAGTNLEGKAVEITTLEKLKDALK GGGS MQIYEGKLTAEGLRFGIVASRFNHALVDRLVEGAIDCIVRHGGREEDITLVRVPGSWEIPVAAGELARKEDIDAVIAIGVLIRGATPHFDYIASEVSKGLANLSLELRKPITFGVITADTLEQAIERAGTKHNK GWEAALSAIEMANLFKSLR 19 OspA serotype 6-lumazine synthase MDEKNSVSVDLPGGMTVLVSKEKDKDGKYSLEATVDKLELKGTSDKNNGSGTLEGEKTDKSKVKSTIADDLSQTKFEIFKEDGKTLVSKKVTLKDKSSTEEKFNGKGETSEKTIVRANGTRLEYTDIKSDGSGKAKEVLKDFTLEGTLAADGKTTLKVTEGTVVLSKNILKSGEITAALDDSDTTRAT KKTGKWDSKTSTLTISVNSQKTKNLVFTKEDTITVQRYDSAGTNLEGKAVEITTLKELKNALK GGGS MQIYEGKLTAEGLRFGIVASRFNHALVDRLVEGAIDCIVRHGGREEDITLVRVPGSWEIPVAAGELARKEDIDAVIAIGVLIRGATPHFDYIASEVSKGLANLSLELRKPITFGVITADTLEQAIERAGTKHGNKGWEA ALSAIEMANLFKSLR 20 OspA serotype 7-lumazine synthase MDEKNSVSVDLPGEMKVLVSKEKDKDGKYSLEATVDKLELKGTSDKNNGSGVLEGVKAAKSKAKLTIADDLSQTKFEIFKEDGKTLVSKKVTLKDKSSTEEKFNDKGKLSEKVVTRANGTRLEYTEIQNDGSGKAKEVLKSLTLEGTLTADGETKLTVEAGTVTLSKNISESGEITVELKDTET TPADKKSGTWDSKTSTLTISKNSQKTKQLVFTKENTITVQKYNTAGTKLEGSPAEIKDLEALKAALK GGGS MQIYEGKLTAEGLRFGIVASRFNHALVDRLVEGAIDCIVRHGGREEDITLVRVPGSWEIPVAAGELARKEDIDAVIAIGVLIRGATPHFDYIASEVSKGLANLSLELRKPITFGVITADTLEQAIERAGTKHG NKGWEAALSAIEMANLFKSLR 21 OspA serotype 1; replacement of LFA-1 by RD2 - human ferritin heavy chain MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG YTLEGQLSD EKTTLVVKEGTVTLSKNISKSGEVSVELND TDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK GS MTTASTSQVRQNYHQDSEAAINRQINLELYASYVYLSMSYYFDRDDVALKNFAKYFLHQSHEEREHAEKLMKLQNQRGGRIFLQDIKKPDCDDWESGLNAMECALHLEKNVNQSLLELH KLATDKNDPHLCDFIETHYLNEQVKAIKELGDHVTNLRKMGAPESGLAEYLFDKHTLGDSDNES 22 OspA serotype 1; replacement of LFA-1 with RD1 - human ferritin heavy chain MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG YDLKGELSS EKTTLVVKEGTVTLSKNISKSGEVSVELND TDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK GS MTTASTSQVRQNYHQDSEAAINRQINLELYASYVYLSMSYYFDRDDVALKNFAKYFLHQSHEEREHAEKLMKLQNQRGGRIFLQDIKKPDCDDWESGLNAMECALHLEKNVNQSLLELH KLATDKNDPHLCDFIETHYLNEQVKAIKELGDHVTNLRKMGAPESGLAEYLFDKHTLGDSDNES 23 OspA serotype 1; replacement of LFA-1 serotype 2 - human ferritin heavy chain MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG FTLEGKVAN EKTTLVVKEGTVTLSKNISKSGEVSVELND TDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK GS MTTASTSQVRQNYHQDSEAAINRQINLELYASYVYLSMSYYFDRDDVALKNFAKYFLHQSHEEREHAEKLMKLQNQRGGRIFLQDIKKPDCDDWESGLNAMECALHLEKNVNQSLLELH KLATDKNDPHLCDFIETHYLNEQVKAIKELGDHVTNLRKMGAPESGLAEYLFDKHTLGDSDNES 24 OspA serotype 1; replacement of LFA-1 serotype 3 - human ferritin heavy chain MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG FALEGTLTD EKTTLVVKEGTVTLSKNISKSGEVSVELNDT DSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK GS MTTASTSQVRQNYHQDSEAAINRQINLELYASYVYLSMSYYFDRDDVALKNFAKYFLHQSHEEREHAEKLMKLQNQRGGRIFLQDIKKPDCDDWESGLNAMECALHLEKNVNQSLLELHK LATDKNDPHLCDFIETHYLNEQVKAIKELGDHVTNLRKMGAPESGLAEYLFDKHTLGDSDNES 25 OspA serotype 2 - human ferritin heavy chain MDEKNSASVDLPGEMKVLVSKEKDKDGKYSLKATVDKIELKGTSDKDNGSGVLEGTKDDKSKAKLTIADDLSKTTFELFKEDGKTLVSRKVSSKDKTSTDEMFNEKGELSAKTMTRENGTKLEYTEMKSDGTGKAKEVLKNFTLEGKVANDKVTLEVKEGTVTLSKEIAKSGEVTVALNDTNTTQAT KKTGAWDSKTSTLTISVNSKKTTQLVFTKQDTITVQKYDSAGTNLEGTAVEIKTLDELKNALK GS MTTASTSQVRQNYHQDSEAAINRQINLELYASYVYLSMSYYFDRDDVALKNFAKYFLHQSHEEREHAEKLMKLQNQRGGRIFLQDIKKPDCDDWESGLNAMECALHLEKNVNQSLLELHKLATDK NDPHLCDFIETHYLNEQVKAIKELGDHVTNLRKMGAPESGLAEYLFDKHTLGDSDNES 26 OspA serotype 3 - human ferritin heavy chain MDEKNSVSVDLPGGMKVLVSKEKDKDGKYSLMATVEKLELKGTSDKSNGSGVLEGEKADKSKAKLTISQDLNQTTFEIFKEDGKTLVSRKVNSKDKSSTEEKFNDKGKLSEKVVTRANGTRLEYTEIKNDGSGKAKEVLKGFALEGTLTDGGETKLTVTEGTVTLSKNISKSGEITVALNDTETTPADKK TGEWKSDTSTLTISKNSQKPKQLVFTKENTITVQNYNRAGNALEGSPAEIKDLAELKAALK GS MTTASTSQVRQNYHQDSEAAINRQINLELYASYVYLSMSYYFDRDDVALKNFAKYFLHQSHEEREHAEKLMKLQNQRGGRIFLQDIKKPDCDDWESGLNAMECALHLEKNVNQSLLELHKLATDKNDPHLCDF IETHYLNEQVKAIKELGDHVTNLRKMGAPESGLAEYLFDKHTLGDSDNES 27 OspA serotype 4 - human ferritin heavy chain MDEKNSVSVDLPGEMKVLVSKEKDKDGKYSLMATVDKLELKGTSDKSNGSGTLEGEKSDKSKAKLTISEDLSKTTFEIFKEDGKTLVSKKVNSKDKSSIEEKFNAKGELSEKTILRANGTRLEYTEIKSDGTGKAKEVLKDFALEGTLAADKTTLKVTEGTVVLSKHIPNSGEITVELNDSNSTQATKK TGKWDSNTSTLTISVNSKKTKNIVFTKEDTITVQKYDSAGTNLEGNAVEIKTLDELKNALK GS MTTASTSQVRQNYHQDSEAAINRQINLELYASYVYLSMSYYFDRDDVALKNFAKYFLHQSHEEREHAEKLMKLQNQRGGRIFLQDIKKPDCDDWESGLNAMECALHLEKNVNQSLLELHKLATDKNDPH LCDFIETHYLNEQVKAIKELGDHVTTNLRKMGAPESGLAEYLFDKHTLGDSDNES 28 OspA serotype 5 - human ferritin heavy chain MDEKNSVSVDLPGGMKVLVSKEKDKDGKYSLMATVEKLELKGTSDKNNGSGTLEGEKTDKSKVKLTIAEDLSKTTFEIFKEDGKTLVSKKVTLKDKSSTEEKFNEKGEISEKTIVRANGTRLEYTDIKSDGSGKAKEVLKDFTLEGTLAADGKTTLKVTEGTVVLSKNILKSGEITVALDDSDTTQ ATKKTGKWDSKTSTLTISVNSQKTKNLVFTKEDTITVQKYDSAGTNLEGKAVEITTLEKLKDALK GS MTTASTSQVRQNYHQDSEAAINRQINLELYASYVYLSMSYYFDRDDVALKNFAKYFLHQSHEEREHAEKLMKLQNQRGGRIFLQDIKKPDCDDWESGLNAMECALHLEKNVNQSLLELHKLA TDKNDPHLCDFIETHYLNEQVKAIKELGDHVTNLRKMGAPESGLAEYLFDKHTLGDSDNES 29 OspA serotype 6 - human ferritin heavy chain MDEKNSVSVDLPGGMTVLVSKEKDKDGKYSLEATVDKLELKGTSDKNNGSGTLEGEKTDKSKVKSTIADDLSQTKFEIFKEDGKTLVSKKVTLKDKSSTEEKFNGKGETSEKTIVRANGTRLEYTDIKSDGSGKAKEVLKDFTLEGTLAADGKTTLKVTEGTVVLSKNILKSGEITAALDDSDTTRAT KKTGKWDSKTSTLTISVNSQKTKNLVFTKEDTITVQRYDSAGTNLEGKAVEITTLKELKNALK GS MTTASTSQVRQNYHQDSEAAINRQINLELYASYVYLSMSYYFDRDDVALKNFAKYFLHQSHEEREHAEKLMKLQNQRGGRIFLQDIKKPDCDDWESGLNAMECALHLEKNVNQSLLELHKLATDKND PHLCDFIETHYLNEQVKAIKELGDHVTNLRKMGAPESGLAEYLFDKHTLGDSDNES thirty OspA serotype 7 - human ferritin heavy chain MDEKNSVSVDLPGEMKVLVSKEKDKDGKYSLEATVDKLELKGTSDKNNGSGVLEGVKAAKSKAKLTIADDLSQTKFEIFKEDGKTLVSKKVTLKDKSSTEEKFNDKGKLSEKVVTRANGTRLEYTEIQNDGSGKAKEVLKSLTLEGTLTADGETKLTVEAGTVTLSKNISESGEITVELKDTET TPADKKSGTWDSKTSTLTISKNSQKTKQLVFTKENTITVQKYNTAGTKLEGSPAEIKDLEALKAALK GS MTTASTSQVRQNYHQDSEAAINRQINLELYASYVYLSMSYYFDRDDVALKNFAKYFLHQSHEEREHAEKLMKLQNQRGGRIFLQDIKKPDCDDWESGLNAMECALHLEKNVNQSLLELHK LATDKNDPHLCDFIETHYLNEQVKAIKELGDHVTNLRKMGAPESGLAEYLFDKHTLGDSDNES 31 OspA serotype 1; replacement of LFA-1 with RD2 - ferritin Pyrococcus furiosus MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG YTLEGQLSD EKTTLVVKEGTVTLSKNISKSGEVSVELND TDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK GS MLSERMLKALNDQLNRELYSAYLYFAMAAYFEDLGLEGFANWMKAQAEEEIGHALRFYNYIYDRNGRVELDEIPKPPKEWESPLKAFEAAYEHEKFISKSIYELAALAEEEKDYSTRAFLEWFINE QVEEEASVKKILDKLKFAKDSPQILFMLDKELSARAPKLPGLLMQGGE 32 OspA serotype 1; replacement of LFA-1 with RD1 - ferritin Pyrococcus furiosus MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG YDLKGELSS EKTTLVVKEGTVTLSKNISKSGEVSVELND TDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK GS MLSERMLKALNDQLNRELYSAYLYFAMAAYFEDLGLEGFANWMKAQAEEEIGHALRFYNYIYDRNGRVELDEIPKPPKEWESPLKAFEAAYEHEKFISKSIYELAALAEEEKDYSTRAFLEWFINE QVEEEASVKKILDKLKFAKDSPQILFMLDKELSARAPKLPGLLMQGGE 33 OspA serotype 1; replacement of LFA-1 serotype 2 - ferritin Pyrococcus furiosus MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG FTLEGKVAN EKTTLVVKEGTVTLSKNISKSGEVSVELND TDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK GS MLSERMLKALNDQLNRELYSAYLYFAMAAYFEDLGLEGFANWMKAQAEEEIGHALRFYNYIYDRNGRVELDEIPKPPKEWESPLKAFEAAYEHEKFISKSIYELAALAEEEKDYSTRAFLEWFINE QVEEEASVKKILDKLKFAKDSPQILFMLDKELSARAPKLPGLLMQGGE 34 OspA serotype 1; replacement of LFA-1 serotype 3 - ferritin Pyrococcus furiosus MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG FALEGTLTD EKTTLVVKEGTVTLSKNISKSGEVSVELNDT DSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK GS MLSERMLKALNDQLNRELYSAYLYFAMAAYFEDLGLEGFANWMKAQAEEEIGHALRFYNYIYDRNGRVELDEIPKPPKEWESPLKAFEAAYEHEKFISKSIYELAALAEEEKDYSTRAFLEWFINEQ VEEEASVKKILDKLKFAKDSPQILFMLDKELSARAPKLPGLLMQGGE 35 OspA serotype 2 - ferritin Pyrococcus furiosus MDEKNSASVDLPGEMKVLVSKEKDKDGKYSLKATVDKIELKGTSDKDNGSGVLEGTKDDKSKAKLTIADDLSKTTFELFKEDGKTLVSRKVSSKDKTSTDEMFNEKGELSAKTMTRENGTKLEYTEMKSDGTGKAKEVLKNFTLEGKVANDKVTLEVKEGTVTLSKEIAKSGEVTVALNDTNTTQAT KKTGAWDSKTSTLTISVNSKKTTQLVFTKQDTITVQKYDSAGTNLEGTAVEIKTLDELKNALK GS MLSERMLKALNDQLNRELYSAYLYFAMAAYFEDLGLEGFANWMKAQAEEEIGHALRFYNYIYDRNGRVELDEIPKPPKEWESPLKAFEAAYEHEKFISKSIYELAALAEEEKDYSTRAFLEWFINEQVEEEAS VKKILDKLKFAKDSPQILFMLDKELSARAPKLPGLLMQGGE 36 OspA serotype 3 - ferritin Pyrococcus furiosus MDEKNSVSVDLPGGMKVLVSKEKDKDGKYSLMATVEKLELKGTSDKSNGSGVLEGEKADKSKAKLTISQDLNQTTFEIFKEDGKTLVSRKVNSKDKSSTEEKFNDKGKLSEKVVTRANGTRLEYTEIKNDGSGKAKEVLKGFALEGTLTDGGETKLTVTEGTVTLSKNISKSGEITVALNDTETTPADKK TGEWKSDTSTLTISKNSQKPKQLVFTKENTITVQNYNRAGNALEGSPAEIKDLAELKAALK GS MLSERMLKALNDQLNRELYSAYLYFAMAAYFEDLGLEGFANWMKAQAEEEIGHALRFYNYIYDRNGRVELDEIPKPPKEWESPLKAFEAAYEHEKFISKSIYELAALAEEKDYSTRAFLEWFINEQVEEEASVKKI LDKLKFAKDSPQILFMLDKELSARAPKLPGLLMQGGE 37 OspA serotype 4 - ferritin Pyrococcus furiosus MDEKNSVSVDLPGEMKVLVSKEKDKDGKYSLMATVDKLELKGTSDKSNGSGTLEGEKSDKSKAKLTISEDLSKTTFEIFKEDGKTLVSKKVNSKDKSSIEEKFNAKGELSEKTILRANGTRLEYTEIKSDGTGKAKEVLKDFALEGTLAADKTTLKVTEGTVVLSKHIPNSGEITVELNDSNSTQATKK TGKWDSNTSTLTISVNSKKTKNIVFTKEDTITVQKYDSAGTNLEGNAVEIKTLDELKNALK GS MLSERMLKALNDQLNRELYSAYLYFAMAAYFEDLGLEGFANWMKAQAEEEIGHALRFYNYIYDRNGRVELDEIPKPPKEWESPLKAFEAAYEHEKFISKSIYELAALAEEEKDYSTRAFLEWFINEQVEEEASVK KILDKLKFAKDSPQILFMLDKELSARAPKLPGLLMQGGE 38 OspA serotype 5 - ferritin Pyrococcus furiosus MDEKNSVSVDLPGGMKVLVSKEKDKDGKYSLMATVEKLELKGTSDKNNGSGTLEGEKTDKSKVKLTIAEDLSKTTFEIFKEDGKTLVSKKVTLKDKSSTEEKFNEKGEISEKTIVRANGTRLEYTDIKSDGSGKAKEVLKDFTLEGTLAADGKTTLKVTEGTVVLSKNILKSGEITVALDDSDTTQ ATKKTGKWDSKTSTLTISVNSQKTKNLVFTKEDTITVQKYDSAGTNLEGKAVEITTLEKLKDALK GS MLSERMLKALNDQLNRELYSAYLYFAMAAYFEDLGLEGFANWMKAQAEEEIGHALRFYNYIYDRNGRVELDEIPKPPKEWESPLKAFEAAYEHEKFISKSIYELAALAEEEKDYSTRAFLEWFINEQVE EEASVKKILDKLKFAKDSPQILFMLDKELSARAPKLPGLLMQGGE 39 OspA serotype 6 - ferritin Pyrococcus furiosus MDEKNSVSVDLPGGMTVLVSKEKDKDGKYSLEATVDKLELKGTSDKNNGSGTLEGEKTDKSKVKSTIADDLSQTKFEIFKEDGKTLVSKKVTLKDKSSTEEKFNGKGETSEKTIVRANGTRLEYTDIKSDGSGKAKEVLKDFTLEGTLAADGKTTLKVTEGTVVLSKNILKSGEITAALDDSDTTRAT KKTGKWDSKTSTLTISVNSQKTKNLVFTKEDTITVQRYDSAGTNLEGKAVEITTLKELKNALK GS MLSERMLKALNDQLNRELYSAYLYFAMAAYFEDLGLEGFANWMKAQAEEEIGHALRFYNYIYDRNGRVELDEIPKPPKEWESPLKAFEAAYEHEKFISKSIYELAALAEEEKDYSTRAFLEWFINEQVEEEASV KKILDKLKFAKDSPQILFMLDKELSARAPKLPGLLMQGGE 40 OspA serotype 7 - ferritin Pyrococcus furiosus MDEKNSVSVDLPGEMKVLVSKEKDKDGKYSLEATVDKLELKGTSDKNNGSGVLEGVKAAKSKAKLTIADDLSQTKFEIFKEDGKTLVSKKVTLKDKSSTEEKFNDKGKLSEKVVTRANGTRLEYTEIQNDGSGKAKEVLKSLTLEGTLTADGETKLTVEAGTVTLSKNISESGEITVELKDTET TPADKKSGTWDSKTSTLTISKNSQKTKQLVFTKENTITVQKYNTAGTKLEGSPAEIKDLEALKAALK GS MLSERMLKALNDQLNRELYSAYLYFAMAAYFEDLGLEGFANWMKAQAEEEIGHALRFYNYIYDRNGRVELDEIPKPPKEWESPLKAFEAAYEHEKFISKSIYELAALAEEEKDYSTRAFLEWFINEQ VEEEASVKKILDKLKFAKDSPQILFMLDKELSARAPKLPGLLMQGGE 41 OspA serotype 1; replacement of LFA-1 with RD2 - ferritin Trichoplusia Ni MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG YTLEGQLSD EKTTLVVKEGTVTLSKNISKSGEVSVELND TDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK GS TQCNVNPVQIPKDWITMHRSCRNSMRQQIQMEVGASLQYLAMGAHFSKDVVNRPGFAQLFFDAASEEREHAMKLIEYLLMRGELTNDVSSLLQVRPPTRSSWKGGVEALEHALSMESDVTKSIRNVIK ACEDDSEFNDYHLVDYLTGDFLEEQYKGQRDLAGKASTLKKLMDRHEALGEFIFDKKLLGIDV 42 OspA serotype 1; replacement of LFA-1 with RD1-ferritin Trichoplusia Ni MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG YDLKGELSS EKTTLVVKEGTVTLSKNISKSGEVSVELND TDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK GS TQCNVNPVQIPKDWITMHRSCRNSMRQQIQMEVGASLQYLAMGAHFSKDVVNRPGFAQLFFDAASEEREHAMKLIEYLLMRGELTNDVSSLLQVRPPTRSSWKGGVEALEHALSMESDVTKSIRNVIK ACEDDSEFNDYHLVDYLTGDFLEEQYKGQRDLAGKASTLKKLMDRHEALGEFIFDKKLLGIDV 43 OspA serotype 1; replacement of LFA-1 serotype 2 - ferritin Trichoplusia Ni MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG FTLEGKVAN EKTTLVVKEGTVTLSKNISKSGEVSVELND TDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK GS TQCNVNPVQIPKDWITMHRSCRNSMRQQIQMEVGASLQYLAMGAHFSKDVVNRPGFAQLFFDAASEEREHAMKLIEYLLMRGELTNDVSSLLQVRPPTRSSWKGGVEALEHALSMESDVTKSIRNVIK ACEDDSEFNDYHLVDYLTGDFLEEQYKGQRDLAGKASTLKKLMDRHEALGEFIFDKKLLGIDV 44 OspA serotype 1; replacement of LFA-1 serotype 3 - ferritin Trichoplusia Ni MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG FALEGTLTD EKTTLVVKEGTVTLSKNISKSGEVSVELNDT DSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK GS TQCNVNPVQIPKDWITMHRSCRNSMRQQIQMEVGASLQYLAMGAHFSKDVVNRPGFAQLFFDAASEEREHAMKLIEYLLMRGELTNDVSSLLQVRPPTRSSWKGGVEALEHALSMESDVTKSIRNVIKACE DDSEFNDYHLVDYLTGDFLEEQYKGQRDLAGKASTLKKLMDRHEALGEFIFDKKLLGIDV 45 OspA serotype 2 - ferritin Trichoplusia Ni MDEKNSASVDLPGEMKVLVSKEKDKDGKYSLKATVDKIELKGTSDKDNGSGVLEGTKDDKSKAKLTIADDLSKTTFELFKEDGKTLVSRKVSSKDKTSTDEMFNEKGELSAKTMTRENGTKLEYTEMKSDGTGKAKEVLKNFTLEGKVANDKVTLEVKEGTVTLSKEIAKSGEVTVALNDTNTTQAT KKTGAWDSKTSTLTISVNSKKTTQLVFTKQDTITVQKYDSAGTNLEGTAVEIKTLDELKNALK GS TQCNVNPVQIPKDWITMHRSCRNSMRQQIQMEVGASLQYLAMGAHFSKDVVNRPGFAQLFFDAASEEREHAMKLIEYLLMRGELTNDVSSLLQVRPPTRSSWKGGVEALEHALSMESDVTKSIRNVIKACEDDSEF NDYHLVDYLTGDFLEEQYKGQRDLAGKASTLKKLMDRHEALGEFIFDKKLLGIDV 46 OspA serotype 3 - ferritin Trichoplusia Ni MDEKNSVSVDLPGGMKVLVSKEKDKDGKYSLMATVEKLELKGTSDKSNGSGVLEGEKADKSKAKLTISQDLNQTTFEIFKEDGKTLVSRKVNSKDKSSTEEKFNDKGKLSEKVVTRANGTRLEYTEIKNDGSGKAKEVLKGFALEGTLTDGGETKLTVTEGTVTLSKNISKSGEITVALNDTETTPADKK TGEWKSDTSTLTISKNSQKPKQLVFTKENTITVQNYNRAGNALEGSPAEIKDLAELKAALK GS TQCNVNPVQIPKDWITMHRSCRNSMRQQIQMEVGASLQYLAMGAHFSKDVVNRPGFAQLFFDAASEEREHAMKLIEYLLMRGELTNDVSSLLQVRPPTRSSWKGGVEALEHALSMESDVTKSIRNVIKACEDDSEFNDYHLV DYLTGDFLEEQYKGQRDLAGKASTLKKLMDRHEALGEFIFDKKLLGIDV 47 OspA serotype 4 - ferritin Trichoplusia Ni MDEKNSVSVDLPGEMKVLVSKEKDKDGKYSLMATVDKLELKGTSDKSNGSGTLEGEKSDKSKAKLTISEDLSKTTFEIFKEDGKTLVSKKVNSKDKSSIEEKFNAKGELSEKTILRANGTRLEYTEIKSDGTGKAKEVLKDFALEGTLAADKTTLKVTEGTVVLSKHIPNSGEITVELNDSNSTQATKK TGKWDSNTSTLTISVNSKKTKNIVFTKEDTITVQKYDSAGTNLEGNAVEIKTLDELKNALK GS TQCNVNPVQIPKDWITMHRSCRNSMRQQIQMEVGASLQYLAMGAHFSKDVVNRPGFAQLFFDAASEEREHAMKLIEYLLMRGELTNDVSSLLQVRPPTRSSWKGGVEALEHALSMESDVTKSIRNVIKACEDDSEFNDY HLVDYLTGDFLEEQYKGQRDLAGKASTLKKLMDRHEALGEFIFDKKLLGIDV 48 OspA serotype 5 - ferritin Trichoplusia Ni MDEKNSVSVDLPGGMKVLVSKEKDKDGKYSLMATVEKLELKGTSDKNNGSGTLEGEKTDKSKVKLTIAEDLSKTTFEIFKEDGKTLVSKKVTLKDKSSTEEKFNEKGEISEKTIVRANGTRLEYTDIKSDGSGKAKEVLKDFTLEGTLAADGKTTLKVTEGTVVLSKNILKSGEITVALDDSDTTQ ATKKTGKWDSKTSTLTISVNSQKTKNLVFTKEDTITVQKYDSAGTNLEGKAVEITTLEKLKDALK GS TQCNVNPVQIPKDWITMHRSCRNSMRQQIQMEVGASLQYLAMGAHFSKDVVNRPGFAQLFFDAASEEREHAMKLIEYLLMRGELTNDVSSLLQVRPPTRSSWKGGVEALEHALSMESDVTKSIRNVIKACED DSEFNDYHLVDYLTGDFLEEQYKGQRDLAGKASTLKKLMDRHEALGEFIFDKKLLGIDV 49 OspA serotype 6 - ferritin Trichoplusia Ni MDEKNSVSVDLPGGMTVLVSKEKDKDGKYSLEATVDKLELKGTSDKNNGSGTLEGEKTDKSKVKSTIADDLSQTKFEIFKEDGKTLVSKKVTLKDKSSTEEKFNGKGETSEKTIVRANGTRLEYTDIKSDGSGKAKEVLKDFTLEGTLAADGKTTLKVTEGTVVLSKNILKSGEITAALDDSDTTRAT KKTGKWDSKTSTLTISVNSQKTKNLVFTKEDTITVQRYDSAGTNLEGKAVEITTLKELKNALK GS TQCNVNPVQIPKDWITMHRSCRNSMRQQIQMEVGASLQYLAMGAHFSKDVVNRPGFAQLFFDAASEEREHAMKLIEYLLMRGELTNDVSSLLQVRPPTRSSWKGGVEALEHALSMESDVTKSIRNVIKACEDDSEFND YHLVDYLTGDFLEQYKGQRDLAGKASTLKKLMDRHEALGEFIFDKKLLGIDV 50 OspA serotype 7 - ferritin Trichoplusia Ni MDEKNSVSVDLPGEMKVLVSKEKDKDGKYSLEATVDKLELKGTSDKNNGSGVLEGVKAAKSKAKLTIADDLSQTKFEIFKEDGKTLVSKKVTLKDKSSTEEKFNDKGKLSEKVVTRANGTRLEYTEIQNDGSGKAKEVLKSLTLEGTLTADGETKLTVEAGTVTLSKNISESGEITVELKDTET TPADKKSGTWDSKTSTLTISKNSQKTKQLVFTKENTITVQKYNTAGTKLEGSPAEIKDLEALKAALK GS TQCNVNPVQIPKDWITMHRSCRNSMRQQIQMEVGASLQYLAMGAHFSKDVVNRPGFAQLFFDAASEEREHAMKLIEYLLMRGELTNDVSSLLQVRPPTRSSWKGGVEALEHALSMESDVTKSIRNVIKACE DDSEFNDYHLVDYLTGDFLEEQYKGQRDLAGKASTLKKLMDRHEALGEFIFDKKLLGIDV 51 Replacement of LFA-1 serotype 1 with RD2-OspA-ferritin MDSKGSSQKGSRLLLLLVVSNLLLPQGVLA MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG YTLEGQLS D EKTTLVVKEGTVTLSKNISKSGEVSVELNDTDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEG LTQIFQKAYEHEQHISESINNIVDHAIK C KDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 52 Replacement of non-glycosylated LFA-1 serotype 1 with RD2-OspA-ferritin MDSKGSSQKGSRLLLLLVVSNLLLPQGVLA MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKN Q GSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG YTLEGQ LSD EKTTLVVKEGTVTLSK Q ISKSGEVSVEL Q DTDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDS Q GTKLEGSAVEITKLDEIKNALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENVPVQLTSISAPEHK FEGLTQIFQKAYEHEQHISESINNIVDHAIK C KDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 53 OspA ferritin serotype 1 with LFA-1 site replaced by serotype 2 MDSKGSSQKGSRLLLLLVVSNLLLPQGVLA MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG FTLEGKV AN EKTTLVVKEGTVTLSKNISKSGEVSVELNDTDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEG LTQIFQKAYEHEQHISESINNIVDHAIK C KDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 54 Unglycosylated OspA ferritin serotype 1 with the LFA-1 site replaced by serotype 2 MDSKGSSQKGSRLLLLLVVSNLLLPQGVLA MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKN Q GSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG FTLEGK VAN EKTTLVVKEGTVTLSK Q ISKSGEVSVEL Q DTDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDS Q GTKLEGSAVEITKLDEIKNALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENVPVQLTSISAPEHK FEGLTQIFQKAYEHEQHISESINNIVDHAIK C KDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 55 OspA ferritin serotype 1 with LFA-1 site replaced by serotype 3 MDSKGSSQKGSRLLLLLVVSNLLLPQGVLA MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG FALEGTLTD EKTTLVVKEGTVTLSKNISKSGEVSVELNDTDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLT QIFQKAYEHEQHISESINNIVDHAIK C KDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 56 Unglycosylated OspA ferritin serotype 1 with the LFA-1 site replaced by serotype 3 MDSKGSSQKGSRLLLLLVVSNLLLPQGVLA MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKN Q GSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG FALEGTL TD EKTTLVVKEGTVTLSK Q ISKSGEVSVEL Q DTDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDS Q GTKLEGSAVEITKLDEIKNALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENVPVQLTSISAPEHKF EGLTQIFQKAYEHEQHISESINNIVDHAIK C KDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 57 OspA ferritin serotype 1 with LFA-1 site replaced by RD1 MDSKGSSQKGSRLLLLLVVSNLLLPQGVLA MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG YDLKGEL SS EKTTLVVKEGTVTLSKNISKSGEVSVELNDTDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEG LTQIFQKAYEHEQHISESINNIVDHAIK C KDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 58 Unglycosylated OspA ferritin serotype 1 with the LFA-1 site replaced by RD1 MDSKGSSQKGSRLLLLLVVSNLLLPQGVLA MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKN Q GSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG YDLKG ELSS EKTTLVVKEGTVTLSK Q ISKSGEVSVEL Q DTDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDS Q GTKLEGSAVEITKLDEIKNALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHK FEGLTQIFQKAYEHEQHISESINNIVDHAIK C KDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 59 Non-glycosylated OspA-ferritin serotype 1, LFA-1 to RD2 substitution, 1x GGGS linker (SEQ ID NO: 226) MDSKGSSQKGSRLLLLLVVSNLLLPQGVLA MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKN Q GSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG YTLEGQ LSD EKTTLVVKEGTVTLSK Q ISKSGEVSVEL Q DTDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDS Q GTKLEGSAVEITKLDEIKNALK GGGS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEH KFEGLTQIFQKAYEHEQHISESINNIVDHAIK C KDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 60 Non-glycosylated OspA-ferritin serotype 1, LFA-1 to RD2 substitution, 2x GGGS linker (SEQ ID NO: 91) MDSKGSSQKGSRLLLLLVVSNLLLPQGVLA MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKN Q GSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG YTLEGQ LSD EKTTLVVKEGTVTLSK Q ISKSGEVSVEL Q DTDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDS Q GTKLEGSAVEITKLDEIKNALK GGGSGGGS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISA PEHKFEGLTQIFQKAYEHEQHISESINNIVDHAIK C KDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 61 Unglycosylated OspA-ferritin serotype 1, LFA-1 to RD2 substitution, 5 x GGGS linker (SEQ ID NO: 92) MDSKGSSQKGSRLLLLLVVSNLLLPQGVLA MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKN Q GSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG YTLEGQ LSD EKTTLVVKEGTVTLSK Q ISKSGEVSVEL Q DTDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDS Q GTKLEGSAVEITKLDEIKNALK GGGSGGGSGGGSGGGSGGGS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNEN NVPVQLTSISAPEHKFEGLTQIFQKAYEHEQHISESINNIVDHAIK C KDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 62 Non-glycosylated (alanine) OspA-ferritin, LFA1 to RD2 substitution, serotype 1 MDSKGSSQKGSRLLLLLVVSNLLLPQGVLA MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNG A GVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG YTLEGQ LSD EKTTLVVKEGTVTLSKNI A KSGEVSVELND A DSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNG A KLEGSAVEITKLDEIKNALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENVPVQLTSISAPEHK FEGLTQIFQKAYEHEQHISESINNIVDHAIK C KDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 63 OspA-ferritin serotype 1 MDSKGSSQKGSRLLLLLVVSNLLLPQGVLA MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKGYVLEGTL TAEKTTLVVKEGTVTLSKNISKSGEVSVELNDTDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEG LTQIFQKAYEHEQHISESINNIVDHAIK C KDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 64 OspA serotype 2-ferritin MDSKGSSQKGSRLLLLLVVSNLLLPQGVLA MDEKNSASVDLPGEMKVLVSKEKDKDGKYSLKATVDKIELKGTSDKDNGSGVLEGTKDDKSKAKLTIADDLSKTTFELFKEDGKTLVSRKVSSKDKTSTDEMFNEKGELSAKTMTRENGTKLEYTEMKSDGTGKAKEVLKNFTLEGKVANDKVT LEVKEGTVTLSKEIAKSGEVTVALNDTNTTQATKKTGAWDSKTSTLTISVNSKKTTQLVFTKQDTITVQKYDSAGTNLEGTAVEIKTLDELKNALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLTQIFQ KAYEHEQHISESINNIVDHAIK C KDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 65 Non-glycosylated OspA-ferritin serotype 2 MDSKGSSQKGSRLLLLLVVSNLLLPQGVLA MDEKNSASVDLPGEMKVLVSKEKDKDGKYSLKATVDKIELKGTSDKD Q GSGVLEGTKDDKSKAKLTIADDLSKTTFELFKEDGKTLVSRKVSSKDKTSTDEMFNEKGELSAKTMTRE Q GTKLEYTEMKSDGTGKAKEVLK Q FTLEGKVAND KVTLEVKEGTVTLSKEIAKSGEVTVAL Q DT Q TTQATKKTGAWDSKTSTLTISVNSKKTTQLVFTKQDTITVQKYDSAGTNLEGTAVEIKTLDELKNALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENVPVQLTSISAPEHKF EGLTQIFQKAYEHEQHISESINNIVDHAIK C KDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 66 OspA serotype 3-ferritin MDSKGSSQKGSRLLLLLVVSNLLLPQGVLA MDEKNSVSVDLPGGMKVLVSKEKDKDGKYSLMATVEKLELKGTSDKSNGSGVLEGEKADKSKAKLTISQDLNQTTFEIFKEDGKTLVSRKVNSKDKSSTEEKFNDKGKLSEKVVTRANGTRLEYTEIKNDGSGKAKEVLKGFALEGTLTDGGETKLT VTEGTVTLSKNISKSGEITVALNDTETTPADKKTGEWKSDTSTLTISKNSQKPKQLVFTKENTITVQNYNRAGNALEGSPAEIKDLAELKAALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLTQIFQKAYEHE QHISESINNIVDHAIK C KDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 67 Non-glycosylated OspA-ferritin serotype 3 MDSKGSSQKGSRLLLLLVVSNLLLPQGVLA MDEKNSVSVDLPGGMKVLVSKEKDKDGKYSLMATVEKLELKGTSDKS Q GSGVLEGEKADKSKAKLTISQDL Q QTTFEIFKEDGKTLVSRKVNSKDKSSTEEKFNDKGKLSEKVVTRA Q GTRLEYTEIKNDGSGKAKEVLKGFALEGTLTDGGETK LTVTEGTVTLSK Q ISKSGEITVAL Q DTETTPADKKTGEWKSDTSTLTISKNSQKPKQLVFTKENTITVQNYNRAGNALEGSPAEIKDLAELKAALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLTQIFQKAY EHEQHISESINNIVDHAIK C KDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 68 OspA serotype 4-ferritin MDSKGSSQKGSRLLLLLVVSNLLLPQGVLA MDEKNSVSVDLPGEMKVLVSKEKDKDGKYSLMATVDKLELKGTSDKSNGSGTLEGEKSDKSKAKLTISEDLSKTTFEIFKEDGKTLVSKKVNSKDKSSIEEKFNAKGELSEKTILRANGTRLEYTEIKSDGTGKAKEVLKDFALEGTLAADKTTLK VTEGTVVLSKHIPNSGEITVELNDSNSTQATKKTGKWDSNTSTLTISVNSKKTKNIVFTKEDTITVQKYDSAGTNLEGNAVEIKTLDELKNALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLTQIFQKAY EHEQHISESINNIVDHAIK C KDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 69 Unglycosylated OspA-ferritin serotype 4 MDSKGSSQKGSRLLLLLVVSNLLLPQGVLA MDEKNSVSVDLPGEMKVLVSKEKDKDGKYSLMATVDKLELKGTSDKS Q GSGTLEGEKSDKSKAKLTISEDLSKTTFEIFKEDGKTLVSKKVNSKDKSSIEEKFNAKGELSEKTILRA Q GTRLEYTEIKSDGTGKAKEVLKDFALEGTLAADKTTL KVTEGTVVLSKHIPNSGEITVEL Q DS Q STQATKKTGKWDS Q TSTLTISVNSKKTKNIVFTKEDTITVQKYDSAGTNLEGNAVEIKTLDELKNALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLT QIFQKAYEHEQHISESINNIVDHAIK C KDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 70 OspA-ferritin serotype 5 MDSKGSSQKGSRLLLLLVVSNLLLPQGVLA MDEKNSVSVDLPGGMKVLVSKEKDKDGKYSLMATVEKLELKGTSDKNNGSGTLEGEKTDKSKVKLTIAEDLSKTTFEIFKEDGKTLVSKKVTLKDKSSTEEKFNEKGEISEKTIVRANGTRLEYTDIKSDGSGKAKEVLKDFTLEGTLAADGK TTLKVTEGTVVLSKNILKSGEITVALDDSDTTQATKKTGKWDSKTSTLTISVNSQKTKNLVFTKEDTITVQKYDSAGTNLEGKAVEITTLEKLKDALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLTQ IFQKAYEHEQHISESINNIVDHAIK C KDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 71 Unglycosylated OspA serotype 5-ferritin MDSKGSSQKGSRLLLLLVVSNLLLPQGVLA MDEKNSVSVDLPGGMKVLVSKEKDKDGKYSLMATVEKLELKGTSDKN Q GSGTLEGEKTDKSKVKLTIAEDLSKTTFEIFKEDGKTLVSKKVTLKDKSSTEEKFNEKGEISEKTIVRA Q GTRLEYTDIKSDGSGKAKEVLKDFTLEGTLAADG KTTLKVTEGTVVLSKNILKSGEITVALDDSDTTQATKKTGKWDSKTSTLTISVNSQKTKNLVFTKEDTITVQKYDSAGTNLEGKAVEITTLEKLKDALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLT QIFQKAYEHEQHISESINNIVDHAIK C KDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 72 Unglycosylated OspA serotype 6-ferritin MDSKGSSQKGSRLLLLLVVSNLLLPQGVLA MDEKNSVSVDLPGGMTVLVSKEKDKDGKYSLEATVDKLELKGTSDKN Q GSGTLEGEKTDKSKVKSTIADDLSQTKFEIFKEDGKTLVSKKVTLKDKSSTEEKFNGKGETSEKTIVRA Q GTRLEYTDIKSDGSGKAKEVLKDFTLEGTLAADG KTTLKVTEGTVVLSKNILKSGEITAALDDSDTTRATKKTGKWDSKTSTLTISVNSQKTKNLVFTKEDTITVQRYDSAGTNLEGKAVEITTLKELKNALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLTQIFQ KAYEHEQHISESINNIVDHAIK C KDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 73 OspA serotype 6-ferritin MDSKGSSQKGSRLLLLLVVSNLLLPQGVLA MDEKNSVSVDLPGGMTVLVSKEKDKDGKYSLEATVDKLELKGTSDKNNGSGTLEGEKTDKSKVKSTIADDLSQTKFEIFKEDGKTLVSKKVTLKDKSSTEEKFNGKGETSEKTIVRANGTRLEYTDIKSDGSGKAKEVLKDFTLEGTLAADGK TTLKVTEGTVVLSKNILKSGEITAALDDSDTTRATKKTGKWDSKTSTLTISVNSQKTKNLVFTKEDTITVQRYDSAGTNLEGKAVEITTLKELKNALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLTQIFQK AYEHEQHISESINNIVDHAIK C KDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 74 OspA-ferritin serotype 7 MDSKGSSQKGSRLLLLLVVSNLLLPQGVLA MDEKNSVSVDLPGEMKVLVSKEKDKDGKYSLEATVDKLELKGTSDKNNGSGVLEGVKAAKSKAKLTIADDLSQTKFEIFKEDGKTLVSKKVTLKDKSSTEEKFNDKGKLSEKVVTRANGTRLEYTEIQNDGSGKAKEVLKSLTLEGTLTAD GETKLTVEAGTVTLSKNISESGEITVELKDTETTPADKKSGTWDSKTSTLTISKNSQKTKQLVFTKENTITVQKYNTAGTKLEGSPAEIKDLEALKAALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLT QIFQKAYEHEQHISESINNIVDHAIK C KDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 75 Unglycosylated OspA serotype 7-ferritin MDSKGSSQKGSRLLLLLVVSNLLLPQGVLA MDEKNSVSVDLPGEMKVLVSKEKDKDGKYSLEATVDKLELKGTSDKN Q GSGVLEGVKAAKSKAKLTIADDLSQTKFEIFKEDGKTLVSKKVTLKDKSSTEEKFNDKGKLSEKVVTRA Q GTRLEYTEIQNDGSGKAKEVLKSLTLEGTLTA DGETKLTVEAGTVTLSK Q ISESGEITVELKDTETTPADKKSGTWDSKTSTLTISKNSQKTKQLVFTKENTITVQKYNTAGTKLEGSPAEIKDLEALKAALK GS ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEG LTQIFQKAYEHEQHISESINNIVDHAIK C KDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 76 Amino acids 165-173 of OspA serotype 1 YVLEGTLTA 77 hLFA-1 sequence sharing homology with amino acids 165-173 of OspA serotype 1 YVIEGTSKQ 78 Sequence S2 from OspA serotype 2 FTLEGKVAN 79 Sequence of S3 from OspA serotype 3 FALEGTLTD 80 RD2 YTLEGQLSD 81 RD1 YDLKGELSS 82 Illustrative OspA serotype 1 (strain WP_010890378.1) MKKYLLGIGL ILALIA C KQN VSSLDEKNSV SVDLPGEMKV LVSKEKNKDG KYDLIATVDK LELKGTSDKN NGSGVLEGVK ADKSKVKLTI SDDLGQTTLE VFKEDGKTLV SKKVTSKDKS STEEKFNEKG EVSEKIITRA DGTRLEYTGI KSDGSGKAKE VLKGYVLEGT LTAEKTTLVV KEGTVTLSKN ISKSGEV SVE LNDTDSSAAT KKTAAWNSGT STLTITVNSK KTKDLVFTKE
NTITVQQYDS NGTKLEGSAV EITKLDEIKN ALK 83 Illustrative OspA serotype 2
(strain WP_011703777.1) MKKYLLGIGL ILALIA C KQN VSSLDEKNSA SVDLPGEMKV LVSKEKDKDG KYSLKATVDK IELKGTSDKD NGSGVLEGTK DDKSKAKLTI ADDLSKTTFE LFKEDGKTLV SRKVSSKDKT STDEMFNEKG ELSAKTMTRE NGTKLEYTEM KSDGTGKAKE VLKNFTLEGK VANDKVTLEV KEGTVTLSKE IAKS GEVTVA LNDTNTTQAT KKTGAWDSKT STLTISVNSK KTTQLVFTKQ
DTITVQKYDS AGTNLEGTAV EIKTLDELKN ALK 84 Illustrative OspA serotype 3
(strain CAA56549.1) MKKYLLGIGL ILALIA C KQN VSSLDEKNSV SVDLPGGMKV LVSKEKDKDG KYSLMATVEK LELKGTSDKS NGSGVLEGEK ADKSKAKLTI SQDLNQTTFE IFKEDGKTLV SRKVNSKDKS STEEKFNDKG KLSEKVVTRA NGTRLEYTEI KNDGSGKAKE VLKGFALEGT LTDGGETKLT VTEGTVTLSK NISKSGEITV ALNDTETTPA DKKTGEWKSD TSTLTISKNS QKPKQLVFTK
ENTITVQNYN RAGNALEGSP AEIKDLAELK AALK 85 Illustrative OspA serotype 4
(strain WP_011187157.1) MKKYLLGIGL ILALIA C KQN VSSLDEKNSV SVDLPGEMKV LVSKEKDKDG KYSLMATVDK LELKGTSDKS NGSGTLEGEK SDKSKAKLTI SEDLSKTTFE IFKEDGKTLV SKKVNSKDKS SIEEKFNAKG ELSEKTILRA NGTRLEYTEI KSDGTGKAKE VLKDFALEGT LAADKTTLKV TEGTVVLSKH IPNSGEITVE LNDSNSTQAT KKTGKWDSNT STLTISVNSK KTKNIVFTKE
DTITVQKYDS AGTNLEGNAV EIKTLDELKN ALK 86 Illustrative OspA serotype 5
(strain CAA59727.1) MKKYLLGIGL ILALIA C KQN VSSLDEKNSV SVDLPGGMKV LVSKEKDKDG KYSLMATVEK LELKGTSDKN NGSGTLEGEK TDKSKVKLTI AEDLSKTTFE IFKEDGKTLV SKKVTLKDKS STEEKFNEKG EISEKTIVRA NGTRLEYTDI KSDGSGKAKE VLKDFTLEGT LAADGKTTLK VTEGTVVLSK NILKS GEITV ALDDSDTTQA TKKTGKWDSK TSTLTISVNS QKTKNLVFTK
EDTITVQKYD SAGTNLEGKA VEITTLEKLK DALK 87 Illustrative OspA serotype 6
(strain CAA45010.1) MKKYLLGIGL ILALIA C KQN VSSLDEKNSV SVDLPGGMTV LVSKEKDKDG KYSLEATVDK LELKGTSDKN NGSGTLEGEK TDKSKVKSTI ADDLSQTKFE IFKEDGKTLV SKKVTLKDKS STEEKFNGKG ETSEKTIVRA NGTRLEYTDI KSDGSGKAKE VLKDFTLEGT LAADGKTTLK VTEGTVVLSK NILKSGE ITA ALDDSDTTRA TKKTGKWDSK TSTLTISVNS QKTKNLVFTK
EDTITVQRYD SAGTNLEGKA VEITTLKELK NALK 88 Illustrative OspA serotype 7
(strain CAA56547.1) MKKYLLGIGL ILALIA C KQN VSSLDT AGTKLEGSP AEIKDLEALK AALK 89 Ferritin from H. pylori with an 8 amino acid bullfrog sequence at the N-terminus ESQVRQQF SKDIEKLLNEQVNKEM Q SSNLYMSMSSW S YTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLTQIFQKAYEHEQHISESINNIVDHAIK C KDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 90 Linker GS2 GGGSGGGS 91 Linker GS5 GGGSGGGSGGGSGGGSGGGS 92 Illustrative lumazine synthase MQIYEGKLTAEGLRFGIVASRFNHALVDRLVEGAIDCIVRHGGREEDITLVRVPGSWEIPVAAGELARKEDIDAVIAIGVLIRGATPHFDYIASEVSKGLANLSLELRKPITFGVITADTLEQAIERAGTKHGNKGWEAALSAIEMANLFKSLR 93 RD2-OspA serotype 1 MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG YTLEGQLSD EKTTLVVKEGTVTLSKNISKSGEVSVELND TDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK 94 RD1-OspA serotype 1 MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG YDLKGELSS EKTTLVVKEGTVTLSKNISKSGEVSVELND TDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK 95 OspA serotype 1; replacement of LFA-1 serotype 2 MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG FTLEGKVAN EKTTLVVKEGTVTLSKNISKSGEVSVELND TDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK 96 OspA serotype 1; replacement for LFA-1 serotype 3 MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG FALEGTLTD EKTTLVVKEGTVTLSKNISKSGEVSVELNDT DSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSNGTKLEGSAVEITKLDEIKNALK 97 Replacement of non-glycosylated LFA-1 serotype 1 with RD2-OspA MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKN Q GSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG YTLEGQLSD EKTTLVVKEGTVTLSK Q ISKSGEVSVEL Q DTDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDS Q GTKLEGSAVEITKLDEIKNALK 98 Unglycosylated OspA serotype 1 with the LFA-1 site replaced by serotype 2 MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKN Q GSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG FTLEGKVAN EKTTLVVKEGTVTLSK Q ISKSGEVSVEL Q DTDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDS Q GTKLEGSAVEITKLDEIKNALK 99 Unglycosylated OspA serotype 1 with the LFA-1 site replaced by serotype 3 MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKN Q GSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG FALEGTLTD EKTTLVVKEGTVTLSK Q ISKSGEVSVEL Q DTDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDS Q GTKLEGSAVEITKLDEIKNALK 100 Unglycosylated OspA serotype 1 with the LFA-1 site replaced by RD1 MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKN Q GSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG YDLKGELSS EKTTLVVKEGTVTLSK Q ISKSGEVSVEL Q DTDSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDS Q GTKLEGSAVEITKLDEIKNALK 101 Modified OspA serotype 1 (X=any amino acid; XXXXXXXXX is not SEQ ID NO: 77; Z=N or Q) MDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNZGSGVLEGVKADKSKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG XXXXXXXXX EKTTLVVKEGTVTLSKZISKSGEVSVELZDT DSSAATKKTAAWNSGTSTLTITVNSKKTKDLVFTKENTITVQQYDSZGTKLEGSAVEITKLDEIKNALK 102 Not used 103-200 bfpFerritin-N19Q/C31S/S26C ESQVRQQFSKDIEKLLNEQVNKEMQSSNLYMCMSSWSYTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLTQIFQKAYEHEQHISESINNIVDHAIKSKDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 201 bfpFerritin-N19Q/C31S/S72C ESQVRQQFSKDIEKLLNEQVNKEMQSSNLYMSMSSWSYTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTCISAPEHKFEGLTQIFQKAYEHEQHISESINNIVDHAIKSKDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 202 bfpFerritin-N19Q/C31S/A75C ESQVRQQFSKDIEKLLNEQVNKEMQSSNLYMSMSSWSYTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENVPVQLTSISCPEHKFEGLTQIFQKAYEHEQHISESINNIVDHAIKSKDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 203 bfpFerritin- N19Q/C31S/K79C ESQVRQQFSKDIEKLLNEQVNKEMQSSNLYMSMSSWSYTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHCFEGLTQIFQKAYEHEQHISESINNIVDHAIKSKDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 204 bfpFerritin-N19Q/C31S/S100C ESQVRQQFSKDIEKLLNEQVNKEMQSSNLYMSMSSWSYTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLTQIFQKAYEHEQHISECINNIVDHAIKSKDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 205 bfpFerritin-N19Q/C31S/S111C ESQVRQQFSKDIEKLLNEQVNKEMQSSNLYMSSWSYTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLTQIFQKAYEHEQHISESINNIVDHAIKCKDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 206 bfpFerritin-N19Q/C31S/E12C ESQVRQQFSKDIEKLLNCQVNKEMQSSNLYMSSWSYTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLTQIFQKAYEHEQHISESINNIVDHAIKSKDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 207 Illustrative ferritin from H. pylori with bullfrog linker ESQVRQQFSKDIEKLLNEQVNKEMNSSNLYMSMSSWCYTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLTQIFQKAYEHEQHISESINNIVDHAIKSKDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 208 Exemplary ferritin from wild-type H. pylori (GenBank accession no. AAD06160.1) (no bullfrog linker or N-terminal Met) LSKDIIKLLNEQVNKEMNSSNLYMSMSSWCYTHSLDGAGLFLFDHAAEEYEHAKKLIIFLNENNVPVQLTSISAPEHKFEGLTQIFQKAYEHEQHISESINNIVDHAIKSKDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS 209 CpG (ISS-1018) TGACTGTGAACGTTCGAGATGA 210 Trichoplusia ni ferritin heavy chain TQCNVNPVQIPKDWITMHRSCRNSMRQQIQMEVGASLQYLAMGAHFSKDVVNRPGFAQLFFDAASEEREHAMKLIEYLLMRGELTNDVSSLLQVRPPTRSSWKGGVEALEHALSMESDVTKSIRNVIKACEDDSEFNDYHLVDYLTGDFLEEQYKGQRDLAGKASTLKKLMDRHEALGEF
IFDKKLLGIDV 211 Trichoplusia ni ferritin light chain ADTCYNDVALDCGITSNSLALPRCNAVYGEYGSHGNVATELQAYAKLHLERSYDYLLSAAYFNNYQTNRAGFSKLFKKLSDEAWSKTIDIIKHVTKRGDKMNFDQHSTMKTERKNYTAENHELEALAKALDTQKELAERAFYIHREATRNSQHLHDPEIAQYLEEEFIEDHAEKIRTLAGHTSDLKKFITANNGHDLSLALYV FDEYLQKTV 212 Ferritin from Pyrococcus furiosus MLSERMLKALNDQLNRELYSAYLYFAMAAYFEDLGLEGFANWMKAQAEEEIGHALRFYNY
IYDRNGRVELDEIPKPPKEWESPLKAFEAAYEHEKFISKSIYELAALAEEEKDYSTRAFL
EWFINEQVEEEASVKKILDKLKFAKDSPQILFMLDKELSARAPKLPGLLMQGGE 213 Human ferritin heavy chain MTTASTSQVRQNYHQDSEAAINRQINLELYASYVYLSMSYYFDRDDVALKNFAKYFLHQSHEEREHAEKLMKLQNQRGGRIFLQDIKKPDCDDWESGLNAMECALHLEKNVQQSLLELHKLATDKNDPHLCDFIETHYLNEQVKAIKELGDHVTNLRKMGAPESGLAEYLFDKHTLGDSDQES 214 Human ferritin light chain (signal peptide underlined) MDSKGSSQKGSRLLLLLVVSNLLLPQGVLA SSQIRQNYSTDVEAAVNSLVNLYLQASYTYLSLGFYFDRDDVALEGVSHFFRELAEEKREGYERLLKMQNQRGGRALFQDIKKPAEDEWGKTPDAMKAAMALEKKLNQALLDLHALGSARTDPHLCDFLETHFLDEEVKLIKKMGDHLTNLHRLGGPEAGLGEYLFERLT LKHD 215 Lumazine synthase from Aquifex aeolicus MQIYEGKLTAEGLRFGIVASRFNHALVDRLVEGAIDCIVRHGGREEDITLVRVPGSWEIPVAAGELARKEDIDAVIAIGVLIRGATPHFDYIASEVSKGLANLSLELRKPITFGVITADTLEQAIERAGTKHGNKGWEAALSAIEMANLFKSLR 216 Bullfrog Linker ESQVRQQF 217 Linker cysteine-thrombin-His CLVPRGSLEHHHHHH 218 6,7-Dimethyl-8-ribityllumazine synthase from E. coli MNIIEANVATPDARVAITIARFNNFINDSLLEGAIDALKRIGQVKDENITVVWVPGAYELPLAAGALAKTGKYDAVIALGTVIRGGTAHFEYVAGGASNGLAHVAQDSEIPVAFGVLTTESIEQAIERAGTKAGNKGAEAALTALEMINVLKAIKA 219 16 amino acid linker GGGGSGGGGSGGGGSG 220 28 amino acid linker GGSGSGSNSSSASSGASSGGASGGGSGGSG 221 46 amino acid linker GGSGSASSGASASGSSNGSGSGSGSNSSASSGASSGGASGGGSGGSG 222 FR1 GGSGSASAEAAAKEAAAKAGGGSGGSG 223 FR2 GGSGSASAEAAAKEAAAKEAAAKASGGSGGSG 224 47 amino acid linker including C for conjugation SGGGSGSASSGASASGSSCSGSGSGSSSASSGASSGGASGGGSGGSG 225

EXAMPLES

[00294] The following examples are provided to illustrate certain embodiments disclosed and should not be construed as limiting the scope of this disclosure in any way.

1. Obtaining antigenic polypeptides OspA-ferritin

[00295] Antigenic polypeptides were prepared including OspA and ferritin.

[00296] OspA was synthesized using Genescript from the following sequences: Sequence with NBCI ID WP_010890378.1 strain B31 (serotype 1)Borrelia burgdorferi, sequence in NCBIBorrelia afzelii strain PKO (serotype 2): WP_011703777.1, strain PBr (serotype 3)Borrelia garinii with GenBank accession number CAA56549.1, sequence with NCBI ID WP_011187157.1Borrelia bavariensis (serotype 4),Borrelia garinii (serotype 5) with GenBank accession number CAA59727.1,Borrelia garinii (serotype 6) with GenBank accession number: CAA45010.1 andBorrelia garinii (serotype 7) with GenBank accession number CAA56547.1. Ferritin fromH. pylori with the N-terminal bullfrog ferritin sequence inserted was synthesized using Genescript, and the bullfrog ferritin sequence is similar to the bullfrog ferritin sequence from a previous study (see Kanekiyo, M., et al., Cell 162(5):1090-100 (2015)). The pet21a vector was used to express both His-tagged OspA and OspA-ferritin nanoparticles.E. coli. A mammalian expression vector similar to that used previously was used for expression in Expi293 cells (see Fig. Xu, L., et al., Science 358(6359):85-90 (2017)).

[00297] OspA-ferritin nanoparticles were created by genetically fusing the OspA ectodomain to the amino terminus of ferritin to produce an antigenic polypeptide (Figure 1A). OspA is a 31-kDa lipoprotein with an extended β-sheet structure consisting of 21 consecutive antiparallel β-strands with only one carboxy-terminal α-helix (Fig. 1B) (see Kitahara, R., et al. , Biophys J 102(4):916-26 (2012)). The carboxy terminus of OspA also has an unusually large cavity (∼200A) that provides a site compatible for binding to ferritin via a glycine-serine sequence ( Fig. 1B ). The 24 ferritin subunits spontaneously assembled into a hollow, spherical nanoparticle (Figure 1C). The ferritin used in this study contains the amino-terminal sequence of bullfrog ferritin fused to Helicobacter pylori ferritin to form a chimera minimally related to human ferritin (see Kanekiyo 2015). The amino-terminal bullfrog ferritin sequence projects radially from the nanoparticle core (see Trikha, J., et al . J Mol Biol 248(5):949-67 (1995)), facilitating uniform presentation of OspA on the nanoparticle surface.

[00298] Three additional changes were made to the structure of ferritin to improve its functionality: N19Q, C31S and S111C. The N19Q substitution resulted in the removal of a potential amino-terminal glycosylation site. The S111C substitution results in the incorporation of surface-exposed cysteine into ferritin, which can be used for conjugation of adjuvants, for example, using click chemistry. Finally, cysteine 31 was modified to serine such that only one cysteine could be modified by conjugation. Display of OspA on the nanoparticle surface results in the formation of a 24-mer antigenic nanoparticle ( Figure 1D ).

[00299] For purification of E. coli, the present inventors used BL21 Star (DE3) (Invitrogen, catalog no. C601003). The present inventors induced protein production with 100 μM IPTG overnight at 16°C. The cell pellet was lysed by sonication in Tris buffer, pH 8, 50 mM NaCl. The filter-sterilized supernatant was purified on an anion exchange chromatography column (HiTrap Q HP, GE) by collecting OspA-ferritin nanoparticles from the filtrate. Endotoxin was then removed by extraction with 1% Triton X114, which was repeated 6 times. The aqueous phase was then concentrated using an Amicon 100 MW molecular weight cutoff filter (Millipore, Cat# UFC910096), and the nanoparticles were then further purified on a preparative SEC column with 120 mL of Superose 6 at 4°C. For purification from mammalian cell culture, Expi293 cells were transfected with plasmid DNA using FectoPRO transfection reagent (Polyplus, catalog no. 116-100) according to the manufacturer's instructions. Transfected cells were cultured, and on day 5 the supernatant was collected and filtered. Endotoxin-free protocols were followed using endotoxin-free reagents and glassware. Q Sepharose Fast flow beads (GE, catalog no. 17-0510-01) were prepared with 50 mM Tris pH7, 50 mM NaCl and added to the filter-sterilized supernatant by gravity flow. The filtrate was collected and concentrated to 4 mL using an Amicon 100 MW molecular weight cutoff filter. The nanoparticles were then further purified on a preparative SEC column with 120 mL of Superose 6 at room temperature.

[00300] To purify His ₆ -tagged (SEQ ID NO: 227) OspA, OspA serotypes 1, 4, 5, and 7 were purified from E. coli BL21 (DE3) (Invitrogen, Cat. No. C600003), and OspA serotypes 2 and 3 purified from Expi293 cells. These constructs lacked the transmembrane domain containing the C-terminal His ₆ tag (SEQ ID NO: 227) and were otherwise wild type. For purification from E. coli, protein production was induced with 500 μM IPTG for 5 hours and cells were pelleted and frozen at -20°C. The pellet was resuspended in 1% Triton in TBS buffer with complete protease inhibitor (Sigma-Aldrich, cat. no. 11697498001) and sonicated to lyse the cells. The supernatant was sterilized using a filter. For mammalian cell culture, the supernatant was collected on day 5 post-transfection and filter sterilized. The supernatant was passed through a 5 mL GE HiTrap HP column (cat. no. 17-5248-02) attached to an AKTA Pure FPLC. The column was washed, loaded, and washed again with 20 mM imidizole in TBS. The final protein was eluted with 250 mM imidizole in TBS.

[00301] Ferritin-fused OspA serotype 1 from B. burgdorferi strain B31 was expressed in the transformed human kidney epithelial cell line Expi293 (FIGS. 2A-2D; SEQ ID NO: 52). Nanoparticle formation and protein purity were confirmed by size exclusion column chromatography (SEC) and SDS-PAGE (Figures 2A and 2B, respectively). SEC analysis revealed a single symmetrical peak of expected retention time (Figure 2A).

[00302] Dynamic light scattering (DLS) analysis was also performed. Purified nanoparticles were loaded into a black clear-bottom 384-well plate (Corning, catalog no. 3540) at a concentration of ~0.4 μg/mL. Samples were read using DynaPro Plater Reader II (Wyatt) at a control temperature of 25°C. DLS recorded a particle size of 13 nm with low polydispersity (7.4%) that was pure and free of aggregates (Figure 2C). Removal of the OspA transmembrane domain (aa 1–25) containing the lipidation site facilitated purification. The OspA sequence contains four potential amino-linked glycosylation sites, and OspA-ferritin purified from mammalian cells migrated at a higher molecular weight consistent with the addition of glycans (Fig. 2B).

[00303] Transmission electron microscopy negative stain imaging and 2D class averaging analysis were performed on OspA-ferritin nanoparticles (Figure 2D). A sample of OspA-ferritin nanoparticles was diluted 300-fold in 1xTBS and imaged over a layer of continuous carbon supported by nitrocellulose on a 400 mesh copper grid. Grids were prepared by applying 3 μl of sample suspension to a cleaned grid, blotting with filter paper, and immediately staining with uranyl formate. Electron microscopy was performed using an FEI Tecnai T12 electron microscope equipped with an FEI Eagle 4k x 4K CCD camera. High-magnification images were acquired at 67,000 magnification (0.16 nm/pixel). Images were acquired at nominal underfocusing from -1.9 µm to -0.8 µm and electron doses of ~30 e^-/Ų. Individual particles in the 67000x high magnification images were selected using automatic selection protocols (see Fig. Lander, G.C., et al., J Struct Biol, 166(1):95-102 (2009)). A reference-free alignment strategy was used based on the XMIPP processing package (see Sorzano, C.O., et al., J Struct Biol 148(2): p. 194-204 (2004)). The algorithms in this package allow you to align selected particles and sort them into groups or classes based on the similarity of the particles to each other.

[00304] The ferritin nanoparticle appeared as a concentrated ring-shaped seal with a hollow center in the middle (Figure 2D). Each nanoparticle was surrounded by numerous short, uniform, slightly oblong OspA spine-like extensions. The particles have an overall diameter ranging from ~194-220 Å with a ferritin core of 125 Å in diameter. The spine-like processes were uniform in size, shape, and orientation on the particle surface, and their length was up to 45 Å. OspA spines were ∼30 Å wide and tapered to minimal density at the glycine-serine ferritin linker.

[00305] When the LYMErix vaccine was produced in 2002^TM was discontinued, there were concerns that the vaccine contained an epitope (amino acids 165-173 of SEQ ID NO: 83) with homology to a nonapeptide segment (SEQ ID NO: 78) from human leukocyte function-associated antigen-1 (hLFA-1, see Gross, D.M., et al., Science 281(5377): p. 703-6 (1998)) (Fig. 5A). Amino acids 165-173 of SEQ ID NO: 83 are referred to as the site of homology with hLFA-1. OspA serotype 1 is the only serotype that exhibits this sequence homology (Fig. 5B). To avoid any potential problems associated with this sequence, the hLFA-1 homology site was replaced with either the corresponding OspA serotype 2 (SEQ ID NO: 79) or serotype 3 (SEQ ID NO: 80) nonapeptide sequences, or point substitutions were inserted that reduced similarity to hLFA-1 and were designed to prevent the formation of antibodies that bind to hLFA-1 (RD2, SEQ ID NO: 81) (Fig. 5C). In the case of point substitutions, surface-exposed amino acids were replaced to reduce similarity to hLFA-1, thereby eliminating or minimizing destabilization of the β-sheet structure.

[00306] The immunogenicity of hLFA-1 nanoparticles with a modified hLFA-1 homology site was tested in mice to compare the immune response compared to an OspA-ferritin nanoparticle without such modification (Figure 5D). Antibody titers induced by nanoparticles with a modified hLFA-1 homology site were stable and did not differ significantly from nanoparticles with an unmodified hLFA-1 homology site.

2. Characteristics of the immunogenicity of OspA-ferritin nanoparticles

[00307] To evaluate the immunogenicity of OspA-ferritin nanoparticles, C3H mice were immunized twice with OspA serotype 1-ferritin nanoparticles in the presence of Ribi or RECOMBITEK® Lyme adjuvant (a liquid suspension of purified outer surface protein A (OspA) fromBorrelia burgdorferi), a canine vaccine in which OspA is full-length, lipidated, recombinant and serotype 1 (Fig. 4). C3H/HeN mice were vaccinated intramuscularly at week zero and week 4. ELISA was performed using blood serum 2 weeks after administration of the 2nd doses. Ribi (Sigma adjuvant system, catalog no. S6322-1vl) was resuspended in 1 ml PBS and vortexed for 1 minute and then added in an equal volume to the antigen before immunization.

[00308] Antibody response was determined using a recombinant OspA enzyme-linked immunosorbent assay (ELISA). Briefly, 96-well plates were coated with 1 μg/ml OspA-His diluted in PBS and incubated overnight at 4°C. OspA-His was removed and plates were blocked with 5% skim milk dissolved in PBST. After removal of the blocking reagent, primary serum samples were added after serial dilution in PBST. Primary samples were added in equal volume to the blocking solution to obtain a final blocking solution concentration of 50%. After incubation for 1 hour, plates were washed with PBST and incubated with goat anti-mouse IgG, an HRP-linked secondary antibody (1:5000 dilution in blocking solution) for 1 hour at room temperature. The secondary antibody was removed by aspiration and washed, and the plates were incubated with Sure Blue TMB peroxidase substrate (KPL, Gaithersburg, MD) followed by an equal volume of stop solution (0.5 N sulfuric acid). Optical density was measured at 450 nm.

[00309] Immunization with OspA-ferritin nanoparticles resulted in an induction of endpoint titers 4.4 times higher than RECOMBITEK® Lyme at week six (p<0.001). The antibody titer at week 25 was also significantly higher than with RECOMBITEK® Lyme (p < 0.005) (Figure 4).

3. Glycosylation mutants; efficiency mark

[00310] To evaluate the protective efficacy of these OspA-ferritin nanoparticles, an infection model was used in which immunized or control mice were infected with ticks carryingB. burgdorferi (cm. Rosa, P. A., et al. Nat Rev Microbiol 3(2): p. 129-43 (2005)).

[00311] C3H/HeN mice were vaccinated intramuscularly with either 1 μg OspA-ferritin nanoparticles mixed with AddaVax ^TM 1:1 or 1 μg ferritin nanoparticles. Mice were vaccinated at week zero and week 4. An OspA serotype 1-ferritin nanoparticle with rationally designed hLFA-1 homology site modifications and modifications to remove all potential N-glycosylation sites (SEQ ID NO: 53) was used to immunize mice because the natural bacterial expressed OspA is not glycosylated at these positions. The sequence contained the following N>Q substitutions to prevent glycosylation: N71Q, N190Q, N202Q, and N251Q. Its immunogenicity was similar to that of the glycosylated nanoparticle (Fig. 13).

[00312] OspA-ferritin glycosylation mutants were also tested when the serine/threonines at the glycosylation sites were mutated to alanine (SEQ ID NO: 63). Both this construct and the N>Q construct described above provided a robust immune response compared to wild-type OspA-ferritin nanoparticles (SEQ ID NO: 52) and were superior to the RECOMBITEK® Lyme control (Figure 14 ).

[00313] In an additional experiment to evaluate the protective effectiveness of OspA-ferritin nanoparticles in a tick infestation model , Ixodes scapularis tick larvae were obtained from the National Tick Research and Education Center at Oklahoma State University (Stillwater, Oklahoma). B. burgdorferi -infected nymphs were produced by allowing uninfected larvae to feed until satiation on SCID mice infected with B. burgdorferi strain N40. The swollen larvae were collected and allowed to molt into nymphs for 4-6 weeks at room temperature and high relative humidity. The prevalence of B. burgdorferi infection in fed larvae was determined by culturing a portion of recovered ticks from each batch.

[00314] Mice were immunized with two 1 μg doses of OspA-ferritin nanoparticles (SEQ ID NO: 53) with AddaVax ^™ adjuvant or ferritin control at week 0 and week 4, and a control group was immunized in parallel with RECOMBITEK® Lyme. Mice were challenged at week 6 (i.e., 2 weeks after the second vaccine dose) by allowing 5–6 nymphal stage ticks infected with B. burgdorferi to feed until satiated. Fattened nymphs were collected and analyzed for B. burgdorferi infection by culture in BSK medium. Two weeks postinfection, mice were sacrificed and assayed for B. burgdorferi infection by ear tissue culture, ankle tissue culture, and heart tissue culture. The presence of B. burgdorferi was determined by observing cultures using dark-field microscopy. A mouse was considered infected with B. burgdorferi if one or more organ cultures were found to be positive for infection by dark-field microscopy. Negative cultures were also tested using B. burgdorferi-specific PCR.

[00315] Mice were sacrificed after two weeks. Tissue samples from the heart, ankle, and ear were cultured in BSK medium with antibiotics against B. burgdorferi for 6 weeks. Specimens negative for infection were tested by PCR for the presence of B. burgdorferi. All cultures negative for infection were also PCR negative. Protection was calculated as the percentage of uninfected mice.

[00316] The composition containing OspA-ferritin nanoparticles and AddaVax ^™ adjuvant showed no infection (0/4) in contrast to ferritin as a negative control, which caused 4 out of 5 animals to be infected (Table 2; p<0.01 ).

Table 2. Protective efficacy of OspA-ferritin nanoparticles

Antigen Mice/group Number of infected mice % infected Control particle 5 4 80 OspA-ferritin+AddaVax ^TM 4 0 0 RECOMBITEK® Lyme 4 0 0

4. Evaluation of the effectiveness of OspA-ferritin nanoparticles conjugated with immunostimulating fragments

[00317] The self-adjuvant construct was prepared by engineering a cysteine (S111C) on the surface of a ferritin nanoparticle, allowing direct conjugation of immunostimulatory moieties such as TLR agonists (Figure 6A) or CpG (SEQ ID NO: 210; ISS-1018, Figure 7A ), using click chemistry. The direct conjugation procedure was as follows: Mammalian-derived material was reduced to remove cysteinylation with 10 mM TCEP (Amresco K831-10G) in 50 mM Tris pH 8.5 for 1 hour. The protein was then dialyzed into 100 mM Tris pH 8, 50 mM NaCl to remove TCEP. Material derived from E. coli does not need to be reconstituted. DBCO-PEG4-maleimide linker (Sigma-Aldrich, cat. no. 760676-5mg) was resuspended at 5 mg/ml in DMSO. 2.5 mg of linker was added to 3 mg of protein in a volume of 10 ml (final DMSO concentration was 5%). The linker was incubated with the reduced protein for 30 minutes at room temperature. An Ambicon 100 MW molecular weight cutoff filter concentrator was used to remove excess linker via buffer exchange (Millipore, cat. no. UFC910096). Azide-PEG4-3M-012 (in-house synthesized) and azide-CPG (ISS-1018, custom synthesized at IDT) were used in the final click chemistry step. 0.5 mg of adjuvant was added to 0.5 mg of protein in the final conjugation step and incubated at 37°C for 6 hours and then at 4°C overnight. Excess adjuvant was removed by buffer exchange using an Ambicon 100 MW molecular weight cutoff filter concentrator. Conjugation efficiency was confirmed by mass spectrometry for 3M-012 and SDS-PAGE analysis for CPG.

[00318] The TLR 7/8 agonist 3M-012 was used, which has previously been shown to enhance antibody responses when directly conjugated to the HIV Gag protein (see Wille-Reece, U., et al., Proc Natl Acad Sci U S A 102(42): p. 15190-4 (2005)). A two-step click chemistry approach was used to attach 3M-012 to the nanoparticle under SEQ ID NO: 53. First, the DBCO-PEG4-maleimide linker was coupled to cysteine, and then the modified 3M-012 with PEG4-azide linker was added via azide-alkyne cycloadditions without the participation of copper (Fig. 6A). Conjugation efficiency of >99% was confirmed by mass spectrometry with a mass change of 587 Daltons (Figure 12). In addition to azide-3M-012, azide-CPG was also successfully added (Figure 7A), for which conjugation could be confirmed by gel shift (Figure 7B).

[00319] Almost complete conjugation of ferritin was observed, indicating that most nanoparticles carry 24 agonist molecules. The immunogenicity of OspA-ferritin conjugated nanoparticles was then assessed in mice. C3H/HeN mice were vaccinated intramuscularly at week zero and week 4. ELISA was performed using blood serum 2 weeks after administration of the 2nd doses. Aluminum alum (Alyhydrogel '85 2%; Brenntag, catalog no. 21645-51-2) was added in an equal volume to the antigen before immunization. Ribi (Sigma adjuvant system, catalog no. S6322-1vl) was resuspended in 1 ml PBS and vortexed for 1 minute and then added in an equal volume to the antigen before immunization.

[00320] Mice immunized with 3M-012-conjugated particles exhibited 4.5-fold higher anti-OspA antibody responses than unconjugated material (Figure 6B, p < 0.05). Antibody responses induced by particles conjugated to 3M-012 were greater than those produced by particles mixed with a molar equivalent amount of 3M-012 (29 ng) and comparable to particles mixed with a 1000-fold higher dose (20 µg) 3M-012 or standard aluminum alum adjuvant (Alyhydrogel '85 2%; Brenntag, catalog no. 21645-51-2).

[00321] A similar increase in antibody production was observed with CPG-conjugated OspA-ferritin nanoparticle (SEQ ID NO: 53) with a 6.3-fold increase in immune response compared to unconjugated particles and a 4.7-fold increase compared to an equivalent amount of unconjugated CPG mixed with nanoparticles (Figure 7C).

[00322] Thus, targeted delivery of an adjuvant conjugated to an OspA-ferritin nanoparticle can significantly reduce the amount of adjuvant while stimulating an effective and specific antibody response.

5. Assessment of the immunogenicity of OspA-ferritin nanoparticles, including various serotypes

[00323] While OspA serotype 1 strainB. burgdorferi causes disease in the United States,B. afzelii(serotype 2),B. garinii(serotype 3, 5, 6, 7) andB.bavariensis(serotype 4) cause disease in Europe, Asia and other places. To obtain a composition with broad cross-protection, OspA-ferritin nanoparticles were developed for serotypes 1, 2, 3, 4, 5 and 7 (SEQ ID NO: 1, 5, 6, 7, 8 and 10). These particles were expressed and purified fromE. coli using anion exchange and size exclusion chromatography (Fig. 3A). All OspA-ferritin antigenic polypeptides have the expected molecular weight of 47 kDa, and DLS analysis and transmission electron microscopy also confirmed the formation of all six OspA nanoparticles (Fig. 3B).

[00324] A six-component composition was prepared by combining each of serotypes 1-5 and 7 OspA-ferritin nanoparticles in equimolar proportions.

[00325] The immunogenicity of this six-component (ie, hexavalent) alum composition was compared in mice with particles of the same serotype (ie, monovalent) with the same adjuvant (Figures 8A-8F). The monovalent composition was given at a dose of 1 μg and the hexavalent composition was given at a dose of 1 μg for each serotype (total dose was 6 μg). Aluminum alum (Alyhydrogel '85 2%; Brenntag, catalog no. 21645-51-2) was added in an equal volume to the antigen before immunization. The six-component formulation induced a robust response with antibodies to all six OspA serotypes 1-5 and 7. Moreover, the response to the single-serotype control was similar to the mixture, indicating that there was no interference in the combination of the six serotypes. An improved immune response was observed against serotype 4 with the hexavalent formulation compared to the single component formulation (see fig. 8D, serotype 4).

[00326] After establishing that the hexavalent composition was immunogenic, and in some cases superior to the monovalent composition, 3M-012 and CpG conjugates of each of the six OspA-ferritin nanoparticles were prepared. Two six-component conjugated compositions were created by combining six OspA-ferritin nanoparticles conjugated to 3M-012 and, separately, by combining six OspA-ferritin nanoparticles conjugated to CpG. The CpG-conjugated and 3M-012-conjugated hexavalent formulations demonstrated significantly increased antibody responses in mice compared to the unconjugated hexavalent formulation for all seven OspA serotypes found worldwide (Figures 9A-9G), indicating that the hexavalent formulation also provides protection against serotype 6 even if the serotype 6 OspA polypeptide was not present in the composition.

[00327] When tested in non-human primates (NHP [rhesus monkeys]), the hexavalent nanoparticle formulation (unconjugated) with adjuvant AF03 outperformed the RECOMBITEK® Lyme control with an 11- to 200-fold increase in Ab titer to all seven circulating Borrelia serotypes ( Fig. 10A-10G). As in mice, the hexavalent formulation induced a high-titer Ab response in the presence of an adjuvant. Compositions conjugated to 3M-012 and CpG induced a response similar to that of the RECOMBITEK® Lyme control in NHPs (compare Figures 10A-G and 10H-N, respectively). Antibody titers for the hexavalent vaccine in NHP were sustained up to 19 weeks after the booster dose and maintained an advantage over the RECOMBITEK® Lyme control (Figure 25).

[00328] The conjugated compositions were also tested in a tick infestation model. Mice were vaccinated with a 1 μg dose of antigens at week 0 and week 4. The monovalent formulation contained 1 μg of OspA-ferritin serotype 1 nanoparticles conjugated to 3M-012. The hexavalent composition contained OspA serotypes 1, 2, 3, 4, 5 and 7, 1 μg each, conjugated to 3M-012. Mice were infected with 5-6 ticks infected with Borrelia burgdorferi strain N40 (serotype 1) for 5 days two weeks after the second immunization and sacrificed two weeks later. Tissue samples from the heart, ankle, and ear were cultured in BSK medium with antibiotics against B. burgdorferi for 6 weeks. Specimens negative for infection were tested by PCR for the presence of B. burgdorferi. Specimens positive for infection were either culture or PCR positive (Fig. 11).

[00329] The present inventors further tested a heptavalent vaccine containing all seven serotypes in mice. Mice were immunized intramuscularly at week 0 and week 4 with heptavalent OspA-ferritin nanoparticle formulations, 1 μg each of OspA-ferritin nanoparticles corresponding to OspA serotypes 1-7 (7 μg total), to which either aluminum alum was added as an adjuvant. , either AF03, or with RECOMBITEK® Lyme (dose was 1 μg). The antibody response was analyzed 2 weeks after immunization by endpoint titer measured by ELISA. A robust immune response was demonstrated compared to RECOMBITEK® (FIG. 24A-G).

[00330] In summary, OspA-ferritin nanoparticles induced high titer antibody responses to seven major serotypes. In addition, the seven-component Lyme disease vaccine candidate helps control the global spread of Lyme disease.

6. Characteristics of OspA-ferritin constructs with various flexible linkers

[00331] Seven different linkers were tested to provide flexibility between OspA and ferritin. The constructs ranged from one to five GGGS sequences (SEQ ID NO: 226). Different linker constructs purified and formed nanoparticles of uniform size.

[00332] All OspA-linker-ferritin constructs containing GS1 (GGGS (SEQ ID NO: 226)), GS2 (SEQ ID NO: 91) or GS5 (SEQ ID NO: 92) linkers could be expressed (Fig. 15A ) and showed consistent DLS (Fig. 15B, 15C and 15E) and EM (Fig. 15D) profiles.

[00333] In addition, all other GGGS (SEQ ID NO: 226) linker constructs (1x GGGS linker (SEQ ID NO: 226) [SEQ ID NO: 60], 2x GGGS linker (SEQ ID NO: 91) [SEQ ID NO: 61] and 5x GGGS linker (SEQ ID NO: 92) [SEQ ID NO: 62]) showed strong immune responses in C3H mice (Fig. 16).

7. Characteristics of lumazine synthase-OspA nanoparticles

[00334] Another nanoparticle, lumazine synthase from Aquifex aeolicus , was examined for the antigenic expression of OspA. OspA-lumazine synthase particles containing different serotypes were readily purified from E. coli cells by anion exchange and size exclusion chromatography. Constructs were generated and characterized as containing OspA serotype 1 (SEQ ID NO: 12, Fig. 19A-19C); OspA serotype 2 (SEQ ID NO: 16, Fig. 20A-20C); OspA serotype 3 (SEQ ID NO: 17, Fig. 21A-21B); OspA serotype 4 (SEQ ID NO: 18, Fig. 17A-17C); OspA serotype 5 (SEQ ID NO: 19, Figs. 22A-22C) and OspA serotype 7 (SEQ ID NO: 21, Figs. 23A-23C). OspA-lumazine synthase particles formed a 15.8 nm particle size by EM and were uniform in size by DLS.

[00335] OspA serotype 4-lumazine synthase particles (SEQ ID NO: 18) were tested in mice for immunogenicity (Figure 18). OspA-lumazine synthase particles with and without alum provided a potent immune response that was at least as robust as that of the similar OspA serotype 4-ferritin nanoparticle (SEQ ID NO: 7).

[00336] Thus, antigenic polypeptides containing lumazine synthase and OspA polypeptide can also be used to induce anti-OspA antibody responses.

--->

LIST OF SEQUENCES

<110>SANOFI

<120> Antigenic polypeptides based on the OspA sequence

<130> 01121-0033-00PCT

<140>

<141>

<150> 62/652,210

<151> 2018-04-03

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<170> PatentIn version 3.5

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Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

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Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

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Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

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Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

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Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

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Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

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Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

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Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Tyr Thr Leu

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Glu Gly Gln Leu Ser Asp Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val

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Glu Leu Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

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Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys Gly Ser Glu Ser Gln Val

245 250 255

Arg Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val

260 265 270

Asn Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp

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Ser Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His

290 295 300

Ala Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn

305 310 315 320

Glu Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His

325 330 335

Lys Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu

340 345 350

Gln His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys

355 360 365

Cys Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu

370 375 380

Gln His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu

385 390 395 400

Leu Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val

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Lys Gly Ile Ala Lys Ser Arg Lys Ser

420 425

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Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

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Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

100 105 110

Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Tyr Asp Leu

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Lys Gly Glu Leu Ser Ser Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val

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Glu Leu Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

180 185 190

Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys Gly Ser Glu Ser Gln Val

245 250 255

Arg Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val

260 265 270

Asn Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp

275 280 285

Ser Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His

290 295 300

Ala Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn

305 310 315 320

Glu Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His

325 330 335

Lys Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu

340 345 350

Gln His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys

355 360 365

Cys Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu

370 375 380

Gln His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu

385 390 395 400

Leu Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val

405 410 415

Lys Gly Ile Ala Lys Ser Arg Lys Ser

420 425

<210> 3

<211> 425

<212> PROTEIN

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Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

100 105 110

Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Phe Thr Leu

130 135 140

Glu Gly Lys Val Ala Asn Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val

165 170 175

Glu Leu Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

180 185 190

Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys Gly Ser Glu Ser Gln Val

245 250 255

Arg Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val

260 265 270

Asn Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp

275 280 285

Ser Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His

290 295 300

Ala Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn

305 310 315 320

Glu Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His

325 330 335

Lys Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu

340 345 350

Gln His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys

355 360 365

Cys Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu

370 375 380

Gln His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu

385 390 395 400

Leu Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val

405 410 415

Lys Gly Ile Ala Lys Ser Arg Lys Ser

420 425

<210> 4

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Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

100 105 110

Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Phe Ala Leu

130 135 140

Glu Gly Thr Leu Thr Asp Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val

165 170 175

Glu Leu Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

180 185 190

Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys Gly Ser Glu Ser Gln Val

245 250 255

Arg Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val

260 265 270

Asn Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp

275 280 285

Ser Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His

290 295 300

Ala Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn

305 310 315 320

Glu Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His

325 330 335

Lys Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu

340 345 350

Gln His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys

355 360 365

Cys Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu

370 375 380

Gln His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu

385 390 395 400

Leu Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val

405 410 415

Lys Gly Ile Ala Lys Ser Arg Lys Ser

420 425

<210> 5

<211> 425

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

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Met Asp Glu Lys Asn Ser Ala Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Lys

20 25 30

Ala Thr Val Asp Lys Ile Glu Leu Lys Gly Thr Ser Asp Lys Asp Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Thr Lys Asp Asp Lys Ser Lys Ala Lys

50 55 60

Leu Thr Ile Ala Asp Asp Leu Ser Lys Thr Thr Phe Glu Leu Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Arg Lys Val Ser Ser Lys Asp Lys

85 90 95

Thr Ser Thr Asp Glu Met Phe Asn Glu Lys Gly Glu Leu Ser Ala Lys

100 105 110

Thr Met Thr Arg Glu Asn Gly Thr Lys Leu Glu Tyr Thr Glu Met Lys

115 120 125

Ser Asp Gly Thr Gly Lys Ala Lys Glu Val Leu Lys Asn Phe Thr Leu

130 135 140

Glu Gly Lys Val Ala Asn Asp Lys Val Thr Leu Glu Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Glu Ile Ala Lys Ser Gly Glu Val Thr Val

165 170 175

Ala Leu Asn Asp Thr Asn Thr Thr Gln Ala Thr Lys Lys Thr Gly Ala

180 185 190

Trp Asp Ser Lys Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Lys Lys

195 200 205

Thr Thr Gln Leu Val Phe Thr Lys Gln Asp Thr Ile Thr Val Gln Lys

210 215 220

Tyr Asp Ser Ala Gly Thr Asn Leu Glu Gly Thr Ala Val Glu Ile Lys

225 230 235 240

Thr Leu Asp Glu Leu Lys Asn Ala Leu Lys Gly Ser Glu Ser Gln Val

245 250 255

Arg Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val

260 265 270

Asn Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp

275 280 285

Ser Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His

290 295 300

Ala Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn

305 310 315 320

Glu Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His

325 330 335

Lys Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu

340 345 350

Gln His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys

355 360 365

Cys Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu

370 375 380

Gln His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu

385 390 395 400

Leu Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val

405 410 415

Lys Gly Ile Ala Lys Ser Arg Lys Ser

420 425

<210> 6

<211> 426

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

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Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Gly Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Met

20 25 30

Ala Thr Val Glu Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Ser Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Glu Lys Ala Asp Lys Ser Lys Ala Lys

50 55 60

Leu Thr Ile Ser Gln Asp Leu Asn Gln Thr Thr Phe Glu Ile Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Arg Lys Val Asn Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Asp Lys Gly Lys Leu Ser Glu Lys

100 105 110

Val Val Thr Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Glu Ile Lys

115 120 125

Asn Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Phe Ala Leu

130 135 140

Glu Gly Thr Leu Thr Asp Gly Gly Glu Thr Lys Leu Thr Val Thr Glu

145 150 155 160

Gly Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Ile Thr

165 170 175

Val Ala Leu Asn Asp Thr Glu Thr Thr Pro Ala Asp Lys Lys Thr Gly

180 185 190

Glu Trp Lys Ser Asp Thr Ser Thr Leu Thr Ile Ser Lys Asn Ser Gln

195 200 205

Lys Pro Lys Gln Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln

210 215 220

Asn Tyr Asn Arg Ala Gly Asn Ala Leu Glu Gly Ser Pro Ala Glu Ile

225 230 235 240

Lys Asp Leu Ala Glu Leu Lys Ala Ala Leu Lys Gly Ser Glu Ser Gln

245 250 255

Val Arg Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln

260 265 270

Val Asn Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser

275 280 285

Trp Ser Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp

290 295 300

His Ala Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu

305 310 315 320

Asn Glu Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu

325 330 335

His Lys Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His

340 345 350

Glu Gln His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile

355 360 365

Lys Cys Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala

370 375 380

Glu Gln His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile

385 390 395 400

Glu Leu Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr

405 410 415

Val Lys Gly Ile Ala Lys Ser Arg Lys Ser

420 425

<210> 7

<211> 425

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 7

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Met

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Ser Asn

35 40 45

Gly Ser Gly Thr Leu Glu Gly Glu Lys Ser Asp Lys Ser Lys Ala Lys

50 55 60

Leu Thr Ile Ser Glu Asp Leu Ser Lys Thr Thr Phe Glu Ile Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Asn Ser Lys Asp Lys

85 90 95

Ser Ser Ile Glu Glu Lys Phe Asn Ala Lys Gly Glu Leu Ser Glu Lys

100 105 110

Thr Ile Leu Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Glu Ile Lys

115 120 125

Ser Asp Gly Thr Gly Lys Ala Lys Glu Val Leu Lys Asp Phe Ala Leu

130 135 140

Glu Gly Thr Leu Ala Ala Asp Lys Thr Thr Leu Lys Val Thr Glu Gly

145 150 155 160

Thr Val Val Leu Ser Lys His Ile Pro Asn Ser Gly Glu Ile Thr Val

165 170 175

Glu Leu Asn Asp Ser Asn Ser Thr Gln Ala Thr Lys Lys Thr Gly Lys

180 185 190

Trp Asp Ser Asn Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Lys Lys

195 200 205

Thr Lys Asn Ile Val Phe Thr Lys Glu Asp Thr Ile Thr Val Gln Lys

210 215 220

Tyr Asp Ser Ala Gly Thr Asn Leu Glu Gly Asn Ala Val Glu Ile Lys

225 230 235 240

Thr Leu Asp Glu Leu Lys Asn Ala Leu Lys Gly Ser Glu Ser Gln Val

245 250 255

Arg Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val

260 265 270

Asn Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp

275 280 285

Ser Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His

290 295 300

Ala Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn

305 310 315 320

Glu Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His

325 330 335

Lys Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu

340 345 350

Gln His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys

355 360 365

Cys Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu

370 375 380

Gln His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu

385 390 395 400

Leu Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val

405 410 415

Lys Gly Ile Ala Lys Ser Arg Lys Ser

420 425

<210> 8

<211> 426

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 8

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Gly Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Met

20 25 30

Ala Thr Val Glu Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Thr Leu Glu Gly Glu Lys Thr Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ala Glu Asp Leu Ser Lys Thr Thr Phe Glu Ile Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Leu Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Ile Ser Glu Lys

100 105 110

Thr Ile Val Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Asp Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Asp Phe Thr Leu

130 135 140

Glu Gly Thr Leu Ala Ala Asp Gly Lys Thr Thr Leu Lys Val Thr Glu

145 150 155 160

Gly Thr Val Val Leu Ser Lys Asn Ile Leu Lys Ser Gly Glu Ile Thr

165 170 175

Val Ala Leu Asp Asp Ser Asp Thr Thr Gln Ala Thr Lys Lys Thr Gly

180 185 190

Lys Trp Asp Ser Lys Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Gln

195 200 205

Lys Thr Lys Asn Leu Val Phe Thr Lys Glu Asp Thr Ile Thr Val Gln

210 215 220

Lys Tyr Asp Ser Ala Gly Thr Asn Leu Glu Gly Lys Ala Val Glu Ile

225 230 235 240

Thr Thr Leu Glu Lys Leu Lys Asp Ala Leu Lys Gly Ser Glu Ser Gln

245 250 255

Val Arg Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln

260 265 270

Val Asn Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser

275 280 285

Trp Ser Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp

290 295 300

His Ala Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu

305 310 315 320

Asn Glu Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu

325 330 335

His Lys Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His

340 345 350

Glu Gln His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile

355 360 365

Lys Cys Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala

370 375 380

Glu Gln His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile

385 390 395 400

Glu Leu Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr

405 410 415

Val Lys Gly Ile Ala Lys Ser Arg Lys Ser

420 425

<210> 9

<211> 426

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 9

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Gly Met Thr

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Glu

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Thr Leu Glu Gly Glu Lys Thr Asp Lys Ser Lys Val Lys

50 55 60

Ser Thr Ile Ala Asp Asp Leu Ser Gln Thr Lys Phe Glu Ile Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Leu Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Gly Lys Gly Glu Thr Ser Glu Lys

100 105 110

Thr Ile Val Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Asp Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Asp Phe Thr Leu

130 135 140

Glu Gly Thr Leu Ala Ala Asp Gly Lys Thr Thr Leu Lys Val Thr Glu

145 150 155 160

Gly Thr Val Val Leu Ser Lys Asn Ile Leu Lys Ser Gly Glu Ile Thr

165 170 175

Ala Ala Leu Asp Asp Ser Asp Thr Thr Arg Ala Thr Lys Lys Thr Gly

180 185 190

Lys Trp Asp Ser Lys Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Gln

195 200 205

Lys Thr Lys Asn Leu Val Phe Thr Lys Glu Asp Thr Ile Thr Val Gln

210 215 220

Arg Tyr Asp Ser Ala Gly Thr Asn Leu Glu Gly Lys Ala Val Glu Ile

225 230 235 240

Thr Thr Leu Lys Glu Leu Lys Asn Ala Leu Lys Gly Ser Glu Ser Gln

245 250 255

Val Arg Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln

260 265 270

Val Asn Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser

275 280 285

Trp Ser Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp

290 295 300

His Ala Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu

305 310 315 320

Asn Glu Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu

325 330 335

His Lys Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His

340 345 350

Glu Gln His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile

355 360 365

Lys Cys Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala

370 375 380

Glu Gln His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile

385 390 395 400

Glu Leu Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr

405 410 415

Val Lys Gly Ile Ala Lys Ser Arg Lys Ser

420 425

<210> 10

<211> 426

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 10

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Glu

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Ala Lys Ser Lys Ala Lys

50 55 60

Leu Thr Ile Ala Asp Asp Leu Ser Gln Thr Lys Phe Glu Ile Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Leu Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Asp Lys Gly Lys Leu Ser Glu Lys

100 105 110

Val Val Thr Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Glu Ile Gln

115 120 125

Asn Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Ser Leu Thr Leu

130 135 140

Glu Gly Thr Leu Thr Ala Asp Gly Glu Thr Lys Leu Thr Val Glu Ala

145 150 155 160

Gly Thr Val Thr Leu Ser Lys Asn Ile Ser Glu Ser Gly Glu Ile Thr

165 170 175

Val Glu Leu Lys Asp Thr Glu Thr Thr Pro Ala Asp Lys Lys Ser Gly

180 185 190

Thr Trp Asp Ser Lys Thr Ser Thr Leu Thr Ile Ser Lys Asn Ser Gln

195 200 205

Lys Thr Lys Gln Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln

210 215 220

Lys Tyr Asn Thr Ala Gly Thr Lys Leu Glu Gly Ser Pro Ala Glu Ile

225 230 235 240

Lys Asp Leu Glu Ala Leu Lys Ala Ala Leu Lys Gly Ser Glu Ser Gln

245 250 255

Val Arg Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln

260 265 270

Val Asn Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser

275 280 285

Trp Ser Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp

290 295 300

His Ala Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu

305 310 315 320

Asn Glu Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu

325 330 335

His Lys Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His

340 345 350

Glu Gln His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile

355 360 365

Lys Cys Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala

370 375 380

Glu Gln His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile

385 390 395 400

Glu Leu Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr

405 410 415

Val Lys Gly Ile Ala Lys Ser Arg Lys Ser

420 425

<210> 11

<211> 265

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 11

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Met

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Ser Asn

35 40 45

Gly Ser Gly Thr Leu Glu Gly Glu Lys Ser Asp Lys Ser Lys Ala Lys

50 55 60

Leu Thr Ile Ser Glu Asp Leu Ser Lys Thr Thr Phe Glu Ile Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Asn Ser Lys Asp Lys

85 90 95

Ser Ser Ile Glu Glu Lys Phe Asn Ala Lys Gly Glu Leu Ser Glu Lys

100 105 110

Thr Ile Leu Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Glu Ile Lys

115 120 125

Ser Asp Gly Thr Gly Lys Ala Lys Glu Val Leu Lys Asp Phe Ala Leu

130 135 140

Glu Gly Thr Leu Ala Ala Asp Lys Thr Thr Leu Lys Val Thr Glu Gly

145 150 155 160

Thr Val Val Leu Ser Lys His Ile Pro Asn Ser Gly Glu Ile Thr Val

165 170 175

Glu Leu Asn Asp Ser Asn Ser Thr Gln Ala Thr Lys Lys Thr Gly Lys

180 185 190

Trp Asp Ser Asn Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Lys Lys

195 200 205

Thr Lys Asn Ile Val Phe Thr Lys Glu Asp Thr Ile Thr Val Gln Lys

210 215 220

Tyr Asp Ser Ala Gly Thr Asn Leu Glu Gly Asn Ala Val Glu Ile Lys

225 230 235 240

Thr Leu Asp Glu Leu Lys Asn Ala Leu Lys Cys Leu Val Pro Arg Gly

245 250 255

Ser Leu Glu His His His His His

260 265

<210> 12

<211> 408

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 12

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

100 105 110

Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Tyr Thr Leu

130 135 140

Glu Gly Gln Leu Ser Asp Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val

165 170 175

Glu Leu Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

180 185 190

Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys Gly Gly Gly Ser Met Gln

245 250 255

Ile Tyr Glu Gly Lys Leu Thr Ala Glu Gly Leu Arg Phe Gly Ile Val

260 265 270

Ala Ser Arg Phe Asn His Ala Leu Val Asp Arg Leu Val Glu Gly Ala

275 280 285

Ile Asp Cys Ile Val Arg His Gly Gly Arg Glu Glu Asp Ile Thr Leu

290 295 300

Val Arg Val Pro Gly Ser Trp Glu Ile Pro Val Ala Ala Gly Glu Leu

305 310 315 320

Ala Arg Lys Glu Asp Ile Asp Ala Val Ile Ala Ile Gly Val Leu Ile

325 330 335

Arg Gly Ala Thr Pro His Phe Asp Tyr Ile Ala Ser Glu Val Ser Lys

340 345 350

Gly Leu Ala Asn Leu Ser Leu Glu Leu Arg Lys Pro Ile Thr Phe Gly

355 360 365

Val Ile Thr Ala Asp Thr Leu Glu Gln Ala Ile Glu Arg Ala Gly Thr

370 375 380

Lys His Gly Asn Lys Gly Trp Glu Ala Ala Leu Ser Ala Ile Glu Met

385 390 395 400

Ala Asn Leu Phe Lys Ser Leu Arg

405

<210> 13

<211> 408

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 13

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

100 105 110

Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Tyr Asp Leu

130 135 140

Lys Gly Glu Leu Ser Ser Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val

165 170 175

Glu Leu Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

180 185 190

Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys Gly Gly Gly Ser Met Gln

245 250 255

Ile Tyr Glu Gly Lys Leu Thr Ala Glu Gly Leu Arg Phe Gly Ile Val

260 265 270

Ala Ser Arg Phe Asn His Ala Leu Val Asp Arg Leu Val Glu Gly Ala

275 280 285

Ile Asp Cys Ile Val Arg His Gly Gly Arg Glu Glu Asp Ile Thr Leu

290 295 300

Val Arg Val Pro Gly Ser Trp Glu Ile Pro Val Ala Ala Gly Glu Leu

305 310 315 320

Ala Arg Lys Glu Asp Ile Asp Ala Val Ile Ala Ile Gly Val Leu Ile

325 330 335

Arg Gly Ala Thr Pro His Phe Asp Tyr Ile Ala Ser Glu Val Ser Lys

340 345 350

Gly Leu Ala Asn Leu Ser Leu Glu Leu Arg Lys Pro Ile Thr Phe Gly

355 360 365

Val Ile Thr Ala Asp Thr Leu Glu Gln Ala Ile Glu Arg Ala Gly Thr

370 375 380

Lys His Gly Asn Lys Gly Trp Glu Ala Ala Leu Ser Ala Ile Glu Met

385 390 395 400

Ala Asn Leu Phe Lys Ser Leu Arg

405

<210> 14

<211> 408

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 14

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

100 105 110

Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Phe Thr Leu

130 135 140

Glu Gly Lys Val Ala Asn Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val

165 170 175

Glu Leu Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

180 185 190

Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys Gly Gly Gly Ser Met Gln

245 250 255

Ile Tyr Glu Gly Lys Leu Thr Ala Glu Gly Leu Arg Phe Gly Ile Val

260 265 270

Ala Ser Arg Phe Asn His Ala Leu Val Asp Arg Leu Val Glu Gly Ala

275 280 285

Ile Asp Cys Ile Val Arg His Gly Gly Arg Glu Glu Asp Ile Thr Leu

290 295 300

Val Arg Val Pro Gly Ser Trp Glu Ile Pro Val Ala Ala Gly Glu Leu

305 310 315 320

Ala Arg Lys Glu Asp Ile Asp Ala Val Ile Ala Ile Gly Val Leu Ile

325 330 335

Arg Gly Ala Thr Pro His Phe Asp Tyr Ile Ala Ser Glu Val Ser Lys

340 345 350

Gly Leu Ala Asn Leu Ser Leu Glu Leu Arg Lys Pro Ile Thr Phe Gly

355 360 365

Val Ile Thr Ala Asp Thr Leu Glu Gln Ala Ile Glu Arg Ala Gly Thr

370 375 380

Lys His Gly Asn Lys Gly Trp Glu Ala Ala Leu Ser Ala Ile Glu Met

385 390 395 400

Ala Asn Leu Phe Lys Ser Leu Arg

405

<210> 15

<211> 408

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 15

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

100 105 110

Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Phe Ala Leu

130 135 140

Glu Gly Thr Leu Thr Asp Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val

165 170 175

Glu Leu Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

180 185 190

Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys Gly Gly Gly Ser Met Gln

245 250 255

Ile Tyr Glu Gly Lys Leu Thr Ala Glu Gly Leu Arg Phe Gly Ile Val

260 265 270

Ala Ser Arg Phe Asn His Ala Leu Val Asp Arg Leu Val Glu Gly Ala

275 280 285

Ile Asp Cys Ile Val Arg His Gly Gly Arg Glu Glu Asp Ile Thr Leu

290 295 300

Val Arg Val Pro Gly Ser Trp Glu Ile Pro Val Ala Ala Gly Glu Leu

305 310 315 320

Ala Arg Lys Glu Asp Ile Asp Ala Val Ile Ala Ile Gly Val Leu Ile

325 330 335

Arg Gly Ala Thr Pro His Phe Asp Tyr Ile Ala Ser Glu Val Ser Lys

340 345 350

Gly Leu Ala Asn Leu Ser Leu Glu Leu Arg Lys Pro Ile Thr Phe Gly

355 360 365

Val Ile Thr Ala Asp Thr Leu Glu Gln Ala Ile Glu Arg Ala Gly Thr

370 375 380

Lys His Gly Asn Lys Gly Trp Glu Ala Ala Leu Ser Ala Ile Glu Met

385 390 395 400

Ala Asn Leu Phe Lys Ser Leu Arg

405

<210> 16

<211> 408

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 16

Met Asp Glu Lys Asn Ser Ala Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Lys

20 25 30

Ala Thr Val Asp Lys Ile Glu Leu Lys Gly Thr Ser Asp Lys Asp Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Thr Lys Asp Asp Lys Ser Lys Ala Lys

50 55 60

Leu Thr Ile Ala Asp Asp Leu Ser Lys Thr Thr Phe Glu Leu Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Arg Lys Val Ser Ser Lys Asp Lys

85 90 95

Thr Ser Thr Asp Glu Met Phe Asn Glu Lys Gly Glu Leu Ser Ala Lys

100 105 110

Thr Met Thr Arg Glu Asn Gly Thr Lys Leu Glu Tyr Thr Glu Met Lys

115 120 125

Ser Asp Gly Thr Gly Lys Ala Lys Glu Val Leu Lys Asn Phe Thr Leu

130 135 140

Glu Gly Lys Val Ala Asn Asp Lys Val Thr Leu Glu Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Glu Ile Ala Lys Ser Gly Glu Val Thr Val

165 170 175

Ala Leu Asn Asp Thr Asn Thr Thr Gln Ala Thr Lys Lys Thr Gly Ala

180 185 190

Trp Asp Ser Lys Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Lys Lys

195 200 205

Thr Thr Gln Leu Val Phe Thr Lys Gln Asp Thr Ile Thr Val Gln Lys

210 215 220

Tyr Asp Ser Ala Gly Thr Asn Leu Glu Gly Thr Ala Val Glu Ile Lys

225 230 235 240

Thr Leu Asp Glu Leu Lys Asn Ala Leu Lys Gly Gly Gly Ser Met Gln

245 250 255

Ile Tyr Glu Gly Lys Leu Thr Ala Glu Gly Leu Arg Phe Gly Ile Val

260 265 270

Ala Ser Arg Phe Asn His Ala Leu Val Asp Arg Leu Val Glu Gly Ala

275 280 285

Ile Asp Cys Ile Val Arg His Gly Gly Arg Glu Glu Asp Ile Thr Leu

290 295 300

Val Arg Val Pro Gly Ser Trp Glu Ile Pro Val Ala Ala Gly Glu Leu

305 310 315 320

Ala Arg Lys Glu Asp Ile Asp Ala Val Ile Ala Ile Gly Val Leu Ile

325 330 335

Arg Gly Ala Thr Pro His Phe Asp Tyr Ile Ala Ser Glu Val Ser Lys

340 345 350

Gly Leu Ala Asn Leu Ser Leu Glu Leu Arg Lys Pro Ile Thr Phe Gly

355 360 365

Val Ile Thr Ala Asp Thr Leu Glu Gln Ala Ile Glu Arg Ala Gly Thr

370 375 380

Lys His Gly Asn Lys Gly Trp Glu Ala Ala Leu Ser Ala Ile Glu Met

385 390 395 400

Ala Asn Leu Phe Lys Ser Leu Arg

405

<210> 17

<211> 409

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 17

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Gly Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Met

20 25 30

Ala Thr Val Glu Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Ser Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Glu Lys Ala Asp Lys Ser Lys Ala Lys

50 55 60

Leu Thr Ile Ser Gln Asp Leu Asn Gln Thr Thr Phe Glu Ile Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Arg Lys Val Asn Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Asp Lys Gly Lys Leu Ser Glu Lys

100 105 110

Val Val Thr Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Glu Ile Lys

115 120 125

Asn Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Phe Ala Leu

130 135 140

Glu Gly Thr Leu Thr Asp Gly Gly Glu Thr Lys Leu Thr Val Thr Glu

145 150 155 160

Gly Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Ile Thr

165 170 175

Val Ala Leu Asn Asp Thr Glu Thr Thr Pro Ala Asp Lys Lys Thr Gly

180 185 190

Glu Trp Lys Ser Asp Thr Ser Thr Leu Thr Ile Ser Lys Asn Ser Gln

195 200 205

Lys Pro Lys Gln Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln

210 215 220

Asn Tyr Asn Arg Ala Gly Asn Ala Leu Glu Gly Ser Pro Ala Glu Ile

225 230 235 240

Lys Asp Leu Ala Glu Leu Lys Ala Ala Leu Lys Gly Gly Gly Ser Met

245 250 255

Gln Ile Tyr Glu Gly Lys Leu Thr Ala Glu Gly Leu Arg Phe Gly Ile

260 265 270

Val Ala Ser Arg Phe Asn His Ala Leu Val Asp Arg Leu Val Glu Gly

275 280 285

Ala Ile Asp Cys Ile Val Arg His Gly Gly Arg Glu Glu Asp Ile Thr

290 295 300

Leu Val Arg Val Pro Gly Ser Trp Glu Ile Pro Val Ala Ala Gly Glu

305 310 315 320

Leu Ala Arg Lys Glu Asp Ile Asp Ala Val Ile Ala Ile Gly Val Leu

325 330 335

Ile Arg Gly Ala Thr Pro His Phe Asp Tyr Ile Ala Ser Glu Val Ser

340 345 350

Lys Gly Leu Ala Asn Leu Ser Leu Glu Leu Arg Lys Pro Ile Thr Phe

355 360 365

Gly Val Ile Thr Ala Asp Thr Leu Glu Gln Ala Ile Glu Arg Ala Gly

370 375 380

Thr Lys His Gly Asn Lys Gly Trp Glu Ala Ala Leu Ser Ala Ile Glu

385 390 395 400

Met Ala Asn Leu Phe Lys Ser Leu Arg

405

<210> 18

<211> 408

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 18

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Met

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Ser Asn

35 40 45

Gly Ser Gly Thr Leu Glu Gly Glu Lys Ser Asp Lys Ser Lys Ala Lys

50 55 60

Leu Thr Ile Ser Glu Asp Leu Ser Lys Thr Thr Phe Glu Ile Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Asn Ser Lys Asp Lys

85 90 95

Ser Ser Ile Glu Glu Lys Phe Asn Ala Lys Gly Glu Leu Ser Glu Lys

100 105 110

Thr Ile Leu Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Glu Ile Lys

115 120 125

Ser Asp Gly Thr Gly Lys Ala Lys Glu Val Leu Lys Asp Phe Ala Leu

130 135 140

Glu Gly Thr Leu Ala Ala Asp Lys Thr Thr Leu Lys Val Thr Glu Gly

145 150 155 160

Thr Val Val Leu Ser Lys His Ile Pro Asn Ser Gly Glu Ile Thr Val

165 170 175

Glu Leu Asn Asp Ser Asn Ser Thr Gln Ala Thr Lys Lys Thr Gly Lys

180 185 190

Trp Asp Ser Asn Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Lys Lys

195 200 205

Thr Lys Asn Ile Val Phe Thr Lys Glu Asp Thr Ile Thr Val Gln Lys

210 215 220

Tyr Asp Ser Ala Gly Thr Asn Leu Glu Gly Asn Ala Val Glu Ile Lys

225 230 235 240

Thr Leu Asp Glu Leu Lys Asn Ala Leu Lys Gly Gly Gly Ser Met Gln

245 250 255

Ile Tyr Glu Gly Lys Leu Thr Ala Glu Gly Leu Arg Phe Gly Ile Val

260 265 270

Ala Ser Arg Phe Asn His Ala Leu Val Asp Arg Leu Val Glu Gly Ala

275 280 285

Ile Asp Cys Ile Val Arg His Gly Gly Arg Glu Glu Asp Ile Thr Leu

290 295 300

Val Arg Val Pro Gly Ser Trp Glu Ile Pro Val Ala Ala Gly Glu Leu

305 310 315 320

Ala Arg Lys Glu Asp Ile Asp Ala Val Ile Ala Ile Gly Val Leu Ile

325 330 335

Arg Gly Ala Thr Pro His Phe Asp Tyr Ile Ala Ser Glu Val Ser Lys

340 345 350

Gly Leu Ala Asn Leu Ser Leu Glu Leu Arg Lys Pro Ile Thr Phe Gly

355 360 365

Val Ile Thr Ala Asp Thr Leu Glu Gln Ala Ile Glu Arg Ala Gly Thr

370 375 380

Lys His Gly Asn Lys Gly Trp Glu Ala Ala Leu Ser Ala Ile Glu Met

385 390 395 400

Ala Asn Leu Phe Lys Ser Leu Arg

405

<210> 19

<211> 409

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 19

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Gly Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Met

20 25 30

Ala Thr Val Glu Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Thr Leu Glu Gly Glu Lys Thr Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ala Glu Asp Leu Ser Lys Thr Thr Phe Glu Ile Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Leu Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Ile Ser Glu Lys

100 105 110

Thr Ile Val Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Asp Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Asp Phe Thr Leu

130 135 140

Glu Gly Thr Leu Ala Ala Asp Gly Lys Thr Thr Leu Lys Val Thr Glu

145 150 155 160

Gly Thr Val Val Leu Ser Lys Asn Ile Leu Lys Ser Gly Glu Ile Thr

165 170 175

Val Ala Leu Asp Asp Ser Asp Thr Thr Gln Ala Thr Lys Lys Thr Gly

180 185 190

Lys Trp Asp Ser Lys Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Gln

195 200 205

Lys Thr Lys Asn Leu Val Phe Thr Lys Glu Asp Thr Ile Thr Val Gln

210 215 220

Lys Tyr Asp Ser Ala Gly Thr Asn Leu Glu Gly Lys Ala Val Glu Ile

225 230 235 240

Thr Thr Leu Glu Lys Leu Lys Asp Ala Leu Lys Gly Gly Gly Ser Met

245 250 255

Gln Ile Tyr Glu Gly Lys Leu Thr Ala Glu Gly Leu Arg Phe Gly Ile

260 265 270

Val Ala Ser Arg Phe Asn His Ala Leu Val Asp Arg Leu Val Glu Gly

275 280 285

Ala Ile Asp Cys Ile Val Arg His Gly Gly Arg Glu Glu Asp Ile Thr

290 295 300

Leu Val Arg Val Pro Gly Ser Trp Glu Ile Pro Val Ala Ala Gly Glu

305 310 315 320

Leu Ala Arg Lys Glu Asp Ile Asp Ala Val Ile Ala Ile Gly Val Leu

325 330 335

Ile Arg Gly Ala Thr Pro His Phe Asp Tyr Ile Ala Ser Glu Val Ser

340 345 350

Lys Gly Leu Ala Asn Leu Ser Leu Glu Leu Arg Lys Pro Ile Thr Phe

355 360 365

Gly Val Ile Thr Ala Asp Thr Leu Glu Gln Ala Ile Glu Arg Ala Gly

370 375 380

Thr Lys His Gly Asn Lys Gly Trp Glu Ala Ala Leu Ser Ala Ile Glu

385 390 395 400

Met Ala Asn Leu Phe Lys Ser Leu Arg

405

<210> 20

<211> 409

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 20

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Gly Met Thr

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Glu

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Thr Leu Glu Gly Glu Lys Thr Asp Lys Ser Lys Val Lys

50 55 60

Ser Thr Ile Ala Asp Asp Leu Ser Gln Thr Lys Phe Glu Ile Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Leu Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Gly Lys Gly Glu Thr Ser Glu Lys

100 105 110

Thr Ile Val Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Asp Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Asp Phe Thr Leu

130 135 140

Glu Gly Thr Leu Ala Ala Asp Gly Lys Thr Thr Leu Lys Val Thr Glu

145 150 155 160

Gly Thr Val Val Leu Ser Lys Asn Ile Leu Lys Ser Gly Glu Ile Thr

165 170 175

Ala Ala Leu Asp Asp Ser Asp Thr Thr Arg Ala Thr Lys Lys Thr Gly

180 185 190

Lys Trp Asp Ser Lys Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Gln

195 200 205

Lys Thr Lys Asn Leu Val Phe Thr Lys Glu Asp Thr Ile Thr Val Gln

210 215 220

Arg Tyr Asp Ser Ala Gly Thr Asn Leu Glu Gly Lys Ala Val Glu Ile

225 230 235 240

Thr Thr Leu Lys Glu Leu Lys Asn Ala Leu Lys Gly Gly Gly Ser Met

245 250 255

Gln Ile Tyr Glu Gly Lys Leu Thr Ala Glu Gly Leu Arg Phe Gly Ile

260 265 270

Val Ala Ser Arg Phe Asn His Ala Leu Val Asp Arg Leu Val Glu Gly

275 280 285

Ala Ile Asp Cys Ile Val Arg His Gly Gly Arg Glu Glu Asp Ile Thr

290 295 300

Leu Val Arg Val Pro Gly Ser Trp Glu Ile Pro Val Ala Ala Gly Glu

305 310 315 320

Leu Ala Arg Lys Glu Asp Ile Asp Ala Val Ile Ala Ile Gly Val Leu

325 330 335

Ile Arg Gly Ala Thr Pro His Phe Asp Tyr Ile Ala Ser Glu Val Ser

340 345 350

Lys Gly Leu Ala Asn Leu Ser Leu Glu Leu Arg Lys Pro Ile Thr Phe

355 360 365

Gly Val Ile Thr Ala Asp Thr Leu Glu Gln Ala Ile Glu Arg Ala Gly

370 375 380

Thr Lys His Gly Asn Lys Gly Trp Glu Ala Ala Leu Ser Ala Ile Glu

385 390 395 400

Met Ala Asn Leu Phe Lys Ser Leu Arg

405

<210> 21

<211> 409

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 21

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Glu

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Ala Lys Ser Lys Ala Lys

50 55 60

Leu Thr Ile Ala Asp Asp Leu Ser Gln Thr Lys Phe Glu Ile Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Leu Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Asp Lys Gly Lys Leu Ser Glu Lys

100 105 110

Val Val Thr Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Glu Ile Gln

115 120 125

Asn Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Ser Leu Thr Leu

130 135 140

Glu Gly Thr Leu Thr Ala Asp Gly Glu Thr Lys Leu Thr Val Glu Ala

145 150 155 160

Gly Thr Val Thr Leu Ser Lys Asn Ile Ser Glu Ser Gly Glu Ile Thr

165 170 175

Val Glu Leu Lys Asp Thr Glu Thr Thr Pro Ala Asp Lys Lys Ser Gly

180 185 190

Thr Trp Asp Ser Lys Thr Ser Thr Leu Thr Ile Ser Lys Asn Ser Gln

195 200 205

Lys Thr Lys Gln Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln

210 215 220

Lys Tyr Asn Thr Ala Gly Thr Lys Leu Glu Gly Ser Pro Ala Glu Ile

225 230 235 240

Lys Asp Leu Glu Ala Leu Lys Ala Ala Leu Lys Gly Gly Gly Ser Met

245 250 255

Gln Ile Tyr Glu Gly Lys Leu Thr Ala Glu Gly Leu Arg Phe Gly Ile

260 265 270

Val Ala Ser Arg Phe Asn His Ala Leu Val Asp Arg Leu Val Glu Gly

275 280 285

Ala Ile Asp Cys Ile Val Arg His Gly Gly Arg Glu Glu Asp Ile Thr

290 295 300

Leu Val Arg Val Pro Gly Ser Trp Glu Ile Pro Val Ala Ala Gly Glu

305 310 315 320

Leu Ala Arg Lys Glu Asp Ile Asp Ala Val Ile Ala Ile Gly Val Leu

325 330 335

Ile Arg Gly Ala Thr Pro His Phe Asp Tyr Ile Ala Ser Glu Val Ser

340 345 350

Lys Gly Leu Ala Asn Leu Ser Leu Glu Leu Arg Lys Pro Ile Thr Phe

355 360 365

Gly Val Ile Thr Ala Asp Thr Leu Glu Gln Ala Ile Glu Arg Ala Gly

370 375 380

Thr Lys His Gly Asn Lys Gly Trp Glu Ala Ala Leu Ser Ala Ile Glu

385 390 395 400

Met Ala Asn Leu Phe Lys Ser Leu Arg

405

<210> 22

<211> 435

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 22

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

100 105 110

Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Tyr Thr Leu

130 135 140

Glu Gly Gln Leu Ser Asp Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val

165 170 175

Glu Leu Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

180 185 190

Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys Gly Ser Met Thr Thr Ala

245 250 255

Ser Thr Ser Gln Val Arg Gln Asn Tyr His Gln Asp Ser Glu Ala Ala

260 265 270

Ile Asn Arg Gln Ile Asn Leu Glu Leu Tyr Ala Ser Tyr Val Tyr Leu

275 280 285

Ser Met Ser Tyr Tyr Phe Asp Arg Asp Asp Val Ala Leu Lys Asn Phe

290 295 300

Ala Lys Tyr Phe Leu His Gln Ser His Glu Glu Arg Glu His Ala Glu

305 310 315 320

Lys Leu Met Lys Leu Gln Asn Gln Arg Gly Gly Arg Ile Phe Leu Gln

325 330 335

Asp Ile Lys Lys Pro Asp Cys Asp Asp Trp Glu Ser Gly Leu Asn Ala

340 345 350

Met Glu Cys Ala Leu His Leu Glu Lys Asn Val Asn Gln Ser Leu Leu

355 360 365

Glu Leu His Lys Leu Ala Thr Asp Lys Asn Asp Pro His Leu Cys Asp

370 375 380

Phe Ile Glu Thr His Tyr Leu Asn Glu Gln Val Lys Ala Ile Lys Glu

385 390 395 400

Leu Gly Asp His Val Thr Asn Leu Arg Lys Met Gly Ala Pro Glu Ser

405 410 415

Gly Leu Ala Glu Tyr Leu Phe Asp Lys His Thr Leu Gly Asp Ser Asp

420 425 430

Asn Glu Ser

435

<210> 23

<211> 435

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 23

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

100 105 110

Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Tyr Asp Leu

130 135 140

Lys Gly Glu Leu Ser Ser Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val

165 170 175

Glu Leu Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

180 185 190

Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys Gly Ser Met Thr Thr Ala

245 250 255

Ser Thr Ser Gln Val Arg Gln Asn Tyr His Gln Asp Ser Glu Ala Ala

260 265 270

Ile Asn Arg Gln Ile Asn Leu Glu Leu Tyr Ala Ser Tyr Val Tyr Leu

275 280 285

Ser Met Ser Tyr Tyr Phe Asp Arg Asp Asp Val Ala Leu Lys Asn Phe

290 295 300

Ala Lys Tyr Phe Leu His Gln Ser His Glu Glu Arg Glu His Ala Glu

305 310 315 320

Lys Leu Met Lys Leu Gln Asn Gln Arg Gly Gly Arg Ile Phe Leu Gln

325 330 335

Asp Ile Lys Lys Pro Asp Cys Asp Asp Trp Glu Ser Gly Leu Asn Ala

340 345 350

Met Glu Cys Ala Leu His Leu Glu Lys Asn Val Asn Gln Ser Leu Leu

355 360 365

Glu Leu His Lys Leu Ala Thr Asp Lys Asn Asp Pro His Leu Cys Asp

370 375 380

Phe Ile Glu Thr His Tyr Leu Asn Glu Gln Val Lys Ala Ile Lys Glu

385 390 395 400

Leu Gly Asp His Val Thr Asn Leu Arg Lys Met Gly Ala Pro Glu Ser

405 410 415

Gly Leu Ala Glu Tyr Leu Phe Asp Lys His Thr Leu Gly Asp Ser Asp

420 425 430

Asn Glu Ser

435

<210> 24

<211> 435

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 24

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

100 105 110

Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Phe Thr Leu

130 135 140

Glu Gly Lys Val Ala Asn Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val

165 170 175

Glu Leu Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

180 185 190

Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys Gly Ser Met Thr Thr Ala

245 250 255

Ser Thr Ser Gln Val Arg Gln Asn Tyr His Gln Asp Ser Glu Ala Ala

260 265 270

Ile Asn Arg Gln Ile Asn Leu Glu Leu Tyr Ala Ser Tyr Val Tyr Leu

275 280 285

Ser Met Ser Tyr Tyr Phe Asp Arg Asp Asp Val Ala Leu Lys Asn Phe

290 295 300

Ala Lys Tyr Phe Leu His Gln Ser His Glu Glu Arg Glu His Ala Glu

305 310 315 320

Lys Leu Met Lys Leu Gln Asn Gln Arg Gly Gly Arg Ile Phe Leu Gln

325 330 335

Asp Ile Lys Lys Pro Asp Cys Asp Asp Trp Glu Ser Gly Leu Asn Ala

340 345 350

Met Glu Cys Ala Leu His Leu Glu Lys Asn Val Asn Gln Ser Leu Leu

355 360 365

Glu Leu His Lys Leu Ala Thr Asp Lys Asn Asp Pro His Leu Cys Asp

370 375 380

Phe Ile Glu Thr His Tyr Leu Asn Glu Gln Val Lys Ala Ile Lys Glu

385 390 395 400

Leu Gly Asp His Val Thr Asn Leu Arg Lys Met Gly Ala Pro Glu Ser

405 410 415

Gly Leu Ala Glu Tyr Leu Phe Asp Lys His Thr Leu Gly Asp Ser Asp

420 425 430

Asn Glu Ser

435

<210> 25

<211> 435

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 25

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

100 105 110

Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Phe Ala Leu

130 135 140

Glu Gly Thr Leu Thr Asp Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val

165 170 175

Glu Leu Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

180 185 190

Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys Gly Ser Met Thr Thr Ala

245 250 255

Ser Thr Ser Gln Val Arg Gln Asn Tyr His Gln Asp Ser Glu Ala Ala

260 265 270

Ile Asn Arg Gln Ile Asn Leu Glu Leu Tyr Ala Ser Tyr Val Tyr Leu

275 280 285

Ser Met Ser Tyr Tyr Phe Asp Arg Asp Asp Val Ala Leu Lys Asn Phe

290 295 300

Ala Lys Tyr Phe Leu His Gln Ser His Glu Glu Arg Glu His Ala Glu

305 310 315 320

Lys Leu Met Lys Leu Gln Asn Gln Arg Gly Gly Arg Ile Phe Leu Gln

325 330 335

Asp Ile Lys Lys Pro Asp Cys Asp Asp Trp Glu Ser Gly Leu Asn Ala

340 345 350

Met Glu Cys Ala Leu His Leu Glu Lys Asn Val Asn Gln Ser Leu Leu

355 360 365

Glu Leu His Lys Leu Ala Thr Asp Lys Asn Asp Pro His Leu Cys Asp

370 375 380

Phe Ile Glu Thr His Tyr Leu Asn Glu Gln Val Lys Ala Ile Lys Glu

385 390 395 400

Leu Gly Asp His Val Thr Asn Leu Arg Lys Met Gly Ala Pro Glu Ser

405 410 415

Gly Leu Ala Glu Tyr Leu Phe Asp Lys His Thr Leu Gly Asp Ser Asp

420 425 430

Asn Glu Ser

435

<210> 26

<211> 435

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 26

Met Asp Glu Lys Asn Ser Ala Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Lys

20 25 30

Ala Thr Val Asp Lys Ile Glu Leu Lys Gly Thr Ser Asp Lys Asp Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Thr Lys Asp Asp Lys Ser Lys Ala Lys

50 55 60

Leu Thr Ile Ala Asp Asp Leu Ser Lys Thr Thr Phe Glu Leu Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Arg Lys Val Ser Ser Lys Asp Lys

85 90 95

Thr Ser Thr Asp Glu Met Phe Asn Glu Lys Gly Glu Leu Ser Ala Lys

100 105 110

Thr Met Thr Arg Glu Asn Gly Thr Lys Leu Glu Tyr Thr Glu Met Lys

115 120 125

Ser Asp Gly Thr Gly Lys Ala Lys Glu Val Leu Lys Asn Phe Thr Leu

130 135 140

Glu Gly Lys Val Ala Asn Asp Lys Val Thr Leu Glu Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Glu Ile Ala Lys Ser Gly Glu Val Thr Val

165 170 175

Ala Leu Asn Asp Thr Asn Thr Thr Gln Ala Thr Lys Lys Thr Gly Ala

180 185 190

Trp Asp Ser Lys Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Lys Lys

195 200 205

Thr Thr Gln Leu Val Phe Thr Lys Gln Asp Thr Ile Thr Val Gln Lys

210 215 220

Tyr Asp Ser Ala Gly Thr Asn Leu Glu Gly Thr Ala Val Glu Ile Lys

225 230 235 240

Thr Leu Asp Glu Leu Lys Asn Ala Leu Lys Gly Ser Met Thr Thr Ala

245 250 255

Ser Thr Ser Gln Val Arg Gln Asn Tyr His Gln Asp Ser Glu Ala Ala

260 265 270

Ile Asn Arg Gln Ile Asn Leu Glu Leu Tyr Ala Ser Tyr Val Tyr Leu

275 280 285

Ser Met Ser Tyr Tyr Phe Asp Arg Asp Asp Val Ala Leu Lys Asn Phe

290 295 300

Ala Lys Tyr Phe Leu His Gln Ser His Glu Glu Arg Glu His Ala Glu

305 310 315 320

Lys Leu Met Lys Leu Gln Asn Gln Arg Gly Gly Arg Ile Phe Leu Gln

325 330 335

Asp Ile Lys Lys Pro Asp Cys Asp Asp Trp Glu Ser Gly Leu Asn Ala

340 345 350

Met Glu Cys Ala Leu His Leu Glu Lys Asn Val Asn Gln Ser Leu Leu

355 360 365

Glu Leu His Lys Leu Ala Thr Asp Lys Asn Asp Pro His Leu Cys Asp

370 375 380

Phe Ile Glu Thr His Tyr Leu Asn Glu Gln Val Lys Ala Ile Lys Glu

385 390 395 400

Leu Gly Asp His Val Thr Asn Leu Arg Lys Met Gly Ala Pro Glu Ser

405 410 415

Gly Leu Ala Glu Tyr Leu Phe Asp Lys His Thr Leu Gly Asp Ser Asp

420 425 430

Asn Glu Ser

435

<210> 27

<211> 436

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 27

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Gly Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Met

20 25 30

Ala Thr Val Glu Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Ser Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Glu Lys Ala Asp Lys Ser Lys Ala Lys

50 55 60

Leu Thr Ile Ser Gln Asp Leu Asn Gln Thr Thr Phe Glu Ile Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Arg Lys Val Asn Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Asp Lys Gly Lys Leu Ser Glu Lys

100 105 110

Val Val Thr Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Glu Ile Lys

115 120 125

Asn Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Phe Ala Leu

130 135 140

Glu Gly Thr Leu Thr Asp Gly Gly Glu Thr Lys Leu Thr Val Thr Glu

145 150 155 160

Gly Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Ile Thr

165 170 175

Val Ala Leu Asn Asp Thr Glu Thr Thr Pro Ala Asp Lys Lys Thr Gly

180 185 190

Glu Trp Lys Ser Asp Thr Ser Thr Leu Thr Ile Ser Lys Asn Ser Gln

195 200 205

Lys Pro Lys Gln Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln

210 215 220

Asn Tyr Asn Arg Ala Gly Asn Ala Leu Glu Gly Ser Pro Ala Glu Ile

225 230 235 240

Lys Asp Leu Ala Glu Leu Lys Ala Ala Leu Lys Gly Ser Met Thr Thr

245 250 255

Ala Ser Thr Ser Gln Val Arg Gln Asn Tyr His Gln Asp Ser Glu Ala

260 265 270

Ala Ile Asn Arg Gln Ile Asn Leu Glu Leu Tyr Ala Ser Tyr Val Tyr

275 280 285

Leu Ser Met Ser Tyr Tyr Phe Asp Arg Asp Asp Val Ala Leu Lys Asn

290 295 300

Phe Ala Lys Tyr Phe Leu His Gln Ser His Glu Glu Arg Glu His Ala

305 310 315 320

Glu Lys Leu Met Lys Leu Gln Asn Gln Arg Gly Gly Arg Ile Phe Leu

325 330 335

Gln Asp Ile Lys Lys Pro Asp Cys Asp Asp Trp Glu Ser Gly Leu Asn

340 345 350

Ala Met Glu Cys Ala Leu His Leu Glu Lys Asn Val Asn Gln Ser Leu

355 360 365

Leu Glu Leu His Lys Leu Ala Thr Asp Lys Asn Asp Pro His Leu Cys

370 375 380

Asp Phe Ile Glu Thr His Tyr Leu Asn Glu Gln Val Lys Ala Ile Lys

385 390 395 400

Glu Leu Gly Asp His Val Thr Asn Leu Arg Lys Met Gly Ala Pro Glu

405 410 415

Ser Gly Leu Ala Glu Tyr Leu Phe Asp Lys His Thr Leu Gly Asp Ser

420 425 430

Asp Asn Glu Ser

435

<210> 28

<211> 435

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 28

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Met

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Ser Asn

35 40 45

Gly Ser Gly Thr Leu Glu Gly Glu Lys Ser Asp Lys Ser Lys Ala Lys

50 55 60

Leu Thr Ile Ser Glu Asp Leu Ser Lys Thr Thr Phe Glu Ile Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Asn Ser Lys Asp Lys

85 90 95

Ser Ser Ile Glu Glu Lys Phe Asn Ala Lys Gly Glu Leu Ser Glu Lys

100 105 110

Thr Ile Leu Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Glu Ile Lys

115 120 125

Ser Asp Gly Thr Gly Lys Ala Lys Glu Val Leu Lys Asp Phe Ala Leu

130 135 140

Glu Gly Thr Leu Ala Ala Asp Lys Thr Thr Leu Lys Val Thr Glu Gly

145 150 155 160

Thr Val Val Leu Ser Lys His Ile Pro Asn Ser Gly Glu Ile Thr Val

165 170 175

Glu Leu Asn Asp Ser Asn Ser Thr Gln Ala Thr Lys Lys Thr Gly Lys

180 185 190

Trp Asp Ser Asn Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Lys Lys

195 200 205

Thr Lys Asn Ile Val Phe Thr Lys Glu Asp Thr Ile Thr Val Gln Lys

210 215 220

Tyr Asp Ser Ala Gly Thr Asn Leu Glu Gly Asn Ala Val Glu Ile Lys

225 230 235 240

Thr Leu Asp Glu Leu Lys Asn Ala Leu Lys Gly Ser Met Thr Thr Ala

245 250 255

Ser Thr Ser Gln Val Arg Gln Asn Tyr His Gln Asp Ser Glu Ala Ala

260 265 270

Ile Asn Arg Gln Ile Asn Leu Glu Leu Tyr Ala Ser Tyr Val Tyr Leu

275 280 285

Ser Met Ser Tyr Tyr Phe Asp Arg Asp Asp Val Ala Leu Lys Asn Phe

290 295 300

Ala Lys Tyr Phe Leu His Gln Ser His Glu Glu Arg Glu His Ala Glu

305 310 315 320

Lys Leu Met Lys Leu Gln Asn Gln Arg Gly Gly Arg Ile Phe Leu Gln

325 330 335

Asp Ile Lys Lys Pro Asp Cys Asp Asp Trp Glu Ser Gly Leu Asn Ala

340 345 350

Met Glu Cys Ala Leu His Leu Glu Lys Asn Val Asn Gln Ser Leu Leu

355 360 365

Glu Leu His Lys Leu Ala Thr Asp Lys Asn Asp Pro His Leu Cys Asp

370 375 380

Phe Ile Glu Thr His Tyr Leu Asn Glu Gln Val Lys Ala Ile Lys Glu

385 390 395 400

Leu Gly Asp His Val Thr Asn Leu Arg Lys Met Gly Ala Pro Glu Ser

405 410 415

Gly Leu Ala Glu Tyr Leu Phe Asp Lys His Thr Leu Gly Asp Ser Asp

420 425 430

Asn Glu Ser

435

<210> 29

<211> 436

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 29

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Gly Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Met

20 25 30

Ala Thr Val Glu Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Thr Leu Glu Gly Glu Lys Thr Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ala Glu Asp Leu Ser Lys Thr Thr Phe Glu Ile Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Leu Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Ile Ser Glu Lys

100 105 110

Thr Ile Val Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Asp Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Asp Phe Thr Leu

130 135 140

Glu Gly Thr Leu Ala Ala Asp Gly Lys Thr Thr Leu Lys Val Thr Glu

145 150 155 160

Gly Thr Val Val Leu Ser Lys Asn Ile Leu Lys Ser Gly Glu Ile Thr

165 170 175

Val Ala Leu Asp Asp Ser Asp Thr Thr Gln Ala Thr Lys Lys Thr Gly

180 185 190

Lys Trp Asp Ser Lys Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Gln

195 200 205

Lys Thr Lys Asn Leu Val Phe Thr Lys Glu Asp Thr Ile Thr Val Gln

210 215 220

Lys Tyr Asp Ser Ala Gly Thr Asn Leu Glu Gly Lys Ala Val Glu Ile

225 230 235 240

Thr Thr Leu Glu Lys Leu Lys Asp Ala Leu Lys Gly Ser Met Thr Thr

245 250 255

Ala Ser Thr Ser Gln Val Arg Gln Asn Tyr His Gln Asp Ser Glu Ala

260 265 270

Ala Ile Asn Arg Gln Ile Asn Leu Glu Leu Tyr Ala Ser Tyr Val Tyr

275 280 285

Leu Ser Met Ser Tyr Tyr Phe Asp Arg Asp Asp Val Ala Leu Lys Asn

290 295 300

Phe Ala Lys Tyr Phe Leu His Gln Ser His Glu Glu Arg Glu His Ala

305 310 315 320

Glu Lys Leu Met Lys Leu Gln Asn Gln Arg Gly Gly Arg Ile Phe Leu

325 330 335

Gln Asp Ile Lys Lys Pro Asp Cys Asp Asp Trp Glu Ser Gly Leu Asn

340 345 350

Ala Met Glu Cys Ala Leu His Leu Glu Lys Asn Val Asn Gln Ser Leu

355 360 365

Leu Glu Leu His Lys Leu Ala Thr Asp Lys Asn Asp Pro His Leu Cys

370 375 380

Asp Phe Ile Glu Thr His Tyr Leu Asn Glu Gln Val Lys Ala Ile Lys

385 390 395 400

Glu Leu Gly Asp His Val Thr Asn Leu Arg Lys Met Gly Ala Pro Glu

405 410 415

Ser Gly Leu Ala Glu Tyr Leu Phe Asp Lys His Thr Leu Gly Asp Ser

420 425 430

Asp Asn Glu Ser

435

<210> 30

<211> 436

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 30

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Gly Met Thr

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Glu

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Thr Leu Glu Gly Glu Lys Thr Asp Lys Ser Lys Val Lys

50 55 60

Ser Thr Ile Ala Asp Asp Leu Ser Gln Thr Lys Phe Glu Ile Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Leu Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Gly Lys Gly Glu Thr Ser Glu Lys

100 105 110

Thr Ile Val Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Asp Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Asp Phe Thr Leu

130 135 140

Glu Gly Thr Leu Ala Ala Asp Gly Lys Thr Thr Leu Lys Val Thr Glu

145 150 155 160

Gly Thr Val Val Leu Ser Lys Asn Ile Leu Lys Ser Gly Glu Ile Thr

165 170 175

Ala Ala Leu Asp Asp Ser Asp Thr Thr Arg Ala Thr Lys Lys Thr Gly

180 185 190

Lys Trp Asp Ser Lys Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Gln

195 200 205

Lys Thr Lys Asn Leu Val Phe Thr Lys Glu Asp Thr Ile Thr Val Gln

210 215 220

Arg Tyr Asp Ser Ala Gly Thr Asn Leu Glu Gly Lys Ala Val Glu Ile

225 230 235 240

Thr Thr Leu Lys Glu Leu Lys Asn Ala Leu Lys Gly Ser Met Thr Thr

245 250 255

Ala Ser Thr Ser Gln Val Arg Gln Asn Tyr His Gln Asp Ser Glu Ala

260 265 270

Ala Ile Asn Arg Gln Ile Asn Leu Glu Leu Tyr Ala Ser Tyr Val Tyr

275 280 285

Leu Ser Met Ser Tyr Tyr Phe Asp Arg Asp Asp Val Ala Leu Lys Asn

290 295 300

Phe Ala Lys Tyr Phe Leu His Gln Ser His Glu Glu Arg Glu His Ala

305 310 315 320

Glu Lys Leu Met Lys Leu Gln Asn Gln Arg Gly Gly Arg Ile Phe Leu

325 330 335

Gln Asp Ile Lys Lys Pro Asp Cys Asp Asp Trp Glu Ser Gly Leu Asn

340 345 350

Ala Met Glu Cys Ala Leu His Leu Glu Lys Asn Val Asn Gln Ser Leu

355 360 365

Leu Glu Leu His Lys Leu Ala Thr Asp Lys Asn Asp Pro His Leu Cys

370 375 380

Asp Phe Ile Glu Thr His Tyr Leu Asn Glu Gln Val Lys Ala Ile Lys

385 390 395 400

Glu Leu Gly Asp His Val Thr Asn Leu Arg Lys Met Gly Ala Pro Glu

405 410 415

Ser Gly Leu Ala Glu Tyr Leu Phe Asp Lys His Thr Leu Gly Asp Ser

420 425 430

Asp Asn Glu Ser

435

<210> 31

<211> 436

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 31

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Glu

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Ala Lys Ser Lys Ala Lys

50 55 60

Leu Thr Ile Ala Asp Asp Leu Ser Gln Thr Lys Phe Glu Ile Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Leu Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Asp Lys Gly Lys Leu Ser Glu Lys

100 105 110

Val Val Thr Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Glu Ile Gln

115 120 125

Asn Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Ser Leu Thr Leu

130 135 140

Glu Gly Thr Leu Thr Ala Asp Gly Glu Thr Lys Leu Thr Val Glu Ala

145 150 155 160

Gly Thr Val Thr Leu Ser Lys Asn Ile Ser Glu Ser Gly Glu Ile Thr

165 170 175

Val Glu Leu Lys Asp Thr Glu Thr Thr Pro Ala Asp Lys Lys Ser Gly

180 185 190

Thr Trp Asp Ser Lys Thr Ser Thr Leu Thr Ile Ser Lys Asn Ser Gln

195 200 205

Lys Thr Lys Gln Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln

210 215 220

Lys Tyr Asn Thr Ala Gly Thr Lys Leu Glu Gly Ser Pro Ala Glu Ile

225 230 235 240

Lys Asp Leu Glu Ala Leu Lys Ala Ala Leu Lys Gly Ser Met Thr Thr

245 250 255

Ala Ser Thr Ser Gln Val Arg Gln Asn Tyr His Gln Asp Ser Glu Ala

260 265 270

Ala Ile Asn Arg Gln Ile Asn Leu Glu Leu Tyr Ala Ser Tyr Val Tyr

275 280 285

Leu Ser Met Ser Tyr Tyr Phe Asp Arg Asp Asp Val Ala Leu Lys Asn

290 295 300

Phe Ala Lys Tyr Phe Leu His Gln Ser His Glu Glu Arg Glu His Ala

305 310 315 320

Glu Lys Leu Met Lys Leu Gln Asn Gln Arg Gly Gly Arg Ile Phe Leu

325 330 335

Gln Asp Ile Lys Lys Pro Asp Cys Asp Asp Trp Glu Ser Gly Leu Asn

340 345 350

Ala Met Glu Cys Ala Leu His Leu Glu Lys Asn Val Asn Gln Ser Leu

355 360 365

Leu Glu Leu His Lys Leu Ala Thr Asp Lys Asn Asp Pro His Leu Cys

370 375 380

Asp Phe Ile Glu Thr His Tyr Leu Asn Glu Gln Val Lys Ala Ile Lys

385 390 395 400

Glu Leu Gly Asp His Val Thr Asn Leu Arg Lys Met Gly Ala Pro Glu

405 410 415

Ser Gly Leu Ala Glu Tyr Leu Phe Asp Lys His Thr Leu Gly Asp Ser

420 425 430

Asp Asn Glu Ser

435

<210> 32

<211> 426

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 32

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

100 105 110

Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Tyr Thr Leu

130 135 140

Glu Gly Gln Leu Ser Asp Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val

165 170 175

Glu Leu Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

180 185 190

Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys Gly Ser Met Leu Ser Glu

245 250 255

Arg Met Leu Lys Ala Leu Asn Asp Gln Leu Asn Arg Glu Leu Tyr Ser

260 265 270

Ala Tyr Leu Tyr Phe Ala Met Ala Ala Tyr Phe Glu Asp Leu Gly Leu

275 280 285

Glu Gly Phe Ala Asn Trp Met Lys Ala Gln Ala Glu Glu Glu Ile Gly

290 295 300

His Ala Leu Arg Phe Tyr Asn Tyr Ile Tyr Asp Arg Asn Gly Arg Val

305 310 315 320

Glu Leu Asp Glu Ile Pro Lys Pro Pro Lys Glu Trp Glu Ser Pro Leu

325 330 335

Lys Ala Phe Glu Ala Ala Tyr Glu His Glu Lys Phe Ile Ser Lys Ser

340 345 350

Ile Tyr Glu Leu Ala Ala Leu Ala Glu Glu Glu Lys Asp Tyr Ser Thr

355 360 365

Arg Ala Phe Leu Glu Trp Phe Ile Asn Glu Gln Val Glu Glu Glu Ala

370 375 380

Ser Val Lys Lys Ile Leu Asp Lys Leu Lys Phe Ala Lys Asp Ser Pro

385 390 395 400

Gln Ile Leu Phe Met Leu Asp Lys Glu Leu Ser Ala Arg Ala Pro Lys

405 410 415

Leu Pro Gly Leu Leu Met Gln Gly Gly Glu

420 425

<210> 33

<211> 426

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 33

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

100 105 110

Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Tyr Asp Leu

130 135 140

Lys Gly Glu Leu Ser Ser Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val

165 170 175

Glu Leu Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

180 185 190

Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys Gly Ser Met Leu Ser Glu

245 250 255

Arg Met Leu Lys Ala Leu Asn Asp Gln Leu Asn Arg Glu Leu Tyr Ser

260 265 270

Ala Tyr Leu Tyr Phe Ala Met Ala Ala Tyr Phe Glu Asp Leu Gly Leu

275 280 285

Glu Gly Phe Ala Asn Trp Met Lys Ala Gln Ala Glu Glu Glu Ile Gly

290 295 300

His Ala Leu Arg Phe Tyr Asn Tyr Ile Tyr Asp Arg Asn Gly Arg Val

305 310 315 320

Glu Leu Asp Glu Ile Pro Lys Pro Pro Lys Glu Trp Glu Ser Pro Leu

325 330 335

Lys Ala Phe Glu Ala Ala Tyr Glu His Glu Lys Phe Ile Ser Lys Ser

340 345 350

Ile Tyr Glu Leu Ala Ala Leu Ala Glu Glu Glu Lys Asp Tyr Ser Thr

355 360 365

Arg Ala Phe Leu Glu Trp Phe Ile Asn Glu Gln Val Glu Glu Glu Ala

370 375 380

Ser Val Lys Lys Ile Leu Asp Lys Leu Lys Phe Ala Lys Asp Ser Pro

385 390 395 400

Gln Ile Leu Phe Met Leu Asp Lys Glu Leu Ser Ala Arg Ala Pro Lys

405 410 415

Leu Pro Gly Leu Leu Met Gln Gly Gly Glu

420 425

<210> 34

<211> 426

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 34

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

100 105 110

Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Phe Thr Leu

130 135 140

Glu Gly Lys Val Ala Asn Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val

165 170 175

Glu Leu Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

180 185 190

Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys Gly Ser Met Leu Ser Glu

245 250 255

Arg Met Leu Lys Ala Leu Asn Asp Gln Leu Asn Arg Glu Leu Tyr Ser

260 265 270

Ala Tyr Leu Tyr Phe Ala Met Ala Ala Tyr Phe Glu Asp Leu Gly Leu

275 280 285

Glu Gly Phe Ala Asn Trp Met Lys Ala Gln Ala Glu Glu Glu Ile Gly

290 295 300

His Ala Leu Arg Phe Tyr Asn Tyr Ile Tyr Asp Arg Asn Gly Arg Val

305 310 315 320

Glu Leu Asp Glu Ile Pro Lys Pro Pro Lys Glu Trp Glu Ser Pro Leu

325 330 335

Lys Ala Phe Glu Ala Ala Tyr Glu His Glu Lys Phe Ile Ser Lys Ser

340 345 350

Ile Tyr Glu Leu Ala Ala Leu Ala Glu Glu Glu Lys Asp Tyr Ser Thr

355 360 365

Arg Ala Phe Leu Glu Trp Phe Ile Asn Glu Gln Val Glu Glu Glu Ala

370 375 380

Ser Val Lys Lys Ile Leu Asp Lys Leu Lys Phe Ala Lys Asp Ser Pro

385 390 395 400

Gln Ile Leu Phe Met Leu Asp Lys Glu Leu Ser Ala Arg Ala Pro Lys

405 410 415

Leu Pro Gly Leu Leu Met Gln Gly Gly Glu

420 425

<210> 35

<211> 426

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 35

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

100 105 110

Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Phe Ala Leu

130 135 140

Glu Gly Thr Leu Thr Asp Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val

165 170 175

Glu Leu Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

180 185 190

Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys Gly Ser Met Leu Ser Glu

245 250 255

Arg Met Leu Lys Ala Leu Asn Asp Gln Leu Asn Arg Glu Leu Tyr Ser

260 265 270

Ala Tyr Leu Tyr Phe Ala Met Ala Ala Tyr Phe Glu Asp Leu Gly Leu

275 280 285

Glu Gly Phe Ala Asn Trp Met Lys Ala Gln Ala Glu Glu Glu Ile Gly

290 295 300

His Ala Leu Arg Phe Tyr Asn Tyr Ile Tyr Asp Arg Asn Gly Arg Val

305 310 315 320

Glu Leu Asp Glu Ile Pro Lys Pro Pro Lys Glu Trp Glu Ser Pro Leu

325 330 335

Lys Ala Phe Glu Ala Ala Tyr Glu His Glu Lys Phe Ile Ser Lys Ser

340 345 350

Ile Tyr Glu Leu Ala Ala Leu Ala Glu Glu Glu Lys Asp Tyr Ser Thr

355 360 365

Arg Ala Phe Leu Glu Trp Phe Ile Asn Glu Gln Val Glu Glu Glu Ala

370 375 380

Ser Val Lys Lys Ile Leu Asp Lys Leu Lys Phe Ala Lys Asp Ser Pro

385 390 395 400

Gln Ile Leu Phe Met Leu Asp Lys Glu Leu Ser Ala Arg Ala Pro Lys

405 410 415

Leu Pro Gly Leu Leu Met Gln Gly Gly Glu

420 425

<210> 36

<211> 426

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 36

Met Asp Glu Lys Asn Ser Ala Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Lys

20 25 30

Ala Thr Val Asp Lys Ile Glu Leu Lys Gly Thr Ser Asp Lys Asp Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Thr Lys Asp Asp Lys Ser Lys Ala Lys

50 55 60

Leu Thr Ile Ala Asp Asp Leu Ser Lys Thr Thr Phe Glu Leu Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Arg Lys Val Ser Ser Lys Asp Lys

85 90 95

Thr Ser Thr Asp Glu Met Phe Asn Glu Lys Gly Glu Leu Ser Ala Lys

100 105 110

Thr Met Thr Arg Glu Asn Gly Thr Lys Leu Glu Tyr Thr Glu Met Lys

115 120 125

Ser Asp Gly Thr Gly Lys Ala Lys Glu Val Leu Lys Asn Phe Thr Leu

130 135 140

Glu Gly Lys Val Ala Asn Asp Lys Val Thr Leu Glu Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Glu Ile Ala Lys Ser Gly Glu Val Thr Val

165 170 175

Ala Leu Asn Asp Thr Asn Thr Thr Gln Ala Thr Lys Lys Thr Gly Ala

180 185 190

Trp Asp Ser Lys Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Lys Lys

195 200 205

Thr Thr Gln Leu Val Phe Thr Lys Gln Asp Thr Ile Thr Val Gln Lys

210 215 220

Tyr Asp Ser Ala Gly Thr Asn Leu Glu Gly Thr Ala Val Glu Ile Lys

225 230 235 240

Thr Leu Asp Glu Leu Lys Asn Ala Leu Lys Gly Ser Met Leu Ser Glu

245 250 255

Arg Met Leu Lys Ala Leu Asn Asp Gln Leu Asn Arg Glu Leu Tyr Ser

260 265 270

Ala Tyr Leu Tyr Phe Ala Met Ala Ala Tyr Phe Glu Asp Leu Gly Leu

275 280 285

Glu Gly Phe Ala Asn Trp Met Lys Ala Gln Ala Glu Glu Glu Ile Gly

290 295 300

His Ala Leu Arg Phe Tyr Asn Tyr Ile Tyr Asp Arg Asn Gly Arg Val

305 310 315 320

Glu Leu Asp Glu Ile Pro Lys Pro Pro Lys Glu Trp Glu Ser Pro Leu

325 330 335

Lys Ala Phe Glu Ala Ala Tyr Glu His Glu Lys Phe Ile Ser Lys Ser

340 345 350

Ile Tyr Glu Leu Ala Ala Leu Ala Glu Glu Glu Lys Asp Tyr Ser Thr

355 360 365

Arg Ala Phe Leu Glu Trp Phe Ile Asn Glu Gln Val Glu Glu Glu Ala

370 375 380

Ser Val Lys Lys Ile Leu Asp Lys Leu Lys Phe Ala Lys Asp Ser Pro

385 390 395 400

Gln Ile Leu Phe Met Leu Asp Lys Glu Leu Ser Ala Arg Ala Pro Lys

405 410 415

Leu Pro Gly Leu Leu Met Gln Gly Gly Glu

420 425

<210> 37

<211> 427

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 37

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Gly Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Met

20 25 30

Ala Thr Val Glu Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Ser Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Glu Lys Ala Asp Lys Ser Lys Ala Lys

50 55 60

Leu Thr Ile Ser Gln Asp Leu Asn Gln Thr Thr Phe Glu Ile Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Arg Lys Val Asn Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Asp Lys Gly Lys Leu Ser Glu Lys

100 105 110

Val Val Thr Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Glu Ile Lys

115 120 125

Asn Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Phe Ala Leu

130 135 140

Glu Gly Thr Leu Thr Asp Gly Gly Glu Thr Lys Leu Thr Val Thr Glu

145 150 155 160

Gly Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Ile Thr

165 170 175

Val Ala Leu Asn Asp Thr Glu Thr Thr Pro Ala Asp Lys Lys Thr Gly

180 185 190

Glu Trp Lys Ser Asp Thr Ser Thr Leu Thr Ile Ser Lys Asn Ser Gln

195 200 205

Lys Pro Lys Gln Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln

210 215 220

Asn Tyr Asn Arg Ala Gly Asn Ala Leu Glu Gly Ser Pro Ala Glu Ile

225 230 235 240

Lys Asp Leu Ala Glu Leu Lys Ala Ala Leu Lys Gly Ser Met Leu Ser

245 250 255

Glu Arg Met Leu Lys Ala Leu Asn Asp Gln Leu Asn Arg Glu Leu Tyr

260 265 270

Ser Ala Tyr Leu Tyr Phe Ala Met Ala Ala Tyr Phe Glu Asp Leu Gly

275 280 285

Leu Glu Gly Phe Ala Asn Trp Met Lys Ala Gln Ala Glu Glu Glu Ile

290 295 300

Gly His Ala Leu Arg Phe Tyr Asn Tyr Ile Tyr Asp Arg Asn Gly Arg

305 310 315 320

Val Glu Leu Asp Glu Ile Pro Lys Pro Pro Lys Glu Trp Glu Ser Pro

325 330 335

Leu Lys Ala Phe Glu Ala Ala Tyr Glu His Glu Lys Phe Ile Ser Lys

340 345 350

Ser Ile Tyr Glu Leu Ala Ala Leu Ala Glu Glu Glu Lys Asp Tyr Ser

355 360 365

Thr Arg Ala Phe Leu Glu Trp Phe Ile Asn Glu Gln Val Glu Glu Glu

370 375 380

Ala Ser Val Lys Lys Ile Leu Asp Lys Leu Lys Phe Ala Lys Asp Ser

385 390 395 400

Pro Gln Ile Leu Phe Met Leu Asp Lys Glu Leu Ser Ala Arg Ala Pro

405 410 415

Lys Leu Pro Gly Leu Leu Met Gln Gly Gly Glu

420 425

<210> 38

<211> 426

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 38

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Met

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Ser Asn

35 40 45

Gly Ser Gly Thr Leu Glu Gly Glu Lys Ser Asp Lys Ser Lys Ala Lys

50 55 60

Leu Thr Ile Ser Glu Asp Leu Ser Lys Thr Thr Phe Glu Ile Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Asn Ser Lys Asp Lys

85 90 95

Ser Ser Ile Glu Glu Lys Phe Asn Ala Lys Gly Glu Leu Ser Glu Lys

100 105 110

Thr Ile Leu Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Glu Ile Lys

115 120 125

Ser Asp Gly Thr Gly Lys Ala Lys Glu Val Leu Lys Asp Phe Ala Leu

130 135 140

Glu Gly Thr Leu Ala Ala Asp Lys Thr Thr Leu Lys Val Thr Glu Gly

145 150 155 160

Thr Val Val Leu Ser Lys His Ile Pro Asn Ser Gly Glu Ile Thr Val

165 170 175

Glu Leu Asn Asp Ser Asn Ser Thr Gln Ala Thr Lys Lys Thr Gly Lys

180 185 190

Trp Asp Ser Asn Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Lys Lys

195 200 205

Thr Lys Asn Ile Val Phe Thr Lys Glu Asp Thr Ile Thr Val Gln Lys

210 215 220

Tyr Asp Ser Ala Gly Thr Asn Leu Glu Gly Asn Ala Val Glu Ile Lys

225 230 235 240

Thr Leu Asp Glu Leu Lys Asn Ala Leu Lys Gly Ser Met Leu Ser Glu

245 250 255

Arg Met Leu Lys Ala Leu Asn Asp Gln Leu Asn Arg Glu Leu Tyr Ser

260 265 270

Ala Tyr Leu Tyr Phe Ala Met Ala Ala Tyr Phe Glu Asp Leu Gly Leu

275 280 285

Glu Gly Phe Ala Asn Trp Met Lys Ala Gln Ala Glu Glu Glu Ile Gly

290 295 300

His Ala Leu Arg Phe Tyr Asn Tyr Ile Tyr Asp Arg Asn Gly Arg Val

305 310 315 320

Glu Leu Asp Glu Ile Pro Lys Pro Pro Lys Glu Trp Glu Ser Pro Leu

325 330 335

Lys Ala Phe Glu Ala Ala Tyr Glu His Glu Lys Phe Ile Ser Lys Ser

340 345 350

Ile Tyr Glu Leu Ala Ala Leu Ala Glu Glu Glu Lys Asp Tyr Ser Thr

355 360 365

Arg Ala Phe Leu Glu Trp Phe Ile Asn Glu Gln Val Glu Glu Glu Ala

370 375 380

Ser Val Lys Lys Ile Leu Asp Lys Leu Lys Phe Ala Lys Asp Ser Pro

385 390 395 400

Gln Ile Leu Phe Met Leu Asp Lys Glu Leu Ser Ala Arg Ala Pro Lys

405 410 415

Leu Pro Gly Leu Leu Met Gln Gly Gly Glu

420 425

<210> 39

<211> 427

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 39

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Gly Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Met

20 25 30

Ala Thr Val Glu Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Thr Leu Glu Gly Glu Lys Thr Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ala Glu Asp Leu Ser Lys Thr Thr Phe Glu Ile Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Leu Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Ile Ser Glu Lys

100 105 110

Thr Ile Val Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Asp Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Asp Phe Thr Leu

130 135 140

Glu Gly Thr Leu Ala Ala Asp Gly Lys Thr Thr Leu Lys Val Thr Glu

145 150 155 160

Gly Thr Val Val Leu Ser Lys Asn Ile Leu Lys Ser Gly Glu Ile Thr

165 170 175

Val Ala Leu Asp Asp Ser Asp Thr Thr Gln Ala Thr Lys Lys Thr Gly

180 185 190

Lys Trp Asp Ser Lys Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Gln

195 200 205

Lys Thr Lys Asn Leu Val Phe Thr Lys Glu Asp Thr Ile Thr Val Gln

210 215 220

Lys Tyr Asp Ser Ala Gly Thr Asn Leu Glu Gly Lys Ala Val Glu Ile

225 230 235 240

Thr Thr Leu Glu Lys Leu Lys Asp Ala Leu Lys Gly Ser Met Leu Ser

245 250 255

Glu Arg Met Leu Lys Ala Leu Asn Asp Gln Leu Asn Arg Glu Leu Tyr

260 265 270

Ser Ala Tyr Leu Tyr Phe Ala Met Ala Ala Tyr Phe Glu Asp Leu Gly

275 280 285

Leu Glu Gly Phe Ala Asn Trp Met Lys Ala Gln Ala Glu Glu Glu Ile

290 295 300

Gly His Ala Leu Arg Phe Tyr Asn Tyr Ile Tyr Asp Arg Asn Gly Arg

305 310 315 320

Val Glu Leu Asp Glu Ile Pro Lys Pro Pro Lys Glu Trp Glu Ser Pro

325 330 335

Leu Lys Ala Phe Glu Ala Ala Tyr Glu His Glu Lys Phe Ile Ser Lys

340 345 350

Ser Ile Tyr Glu Leu Ala Ala Leu Ala Glu Glu Glu Lys Asp Tyr Ser

355 360 365

Thr Arg Ala Phe Leu Glu Trp Phe Ile Asn Glu Gln Val Glu Glu Glu

370 375 380

Ala Ser Val Lys Lys Ile Leu Asp Lys Leu Lys Phe Ala Lys Asp Ser

385 390 395 400

Pro Gln Ile Leu Phe Met Leu Asp Lys Glu Leu Ser Ala Arg Ala Pro

405 410 415

Lys Leu Pro Gly Leu Leu Met Gln Gly Gly Glu

420 425

<210> 40

<211> 427

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 40

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Gly Met Thr

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Glu

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Thr Leu Glu Gly Glu Lys Thr Asp Lys Ser Lys Val Lys

50 55 60

Ser Thr Ile Ala Asp Asp Leu Ser Gln Thr Lys Phe Glu Ile Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Leu Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Gly Lys Gly Glu Thr Ser Glu Lys

100 105 110

Thr Ile Val Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Asp Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Asp Phe Thr Leu

130 135 140

Glu Gly Thr Leu Ala Ala Asp Gly Lys Thr Thr Leu Lys Val Thr Glu

145 150 155 160

Gly Thr Val Val Leu Ser Lys Asn Ile Leu Lys Ser Gly Glu Ile Thr

165 170 175

Ala Ala Leu Asp Asp Ser Asp Thr Thr Arg Ala Thr Lys Lys Thr Gly

180 185 190

Lys Trp Asp Ser Lys Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Gln

195 200 205

Lys Thr Lys Asn Leu Val Phe Thr Lys Glu Asp Thr Ile Thr Val Gln

210 215 220

Arg Tyr Asp Ser Ala Gly Thr Asn Leu Glu Gly Lys Ala Val Glu Ile

225 230 235 240

Thr Thr Leu Lys Glu Leu Lys Asn Ala Leu Lys Gly Ser Met Leu Ser

245 250 255

Glu Arg Met Leu Lys Ala Leu Asn Asp Gln Leu Asn Arg Glu Leu Tyr

260 265 270

Ser Ala Tyr Leu Tyr Phe Ala Met Ala Ala Tyr Phe Glu Asp Leu Gly

275 280 285

Leu Glu Gly Phe Ala Asn Trp Met Lys Ala Gln Ala Glu Glu Glu Ile

290 295 300

Gly His Ala Leu Arg Phe Tyr Asn Tyr Ile Tyr Asp Arg Asn Gly Arg

305 310 315 320

Val Glu Leu Asp Glu Ile Pro Lys Pro Pro Lys Glu Trp Glu Ser Pro

325 330 335

Leu Lys Ala Phe Glu Ala Ala Tyr Glu His Glu Lys Phe Ile Ser Lys

340 345 350

Ser Ile Tyr Glu Leu Ala Ala Leu Ala Glu Glu Glu Lys Asp Tyr Ser

355 360 365

Thr Arg Ala Phe Leu Glu Trp Phe Ile Asn Glu Gln Val Glu Glu Glu

370 375 380

Ala Ser Val Lys Lys Ile Leu Asp Lys Leu Lys Phe Ala Lys Asp Ser

385 390 395 400

Pro Gln Ile Leu Phe Met Leu Asp Lys Glu Leu Ser Ala Arg Ala Pro

405 410 415

Lys Leu Pro Gly Leu Leu Met Gln Gly Gly Glu

420 425

<210> 41

<211> 427

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 41

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Glu

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Ala Lys Ser Lys Ala Lys

50 55 60

Leu Thr Ile Ala Asp Asp Leu Ser Gln Thr Lys Phe Glu Ile Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Leu Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Asp Lys Gly Lys Leu Ser Glu Lys

100 105 110

Val Val Thr Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Glu Ile Gln

115 120 125

Asn Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Ser Leu Thr Leu

130 135 140

Glu Gly Thr Leu Thr Ala Asp Gly Glu Thr Lys Leu Thr Val Glu Ala

145 150 155 160

Gly Thr Val Thr Leu Ser Lys Asn Ile Ser Glu Ser Gly Glu Ile Thr

165 170 175

Val Glu Leu Lys Asp Thr Glu Thr Thr Pro Ala Asp Lys Lys Ser Gly

180 185 190

Thr Trp Asp Ser Lys Thr Ser Thr Leu Thr Ile Ser Lys Asn Ser Gln

195 200 205

Lys Thr Lys Gln Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln

210 215 220

Lys Tyr Asn Thr Ala Gly Thr Lys Leu Glu Gly Ser Pro Ala Glu Ile

225 230 235 240

Lys Asp Leu Glu Ala Leu Lys Ala Ala Leu Lys Gly Ser Met Leu Ser

245 250 255

Glu Arg Met Leu Lys Ala Leu Asn Asp Gln Leu Asn Arg Glu Leu Tyr

260 265 270

Ser Ala Tyr Leu Tyr Phe Ala Met Ala Ala Tyr Phe Glu Asp Leu Gly

275 280 285

Leu Glu Gly Phe Ala Asn Trp Met Lys Ala Gln Ala Glu Glu Glu Ile

290 295 300

Gly His Ala Leu Arg Phe Tyr Asn Tyr Ile Tyr Asp Arg Asn Gly Arg

305 310 315 320

Val Glu Leu Asp Glu Ile Pro Lys Pro Pro Lys Glu Trp Glu Ser Pro

325 330 335

Leu Lys Ala Phe Glu Ala Ala Tyr Glu His Glu Lys Phe Ile Ser Lys

340 345 350

Ser Ile Tyr Glu Leu Ala Ala Leu Ala Glu Glu Glu Lys Asp Tyr Ser

355 360 365

Thr Arg Ala Phe Leu Glu Trp Phe Ile Asn Glu Gln Val Glu Glu Glu

370 375 380

Ala Ser Val Lys Lys Ile Leu Asp Lys Leu Lys Phe Ala Lys Asp Ser

385 390 395 400

Pro Gln Ile Leu Phe Met Leu Asp Lys Glu Leu Ser Ala Arg Ala Pro

405 410 415

Lys Leu Pro Gly Leu Leu Met Gln Gly Gly Glu

420 425

<210> 42

<211> 443

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 42

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

100 105 110

Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Tyr Thr Leu

130 135 140

Glu Gly Gln Leu Ser Asp Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val

165 170 175

Glu Leu Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

180 185 190

Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys Gly Ser Thr Gln Cys Asn

245 250 255

Val Asn Pro Val Gln Ile Pro Lys Asp Trp Ile Thr Met His Arg Ser

260 265 270

Cys Arg Asn Ser Met Arg Gln Gln Ile Gln Met Glu Val Gly Ala Ser

275 280 285

Leu Gln Tyr Leu Ala Met Gly Ala His Phe Ser Lys Asp Val Val Asn

290 295 300

Arg Pro Gly Phe Ala Gln Leu Phe Phe Asp Ala Ala Ser Glu Glu Arg

305 310 315 320

Glu His Ala Met Lys Leu Ile Glu Tyr Leu Leu Met Arg Gly Glu Leu

325 330 335

Thr Asn Asp Val Ser Ser Leu Leu Gln Val Arg Pro Pro Thr Arg Ser

340 345 350

Ser Trp Lys Gly Gly Val Glu Ala Leu Glu His Ala Leu Ser Met Glu

355 360 365

Ser Asp Val Thr Lys Ser Ile Arg Asn Val Ile Lys Ala Cys Glu Asp

370 375 380

Asp Ser Glu Phe Asn Asp Tyr His Leu Val Asp Tyr Leu Thr Gly Asp

385 390 395 400

Phe Leu Glu Glu Gln Tyr Lys Gly Gln Arg Asp Leu Ala Gly Lys Ala

405 410 415

Ser Thr Leu Lys Lys Leu Met Asp Arg His Glu Ala Leu Gly Glu Phe

420 425 430

Ile Phe Asp Lys Lys Leu Leu Gly Ile Asp Val

435 440

<210> 43

<211> 443

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 43

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

100 105 110

Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Tyr Asp Leu

130 135 140

Lys Gly Glu Leu Ser Ser Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val

165 170 175

Glu Leu Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

180 185 190

Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys Gly Ser Thr Gln Cys Asn

245 250 255

Val Asn Pro Val Gln Ile Pro Lys Asp Trp Ile Thr Met His Arg Ser

260 265 270

Cys Arg Asn Ser Met Arg Gln Gln Ile Gln Met Glu Val Gly Ala Ser

275 280 285

Leu Gln Tyr Leu Ala Met Gly Ala His Phe Ser Lys Asp Val Val Asn

290 295 300

Arg Pro Gly Phe Ala Gln Leu Phe Phe Asp Ala Ala Ser Glu Glu Arg

305 310 315 320

Glu His Ala Met Lys Leu Ile Glu Tyr Leu Leu Met Arg Gly Glu Leu

325 330 335

Thr Asn Asp Val Ser Ser Leu Leu Gln Val Arg Pro Pro Thr Arg Ser

340 345 350

Ser Trp Lys Gly Gly Val Glu Ala Leu Glu His Ala Leu Ser Met Glu

355 360 365

Ser Asp Val Thr Lys Ser Ile Arg Asn Val Ile Lys Ala Cys Glu Asp

370 375 380

Asp Ser Glu Phe Asn Asp Tyr His Leu Val Asp Tyr Leu Thr Gly Asp

385 390 395 400

Phe Leu Glu Glu Gln Tyr Lys Gly Gln Arg Asp Leu Ala Gly Lys Ala

405 410 415

Ser Thr Leu Lys Lys Leu Met Asp Arg His Glu Ala Leu Gly Glu Phe

420 425 430

Ile Phe Asp Lys Lys Leu Leu Gly Ile Asp Val

435 440

<210> 44

<211> 443

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 44

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

100 105 110

Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Phe Thr Leu

130 135 140

Glu Gly Lys Val Ala Asn Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val

165 170 175

Glu Leu Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

180 185 190

Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys Gly Ser Thr Gln Cys Asn

245 250 255

Val Asn Pro Val Gln Ile Pro Lys Asp Trp Ile Thr Met His Arg Ser

260 265 270

Cys Arg Asn Ser Met Arg Gln Gln Ile Gln Met Glu Val Gly Ala Ser

275 280 285

Leu Gln Tyr Leu Ala Met Gly Ala His Phe Ser Lys Asp Val Val Asn

290 295 300

Arg Pro Gly Phe Ala Gln Leu Phe Phe Asp Ala Ala Ser Glu Glu Arg

305 310 315 320

Glu His Ala Met Lys Leu Ile Glu Tyr Leu Leu Met Arg Gly Glu Leu

325 330 335

Thr Asn Asp Val Ser Ser Leu Leu Gln Val Arg Pro Pro Thr Arg Ser

340 345 350

Ser Trp Lys Gly Gly Val Glu Ala Leu Glu His Ala Leu Ser Met Glu

355 360 365

Ser Asp Val Thr Lys Ser Ile Arg Asn Val Ile Lys Ala Cys Glu Asp

370 375 380

Asp Ser Glu Phe Asn Asp Tyr His Leu Val Asp Tyr Leu Thr Gly Asp

385 390 395 400

Phe Leu Glu Glu Gln Tyr Lys Gly Gln Arg Asp Leu Ala Gly Lys Ala

405 410 415

Ser Thr Leu Lys Lys Leu Met Asp Arg His Glu Ala Leu Gly Glu Phe

420 425 430

Ile Phe Asp Lys Lys Leu Leu Gly Ile Asp Val

435 440

<210> 45

<211> 443

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 45

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

100 105 110

Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Phe Ala Leu

130 135 140

Glu Gly Thr Leu Thr Asp Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val

165 170 175

Glu Leu Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

180 185 190

Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys Gly Ser Thr Gln Cys Asn

245 250 255

Val Asn Pro Val Gln Ile Pro Lys Asp Trp Ile Thr Met His Arg Ser

260 265 270

Cys Arg Asn Ser Met Arg Gln Gln Ile Gln Met Glu Val Gly Ala Ser

275 280 285

Leu Gln Tyr Leu Ala Met Gly Ala His Phe Ser Lys Asp Val Val Asn

290 295 300

Arg Pro Gly Phe Ala Gln Leu Phe Phe Asp Ala Ala Ser Glu Glu Arg

305 310 315 320

Glu His Ala Met Lys Leu Ile Glu Tyr Leu Leu Met Arg Gly Glu Leu

325 330 335

Thr Asn Asp Val Ser Ser Leu Leu Gln Val Arg Pro Pro Thr Arg Ser

340 345 350

Ser Trp Lys Gly Gly Val Glu Ala Leu Glu His Ala Leu Ser Met Glu

355 360 365

Ser Asp Val Thr Lys Ser Ile Arg Asn Val Ile Lys Ala Cys Glu Asp

370 375 380

Asp Ser Glu Phe Asn Asp Tyr His Leu Val Asp Tyr Leu Thr Gly Asp

385 390 395 400

Phe Leu Glu Glu Gln Tyr Lys Gly Gln Arg Asp Leu Ala Gly Lys Ala

405 410 415

Ser Thr Leu Lys Lys Leu Met Asp Arg His Glu Ala Leu Gly Glu Phe

420 425 430

Ile Phe Asp Lys Lys Leu Leu Gly Ile Asp Val

435 440

<210> 46

<211> 443

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 46

Met Asp Glu Lys Asn Ser Ala Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Lys

20 25 30

Ala Thr Val Asp Lys Ile Glu Leu Lys Gly Thr Ser Asp Lys Asp Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Thr Lys Asp Asp Lys Ser Lys Ala Lys

50 55 60

Leu Thr Ile Ala Asp Asp Leu Ser Lys Thr Thr Phe Glu Leu Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Arg Lys Val Ser Ser Lys Asp Lys

85 90 95

Thr Ser Thr Asp Glu Met Phe Asn Glu Lys Gly Glu Leu Ser Ala Lys

100 105 110

Thr Met Thr Arg Glu Asn Gly Thr Lys Leu Glu Tyr Thr Glu Met Lys

115 120 125

Ser Asp Gly Thr Gly Lys Ala Lys Glu Val Leu Lys Asn Phe Thr Leu

130 135 140

Glu Gly Lys Val Ala Asn Asp Lys Val Thr Leu Glu Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Glu Ile Ala Lys Ser Gly Glu Val Thr Val

165 170 175

Ala Leu Asn Asp Thr Asn Thr Thr Gln Ala Thr Lys Lys Thr Gly Ala

180 185 190

Trp Asp Ser Lys Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Lys Lys

195 200 205

Thr Thr Gln Leu Val Phe Thr Lys Gln Asp Thr Ile Thr Val Gln Lys

210 215 220

Tyr Asp Ser Ala Gly Thr Asn Leu Glu Gly Thr Ala Val Glu Ile Lys

225 230 235 240

Thr Leu Asp Glu Leu Lys Asn Ala Leu Lys Gly Ser Thr Gln Cys Asn

245 250 255

Val Asn Pro Val Gln Ile Pro Lys Asp Trp Ile Thr Met His Arg Ser

260 265 270

Cys Arg Asn Ser Met Arg Gln Gln Ile Gln Met Glu Val Gly Ala Ser

275 280 285

Leu Gln Tyr Leu Ala Met Gly Ala His Phe Ser Lys Asp Val Val Asn

290 295 300

Arg Pro Gly Phe Ala Gln Leu Phe Phe Asp Ala Ala Ser Glu Glu Arg

305 310 315 320

Glu His Ala Met Lys Leu Ile Glu Tyr Leu Leu Met Arg Gly Glu Leu

325 330 335

Thr Asn Asp Val Ser Ser Leu Leu Gln Val Arg Pro Pro Thr Arg Ser

340 345 350

Ser Trp Lys Gly Gly Val Glu Ala Leu Glu His Ala Leu Ser Met Glu

355 360 365

Ser Asp Val Thr Lys Ser Ile Arg Asn Val Ile Lys Ala Cys Glu Asp

370 375 380

Asp Ser Glu Phe Asn Asp Tyr His Leu Val Asp Tyr Leu Thr Gly Asp

385 390 395 400

Phe Leu Glu Glu Gln Tyr Lys Gly Gln Arg Asp Leu Ala Gly Lys Ala

405 410 415

Ser Thr Leu Lys Lys Leu Met Asp Arg His Glu Ala Leu Gly Glu Phe

420 425 430

Ile Phe Asp Lys Lys Leu Leu Gly Ile Asp Val

435 440

<210> 47

<211> 444

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 47

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Gly Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Met

20 25 30

Ala Thr Val Glu Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Ser Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Glu Lys Ala Asp Lys Ser Lys Ala Lys

50 55 60

Leu Thr Ile Ser Gln Asp Leu Asn Gln Thr Thr Phe Glu Ile Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Arg Lys Val Asn Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Asp Lys Gly Lys Leu Ser Glu Lys

100 105 110

Val Val Thr Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Glu Ile Lys

115 120 125

Asn Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Phe Ala Leu

130 135 140

Glu Gly Thr Leu Thr Asp Gly Gly Glu Thr Lys Leu Thr Val Thr Glu

145 150 155 160

Gly Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Ile Thr

165 170 175

Val Ala Leu Asn Asp Thr Glu Thr Thr Pro Ala Asp Lys Lys Thr Gly

180 185 190

Glu Trp Lys Ser Asp Thr Ser Thr Leu Thr Ile Ser Lys Asn Ser Gln

195 200 205

Lys Pro Lys Gln Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln

210 215 220

Asn Tyr Asn Arg Ala Gly Asn Ala Leu Glu Gly Ser Pro Ala Glu Ile

225 230 235 240

Lys Asp Leu Ala Glu Leu Lys Ala Ala Leu Lys Gly Ser Thr Gln Cys

245 250 255

Asn Val Asn Pro Val Gln Ile Pro Lys Asp Trp Ile Thr Met His Arg

260 265 270

Ser Cys Arg Asn Ser Met Arg Gln Gln Ile Gln Met Glu Val Gly Ala

275 280 285

Ser Leu Gln Tyr Leu Ala Met Gly Ala His Phe Ser Lys Asp Val Val

290 295 300

Asn Arg Pro Gly Phe Ala Gln Leu Phe Phe Asp Ala Ala Ser Glu Glu

305 310 315 320

Arg Glu His Ala Met Lys Leu Ile Glu Tyr Leu Leu Met Arg Gly Glu

325 330 335

Leu Thr Asn Asp Val Ser Ser Leu Leu Gln Val Arg Pro Pro Thr Arg

340 345 350

Ser Ser Trp Lys Gly Gly Val Glu Ala Leu Glu His Ala Leu Ser Met

355 360 365

Glu Ser Asp Val Thr Lys Ser Ile Arg Asn Val Ile Lys Ala Cys Glu

370 375 380

Asp Asp Ser Glu Phe Asn Asp Tyr His Leu Val Asp Tyr Leu Thr Gly

385 390 395 400

Asp Phe Leu Glu Glu Gln Tyr Lys Gly Gln Arg Asp Leu Ala Gly Lys

405 410 415

Ala Ser Thr Leu Lys Lys Leu Met Asp Arg His Glu Ala Leu Gly Glu

420 425 430

Phe Ile Phe Asp Lys Lys Leu Leu Gly Ile Asp Val

435 440

<210> 48

<211> 443

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 48

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Met

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Ser Asn

35 40 45

Gly Ser Gly Thr Leu Glu Gly Glu Lys Ser Asp Lys Ser Lys Ala Lys

50 55 60

Leu Thr Ile Ser Glu Asp Leu Ser Lys Thr Thr Phe Glu Ile Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Asn Ser Lys Asp Lys

85 90 95

Ser Ser Ile Glu Glu Lys Phe Asn Ala Lys Gly Glu Leu Ser Glu Lys

100 105 110

Thr Ile Leu Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Glu Ile Lys

115 120 125

Ser Asp Gly Thr Gly Lys Ala Lys Glu Val Leu Lys Asp Phe Ala Leu

130 135 140

Glu Gly Thr Leu Ala Ala Asp Lys Thr Thr Leu Lys Val Thr Glu Gly

145 150 155 160

Thr Val Val Leu Ser Lys His Ile Pro Asn Ser Gly Glu Ile Thr Val

165 170 175

Glu Leu Asn Asp Ser Asn Ser Thr Gln Ala Thr Lys Lys Thr Gly Lys

180 185 190

Trp Asp Ser Asn Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Lys Lys

195 200 205

Thr Lys Asn Ile Val Phe Thr Lys Glu Asp Thr Ile Thr Val Gln Lys

210 215 220

Tyr Asp Ser Ala Gly Thr Asn Leu Glu Gly Asn Ala Val Glu Ile Lys

225 230 235 240

Thr Leu Asp Glu Leu Lys Asn Ala Leu Lys Gly Ser Thr Gln Cys Asn

245 250 255

Val Asn Pro Val Gln Ile Pro Lys Asp Trp Ile Thr Met His Arg Ser

260 265 270

Cys Arg Asn Ser Met Arg Gln Gln Ile Gln Met Glu Val Gly Ala Ser

275 280 285

Leu Gln Tyr Leu Ala Met Gly Ala His Phe Ser Lys Asp Val Val Asn

290 295 300

Arg Pro Gly Phe Ala Gln Leu Phe Phe Asp Ala Ala Ser Glu Glu Arg

305 310 315 320

Glu His Ala Met Lys Leu Ile Glu Tyr Leu Leu Met Arg Gly Glu Leu

325 330 335

Thr Asn Asp Val Ser Ser Leu Leu Gln Val Arg Pro Pro Thr Arg Ser

340 345 350

Ser Trp Lys Gly Gly Val Glu Ala Leu Glu His Ala Leu Ser Met Glu

355 360 365

Ser Asp Val Thr Lys Ser Ile Arg Asn Val Ile Lys Ala Cys Glu Asp

370 375 380

Asp Ser Glu Phe Asn Asp Tyr His Leu Val Asp Tyr Leu Thr Gly Asp

385 390 395 400

Phe Leu Glu Glu Gln Tyr Lys Gly Gln Arg Asp Leu Ala Gly Lys Ala

405 410 415

Ser Thr Leu Lys Lys Leu Met Asp Arg His Glu Ala Leu Gly Glu Phe

420 425 430

Ile Phe Asp Lys Lys Leu Leu Gly Ile Asp Val

435 440

<210> 49

<211> 444

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 49

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Gly Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Met

20 25 30

Ala Thr Val Glu Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Thr Leu Glu Gly Glu Lys Thr Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ala Glu Asp Leu Ser Lys Thr Thr Phe Glu Ile Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Leu Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Ile Ser Glu Lys

100 105 110

Thr Ile Val Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Asp Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Asp Phe Thr Leu

130 135 140

Glu Gly Thr Leu Ala Ala Asp Gly Lys Thr Thr Leu Lys Val Thr Glu

145 150 155 160

Gly Thr Val Val Leu Ser Lys Asn Ile Leu Lys Ser Gly Glu Ile Thr

165 170 175

Val Ala Leu Asp Asp Ser Asp Thr Thr Gln Ala Thr Lys Lys Thr Gly

180 185 190

Lys Trp Asp Ser Lys Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Gln

195 200 205

Lys Thr Lys Asn Leu Val Phe Thr Lys Glu Asp Thr Ile Thr Val Gln

210 215 220

Lys Tyr Asp Ser Ala Gly Thr Asn Leu Glu Gly Lys Ala Val Glu Ile

225 230 235 240

Thr Thr Leu Glu Lys Leu Lys Asp Ala Leu Lys Gly Ser Thr Gln Cys

245 250 255

Asn Val Asn Pro Val Gln Ile Pro Lys Asp Trp Ile Thr Met His Arg

260 265 270

Ser Cys Arg Asn Ser Met Arg Gln Gln Ile Gln Met Glu Val Gly Ala

275 280 285

Ser Leu Gln Tyr Leu Ala Met Gly Ala His Phe Ser Lys Asp Val Val

290 295 300

Asn Arg Pro Gly Phe Ala Gln Leu Phe Phe Asp Ala Ala Ser Glu Glu

305 310 315 320

Arg Glu His Ala Met Lys Leu Ile Glu Tyr Leu Leu Met Arg Gly Glu

325 330 335

Leu Thr Asn Asp Val Ser Ser Leu Leu Gln Val Arg Pro Pro Thr Arg

340 345 350

Ser Ser Trp Lys Gly Gly Val Glu Ala Leu Glu His Ala Leu Ser Met

355 360 365

Glu Ser Asp Val Thr Lys Ser Ile Arg Asn Val Ile Lys Ala Cys Glu

370 375 380

Asp Asp Ser Glu Phe Asn Asp Tyr His Leu Val Asp Tyr Leu Thr Gly

385 390 395 400

Asp Phe Leu Glu Glu Gln Tyr Lys Gly Gln Arg Asp Leu Ala Gly Lys

405 410 415

Ala Ser Thr Leu Lys Lys Leu Met Asp Arg His Glu Ala Leu Gly Glu

420 425 430

Phe Ile Phe Asp Lys Lys Leu Leu Gly Ile Asp Val

435 440

<210> 50

<211> 444

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 50

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Gly Met Thr

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Glu

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Thr Leu Glu Gly Glu Lys Thr Asp Lys Ser Lys Val Lys

50 55 60

Ser Thr Ile Ala Asp Asp Leu Ser Gln Thr Lys Phe Glu Ile Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Leu Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Gly Lys Gly Glu Thr Ser Glu Lys

100 105 110

Thr Ile Val Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Asp Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Asp Phe Thr Leu

130 135 140

Glu Gly Thr Leu Ala Ala Asp Gly Lys Thr Thr Leu Lys Val Thr Glu

145 150 155 160

Gly Thr Val Val Leu Ser Lys Asn Ile Leu Lys Ser Gly Glu Ile Thr

165 170 175

Ala Ala Leu Asp Asp Ser Asp Thr Thr Arg Ala Thr Lys Lys Thr Gly

180 185 190

Lys Trp Asp Ser Lys Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Gln

195 200 205

Lys Thr Lys Asn Leu Val Phe Thr Lys Glu Asp Thr Ile Thr Val Gln

210 215 220

Arg Tyr Asp Ser Ala Gly Thr Asn Leu Glu Gly Lys Ala Val Glu Ile

225 230 235 240

Thr Thr Leu Lys Glu Leu Lys Asn Ala Leu Lys Gly Ser Thr Gln Cys

245 250 255

Asn Val Asn Pro Val Gln Ile Pro Lys Asp Trp Ile Thr Met His Arg

260 265 270

Ser Cys Arg Asn Ser Met Arg Gln Gln Ile Gln Met Glu Val Gly Ala

275 280 285

Ser Leu Gln Tyr Leu Ala Met Gly Ala His Phe Ser Lys Asp Val Val

290 295 300

Asn Arg Pro Gly Phe Ala Gln Leu Phe Phe Asp Ala Ala Ser Glu Glu

305 310 315 320

Arg Glu His Ala Met Lys Leu Ile Glu Tyr Leu Leu Met Arg Gly Glu

325 330 335

Leu Thr Asn Asp Val Ser Ser Leu Leu Gln Val Arg Pro Pro Thr Arg

340 345 350

Ser Ser Trp Lys Gly Gly Val Glu Ala Leu Glu His Ala Leu Ser Met

355 360 365

Glu Ser Asp Val Thr Lys Ser Ile Arg Asn Val Ile Lys Ala Cys Glu

370 375 380

Asp Asp Ser Glu Phe Asn Asp Tyr His Leu Val Asp Tyr Leu Thr Gly

385 390 395 400

Asp Phe Leu Glu Glu Gln Tyr Lys Gly Gln Arg Asp Leu Ala Gly Lys

405 410 415

Ala Ser Thr Leu Lys Lys Leu Met Asp Arg His Glu Ala Leu Gly Glu

420 425 430

Phe Ile Phe Asp Lys Lys Leu Leu Gly Ile Asp Val

435 440

<210> 51

<211> 444

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 51

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Glu

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Ala Lys Ser Lys Ala Lys

50 55 60

Leu Thr Ile Ala Asp Asp Leu Ser Gln Thr Lys Phe Glu Ile Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Leu Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Asp Lys Gly Lys Leu Ser Glu Lys

100 105 110

Val Val Thr Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Glu Ile Gln

115 120 125

Asn Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Ser Leu Thr Leu

130 135 140

Glu Gly Thr Leu Thr Ala Asp Gly Glu Thr Lys Leu Thr Val Glu Ala

145 150 155 160

Gly Thr Val Thr Leu Ser Lys Asn Ile Ser Glu Ser Gly Glu Ile Thr

165 170 175

Val Glu Leu Lys Asp Thr Glu Thr Thr Pro Ala Asp Lys Lys Ser Gly

180 185 190

Thr Trp Asp Ser Lys Thr Ser Thr Leu Thr Ile Ser Lys Asn Ser Gln

195 200 205

Lys Thr Lys Gln Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln

210 215 220

Lys Tyr Asn Thr Ala Gly Thr Lys Leu Glu Gly Ser Pro Ala Glu Ile

225 230 235 240

Lys Asp Leu Glu Ala Leu Lys Ala Ala Leu Lys Gly Ser Thr Gln Cys

245 250 255

Asn Val Asn Pro Val Gln Ile Pro Lys Asp Trp Ile Thr Met His Arg

260 265 270

Ser Cys Arg Asn Ser Met Arg Gln Gln Ile Gln Met Glu Val Gly Ala

275 280 285

Ser Leu Gln Tyr Leu Ala Met Gly Ala His Phe Ser Lys Asp Val Val

290 295 300

Asn Arg Pro Gly Phe Ala Gln Leu Phe Phe Asp Ala Ala Ser Glu Glu

305 310 315 320

Arg Glu His Ala Met Lys Leu Ile Glu Tyr Leu Leu Met Arg Gly Glu

325 330 335

Leu Thr Asn Asp Val Ser Ser Leu Leu Gln Val Arg Pro Pro Thr Arg

340 345 350

Ser Ser Trp Lys Gly Gly Val Glu Ala Leu Glu His Ala Leu Ser Met

355 360 365

Glu Ser Asp Val Thr Lys Ser Ile Arg Asn Val Ile Lys Ala Cys Glu

370 375 380

Asp Asp Ser Glu Phe Asn Asp Tyr His Leu Val Asp Tyr Leu Thr Gly

385 390 395 400

Asp Phe Leu Glu Glu Gln Tyr Lys Gly Gln Arg Asp Leu Ala Gly Lys

405 410 415

Ala Ser Thr Leu Lys Lys Leu Met Asp Arg His Glu Ala Leu Gly Glu

420 425 430

Phe Ile Phe Asp Lys Lys Leu Leu Gly Ile Asp Val

435 440

<210> 52

<211> 455

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 52

Met Asp Ser Lys Gly Ser Ser Gln Lys Gly Ser Arg Leu Leu Leu Leu

1 5 10 15

Leu Val Val Ser Asn Leu Leu Leu Pro Gln Gly Val Leu Ala Met Asp

20 25 30

Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys Val Leu

35 40 45

Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile Ala Thr

50 55 60

Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn Gly Ser

65 70 75 80

Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys Leu Thr

85 90 95

Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys Glu Asp

100 105 110

Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys Ser Ser

115 120 125

Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys Ile Ile

130 135 140

Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys Ser Asp

145 150 155 160

Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Tyr Thr Leu Glu Gly

165 170 175

Gln Leu Ser Asp Glu Lys Thr Thr Leu Val Val Lys Glu Gly Thr Val

180 185 190

Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val Glu Leu

195 200 205

Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala Trp Asn

210 215 220

Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys Thr Lys

225 230 235 240

Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln Tyr Asp

245 250 255

Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr Lys Leu

260 265 270

Asp Glu Ile Lys Asn Ala Leu Lys Gly Ser Glu Ser Gln Val Arg Gln

275 280 285

Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val Asn Lys

290 295 300

Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp Ser Tyr

305 310 315 320

Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His Ala Ala

325 330 335

Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn Glu Asn

340 345 350

Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His Lys Phe

355 360 365

Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu Gln His

370 375 380

Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys Cys Lys

385 390 395 400

Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu Gln His

405 410 415

Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu Leu Ile

420 425 430

Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val Lys Gly

435 440 445

Ile Ala Lys Ser Arg Lys Ser

450 455

<210> 53

<211> 455

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 53

Met Asp Ser Lys Gly Ser Ser Gln Lys Gly Ser Arg Leu Leu Leu Leu

1 5 10 15

Leu Val Val Ser Asn Leu Leu Leu Pro Gln Gly Val Leu Ala Met Asp

20 25 30

Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys Val Leu

35 40 45

Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile Ala Thr

50 55 60

Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Gln Gly Ser

65 70 75 80

Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys Leu Thr

85 90 95

Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys Glu Asp

100 105 110

Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys Ser Ser

115 120 125

Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys Ile Ile

130 135 140

Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys Ser Asp

145 150 155 160

Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Tyr Thr Leu Glu Gly

165 170 175

Gln Leu Ser Asp Glu Lys Thr Thr Leu Val Val Lys Glu Gly Thr Val

180 185 190

Thr Leu Ser Lys Gln Ile Ser Lys Ser Gly Glu Val Ser Val Glu Leu

195 200 205

Gln Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala Trp Asn

210 215 220

Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys Thr Lys

225 230 235 240

Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln Tyr Asp

245 250 255

Ser Gln Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr Lys Leu

260 265 270

Asp Glu Ile Lys Asn Ala Leu Lys Gly Ser Glu Ser Gln Val Arg Gln

275 280 285

Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val Asn Lys

290 295 300

Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp Ser Tyr

305 310 315 320

Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His Ala Ala

325 330 335

Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn Glu Asn

340 345 350

Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His Lys Phe

355 360 365

Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu Gln His

370 375 380

Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys Cys Lys

385 390 395 400

Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu Gln His

405 410 415

Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu Leu Ile

420 425 430

Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val Lys Gly

435 440 445

Ile Ala Lys Ser Arg Lys Ser

450 455

<210> 54

<211> 455

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 54

Met Asp Ser Lys Gly Ser Ser Gln Lys Gly Ser Arg Leu Leu Leu Leu

1 5 10 15

Leu Val Val Ser Asn Leu Leu Leu Pro Gln Gly Val Leu Ala Met Asp

20 25 30

Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys Val Leu

35 40 45

Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile Ala Thr

50 55 60

Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn Gly Ser

65 70 75 80

Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys Leu Thr

85 90 95

Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys Glu Asp

100 105 110

Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys Ser Ser

115 120 125

Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys Ile Ile

130 135 140

Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys Ser Asp

145 150 155 160

Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Phe Thr Leu Glu Gly

165 170 175

Lys Val Ala Asn Glu Lys Thr Thr Leu Val Val Lys Glu Gly Thr Val

180 185 190

Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val Glu Leu

195 200 205

Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala Trp Asn

210 215 220

Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys Thr Lys

225 230 235 240

Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln Tyr Asp

245 250 255

Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr Lys Leu

260 265 270

Asp Glu Ile Lys Asn Ala Leu Lys Gly Ser Glu Ser Gln Val Arg Gln

275 280 285

Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val Asn Lys

290 295 300

Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp Ser Tyr

305 310 315 320

Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His Ala Ala

325 330 335

Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn Glu Asn

340 345 350

Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His Lys Phe

355 360 365

Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu Gln His

370 375 380

Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys Cys Lys

385 390 395 400

Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu Gln His

405 410 415

Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu Leu Ile

420 425 430

Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val Lys Gly

435 440 445

Ile Ala Lys Ser Arg Lys Ser

450 455

<210> 55

<211> 455

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 55

Met Asp Ser Lys Gly Ser Ser Gln Lys Gly Ser Arg Leu Leu Leu Leu

1 5 10 15

Leu Val Val Ser Asn Leu Leu Leu Pro Gln Gly Val Leu Ala Met Asp

20 25 30

Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys Val Leu

35 40 45

Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile Ala Thr

50 55 60

Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Gln Gly Ser

65 70 75 80

Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys Leu Thr

85 90 95

Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys Glu Asp

100 105 110

Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys Ser Ser

115 120 125

Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys Ile Ile

130 135 140

Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys Ser Asp

145 150 155 160

Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Phe Thr Leu Glu Gly

165 170 175

Lys Val Ala Asn Glu Lys Thr Thr Leu Val Val Lys Glu Gly Thr Val

180 185 190

Thr Leu Ser Lys Gln Ile Ser Lys Ser Gly Glu Val Ser Val Glu Leu

195 200 205

Gln Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala Trp Asn

210 215 220

Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys Thr Lys

225 230 235 240

Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln Tyr Asp

245 250 255

Ser Gln Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr Lys Leu

260 265 270

Asp Glu Ile Lys Asn Ala Leu Lys Gly Ser Glu Ser Gln Val Arg Gln

275 280 285

Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val Asn Lys

290 295 300

Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp Ser Tyr

305 310 315 320

Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His Ala Ala

325 330 335

Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn Glu Asn

340 345 350

Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His Lys Phe

355 360 365

Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu Gln His

370 375 380

Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys Cys Lys

385 390 395 400

Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu Gln His

405 410 415

Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu Leu Ile

420 425 430

Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val Lys Gly

435 440 445

Ile Ala Lys Ser Arg Lys Ser

450 455

<210> 56

<211> 455

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 56

Met Asp Ser Lys Gly Ser Ser Gln Lys Gly Ser Arg Leu Leu Leu Leu

1 5 10 15

Leu Val Val Ser Asn Leu Leu Leu Pro Gln Gly Val Leu Ala Met Asp

20 25 30

Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys Val Leu

35 40 45

Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile Ala Thr

50 55 60

Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn Gly Ser

65 70 75 80

Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys Leu Thr

85 90 95

Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys Glu Asp

100 105 110

Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys Ser Ser

115 120 125

Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys Ile Ile

130 135 140

Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys Ser Asp

145 150 155 160

Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Phe Ala Leu Glu Gly

165 170 175

Thr Leu Thr Asp Glu Lys Thr Thr Leu Val Val Lys Glu Gly Thr Val

180 185 190

Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val Glu Leu

195 200 205

Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala Trp Asn

210 215 220

Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys Thr Lys

225 230 235 240

Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln Tyr Asp

245 250 255

Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr Lys Leu

260 265 270

Asp Glu Ile Lys Asn Ala Leu Lys Gly Ser Glu Ser Gln Val Arg Gln

275 280 285

Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val Asn Lys

290 295 300

Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp Ser Tyr

305 310 315 320

Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His Ala Ala

325 330 335

Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn Glu Asn

340 345 350

Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His Lys Phe

355 360 365

Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu Gln His

370 375 380

Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys Cys Lys

385 390 395 400

Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu Gln His

405 410 415

Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu Leu Ile

420 425 430

Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val Lys Gly

435 440 445

Ile Ala Lys Ser Arg Lys Ser

450 455

<210> 57

<211> 455

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 57

Met Asp Ser Lys Gly Ser Ser Gln Lys Gly Ser Arg Leu Leu Leu Leu

1 5 10 15

Leu Val Val Ser Asn Leu Leu Leu Pro Gln Gly Val Leu Ala Met Asp

20 25 30

Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys Val Leu

35 40 45

Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile Ala Thr

50 55 60

Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Gln Gly Ser

65 70 75 80

Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys Leu Thr

85 90 95

Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys Glu Asp

100 105 110

Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys Ser Ser

115 120 125

Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys Ile Ile

130 135 140

Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys Ser Asp

145 150 155 160

Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Phe Ala Leu Glu Gly

165 170 175

Thr Leu Thr Asp Glu Lys Thr Thr Leu Val Val Lys Glu Gly Thr Val

180 185 190

Thr Leu Ser Lys Gln Ile Ser Lys Ser Gly Glu Val Ser Val Glu Leu

195 200 205

Gln Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala Trp Asn

210 215 220

Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys Thr Lys

225 230 235 240

Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln Tyr Asp

245 250 255

Ser Gln Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr Lys Leu

260 265 270

Asp Glu Ile Lys Asn Ala Leu Lys Gly Ser Glu Ser Gln Val Arg Gln

275 280 285

Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val Asn Lys

290 295 300

Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp Ser Tyr

305 310 315 320

Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His Ala Ala

325 330 335

Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn Glu Asn

340 345 350

Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His Lys Phe

355 360 365

Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu Gln His

370 375 380

Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys Cys Lys

385 390 395 400

Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu Gln His

405 410 415

Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu Leu Ile

420 425 430

Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val Lys Gly

435 440 445

Ile Ala Lys Ser Arg Lys Ser

450 455

<210> 58

<211> 455

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 58

Met Asp Ser Lys Gly Ser Ser Gln Lys Gly Ser Arg Leu Leu Leu Leu

1 5 10 15

Leu Val Val Ser Asn Leu Leu Leu Pro Gln Gly Val Leu Ala Met Asp

20 25 30

Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys Val Leu

35 40 45

Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile Ala Thr

50 55 60

Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn Gly Ser

65 70 75 80

Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys Leu Thr

85 90 95

Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys Glu Asp

100 105 110

Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys Ser Ser

115 120 125

Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys Ile Ile

130 135 140

Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys Ser Asp

145 150 155 160

Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Tyr Asp Leu Lys Gly

165 170 175

Glu Leu Ser Ser Glu Lys Thr Thr Leu Val Val Lys Glu Gly Thr Val

180 185 190

Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val Glu Leu

195 200 205

Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala Trp Asn

210 215 220

Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys Thr Lys

225 230 235 240

Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln Tyr Asp

245 250 255

Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr Lys Leu

260 265 270

Asp Glu Ile Lys Asn Ala Leu Lys Gly Ser Glu Ser Gln Val Arg Gln

275 280 285

Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val Asn Lys

290 295 300

Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp Ser Tyr

305 310 315 320

Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His Ala Ala

325 330 335

Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn Glu Asn

340 345 350

Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His Lys Phe

355 360 365

Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu Gln His

370 375 380

Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys Cys Lys

385 390 395 400

Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu Gln His

405 410 415

Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu Leu Ile

420 425 430

Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val Lys Gly

435 440 445

Ile Ala Lys Ser Arg Lys Ser

450 455

<210> 59

<211> 455

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 59

Met Asp Ser Lys Gly Ser Ser Gln Lys Gly Ser Arg Leu Leu Leu Leu

1 5 10 15

Leu Val Val Ser Asn Leu Leu Leu Pro Gln Gly Val Leu Ala Met Asp

20 25 30

Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys Val Leu

35 40 45

Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile Ala Thr

50 55 60

Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Gln Gly Ser

65 70 75 80

Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys Leu Thr

85 90 95

Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys Glu Asp

100 105 110

Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys Ser Ser

115 120 125

Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys Ile Ile

130 135 140

Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys Ser Asp

145 150 155 160

Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Tyr Asp Leu Lys Gly

165 170 175

Glu Leu Ser Ser Glu Lys Thr Thr Leu Val Val Lys Glu Gly Thr Val

180 185 190

Thr Leu Ser Lys Gln Ile Ser Lys Ser Gly Glu Val Ser Val Glu Leu

195 200 205

Gln Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala Trp Asn

210 215 220

Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys Thr Lys

225 230 235 240

Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln Tyr Asp

245 250 255

Ser Gln Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr Lys Leu

260 265 270

Asp Glu Ile Lys Asn Ala Leu Lys Gly Ser Glu Ser Gln Val Arg Gln

275 280 285

Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val Asn Lys

290 295 300

Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp Ser Tyr

305 310 315 320

Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His Ala Ala

325 330 335

Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn Glu Asn

340 345 350

Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His Lys Phe

355 360 365

Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu Gln His

370 375 380

Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys Cys Lys

385 390 395 400

Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu Gln His

405 410 415

Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu Leu Ile

420 425 430

Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val Lys Gly

435 440 445

Ile Ala Lys Ser Arg Lys Ser

450 455

<210> 60

<211> 457

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 60

Met Asp Ser Lys Gly Ser Ser Gln Lys Gly Ser Arg Leu Leu Leu Leu

1 5 10 15

Leu Val Val Ser Asn Leu Leu Leu Pro Gln Gly Val Leu Ala Met Asp

20 25 30

Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys Val Leu

35 40 45

Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile Ala Thr

50 55 60

Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Gln Gly Ser

65 70 75 80

Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys Leu Thr

85 90 95

Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys Glu Asp

100 105 110

Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys Ser Ser

115 120 125

Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys Ile Ile

130 135 140

Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys Ser Asp

145 150 155 160

Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Tyr Thr Leu Glu Gly

165 170 175

Gln Leu Ser Asp Glu Lys Thr Thr Leu Val Val Lys Glu Gly Thr Val

180 185 190

Thr Leu Ser Lys Gln Ile Ser Lys Ser Gly Glu Val Ser Val Glu Leu

195 200 205

Gln Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala Trp Asn

210 215 220

Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys Thr Lys

225 230 235 240

Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln Tyr Asp

245 250 255

Ser Gln Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr Lys Leu

260 265 270

Asp Glu Ile Lys Asn Ala Leu Lys Gly Gly Gly Ser Glu Ser Gln Val

275 280 285

Arg Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val

290 295 300

Asn Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp

305 310 315 320

Ser Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His

325 330 335

Ala Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn

340 345 350

Glu Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His

355 360 365

Lys Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu

370 375 380

Gln His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys

385 390 395 400

Cys Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu

405 410 415

Gln His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu

420 425 430

Leu Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val

435 440 445

Lys Gly Ile Ala Lys Ser Arg Lys Ser

450 455

<210> 61

<211> 461

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 61

Met Asp Ser Lys Gly Ser Ser Gln Lys Gly Ser Arg Leu Leu Leu Leu

1 5 10 15

Leu Val Val Ser Asn Leu Leu Leu Pro Gln Gly Val Leu Ala Met Asp

20 25 30

Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys Val Leu

35 40 45

Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile Ala Thr

50 55 60

Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Gln Gly Ser

65 70 75 80

Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys Leu Thr

85 90 95

Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys Glu Asp

100 105 110

Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys Ser Ser

115 120 125

Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys Ile Ile

130 135 140

Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys Ser Asp

145 150 155 160

Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Tyr Thr Leu Glu Gly

165 170 175

Gln Leu Ser Asp Glu Lys Thr Thr Leu Val Val Lys Glu Gly Thr Val

180 185 190

Thr Leu Ser Lys Gln Ile Ser Lys Ser Gly Glu Val Ser Val Glu Leu

195 200 205

Gln Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala Trp Asn

210 215 220

Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys Thr Lys

225 230 235 240

Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln Tyr Asp

245 250 255

Ser Gln Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr Lys Leu

260 265 270

Asp Glu Ile Lys Asn Ala Leu Lys Gly Gly Gly Ser Gly Gly Gly Ser

275 280 285

Glu Ser Gln Val Arg Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu

290 295 300

Asn Glu Gln Val Asn Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Ser

305 310 315 320

Met Ser Ser Trp Ser Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe

325 330 335

Leu Phe Asp His Ala Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile

340 345 350

Ile Phe Leu Asn Glu Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser

355 360 365

Ala Pro Glu His Lys Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala

370 375 380

Tyr Glu His Glu Gln His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp

385 390 395 400

His Ala Ile Lys Cys Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp

405 410 415

Tyr Val Ala Glu Gln His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu

420 425 430

Asp Lys Ile Glu Leu Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala

435 440 445

Asp Gln Tyr Val Lys Gly Ile Ala Lys Ser Arg Lys Ser

450 455 460

<210> 62

<211> 473

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 62

Met Asp Ser Lys Gly Ser Ser Gln Lys Gly Ser Arg Leu Leu Leu Leu

1 5 10 15

Leu Val Val Ser Asn Leu Leu Leu Pro Gln Gly Val Leu Ala Met Asp

20 25 30

Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys Val Leu

35 40 45

Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile Ala Thr

50 55 60

Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Gln Gly Ser

65 70 75 80

Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys Leu Thr

85 90 95

Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys Glu Asp

100 105 110

Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys Ser Ser

115 120 125

Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys Ile Ile

130 135 140

Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys Ser Asp

145 150 155 160

Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Tyr Thr Leu Glu Gly

165 170 175

Gln Leu Ser Asp Glu Lys Thr Thr Leu Val Val Lys Glu Gly Thr Val

180 185 190

Thr Leu Ser Lys Gln Ile Ser Lys Ser Gly Glu Val Ser Val Glu Leu

195 200 205

Gln Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala Trp Asn

210 215 220

Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys Thr Lys

225 230 235 240

Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln Tyr Asp

245 250 255

Ser Gln Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr Lys Leu

260 265 270

Asp Glu Ile Lys Asn Ala Leu Lys Gly Gly Gly Ser Gly Gly Gly Ser

275 280 285

Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Glu Ser Gln Val

290 295 300

Arg Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val

305 310 315 320

Asn Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp

325 330 335

Ser Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His

340 345 350

Ala Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn

355 360 365

Glu Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His

370 375 380

Lys Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu

385 390 395 400

Gln His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys

405 410 415

Cys Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu

420 425 430

Gln His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu

435 440 445

Leu Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val

450 455 460

Lys Gly Ile Ala Lys Ser Arg Lys Ser

465 470

<210> 63

<211> 455

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 63

Met Asp Ser Lys Gly Ser Ser Gln Lys Gly Ser Arg Leu Leu Leu Leu

1 5 10 15

Leu Val Val Ser Asn Leu Leu Leu Pro Gln Gly Val Leu Ala Met Asp

20 25 30

Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys Val Leu

35 40 45

Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile Ala Thr

50 55 60

Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn Gly Ala

65 70 75 80

Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys Leu Thr

85 90 95

Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys Glu Asp

100 105 110

Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys Ser Ser

115 120 125

Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys Ile Ile

130 135 140

Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys Ser Asp

145 150 155 160

Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Tyr Thr Leu Glu Gly

165 170 175

Gln Leu Ser Asp Glu Lys Thr Thr Leu Val Val Lys Glu Gly Thr Val

180 185 190

Thr Leu Ser Lys Asn Ile Ala Lys Ser Gly Glu Val Ser Val Glu Leu

195 200 205

Asn Asp Ala Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala Trp Asn

210 215 220

Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys Thr Lys

225 230 235 240

Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln Tyr Asp

245 250 255

Ser Asn Gly Ala Lys Leu Glu Gly Ser Ala Val Glu Ile Thr Lys Leu

260 265 270

Asp Glu Ile Lys Asn Ala Leu Lys Gly Ser Glu Ser Gln Val Arg Gln

275 280 285

Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val Asn Lys

290 295 300

Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp Ser Tyr

305 310 315 320

Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His Ala Ala

325 330 335

Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn Glu Asn

340 345 350

Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His Lys Phe

355 360 365

Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu Gln His

370 375 380

Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys Cys Lys

385 390 395 400

Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu Gln His

405 410 415

Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu Leu Ile

420 425 430

Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val Lys Gly

435 440 445

Ile Ala Lys Ser Arg Lys Ser

450 455

<210> 64

<211> 455

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 64

Met Asp Ser Lys Gly Ser Ser Gln Lys Gly Ser Arg Leu Leu Leu Leu

1 5 10 15

Leu Val Val Ser Asn Leu Leu Leu Pro Gln Gly Val Leu Ala Met Asp

20 25 30

Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys Val Leu

35 40 45

Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile Ala Thr

50 55 60

Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn Gly Ser

65 70 75 80

Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys Leu Thr

85 90 95

Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys Glu Asp

100 105 110

Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys Ser Ser

115 120 125

Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys Ile Ile

130 135 140

Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys Ser Asp

145 150 155 160

Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Tyr Val Leu Glu Gly

165 170 175

Thr Leu Thr Ala Glu Lys Thr Thr Leu Val Val Lys Glu Gly Thr Val

180 185 190

Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val Glu Leu

195 200 205

Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala Trp Asn

210 215 220

Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys Thr Lys

225 230 235 240

Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln Tyr Asp

245 250 255

Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr Lys Leu

260 265 270

Asp Glu Ile Lys Asn Ala Leu Lys Gly Ser Glu Ser Gln Val Arg Gln

275 280 285

Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val Asn Lys

290 295 300

Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp Ser Tyr

305 310 315 320

Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His Ala Ala

325 330 335

Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn Glu Asn

340 345 350

Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His Lys Phe

355 360 365

Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu Gln His

370 375 380

Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys Cys Lys

385 390 395 400

Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu Gln His

405 410 415

Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu Leu Ile

420 425 430

Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val Lys Gly

435 440 445

Ile Ala Lys Ser Arg Lys Ser

450 455

<210> 65

<211> 455

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 65

Met Asp Ser Lys Gly Ser Ser Gln Lys Gly Ser Arg Leu Leu Leu Leu

1 5 10 15

Leu Val Val Ser Asn Leu Leu Leu Pro Gln Gly Val Leu Ala Met Asp

20 25 30

Glu Lys Asn Ser Ala Ser Val Asp Leu Pro Gly Glu Met Lys Val Leu

35 40 45

Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Lys Ala Thr

50 55 60

Val Asp Lys Ile Glu Leu Lys Gly Thr Ser Asp Lys Asp Asn Gly Ser

65 70 75 80

Gly Val Leu Glu Gly Thr Lys Asp Asp Lys Ser Lys Ala Lys Leu Thr

85 90 95

Ile Ala Asp Asp Leu Ser Lys Thr Thr Phe Glu Leu Phe Lys Glu Asp

100 105 110

Gly Lys Thr Leu Val Ser Arg Lys Val Ser Ser Lys Asp Lys Thr Ser

115 120 125

Thr Asp Glu Met Phe Asn Glu Lys Gly Glu Leu Ser Ala Lys Thr Met

130 135 140

Thr Arg Glu Asn Gly Thr Lys Leu Glu Tyr Thr Glu Met Lys Ser Asp

145 150 155 160

Gly Thr Gly Lys Ala Lys Glu Val Leu Lys Asn Phe Thr Leu Glu Gly

165 170 175

Lys Val Ala Asn Asp Lys Val Thr Leu Glu Val Lys Glu Gly Thr Val

180 185 190

Thr Leu Ser Lys Glu Ile Ala Lys Ser Gly Glu Val Thr Val Ala Leu

195 200 205

Asn Asp Thr Asn Thr Thr Gln Ala Thr Lys Lys Thr Gly Ala Trp Asp

210 215 220

Ser Lys Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Lys Lys Thr Thr

225 230 235 240

Gln Leu Val Phe Thr Lys Gln Asp Thr Ile Thr Val Gln Lys Tyr Asp

245 250 255

Ser Ala Gly Thr Asn Leu Glu Gly Thr Ala Val Glu Ile Lys Thr Leu

260 265 270

Asp Glu Leu Lys Asn Ala Leu Lys Gly Ser Glu Ser Gln Val Arg Gln

275 280 285

Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val Asn Lys

290 295 300

Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp Ser Tyr

305 310 315 320

Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His Ala Ala

325 330 335

Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn Glu Asn

340 345 350

Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His Lys Phe

355 360 365

Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu Gln His

370 375 380

Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys Cys Lys

385 390 395 400

Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu Gln His

405 410 415

Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu Leu Ile

420 425 430

Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val Lys Gly

435 440 445

Ile Ala Lys Ser Arg Lys Ser

450 455

<210> 66

<211> 455

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 66

Met Asp Ser Lys Gly Ser Ser Gln Lys Gly Ser Arg Leu Leu Leu Leu

1 5 10 15

Leu Val Val Ser Asn Leu Leu Leu Pro Gln Gly Val Leu Ala Met Asp

20 25 30

Glu Lys Asn Ser Ala Ser Val Asp Leu Pro Gly Glu Met Lys Val Leu

35 40 45

Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Lys Ala Thr

50 55 60

Val Asp Lys Ile Glu Leu Lys Gly Thr Ser Asp Lys Asp Gln Gly Ser

65 70 75 80

Gly Val Leu Glu Gly Thr Lys Asp Asp Lys Ser Lys Ala Lys Leu Thr

85 90 95

Ile Ala Asp Asp Leu Ser Lys Thr Thr Phe Glu Leu Phe Lys Glu Asp

100 105 110

Gly Lys Thr Leu Val Ser Arg Lys Val Ser Ser Lys Asp Lys Thr Ser

115 120 125

Thr Asp Glu Met Phe Asn Glu Lys Gly Glu Leu Ser Ala Lys Thr Met

130 135 140

Thr Arg Glu Gln Gly Thr Lys Leu Glu Tyr Thr Glu Met Lys Ser Asp

145 150 155 160

Gly Thr Gly Lys Ala Lys Glu Val Leu Lys Gln Phe Thr Leu Glu Gly

165 170 175

Lys Val Ala Asn Asp Lys Val Thr Leu Glu Val Lys Glu Gly Thr Val

180 185 190

Thr Leu Ser Lys Glu Ile Ala Lys Ser Gly Glu Val Thr Val Ala Leu

195 200 205

Gln Asp Thr Gln Thr Thr Gln Ala Thr Lys Lys Thr Gly Ala Trp Asp

210 215 220

Ser Lys Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Lys Lys Thr Thr

225 230 235 240

Gln Leu Val Phe Thr Lys Gln Asp Thr Ile Thr Val Gln Lys Tyr Asp

245 250 255

Ser Ala Gly Thr Asn Leu Glu Gly Thr Ala Val Glu Ile Lys Thr Leu

260 265 270

Asp Glu Leu Lys Asn Ala Leu Lys Gly Ser Glu Ser Gln Val Arg Gln

275 280 285

Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val Asn Lys

290 295 300

Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp Ser Tyr

305 310 315 320

Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His Ala Ala

325 330 335

Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn Glu Asn

340 345 350

Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His Lys Phe

355 360 365

Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu Gln His

370 375 380

Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys Cys Lys

385 390 395 400

Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu Gln His

405 410 415

Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu Leu Ile

420 425 430

Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val Lys Gly

435 440 445

Ile Ala Lys Ser Arg Lys Ser

450 455

<210> 67

<211> 456

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 67

Met Asp Ser Lys Gly Ser Ser Gln Lys Gly Ser Arg Leu Leu Leu Leu

1 5 10 15

Leu Val Val Ser Asn Leu Leu Leu Pro Gln Gly Val Leu Ala Met Asp

20 25 30

Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Gly Met Lys Val Leu

35 40 45

Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Met Ala Thr

50 55 60

Val Glu Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Ser Asn Gly Ser

65 70 75 80

Gly Val Leu Glu Gly Glu Lys Ala Asp Lys Ser Lys Ala Lys Leu Thr

85 90 95

Ile Ser Gln Asp Leu Asn Gln Thr Thr Phe Glu Ile Phe Lys Glu Asp

100 105 110

Gly Lys Thr Leu Val Ser Arg Lys Val Asn Ser Lys Asp Lys Ser Ser

115 120 125

Thr Glu Glu Lys Phe Asn Asp Lys Gly Lys Leu Ser Glu Lys Val Val

130 135 140

Thr Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Glu Ile Lys Asn Asp

145 150 155 160

Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Phe Ala Leu Glu Gly

165 170 175

Thr Leu Thr Asp Gly Gly Glu Thr Lys Leu Thr Val Thr Glu Gly Thr

180 185 190

Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Ile Thr Val Ala

195 200 205

Leu Asn Asp Thr Glu Thr Thr Pro Ala Asp Lys Lys Thr Gly Glu Trp

210 215 220

Lys Ser Asp Thr Ser Thr Leu Thr Ile Ser Lys Asn Ser Gln Lys Pro

225 230 235 240

Lys Gln Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Asn Tyr

245 250 255

Asn Arg Ala Gly Asn Ala Leu Glu Gly Ser Pro Ala Glu Ile Lys Asp

260 265 270

Leu Ala Glu Leu Lys Ala Ala Leu Lys Gly Ser Glu Ser Gln Val Arg

275 280 285

Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val Asn

290 295 300

Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp Ser

305 310 315 320

Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His Ala

325 330 335

Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn Glu

340 345 350

Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His Lys

355 360 365

Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu Gln

370 375 380

His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys Cys

385 390 395 400

Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu Gln

405 410 415

His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu Leu

420 425 430

Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val Lys

435 440 445

Gly Ile Ala Lys Ser Arg Lys Ser

450 455

<210> 68

<211> 456

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 68

Met Asp Ser Lys Gly Ser Ser Gln Lys Gly Ser Arg Leu Leu Leu Leu

1 5 10 15

Leu Val Val Ser Asn Leu Leu Leu Pro Gln Gly Val Leu Ala Met Asp

20 25 30

Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Gly Met Lys Val Leu

35 40 45

Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Met Ala Thr

50 55 60

Val Glu Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Ser Gln Gly Ser

65 70 75 80

Gly Val Leu Glu Gly Glu Lys Ala Asp Lys Ser Lys Ala Lys Leu Thr

85 90 95

Ile Ser Gln Asp Leu Gln Gln Thr Thr Phe Glu Ile Phe Lys Glu Asp

100 105 110

Gly Lys Thr Leu Val Ser Arg Lys Val Asn Ser Lys Asp Lys Ser Ser

115 120 125

Thr Glu Glu Lys Phe Asn Asp Lys Gly Lys Leu Ser Glu Lys Val Val

130 135 140

Thr Arg Ala Gln Gly Thr Arg Leu Glu Tyr Thr Glu Ile Lys Asn Asp

145 150 155 160

Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Phe Ala Leu Glu Gly

165 170 175

Thr Leu Thr Asp Gly Gly Glu Thr Lys Leu Thr Val Thr Glu Gly Thr

180 185 190

Val Thr Leu Ser Lys Gln Ile Ser Lys Ser Gly Glu Ile Thr Val Ala

195 200 205

Leu Gln Asp Thr Glu Thr Thr Pro Ala Asp Lys Lys Thr Gly Glu Trp

210 215 220

Lys Ser Asp Thr Ser Thr Leu Thr Ile Ser Lys Asn Ser Gln Lys Pro

225 230 235 240

Lys Gln Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Asn Tyr

245 250 255

Asn Arg Ala Gly Asn Ala Leu Glu Gly Ser Pro Ala Glu Ile Lys Asp

260 265 270

Leu Ala Glu Leu Lys Ala Ala Leu Lys Gly Ser Glu Ser Gln Val Arg

275 280 285

Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val Asn

290 295 300

Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp Ser

305 310 315 320

Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His Ala

325 330 335

Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn Glu

340 345 350

Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His Lys

355 360 365

Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu Gln

370 375 380

His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys Cys

385 390 395 400

Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu Gln

405 410 415

His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu Leu

420 425 430

Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val Lys

435 440 445

Gly Ile Ala Lys Ser Arg Lys Ser

450 455

<210> 69

<211> 455

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 69

Met Asp Ser Lys Gly Ser Ser Gln Lys Gly Ser Arg Leu Leu Leu Leu

1 5 10 15

Leu Val Val Ser Asn Leu Leu Leu Pro Gln Gly Val Leu Ala Met Asp

20 25 30

Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys Val Leu

35 40 45

Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Met Ala Thr

50 55 60

Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Ser Asn Gly Ser

65 70 75 80

Gly Thr Leu Glu Gly Glu Lys Ser Asp Lys Ser Lys Ala Lys Leu Thr

85 90 95

Ile Ser Glu Asp Leu Ser Lys Thr Thr Phe Glu Ile Phe Lys Glu Asp

100 105 110

Gly Lys Thr Leu Val Ser Lys Lys Val Asn Ser Lys Asp Lys Ser Ser

115 120 125

Ile Glu Glu Lys Phe Asn Ala Lys Gly Glu Leu Ser Glu Lys Thr Ile

130 135 140

Leu Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Glu Ile Lys Ser Asp

145 150 155 160

Gly Thr Gly Lys Ala Lys Glu Val Leu Lys Asp Phe Ala Leu Glu Gly

165 170 175

Thr Leu Ala Ala Asp Lys Thr Thr Leu Lys Val Thr Glu Gly Thr Val

180 185 190

Val Leu Ser Lys His Ile Pro Asn Ser Gly Glu Ile Thr Val Glu Leu

195 200 205

Asn Asp Ser Asn Ser Thr Gln Ala Thr Lys Lys Thr Gly Lys Trp Asp

210 215 220

Ser Asn Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Lys Lys Thr Lys

225 230 235 240

Asn Ile Val Phe Thr Lys Glu Asp Thr Ile Thr Val Gln Lys Tyr Asp

245 250 255

Ser Ala Gly Thr Asn Leu Glu Gly Asn Ala Val Glu Ile Lys Thr Leu

260 265 270

Asp Glu Leu Lys Asn Ala Leu Lys Gly Ser Glu Ser Gln Val Arg Gln

275 280 285

Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val Asn Lys

290 295 300

Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp Ser Tyr

305 310 315 320

Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His Ala Ala

325 330 335

Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn Glu Asn

340 345 350

Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His Lys Phe

355 360 365

Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu Gln His

370 375 380

Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys Cys Lys

385 390 395 400

Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu Gln His

405 410 415

Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu Leu Ile

420 425 430

Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val Lys Gly

435 440 445

Ile Ala Lys Ser Arg Lys Ser

450 455

<210> 70

<211> 455

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 70

Met Asp Ser Lys Gly Ser Ser Gln Lys Gly Ser Arg Leu Leu Leu Leu

1 5 10 15

Leu Val Val Ser Asn Leu Leu Leu Pro Gln Gly Val Leu Ala Met Asp

20 25 30

Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys Val Leu

35 40 45

Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Met Ala Thr

50 55 60

Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Ser Gln Gly Ser

65 70 75 80

Gly Thr Leu Glu Gly Glu Lys Ser Asp Lys Ser Lys Ala Lys Leu Thr

85 90 95

Ile Ser Glu Asp Leu Ser Lys Thr Thr Phe Glu Ile Phe Lys Glu Asp

100 105 110

Gly Lys Thr Leu Val Ser Lys Lys Val Asn Ser Lys Asp Lys Ser Ser

115 120 125

Ile Glu Glu Lys Phe Asn Ala Lys Gly Glu Leu Ser Glu Lys Thr Ile

130 135 140

Leu Arg Ala Gln Gly Thr Arg Leu Glu Tyr Thr Glu Ile Lys Ser Asp

145 150 155 160

Gly Thr Gly Lys Ala Lys Glu Val Leu Lys Asp Phe Ala Leu Glu Gly

165 170 175

Thr Leu Ala Ala Asp Lys Thr Thr Leu Lys Val Thr Glu Gly Thr Val

180 185 190

Val Leu Ser Lys His Ile Pro Asn Ser Gly Glu Ile Thr Val Glu Leu

195 200 205

Gln Asp Ser Gln Ser Thr Gln Ala Thr Lys Lys Thr Gly Lys Trp Asp

210 215 220

Ser Gln Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Lys Lys Thr Lys

225 230 235 240

Asn Ile Val Phe Thr Lys Glu Asp Thr Ile Thr Val Gln Lys Tyr Asp

245 250 255

Ser Ala Gly Thr Asn Leu Glu Gly Asn Ala Val Glu Ile Lys Thr Leu

260 265 270

Asp Glu Leu Lys Asn Ala Leu Lys Gly Ser Glu Ser Gln Val Arg Gln

275 280 285

Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val Asn Lys

290 295 300

Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp Ser Tyr

305 310 315 320

Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His Ala Ala

325 330 335

Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn Glu Asn

340 345 350

Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His Lys Phe

355 360 365

Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu Gln His

370 375 380

Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys Cys Lys

385 390 395 400

Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu Gln His

405 410 415

Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu Leu Ile

420 425 430

Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val Lys Gly

435 440 445

Ile Ala Lys Ser Arg Lys Ser

450 455

<210> 71

<211> 456

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 71

Met Asp Ser Lys Gly Ser Ser Gln Lys Gly Ser Arg Leu Leu Leu Leu

1 5 10 15

Leu Val Val Ser Asn Leu Leu Leu Pro Gln Gly Val Leu Ala Met Asp

20 25 30

Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Gly Met Lys Val Leu

35 40 45

Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Met Ala Thr

50 55 60

Val Glu Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn Gly Ser

65 70 75 80

Gly Thr Leu Glu Gly Glu Lys Thr Asp Lys Ser Lys Val Lys Leu Thr

85 90 95

Ile Ala Glu Asp Leu Ser Lys Thr Thr Phe Glu Ile Phe Lys Glu Asp

100 105 110

Gly Lys Thr Leu Val Ser Lys Lys Val Thr Leu Lys Asp Lys Ser Ser

115 120 125

Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Ile Ser Glu Lys Thr Ile

130 135 140

Val Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Asp Ile Lys Ser Asp

145 150 155 160

Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Asp Phe Thr Leu Glu Gly

165 170 175

Thr Leu Ala Ala Asp Gly Lys Thr Thr Leu Lys Val Thr Glu Gly Thr

180 185 190

Val Val Leu Ser Lys Asn Ile Leu Lys Ser Gly Glu Ile Thr Val Ala

195 200 205

Leu Asp Asp Ser Asp Thr Thr Gln Ala Thr Lys Lys Thr Gly Lys Trp

210 215 220

Asp Ser Lys Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Gln Lys Thr

225 230 235 240

Lys Asn Leu Val Phe Thr Lys Glu Asp Thr Ile Thr Val Gln Lys Tyr

245 250 255

Asp Ser Ala Gly Thr Asn Leu Glu Gly Lys Ala Val Glu Ile Thr Thr

260 265 270

Leu Glu Lys Leu Lys Asp Ala Leu Lys Gly Ser Glu Ser Gln Val Arg

275 280 285

Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val Asn

290 295 300

Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp Ser

305 310 315 320

Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His Ala

325 330 335

Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn Glu

340 345 350

Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His Lys

355 360 365

Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu Gln

370 375 380

His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys Cys

385 390 395 400

Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu Gln

405 410 415

His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu Leu

420 425 430

Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val Lys

435 440 445

Gly Ile Ala Lys Ser Arg Lys Ser

450 455

<210> 72

<211> 456

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 72

Met Asp Ser Lys Gly Ser Ser Gln Lys Gly Ser Arg Leu Leu Leu Leu

1 5 10 15

Leu Val Val Ser Asn Leu Leu Leu Pro Gln Gly Val Leu Ala Met Asp

20 25 30

Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Gly Met Lys Val Leu

35 40 45

Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Met Ala Thr

50 55 60

Val Glu Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Gln Gly Ser

65 70 75 80

Gly Thr Leu Glu Gly Glu Lys Thr Asp Lys Ser Lys Val Lys Leu Thr

85 90 95

Ile Ala Glu Asp Leu Ser Lys Thr Thr Phe Glu Ile Phe Lys Glu Asp

100 105 110

Gly Lys Thr Leu Val Ser Lys Lys Val Thr Leu Lys Asp Lys Ser Ser

115 120 125

Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Ile Ser Glu Lys Thr Ile

130 135 140

Val Arg Ala Gln Gly Thr Arg Leu Glu Tyr Thr Asp Ile Lys Ser Asp

145 150 155 160

Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Asp Phe Thr Leu Glu Gly

165 170 175

Thr Leu Ala Ala Asp Gly Lys Thr Thr Leu Lys Val Thr Glu Gly Thr

180 185 190

Val Val Leu Ser Lys Asn Ile Leu Lys Ser Gly Glu Ile Thr Val Ala

195 200 205

Leu Asp Asp Ser Asp Thr Thr Gln Ala Thr Lys Lys Thr Gly Lys Trp

210 215 220

Asp Ser Lys Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Gln Lys Thr

225 230 235 240

Lys Asn Leu Val Phe Thr Lys Glu Asp Thr Ile Thr Val Gln Lys Tyr

245 250 255

Asp Ser Ala Gly Thr Asn Leu Glu Gly Lys Ala Val Glu Ile Thr Thr

260 265 270

Leu Glu Lys Leu Lys Asp Ala Leu Lys Gly Ser Glu Ser Gln Val Arg

275 280 285

Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val Asn

290 295 300

Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp Ser

305 310 315 320

Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His Ala

325 330 335

Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn Glu

340 345 350

Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His Lys

355 360 365

Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu Gln

370 375 380

His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys Cys

385 390 395 400

Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu Gln

405 410 415

His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu Leu

420 425 430

Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val Lys

435 440 445

Gly Ile Ala Lys Ser Arg Lys Ser

450 455

<210> 73

<211> 456

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 73

Met Asp Ser Lys Gly Ser Ser Gln Lys Gly Ser Arg Leu Leu Leu Leu

1 5 10 15

Leu Val Val Ser Asn Leu Leu Leu Pro Gln Gly Val Leu Ala Met Asp

20 25 30

Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Gly Met Thr Val Leu

35 40 45

Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Glu Ala Thr

50 55 60

Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Gln Gly Ser

65 70 75 80

Gly Thr Leu Glu Gly Glu Lys Thr Asp Lys Ser Lys Val Lys Ser Thr

85 90 95

Ile Ala Asp Asp Leu Ser Gln Thr Lys Phe Glu Ile Phe Lys Glu Asp

100 105 110

Gly Lys Thr Leu Val Ser Lys Lys Val Thr Leu Lys Asp Lys Ser Ser

115 120 125

Thr Glu Glu Lys Phe Asn Gly Lys Gly Glu Thr Ser Glu Lys Thr Ile

130 135 140

Val Arg Ala Gln Gly Thr Arg Leu Glu Tyr Thr Asp Ile Lys Ser Asp

145 150 155 160

Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Asp Phe Thr Leu Glu Gly

165 170 175

Thr Leu Ala Ala Asp Gly Lys Thr Thr Leu Lys Val Thr Glu Gly Thr

180 185 190

Val Val Leu Ser Lys Asn Ile Leu Lys Ser Gly Glu Ile Thr Ala Ala

195 200 205

Leu Asp Asp Ser Asp Thr Thr Arg Ala Thr Lys Lys Thr Gly Lys Trp

210 215 220

Asp Ser Lys Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Gln Lys Thr

225 230 235 240

Lys Asn Leu Val Phe Thr Lys Glu Asp Thr Ile Thr Val Gln Arg Tyr

245 250 255

Asp Ser Ala Gly Thr Asn Leu Glu Gly Lys Ala Val Glu Ile Thr Thr

260 265 270

Leu Lys Glu Leu Lys Asn Ala Leu Lys Gly Ser Glu Ser Gln Val Arg

275 280 285

Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val Asn

290 295 300

Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp Ser

305 310 315 320

Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His Ala

325 330 335

Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn Glu

340 345 350

Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His Lys

355 360 365

Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu Gln

370 375 380

His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys Cys

385 390 395 400

Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu Gln

405 410 415

His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu Leu

420 425 430

Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val Lys

435 440 445

Gly Ile Ala Lys Ser Arg Lys Ser

450 455

<210> 74

<211> 456

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 74

Met Asp Ser Lys Gly Ser Ser Gln Lys Gly Ser Arg Leu Leu Leu Leu

1 5 10 15

Leu Val Val Ser Asn Leu Leu Leu Pro Gln Gly Val Leu Ala Met Asp

20 25 30

Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Gly Met Thr Val Leu

35 40 45

Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Glu Ala Thr

50 55 60

Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn Gly Ser

65 70 75 80

Gly Thr Leu Glu Gly Glu Lys Thr Asp Lys Ser Lys Val Lys Ser Thr

85 90 95

Ile Ala Asp Asp Leu Ser Gln Thr Lys Phe Glu Ile Phe Lys Glu Asp

100 105 110

Gly Lys Thr Leu Val Ser Lys Lys Val Thr Leu Lys Asp Lys Ser Ser

115 120 125

Thr Glu Glu Lys Phe Asn Gly Lys Gly Glu Thr Ser Glu Lys Thr Ile

130 135 140

Val Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Asp Ile Lys Ser Asp

145 150 155 160

Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Asp Phe Thr Leu Glu Gly

165 170 175

Thr Leu Ala Ala Asp Gly Lys Thr Thr Leu Lys Val Thr Glu Gly Thr

180 185 190

Val Val Leu Ser Lys Asn Ile Leu Lys Ser Gly Glu Ile Thr Ala Ala

195 200 205

Leu Asp Asp Ser Asp Thr Thr Arg Ala Thr Lys Lys Thr Gly Lys Trp

210 215 220

Asp Ser Lys Thr Ser Thr Leu Thr Ile Ser Val Asn Ser Gln Lys Thr

225 230 235 240

Lys Asn Leu Val Phe Thr Lys Glu Asp Thr Ile Thr Val Gln Arg Tyr

245 250 255

Asp Ser Ala Gly Thr Asn Leu Glu Gly Lys Ala Val Glu Ile Thr Thr

260 265 270

Leu Lys Glu Leu Lys Asn Ala Leu Lys Gly Ser Glu Ser Gln Val Arg

275 280 285

Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val Asn

290 295 300

Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp Ser

305 310 315 320

Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His Ala

325 330 335

Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn Glu

340 345 350

Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His Lys

355 360 365

Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu Gln

370 375 380

His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys Cys

385 390 395 400

Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu Gln

405 410 415

His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu Leu

420 425 430

Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val Lys

435 440 445

Gly Ile Ala Lys Ser Arg Lys Ser

450 455

<210> 75

<211> 456

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 75

Met Asp Ser Lys Gly Ser Ser Gln Lys Gly Ser Arg Leu Leu Leu Leu

1 5 10 15

Leu Val Val Ser Asn Leu Leu Leu Pro Gln Gly Val Leu Ala Met Asp

20 25 30

Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys Val Leu

35 40 45

Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Glu Ala Thr

50 55 60

Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn Gly Ser

65 70 75 80

Gly Val Leu Glu Gly Val Lys Ala Ala Lys Ser Lys Ala Lys Leu Thr

85 90 95

Ile Ala Asp Asp Leu Ser Gln Thr Lys Phe Glu Ile Phe Lys Glu Asp

100 105 110

Gly Lys Thr Leu Val Ser Lys Lys Val Thr Leu Lys Asp Lys Ser Ser

115 120 125

Thr Glu Glu Lys Phe Asn Asp Lys Gly Lys Leu Ser Glu Lys Val Val

130 135 140

Thr Arg Ala Asn Gly Thr Arg Leu Glu Tyr Thr Glu Ile Gln Asn Asp

145 150 155 160

Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Ser Leu Thr Leu Glu Gly

165 170 175

Thr Leu Thr Ala Asp Gly Glu Thr Lys Leu Thr Val Glu Ala Gly Thr

180 185 190

Val Thr Leu Ser Lys Asn Ile Ser Glu Ser Gly Glu Ile Thr Val Glu

195 200 205

Leu Lys Asp Thr Glu Thr Thr Pro Ala Asp Lys Lys Ser Gly Thr Trp

210 215 220

Asp Ser Lys Thr Ser Thr Leu Thr Ile Ser Lys Asn Ser Gln Lys Thr

225 230 235 240

Lys Gln Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Lys Tyr

245 250 255

Asn Thr Ala Gly Thr Lys Leu Glu Gly Ser Pro Ala Glu Ile Lys Asp

260 265 270

Leu Glu Ala Leu Lys Ala Ala Leu Lys Gly Ser Glu Ser Gln Val Arg

275 280 285

Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val Asn

290 295 300

Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp Ser

305 310 315 320

Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His Ala

325 330 335

Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn Glu

340 345 350

Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His Lys

355 360 365

Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu Gln

370 375 380

His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys Cys

385 390 395 400

Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu Gln

405 410 415

His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu Leu

420 425 430

Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val Lys

435 440 445

Gly Ile Ala Lys Ser Arg Lys Ser

450 455

<210> 76

<211> 456

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 76

Met Asp Ser Lys Gly Ser Ser Gln Lys Gly Ser Arg Leu Leu Leu Leu

1 5 10 15

Leu Val Val Ser Asn Leu Leu Leu Pro Gln Gly Val Leu Ala Met Asp

20 25 30

Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys Val Leu

35 40 45

Val Ser Lys Glu Lys Asp Lys Asp Gly Lys Tyr Ser Leu Glu Ala Thr

50 55 60

Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Gln Gly Ser

65 70 75 80

Gly Val Leu Glu Gly Val Lys Ala Ala Lys Ser Lys Ala Lys Leu Thr

85 90 95

Ile Ala Asp Asp Leu Ser Gln Thr Lys Phe Glu Ile Phe Lys Glu Asp

100 105 110

Gly Lys Thr Leu Val Ser Lys Lys Val Thr Leu Lys Asp Lys Ser Ser

115 120 125

Thr Glu Glu Lys Phe Asn Asp Lys Gly Lys Leu Ser Glu Lys Val Val

130 135 140

Thr Arg Ala Gln Gly Thr Arg Leu Glu Tyr Thr Glu Ile Gln Asn Asp

145 150 155 160

Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Ser Leu Thr Leu Glu Gly

165 170 175

Thr Leu Thr Ala Asp Gly Glu Thr Lys Leu Thr Val Glu Ala Gly Thr

180 185 190

Val Thr Leu Ser Lys Gln Ile Ser Glu Ser Gly Glu Ile Thr Val Glu

195 200 205

Leu Lys Asp Thr Glu Thr Thr Pro Ala Asp Lys Lys Ser Gly Thr Trp

210 215 220

Asp Ser Lys Thr Ser Thr Leu Thr Ile Ser Lys Asn Ser Gln Lys Thr

225 230 235 240

Lys Gln Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Lys Tyr

245 250 255

Asn Thr Ala Gly Thr Lys Leu Glu Gly Ser Pro Ala Glu Ile Lys Asp

260 265 270

Leu Glu Ala Leu Lys Ala Ala Leu Lys Gly Ser Glu Ser Gln Val Arg

275 280 285

Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu Asn Glu Gln Val Asn

290 295 300

Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp Ser

305 310 315 320

Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His Ala

325 330 335

Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn Glu

340 345 350

Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His Lys

355 360 365

Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu Gln

370 375 380

His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys Cys

385 390 395 400

Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu Gln

405 410 415

His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu Leu

420 425 430

Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val Lys

435 440 445

Gly Ile Ala Lys Ser Arg Lys Ser

450 455

<210> 77

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 77

Tyr Val Leu Glu Gly Thr Leu Thr Ala

5

<210> 78

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 78

Tyr Val Ile Glu Gly Thr Ser Lys Gln

5

<210> 79

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 79

Phe Thr Leu Glu Gly Lys Val Ala Asn

5

<210> 80

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 80

Phe Ala Leu Glu Gly Thr Leu Thr Asp

5

<210> 81

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 81

Tyr Thr Leu Glu Gly Gln Leu Ser Asp

5

<210> 82

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 82

Tyr Asp Leu Lys Gly Glu Leu Ser Ser

5

<210> 83

<211> 273

<212> PROTEIN

<213> Borreliella burgdorferi

<400> 83

Met Lys Lys Tyr Leu Leu Gly Ile Gly Leu Ile Leu Ala Leu Ile Ala

1 5 10 15

Cys Lys Gln Asn Val Ser Ser Leu Asp Glu Lys Asn Ser Val Ser Val

20 25 30

Asp Leu Pro Gly Glu Met Lys Val Leu Val Ser Lys Glu Lys Asn Lys

35 40 45

Asp Gly Lys Tyr Asp Leu Ile Ala Thr Val Asp Lys Leu Glu Leu Lys

50 55 60

Gly Thr Ser Asp Lys Asn Asn Gly Ser Gly Val Leu Glu Gly Val Lys

65 70 75 80

Ala Asp Lys Ser Lys Val Lys Leu Thr Ile Ser Asp Asp Leu Gly Gln

85 90 95

Thr Thr Leu Glu Val Phe Lys Glu Asp Gly Lys Thr Leu Val Ser Lys

100 105 110

Lys Val Thr Ser Lys Asp Lys Ser Ser Thr Glu Glu Lys Phe Asn Glu

115 120 125

Lys Gly Glu Val Ser Glu Lys Ile Ile Thr Arg Ala Asp Gly Thr Arg

130 135 140

Leu Glu Tyr Thr Gly Ile Lys Ser Asp Gly Ser Gly Lys Ala Lys Glu

145 150 155 160

Val Leu Lys Gly Tyr Val Leu Glu Gly Thr Leu Thr Ala Glu Lys Thr

165 170 175

Thr Leu Val Val Lys Glu Gly Thr Val Thr Leu Ser Lys Asn Ile Ser

180 185 190

Lys Ser Gly Glu Val Ser Val Glu Leu Asn Asp Thr Asp Ser Ser Ala

195 200 205

Ala Thr Lys Lys Thr Ala Ala Trp Asn Ser Gly Thr Ser Thr Leu Thr

210 215 220

Ile Thr Val Asn Ser Lys Lys Thr Lys Asp Leu Val Phe Thr Lys Glu

225 230 235 240

Asn Thr Ile Thr Val Gln Gln Tyr Asp Ser Asn Gly Thr Lys Leu Glu

245 250 255

Gly Ser Ala Val Glu Ile Thr Lys Leu Asp Glu Ile Lys Asn Ala Leu

260 265 270

Lys

<210> 84

<211> 273

<212> PROTEIN

<213> Borreliella afzelii

<400> 84

Met Lys Lys Tyr Leu Leu Gly Ile Gly Leu Ile Leu Ala Leu Ile Ala

1 5 10 15

Cys Lys Gln Asn Val Ser Ser Leu Asp Glu Lys Asn Ser Ala Ser Val

20 25 30

Asp Leu Pro Gly Glu Met Lys Val Leu Val Ser Lys Glu Lys Asp Lys

35 40 45

Asp Gly Lys Tyr Ser Leu Lys Ala Thr Val Asp Lys Ile Glu Leu Lys

50 55 60

Gly Thr Ser Asp Lys Asp Asn Gly Ser Gly Val Leu Glu Gly Thr Lys

65 70 75 80

Asp Asp Lys Ser Lys Ala Lys Leu Thr Ile Ala Asp Asp Leu Ser Lys

85 90 95

Thr Thr Phe Glu Leu Phe Lys Glu Asp Gly Lys Thr Leu Val Ser Arg

100 105 110

Lys Val Ser Ser Lys Asp Lys Thr Ser Thr Asp Glu Met Phe Asn Glu

115 120 125

Lys Gly Glu Leu Ser Ala Lys Thr Met Thr Arg Glu Asn Gly Thr Lys

130 135 140

Leu Glu Tyr Thr Glu Met Lys Ser Asp Gly Thr Gly Lys Ala Lys Glu

145 150 155 160

Val Leu Lys Asn Phe Thr Leu Glu Gly Lys Val Ala Asn Asp Lys Val

165 170 175

Thr Leu Glu Val Lys Glu Gly Thr Val Thr Leu Ser Lys Glu Ile Ala

180 185 190

Lys Ser Gly Glu Val Thr Val Ala Leu Asn Asp Thr Asn Thr Thr Gln

195 200 205

Ala Thr Lys Lys Thr Gly Ala Trp Asp Ser Lys Thr Ser Thr Leu Thr

210 215 220

Ile Ser Val Asn Ser Lys Lys Thr Thr Gln Leu Val Phe Thr Lys Gln

225 230 235 240

Asp Thr Ile Thr Val Gln Lys Tyr Asp Ser Ala Gly Thr Asn Leu Glu

245 250 255

Gly Thr Ala Val Glu Ile Lys Thr Leu Asp Glu Leu Lys Asn Ala Leu

260 265 270

Lys

<210> 85

<211> 274

<212> PROTEIN

<213> Borreliella garinii

<400> 85

Met Lys Lys Tyr Leu Leu Gly Ile Gly Leu Ile Leu Ala Leu Ile Ala

1 5 10 15

Cys Lys Gln Asn Val Ser Ser Leu Asp Glu Lys Asn Ser Val Ser Val

20 25 30

Asp Leu Pro Gly Gly Met Lys Val Leu Val Ser Lys Glu Lys Asp Lys

35 40 45

Asp Gly Lys Tyr Ser Leu Met Ala Thr Val Glu Lys Leu Glu Leu Lys

50 55 60

Gly Thr Ser Asp Lys Ser Asn Gly Ser Gly Val Leu Glu Gly Glu Lys

65 70 75 80

Ala Asp Lys Ser Lys Ala Lys Leu Thr Ile Ser Gln Asp Leu Asn Gln

85 90 95

Thr Thr Phe Glu Ile Phe Lys Glu Asp Gly Lys Thr Leu Val Ser Arg

100 105 110

Lys Val Asn Ser Lys Asp Lys Ser Ser Thr Glu Glu Lys Phe Asn Asp

115 120 125

Lys Gly Lys Leu Ser Glu Lys Val Val Thr Arg Ala Asn Gly Thr Arg

130 135 140

Leu Glu Tyr Thr Glu Ile Lys Asn Asp Gly Ser Gly Lys Ala Lys Glu

145 150 155 160

Val Leu Lys Gly Phe Ala Leu Glu Gly Thr Leu Thr Asp Gly Gly Glu

165 170 175

Thr Lys Leu Thr Val Thr Glu Gly Thr Val Thr Leu Ser Lys Asn Ile

180 185 190

Ser Lys Ser Gly Glu Ile Thr Val Ala Leu Asn Asp Thr Glu Thr Thr

195 200 205

Pro Ala Asp Lys Lys Thr Gly Glu Trp Lys Ser Asp Thr Ser Thr Leu

210 215 220

Thr Ile Ser Lys Asn Ser Gln Lys Pro Lys Gln Leu Val Phe Thr Lys

225 230 235 240

Glu Asn Thr Ile Thr Val Gln Asn Tyr Asn Arg Ala Gly Asn Ala Leu

245 250 255

Glu Gly Ser Pro Ala Glu Ile Lys Asp Leu Ala Glu Leu Lys Ala Ala

260 265 270

Leu Lys

<210> 86

<211> 273

<212> PROTEIN

<213> Borreliella bavariensis

<400> 86

Met Lys Lys Tyr Leu Leu Gly Ile Gly Leu Ile Leu Ala Leu Ile Ala

1 5 10 15

Cys Lys Gln Asn Val Ser Ser Leu Asp Glu Lys Asn Ser Val Ser Val

20 25 30

Asp Leu Pro Gly Glu Met Lys Val Leu Val Ser Lys Glu Lys Asp Lys

35 40 45

Asp Gly Lys Tyr Ser Leu Met Ala Thr Val Asp Lys Leu Glu Leu Lys

50 55 60

Gly Thr Ser Asp Lys Ser Asn Gly Ser Gly Thr Leu Glu Gly Glu Lys

65 70 75 80

Ser Asp Lys Ser Lys Ala Lys Leu Thr Ile Ser Glu Asp Leu Ser Lys

85 90 95

Thr Thr Phe Glu Ile Phe Lys Glu Asp Gly Lys Thr Leu Val Ser Lys

100 105 110

Lys Val Asn Ser Lys Asp Lys Ser Ser Ile Glu Glu Lys Phe Asn Ala

115 120 125

Lys Gly Glu Leu Ser Glu Lys Thr Ile Leu Arg Ala Asn Gly Thr Arg

130 135 140

Leu Glu Tyr Thr Glu Ile Lys Ser Asp Gly Thr Gly Lys Ala Lys Glu

145 150 155 160

Val Leu Lys Asp Phe Ala Leu Glu Gly Thr Leu Ala Ala Asp Lys Thr

165 170 175

Thr Leu Lys Val Thr Glu Gly Thr Val Val Leu Ser Lys His Ile Pro

180 185 190

Asn Ser Gly Glu Ile Thr Val Glu Leu Asn Asp Ser Asn Ser Thr Gln

195 200 205

Ala Thr Lys Lys Thr Gly Lys Trp Asp Ser Asn Thr Ser Thr Leu Thr

210 215 220

Ile Ser Val Asn Ser Lys Lys Thr Lys Asn Ile Val Phe Thr Lys Glu

225 230 235 240

Asp Thr Ile Thr Val Gln Lys Tyr Asp Ser Ala Gly Thr Asn Leu Glu

245 250 255

Gly Asn Ala Val Glu Ile Lys Thr Leu Asp Glu Leu Lys Asn Ala Leu

260 265 270

Lys

<210> 87

<211> 274

<212> PROTEIN

<213> Borreliella garinii

<400> 87

Met Lys Lys Tyr Leu Leu Gly Ile Gly Leu Ile Leu Ala Leu Ile Ala

1 5 10 15

Cys Lys Gln Asn Val Ser Ser Leu Asp Glu Lys Asn Ser Val Ser Val

20 25 30

Asp Leu Pro Gly Gly Met Lys Val Leu Val Ser Lys Glu Lys Asp Lys

35 40 45

Asp Gly Lys Tyr Ser Leu Met Ala Thr Val Glu Lys Leu Glu Leu Lys

50 55 60

Gly Thr Ser Asp Lys Asn Asn Gly Ser Gly Thr Leu Glu Gly Glu Lys

65 70 75 80

Thr Asp Lys Ser Lys Val Lys Leu Thr Ile Ala Glu Asp Leu Ser Lys

85 90 95

Thr Thr Phe Glu Ile Phe Lys Glu Asp Gly Lys Thr Leu Val Ser Lys

100 105 110

Lys Val Thr Leu Lys Asp Lys Ser Ser Thr Glu Glu Lys Phe Asn Glu

115 120 125

Lys Gly Glu Ile Ser Glu Lys Thr Ile Val Arg Ala Asn Gly Thr Arg

130 135 140

Leu Glu Tyr Thr Asp Ile Lys Ser Asp Gly Ser Gly Lys Ala Lys Glu

145 150 155 160

Val Leu Lys Asp Phe Thr Leu Glu Gly Thr Leu Ala Ala Asp Gly Lys

165 170 175

Thr Thr Leu Lys Val Thr Glu Gly Thr Val Val Leu Ser Lys Asn Ile

180 185 190

Leu Lys Ser Gly Glu Ile Thr Val Ala Leu Asp Asp Ser Asp Thr Thr

195 200 205

Gln Ala Thr Lys Lys Thr Gly Lys Trp Asp Ser Lys Thr Ser Thr Leu

210 215 220

Thr Ile Ser Val Asn Ser Gln Lys Thr Lys Asn Leu Val Phe Thr Lys

225 230 235 240

Glu Asp Thr Ile Thr Val Gln Lys Tyr Asp Ser Ala Gly Thr Asn Leu

245 250 255

Glu Gly Lys Ala Val Glu Ile Thr Thr Leu Glu Lys Leu Lys Asp Ala

260 265 270

Leu Lys

<210> 88

<211> 274

<212> PROTEIN

<213> Borreliella burgdorferi

<400> 88

Met Lys Lys Tyr Leu Leu Gly Ile Gly Leu Ile Leu Ala Leu Ile Ala

1 5 10 15

Cys Lys Gln Asn Val Ser Ser Leu Asp Glu Lys Asn Ser Val Ser Val

20 25 30

Asp Leu Pro Gly Gly Met Thr Val Leu Val Ser Lys Glu Lys Asp Lys

35 40 45

Asp Gly Lys Tyr Ser Leu Glu Ala Thr Val Asp Lys Leu Glu Leu Lys

50 55 60

Gly Thr Ser Asp Lys Asn Asn Gly Ser Gly Thr Leu Glu Gly Glu Lys

65 70 75 80

Thr Asp Lys Ser Lys Val Lys Ser Thr Ile Ala Asp Asp Leu Ser Gln

85 90 95

Thr Lys Phe Glu Ile Phe Lys Glu Asp Gly Lys Thr Leu Val Ser Lys

100 105 110

Lys Val Thr Leu Lys Asp Lys Ser Ser Thr Glu Glu Lys Phe Asn Gly

115 120 125

Lys Gly Glu Thr Ser Glu Lys Thr Ile Val Arg Ala Asn Gly Thr Arg

130 135 140

Leu Glu Tyr Thr Asp Ile Lys Ser Asp Gly Ser Gly Lys Ala Lys Glu

145 150 155 160

Val Leu Lys Asp Phe Thr Leu Glu Gly Thr Leu Ala Ala Asp Gly Lys

165 170 175

Thr Thr Leu Lys Val Thr Glu Gly Thr Val Val Leu Ser Lys Asn Ile

180 185 190

Leu Lys Ser Gly Glu Ile Thr Ala Ala Leu Asp Asp Ser Asp Thr Thr

195 200 205

Arg Ala Thr Lys Lys Thr Gly Lys Trp Asp Ser Lys Thr Ser Thr Leu

210 215 220

Thr Ile Ser Val Asn Ser Gln Lys Thr Lys Asn Leu Val Phe Thr Lys

225 230 235 240

Glu Asp Thr Ile Thr Val Gln Arg Tyr Asp Ser Ala Gly Thr Asn Leu

245 250 255

Glu Gly Lys Ala Val Glu Ile Thr Thr Leu Lys Glu Leu Lys Asn Ala

260 265 270

Leu Lys

<210> 89

<211> 214

<212> PROTEIN

<213> Borreliella garinii

<400> 89

Met Lys Lys Tyr Leu Leu Gly Ile Gly Leu Ile Leu Ala Leu Ile Ala

1 5 10 15

Cys Lys Gln Asn Val Ser Ser Leu Asp Glu Lys Asn Ser Val Ser Val

20 25 30

Asp Leu Pro Gly Glu Met Lys Val Leu Val Ser Lys Glu Lys Asp Lys

35 40 45

Asp Gly Lys Tyr Ser Leu Glu Ala Thr Val Asp Lys Leu Glu Leu Lys

50 55 60

Gly Thr Ser Asp Lys Asn Asn Gly Ser Gly Val Leu Glu Gly Val Lys

65 70 75 80

Ala Ala Lys Ser Lys Ala Lys Leu Thr Ile Ala Asp Asp Leu Ser Gln

85 90 95

Thr Lys Phe Glu Ile Phe Lys Glu Asp Gly Lys Thr Leu Val Ser Lys

100 105 110

Lys Val Thr Leu Lys Asp Lys Ser Ser Thr Glu Glu Lys Phe Asn Asp

115 120 125

Lys Gly Lys Leu Ser Glu Lys Val Val Thr Arg Ala Asn Gly Thr Arg

130 135 140

Leu Glu Tyr Thr Glu Ile Gln Asn Asp Gly Ser Gly Lys Ala Lys Glu

145 150 155 160

Val Leu Lys Ser Leu Thr Leu Glu Gly Thr Leu Thr Ala Asp Gly Glu

165 170 175

Thr Lys Leu Thr Glu Asn Thr Ile Thr Val Gln Lys Tyr Asn Thr Ala

180 185 190

Gly Thr Lys Leu Glu Gly Ser Pro Ala Glu Ile Lys Asp Leu Glu Ala

195 200 205

Leu Lys Ala Ala Leu Lys

210

<210> 90

<211> 173

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 90

Glu Ser Gln Val Arg Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu

1 5 10 15

Asn Glu Gln Val Asn Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Ser

20 25 30

Met Ser Ser Trp Ser Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe

35 40 45

Leu Phe Asp His Ala Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile

50 55 60

Ile Phe Leu Asn Glu Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser

65 70 75 80

Ala Pro Glu His Lys Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala

85 90 95

Tyr Glu His Glu Gln His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp

100 105 110

His Ala Ile Lys Cys Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp

115 120 125

Tyr Val Ala Glu Gln His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu

130 135 140

Asp Lys Ile Glu Leu Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala

145 150 155 160

Asp Gln Tyr Val Lys Gly Ile Ala Lys Ser Arg Lys Ser

165 170

<210> 91

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 91

Gly Gly Gly Ser Gly Gly Gly Ser

5

<210> 92

<211> 20

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 92

Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser

1 5 10 15

Gly Gly Gly Ser

20

<210> 93

<211> 154

<212> PROTEIN

<213> Aquifex aeolicus

<400> 93

Met Gln Ile Tyr Glu Gly Lys Leu Thr Ala Glu Gly Leu Arg Phe Gly

1 5 10 15

Ile Val Ala Ser Arg Phe Asn His Ala Leu Val Asp Arg Leu Val Glu

20 25 30

Gly Ala Ile Asp Cys Ile Val Arg His Gly Gly Arg Glu Glu Asp Ile

35 40 45

Thr Leu Val Arg Val Pro Gly Ser Trp Glu Ile Pro Val Ala Ala Gly

50 55 60

Glu Leu Ala Arg Lys Glu Asp Ile Asp Ala Val Ile Ala Ile Gly Val

65 70 75 80

Leu Ile Arg Gly Ala Thr Pro His Phe Asp Tyr Ile Ala Ser Glu Val

85 90 95

Ser Lys Gly Leu Ala Asn Leu Ser Leu Glu Leu Arg Lys Pro Ile Thr

100 105 110

Phe Gly Val Ile Thr Ala Asp Thr Leu Glu Gln Ala Ile Glu Arg Ala

115 120 125

Gly Thr Lys His Gly Asn Lys Gly Trp Glu Ala Ala Leu Ser Ala Ile

130 135 140

Glu Met Ala Asn Leu Phe Lys Ser Leu Arg

145 150

<210> 94

<211> 250

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 94

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

100 105 110

Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Tyr Thr Leu

130 135 140

Glu Gly Gln Leu Ser Asp Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val

165 170 175

Glu Leu Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

180 185 190

Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys

245 250

<210> 95

<211> 250

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 95

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

100 105 110

Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Tyr Asp Leu

130 135 140

Lys Gly Glu Leu Ser Ser Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val

165 170 175

Glu Leu Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

180 185 190

Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys

245 250

<210> 96

<211> 250

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 96

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

100 105 110

Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Phe Thr Leu

130 135 140

Glu Gly Lys Val Ala Asn Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val

165 170 175

Glu Leu Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

180 185 190

Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys

245 250

<210> 97

<211> 250

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 97

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

100 105 110

Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Phe Ala Leu

130 135 140

Glu Gly Thr Leu Thr Asp Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val

165 170 175

Glu Leu Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

180 185 190

Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys

245 250

<210> 98

<211> 250

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 98

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Gln

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

100 105 110

Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Tyr Thr Leu

130 135 140

Glu Gly Gln Leu Ser Asp Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Gln Ile Ser Lys Ser Gly Glu Val Ser Val

165 170 175

Glu Leu Gln Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

180 185 190

Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Gln Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys

245 250

<210> 99

<211> 250

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 99

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Gln

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

100 105 110

Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Phe Thr Leu

130 135 140

Glu Gly Lys Val Ala Asn Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Gln Ile Ser Lys Ser Gly Glu Val Ser Val

165 170 175

Glu Leu Gln Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

180 185 190

Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Gln Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys

245 250

<210> 100

<211> 250

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 100

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Gln

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

100 105 110

Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Phe Ala Leu

130 135 140

Glu Gly Thr Leu Thr Asp Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Gln Ile Ser Lys Ser Gly Glu Val Ser Val

165 170 175

Glu Leu Gln Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

180 185 190

Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Gln Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys

245 250

<210> 101

<211> 250

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 101

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Gln

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

100 105 110

Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Tyr Asp Leu

130 135 140

Lys Gly Glu Leu Ser Ser Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Gln Ile Ser Lys Ser Gly Glu Val Ser Val

165 170 175

Glu Leu Gln Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

180 185 190

Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Gln Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys

245 250

<210> 102

<211> 250

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<220>

<221> OPTION

<222> (48)..(48)

<223> /replace="Gln"

<220>

<221> MOD_RES

<222> (142)..(150)

<223> Any amino acid

<220>

<221> OPTION

<222> (167)..(167)

<223> /replace="Gln"

<220>

<221> OPTION

<222> (179)..(179)

<223> /replace="Gln"

<220>

<221> OPTION

<222> (228)..(228)

<223> /replace="Gln"

<220>

<221> Website

<222> (1)..(250)

<223> /note="residue variants specified in the sequence,

no preference is given to remainders in variant annotations

provisions"

<400> 102

Met Asp Glu Lys Asn Ser Val Ser Val Asp Leu Pro Gly Glu Met Lys

1 5 10 15

Val Leu Val Ser Lys Glu Lys Asn Lys Asp Gly Lys Tyr Asp Leu Ile

20 25 30

Ala Thr Val Asp Lys Leu Glu Leu Lys Gly Thr Ser Asp Lys Asn Asn

35 40 45

Gly Ser Gly Val Leu Glu Gly Val Lys Ala Asp Lys Ser Lys Val Lys

50 55 60

Leu Thr Ile Ser Asp Asp Leu Gly Gln Thr Thr Leu Glu Val Phe Lys

65 70 75 80

Glu Asp Gly Lys Thr Leu Val Ser Lys Lys Val Thr Ser Lys Asp Lys

85 90 95

Ser Ser Thr Glu Glu Lys Phe Asn Glu Lys Gly Glu Val Ser Glu Lys

100 105 110

Ile Ile Thr Arg Ala Asp Gly Thr Arg Leu Glu Tyr Thr Gly Ile Lys

115 120 125

Ser Asp Gly Ser Gly Lys Ala Lys Glu Val Leu Lys Gly Xaa Xaa Xaa

130 135 140

Xaa Xaa Xaa Xaa Xaa Xaa Glu Lys Thr Thr Leu Val Val Lys Glu Gly

145 150 155 160

Thr Val Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val

165 170 175

Glu Leu Asn Asp Thr Asp Ser Ser Ala Ala Thr Lys Lys Thr Ala Ala

180 185 190

Trp Asn Ser Gly Thr Ser Thr Leu Thr Ile Thr Val Asn Ser Lys Lys

195 200 205

Thr Lys Asp Leu Val Phe Thr Lys Glu Asn Thr Ile Thr Val Gln Gln

210 215 220

Tyr Asp Ser Asn Gly Thr Lys Leu Glu Gly Ser Ala Val Glu Ile Thr

225 230 235 240

Lys Leu Asp Glu Ile Lys Asn Ala Leu Lys

245 250

<210> 103

<400> 103

000

<210> 104

<400> 104

000

<210> 105

<400> 105

000

<210> 106

<400> 106

000

<210> 107

<400> 107

000

<210> 108

<400> 108

000

<210> 109

<400> 109

000

<210> 110

<400> 110

000

<210> 111

<400> 111

000

<210> 112

<400> 112

000

<210> 113

<400> 113

000

<210> 114

<400> 114

000

<210> 115

<400> 115

000

<210> 116

<400> 116

000

<210> 117

<400> 117

000

<210> 118

<400> 118

000

<210> 119

<400> 119

000

<210> 120

<400> 120

000

<210> 121

<400> 121

000

<210> 122

<400> 122

000

<210> 123

<400> 123

000

<210> 124

<400> 124

000

<210> 125

<400> 125

000

<210> 126

<400> 126

000

<210> 127

<400> 127

000

<210> 128

<400> 128

000

<210> 129

<400> 129

000

<210> 130

<400> 130

000

<210> 131

<400> 131

000

<210> 132

<400> 132

000

<210> 133

<400> 133

000

<210> 134

<400> 134

000

<210> 135

<400> 135

000

<210> 136

<400> 136

000

<210> 137

<400> 137

000

<210> 138

<400> 138

000

<210> 139

<400> 139

000

<210> 140

<400> 140

000

<210> 141

<400> 141

000

<210> 142

<400> 142

000

<210> 143

<400> 143

000

<210> 144

<400> 144

000

<210> 145

<400> 145

000

<210> 146

<400> 146

000

<210> 147

<400> 147

000

<210> 148

<400> 148

000

<210> 149

<400> 149

000

<210> 150

<400> 150

000

<210> 151

<400> 151

000

<210> 152

<400> 152

000

<210> 153

<400> 153

000

<210> 154

<400> 154

000

<210> 155

<400> 155

000

<210> 156

<400> 156

000

<210> 157

<400> 157

000

<210> 158

<400> 158

000

<210> 159

<400> 159

000

<210> 160

<400> 160

000

<210> 161

<400> 161

000

<210> 162

<400> 162

000

<210> 163

<400> 163

000

<210> 164

<400> 164

000

<210> 165

<400> 165

000

<210> 166

<400> 166

000

<210> 167

<400> 167

000

<210> 168

<400> 168

000

<210> 169

<400> 169

000

<210> 170

<400> 170

000

<210> 171

<400> 171

000

<210> 172

<400> 172

000

<210> 173

<400> 173

000

<210> 174

<400> 174

000

<210> 175

<400> 175

000

<210> 176

<400> 176

000

<210> 177

<400> 177

000

<210> 178

<400> 178

000

<210> 179

<400> 179

000

<210> 180

<400> 180

000

<210> 181

<400> 181

000

<210> 182

<400> 182

000

<210> 183

<400> 183

000

<210> 184

<400> 184

000

<210> 185

<400> 185

000

<210> 186

<400> 186

000

<210> 187

<400> 187

000

<210> 188

<400> 188

000

<210> 189

<400> 189

000

<210> 190

<400> 190

000

<210> 191

<400> 191

000

<210> 192

<400> 192

000

<210> 193

<400> 193

000

<210> 194

<400> 194

000

<210> 195

<400> 195

000

<210> 196

<400> 196

000

<210> 197

<400> 197

000

<210> 198

<400> 198

000

<210> 199

<400> 199

000

<210> 200

<400> 200

000

<210> 201

<211> 173

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 201

Glu Ser Gln Val Arg Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu

1 5 10 15

Asn Glu Gln Val Asn Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Cys

20 25 30

Met Ser Ser Trp Ser Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe

35 40 45

Leu Phe Asp His Ala Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile

50 55 60

Ile Phe Leu Asn Glu Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser

65 70 75 80

Ala Pro Glu His Lys Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala

85 90 95

Tyr Glu His Glu Gln His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp

100 105 110

His Ala Ile Lys Ser Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp

115 120 125

Tyr Val Ala Glu Gln His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu

130 135 140

Asp Lys Ile Glu Leu Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala

145 150 155 160

Asp Gln Tyr Val Lys Gly Ile Ala Lys Ser Arg Lys Ser

165 170

<210> 202

<211> 173

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 202

Glu Ser Gln Val Arg Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu

1 5 10 15

Asn Glu Gln Val Asn Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Ser

20 25 30

Met Ser Ser Trp Ser Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe

35 40 45

Leu Phe Asp His Ala Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile

50 55 60

Ile Phe Leu Asn Glu Asn Asn Val Pro Val Gln Leu Thr Cys Ile Ser

65 70 75 80

Ala Pro Glu His Lys Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala

85 90 95

Tyr Glu His Glu Gln His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp

100 105 110

His Ala Ile Lys Ser Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp

115 120 125

Tyr Val Ala Glu Gln His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu

130 135 140

Asp Lys Ile Glu Leu Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala

145 150 155 160

Asp Gln Tyr Val Lys Gly Ile Ala Lys Ser Arg Lys Ser

165 170

<210> 203

<211> 173

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 203

Glu Ser Gln Val Arg Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu

1 5 10 15

Asn Glu Gln Val Asn Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Ser

20 25 30

Met Ser Ser Trp Ser Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe

35 40 45

Leu Phe Asp His Ala Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile

50 55 60

Ile Phe Leu Asn Glu Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser

65 70 75 80

Cys Pro Glu His Lys Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala

85 90 95

Tyr Glu His Glu Gln His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp

100 105 110

His Ala Ile Lys Ser Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp

115 120 125

Tyr Val Ala Glu Gln His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu

130 135 140

Asp Lys Ile Glu Leu Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala

145 150 155 160

Asp Gln Tyr Val Lys Gly Ile Ala Lys Ser Arg Lys Ser

165 170

<210> 204

<211> 173

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 204

Glu Ser Gln Val Arg Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu

1 5 10 15

Asn Glu Gln Val Asn Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Ser

20 25 30

Met Ser Ser Trp Ser Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe

35 40 45

Leu Phe Asp His Ala Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile

50 55 60

Ile Phe Leu Asn Glu Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser

65 70 75 80

Ala Pro Glu His Cys Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala

85 90 95

Tyr Glu His Glu Gln His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp

100 105 110

His Ala Ile Lys Ser Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp

115 120 125

Tyr Val Ala Glu Gln His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu

130 135 140

Asp Lys Ile Glu Leu Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala

145 150 155 160

Asp Gln Tyr Val Lys Gly Ile Ala Lys Ser Arg Lys Ser

165 170

<210> 205

<211> 173

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 205

Glu Ser Gln Val Arg Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu

1 5 10 15

Asn Glu Gln Val Asn Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Ser

20 25 30

Met Ser Ser Trp Ser Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe

35 40 45

Leu Phe Asp His Ala Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile

50 55 60

Ile Phe Leu Asn Glu Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser

65 70 75 80

Ala Pro Glu His Lys Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala

85 90 95

Tyr Glu His Glu Gln His Ile Ser Glu Cys Ile Asn Asn Ile Val Asp

100 105 110

His Ala Ile Lys Ser Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp

115 120 125

Tyr Val Ala Glu Gln His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu

130 135 140

Asp Lys Ile Glu Leu Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala

145 150 155 160

Asp Gln Tyr Val Lys Gly Ile Ala Lys Ser Arg Lys Ser

165 170

<210> 206

<211> 173

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 206

Glu Ser Gln Val Arg Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu

1 5 10 15

Asn Glu Gln Val Asn Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Ser

20 25 30

Met Ser Ser Trp Ser Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe

35 40 45

Leu Phe Asp His Ala Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile

50 55 60

Ile Phe Leu Asn Glu Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser

65 70 75 80

Ala Pro Glu His Lys Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala

85 90 95

Tyr Glu His Glu Gln His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp

100 105 110

His Ala Ile Lys Cys Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp

115 120 125

Tyr Val Ala Glu Gln His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu

130 135 140

Asp Lys Ile Glu Leu Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala

145 150 155 160

Asp Gln Tyr Val Lys Gly Ile Ala Lys Ser Arg Lys Ser

165 170

<210> 207

<211> 173

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 207

Glu Ser Gln Val Arg Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu

1 5 10 15

Asn Cys Gln Val Asn Lys Glu Met Gln Ser Ser Asn Leu Tyr Met Ser

20 25 30

Met Ser Ser Trp Ser Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe

35 40 45

Leu Phe Asp His Ala Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile

50 55 60

Ile Phe Leu Asn Glu Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser

65 70 75 80

Ala Pro Glu His Lys Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala

85 90 95

Tyr Glu His Glu Gln His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp

100 105 110

His Ala Ile Lys Ser Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp

115 120 125

Tyr Val Ala Glu Gln His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu

130 135 140

Asp Lys Ile Glu Leu Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala

145 150 155 160

Asp Gln Tyr Val Lys Gly Ile Ala Lys Ser Arg Lys Ser

165 170

<210> 208

<211> 173

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 208

Glu Ser Gln Val Arg Gln Gln Phe Ser Lys Asp Ile Glu Lys Leu Leu

1 5 10 15

Asn Glu Gln Val Asn Lys Glu Met Asn Ser Ser Asn Leu Tyr Met Ser

20 25 30

Met Ser Ser Trp Cys Tyr Thr His Ser Leu Asp Gly Ala Gly Leu Phe

35 40 45

Leu Phe Asp His Ala Ala Glu Glu Tyr Glu His Ala Lys Lys Leu Ile

50 55 60

Ile Phe Leu Asn Glu Asn Asn Val Pro Val Gln Leu Thr Ser Ile Ser

65 70 75 80

Ala Pro Glu His Lys Phe Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala

85 90 95

Tyr Glu His Glu Gln His Ile Ser Glu Ser Ile Asn Asn Ile Val Asp

100 105 110

His Ala Ile Lys Ser Lys Asp His Ala Thr Phe Asn Phe Leu Gln Trp

115 120 125

Tyr Val Ala Glu Gln His Glu Glu Glu Val Leu Phe Lys Asp Ile Leu

130 135 140

Asp Lys Ile Glu Leu Ile Gly Asn Glu Asn His Gly Leu Tyr Leu Ala

145 150 155 160

Asp Gln Tyr Val Lys Gly Ile Ala Lys Ser Arg Lys Ser

165 170

<210> 209

<211> 166

<212> PROTEIN

<213> Helicobacter pylori

<400> 209

Leu Ser Lys Asp Ile Ile Lys Leu Leu Asn Glu Gln Val Asn Lys Glu

1 5 10 15

Met Asn Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp Cys Tyr Thr

20 25 30

His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His Ala Ala Glu

35 40 45

Glu Tyr Glu His Ala Lys Lys Leu Ile Ile Phe Leu Asn Glu Asn Asn

50 55 60

Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His Lys Phe Glu

65 70 75 80

Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu Gln His Ile

85 90 95

Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys Ser Lys Asp

100 105 110

His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu Gln His Glu

115 120 125

Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu Leu Ile Gly

130 135 140

Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val Lys Gly Ile

145 150 155 160

Ala Lys Ser Arg Lys Ser

165

<210> 210

<211> 22

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 210

tgactgtgaa cgttcgagat ga 22

<210> 211

<211> 191

<212> PROTEIN

<213> Trichoplusia ni

<400> 211

Thr Gln Cys Asn Val Asn Pro Val Gln Ile Pro Lys Asp Trp Ile Thr

1 5 10 15

Met His Arg Ser Cys Arg Asn Ser Met Arg Gln Gln Ile Gln Met Glu

20 25 30

Val Gly Ala Ser Leu Gln Tyr Leu Ala Met Gly Ala His Phe Ser Lys

35 40 45

Asp Val Val Asn Arg Pro Gly Phe Ala Gln Leu Phe Phe Asp Ala Ala

50 55 60

Ser Glu Glu Arg Glu His Ala Met Lys Leu Ile Glu Tyr Leu Leu Met

65 70 75 80

Arg Gly Glu Leu Thr Asn Asp Val Ser Ser Leu Leu Gln Val Arg Pro

85 90 95

Pro Thr Arg Ser Ser Trp Lys Gly Gly Val Glu Ala Leu Glu His Ala

100 105 110

Leu Ser Met Glu Ser Asp Val Thr Lys Ser Ile Arg Asn Val Ile Lys

115 120 125

Ala Cys Glu Asp Asp Ser Glu Phe Asn Asp Tyr His Leu Val Asp Tyr

130 135 140

Leu Thr Gly Asp Phe Leu Glu Glu Gln Tyr Lys Gly Gln Arg Asp Leu

145 150 155 160

Ala Gly Lys Ala Ser Thr Leu Lys Lys Leu Met Asp Arg His Glu Ala

165 170 175

Leu Gly Glu Phe Ile Phe Asp Lys Lys Leu Leu Gly Ile Asp Val

180 185 190

<210> 212

<211> 212

<212> PROTEIN

<213> Trichoplusia ni

<400> 212

Ala Asp Thr Cys Tyr Asn Asp Val Ala Leu Asp Cys Gly Ile Thr Ser

1 5 10 15

Asn Ser Leu Ala Leu Pro Arg Cys Asn Ala Val Tyr Gly Glu Tyr Gly

20 25 30

Ser His Gly Asn Val Ala Thr Glu Leu Gln Ala Tyr Ala Lys Leu His

35 40 45

Leu Glu Arg Ser Tyr Asp Tyr Leu Leu Ser Ala Ala Tyr Phe Asn Asn

50 55 60

Tyr Gln Thr Asn Arg Ala Gly Phe Ser Lys Leu Phe Lys Lys Leu Ser

65 70 75 80

Asp Glu Ala Trp Ser Lys Thr Ile Asp Ile Ile Lys His Val Thr Lys

85 90 95

Arg Gly Asp Lys Met Asn Phe Asp Gln His Ser Thr Met Lys Thr Glu

100 105 110

Arg Lys Asn Tyr Thr Ala Glu Asn His Glu Leu Glu Ala Leu Ala Lys

115 120 125

Ala Leu Asp Thr Gln Lys Glu Leu Ala Glu Arg Ala Phe Tyr Ile His

130 135 140

Arg Glu Ala Thr Arg Asn Ser Gln His Leu His Asp Pro Glu Ile Ala

145 150 155 160

Gln Tyr Leu Glu Glu Glu Phe Ile Glu Asp His Ala Glu Lys Ile Arg

165 170 175

Thr Leu Ala Gly His Thr Ser Asp Leu Lys Lys Phe Ile Thr Ala Asn

180 185 190

Asn Gly His Asp Leu Ser Leu Ala Leu Tyr Val Phe Asp Glu Tyr Leu

195 200 205

Gln Lys Thr Val

210

<210> 213

<211> 174

<212> PROTEIN

<213> Pyrococcus furiosus

<400> 213

Met Leu Ser Glu Arg Met Leu Lys Ala Leu Asn Asp Gln Leu Asn Arg

1 5 10 15

Glu Leu Tyr Ser Ala Tyr Leu Tyr Phe Ala Met Ala Ala Tyr Phe Glu

20 25 30

Asp Leu Gly Leu Glu Gly Phe Ala Asn Trp Met Lys Ala Gln Ala Glu

35 40 45

Glu Glu Ile Gly His Ala Leu Arg Phe Tyr Asn Tyr Ile Tyr Asp Arg

50 55 60

Asn Gly Arg Val Glu Leu Asp Glu Ile Pro Lys Pro Pro Lys Glu Trp

65 70 75 80

Glu Ser Pro Leu Lys Ala Phe Glu Ala Ala Tyr Glu His Glu Lys Phe

85 90 95

Ile Ser Lys Ser Ile Tyr Glu Leu Ala Ala Leu Ala Glu Glu Glu Lys

100 105 110

Asp Tyr Ser Thr Arg Ala Phe Leu Glu Trp Phe Ile Asn Glu Gln Val

115 120 125

Glu Glu Glu Ala Ser Val Lys Lys Ile Leu Asp Lys Leu Lys Phe Ala

130 135 140

Lys Asp Ser Pro Gln Ile Leu Phe Met Leu Asp Lys Glu Leu Ser Ala

145 150 155 160

Arg Ala Pro Lys Leu Pro Gly Leu Leu Met Gln Gly Gly Glu

165 170

<210> 214

<211> 183

<212> PROTEIN

<213> Homo sapiens

<400> 214

Met Thr Thr Ala Ser Thr Ser Gln Val Arg Gln Asn Tyr His Gln Asp

1 5 10 15

Ser Glu Ala Ala Ile Asn Arg Gln Ile Asn Leu Glu Leu Tyr Ala Ser

20 25 30

Tyr Val Tyr Leu Ser Met Ser Tyr Tyr Phe Asp Arg Asp Asp Val Ala

35 40 45

Leu Lys Asn Phe Ala Lys Tyr Phe Leu His Gln Ser His Glu Glu Arg

50 55 60

Glu His Ala Glu Lys Leu Met Lys Leu Gln Asn Gln Arg Gly Gly Arg

65 70 75 80

Ile Phe Leu Gln Asp Ile Lys Lys Pro Asp Cys Asp Asp Trp Glu Ser

85 90 95

Gly Leu Asn Ala Met Glu Cys Ala Leu His Leu Glu Lys Asn Val Gln

100 105 110

Gln Ser Leu Leu Glu Leu His Lys Leu Ala Thr Asp Lys Asn Asp Pro

115 120 125

His Leu Cys Asp Phe Ile Glu Thr His Tyr Leu Asn Glu Gln Val Lys

130 135 140

Ala Ile Lys Glu Leu Gly Asp His Val Thr Asn Leu Arg Lys Met Gly

145 150 155 160

Ala Pro Glu Ser Gly Leu Ala Glu Tyr Leu Phe Asp Lys His Thr Leu

165 170 175

Gly Asp Ser Asp Gln Glu Ser

180

<210> 215

<211> 204

<212> PROTEIN

<213> Homo sapiens

<400> 215

Met Asp Ser Lys Gly Ser Ser Gln Lys Gly Ser Arg Leu Leu Leu Leu

1 5 10 15

Leu Val Val Ser Asn Leu Leu Leu Pro Gln Gly Val Leu Ala Ser Ser

20 25 30

Gln Ile Arg Gln Asn Tyr Ser Thr Asp Val Glu Ala Ala Val Asn Ser

35 40 45

Leu Val Asn Leu Tyr Leu Gln Ala Ser Tyr Thr Tyr Leu Ser Leu Gly

50 55 60

Phe Tyr Phe Asp Arg Asp Asp Val Ala Leu Glu Gly Val Ser His Phe

65 70 75 80

Phe Arg Glu Leu Ala Glu Glu Lys Arg Glu Gly Tyr Glu Arg Leu Leu

85 90 95

Lys Met Gln Asn Gln Arg Gly Gly Arg Ala Leu Phe Gln Asp Ile Lys

100 105 110

Lys Pro Ala Glu Asp Glu Trp Gly Lys Thr Pro Asp Ala Met Lys Ala

115 120 125

Ala Met Ala Leu Glu Lys Lys Leu Asn Gln Ala Leu Leu Asp Leu His

130 135 140

Ala Leu Gly Ser Ala Arg Thr Asp Pro His Leu Cys Asp Phe Leu Glu

145 150 155 160

Thr His Phe Leu Asp Glu Glu Val Lys Leu Ile Lys Lys Met Gly Asp

165 170 175

His Leu Thr Asn Leu His Arg Leu Gly Gly Pro Glu Ala Gly Leu Gly

180 185 190

Glu Tyr Leu Phe Glu Arg Leu Thr Leu Lys His Asp

195 200

<210> 216

<211> 154

<212> PROTEIN

<213> Aquifex aeolicus

<400> 216

Met Gln Ile Tyr Glu Gly Lys Leu Thr Ala Glu Gly Leu Arg Phe Gly

1 5 10 15

Ile Val Ala Ser Arg Phe Asn His Ala Leu Val Asp Arg Leu Val Glu

20 25 30

Gly Ala Ile Asp Cys Ile Val Arg His Gly Gly Arg Glu Glu Asp Ile

35 40 45

Thr Leu Val Arg Val Pro Gly Ser Trp Glu Ile Pro Val Ala Ala Gly

50 55 60

Glu Leu Ala Arg Lys Glu Asp Ile Asp Ala Val Ile Ala Ile Gly Val

65 70 75 80

Leu Ile Arg Gly Ala Thr Pro His Phe Asp Tyr Ile Ala Ser Glu Val

85 90 95

Ser Lys Gly Leu Ala Asn Leu Ser Leu Glu Leu Arg Lys Pro Ile Thr

100 105 110

Phe Gly Val Ile Thr Ala Asp Thr Leu Glu Gln Ala Ile Glu Arg Ala

115 120 125

Gly Thr Lys His Gly Asn Lys Gly Trp Glu Ala Ala Leu Ser Ala Ile

130 135 140

Glu Met Ala Asn Leu Phe Lys Ser Leu Arg

145 150

<210> 217

<211> 8

<212> PROTEIN

<213> Unidentified

<220>

<221> source

<223> /note="Unknown description: Linker sequence

bullfrog"

<400> 217

Glu Ser Gln Val Arg Gln Gln Phe

5

<210> 218

<211> 15

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 218

Cys Leu Val Pro Arg Gly Ser Leu Glu His His His His His

1 5 10 15

<210> 219

<211> 156

<212> PROTEIN

<213> Escherichia coli

<400> 219

Met Asn Ile Ile Glu Ala Asn Val Ala Thr Pro Asp Ala Arg Val Ala

1 5 10 15

Ile Thr Ile Ala Arg Phe Asn Asn Phe Ile Asn Asp Ser Leu Leu Glu

20 25 30

Gly Ala Ile Asp Ala Leu Lys Arg Ile Gly Gln Val Lys Asp Glu Asn

35 40 45

Ile Thr Val Val Trp Val Pro Gly Ala Tyr Glu Leu Pro Leu Ala Ala

50 55 60

Gly Ala Leu Ala Lys Thr Gly Lys Tyr Asp Ala Val Ile Ala Leu Gly

65 70 75 80

Thr Val Ile Arg Gly Gly Thr Ala His Phe Glu Tyr Val Ala Gly Gly

85 90 95

Ala Ser Asn Gly Leu Ala His Val Ala Gln Asp Ser Glu Ile Pro Val

100 105 110

Ala Phe Gly Val Leu Thr Thr Glu Ser Ile Glu Gln Ala Ile Glu Arg

115 120 125

Ala Gly Thr Lys Ala Gly Asn Lys Gly Ala Glu Ala Ala Leu Thr Ala

130 135 140

Leu Glu Met Ile Asn Val Leu Lys Ala Ile Lys Ala

145 150 155

<210> 220

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 220

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

1 5 10 15

<210> 221

<211> 28

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 221

Gly Gly Ser Gly Ser Gly Ser Asn Ser Ser Ala Ser Ser Gly Ala Ser

1 5 10 15

Ser Gly Gly Ala Ser Gly Gly Ser Gly Gly Ser Gly

20 25

<210> 222

<211> 46

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 222

Gly Gly Ser Gly Ser Ala Ser Ser Gly Ala Ser Ala Ser Gly Ser Ser

1 5 10 15

Asn Gly Ser Gly Ser Gly Ser Gly Ser Asn Ser Ser Ala Ser Ser Gly

20 25 30

Ala Ser Ser Gly Gly Ala Ser Gly Gly Ser Gly Gly Ser Gly

35 40 45

<210> 223

<211> 26

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 223

Gly Gly Ser Gly Ser Ala Ser Ala Glu Ala Ala Ala Lys Glu Ala Ala

1 5 10 15

Ala Lys Ala Gly Gly Ser Gly Gly Ser Gly

20 25

<210> 224

<211> 32

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 224

Gly Gly Ser Gly Ser Ala Ser Ala Glu Ala Ala Ala Lys Glu Ala Ala

1 5 10 15

Ala Lys Glu Ala Ala Ala Lys Ala Ser Gly Gly Ser Gly Gly Ser Gly

20 25 30

<210> 225

<211> 47

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide"

<400> 225

Ser Gly Gly Gly Ser Gly Ser Ala Ser Ser Gly Ala Ser Ala Ser Gly

1 5 10 15

Ser Ser Cys Ser Gly Ser Gly Ser Gly Ser Ser Ser Ala Ser Ser Gly

20 25 30

Ala Ser Ser Gly Gly Ala Ser Gly Gly Gly Ser Gly Gly Ser Gly

35 40 45

<210> 226

<211> 4

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<400> 226

Gly Gly Gly Ser

1

<210> 227

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic 6xHis tag"

<400> 227

His His His His His

5

<210> 228

<211> 21

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic oligonucleotide"

<400> 228

tgactgtgaa cgttcgagat g 21

<---

Claims (19)

1. An antigenic polypeptide based on an OspA sequence for inducing an immune response against Borrelia or protecting a subject against Lyme disease, comprising an OspA polypeptide from Borrelia , wherein the OspA polypeptide from Borrelia does not contain the sequence SEQ ID NO: 77 and contains a sequence having at least 95 % identity with the sequence of the OspA polypeptide according to any of SEQ ID NO: 1-10, 22-76, 83-89, in which the transmembrane domain or part of the transmembrane domain is missing, or 94-102, and additionally contains a ferritin protein containing a sequence having at least 95% identity with SEQ ID NO: 90. 2. Antigenic polypeptide based on the OspA sequence according to claim 1, where ferritin contains a mutation with the replacement of an amino acid exposed on the surface with cysteine. 3. An antigenic polypeptide based on the OspA sequence for inducing an immune response against Borrelia or protecting a subject against Lyme disease, comprising an OspA polypeptide from Borrelia and ferritin, wherein ferritin contains a sequence having at least 95% identity with SEQ ID NO: 90, and a mutation to replace a surface-exposed amino acid with cysteine, and the OspA polypeptide from Borrelia contains a sequence having at least 95% identity with the sequence of the OspA polypeptide according to any of SEQ ID NO: 1-10, 22-76, 83-89, in which missing transmembrane domain or part of a transmembrane domain, or 94-102. 4. Antigenic polypeptide based on the OspA sequence according to any one of paragraphs. 1-3, wherein the ferritin contains one or more of the mutations E11C, S25C, S71C, A74C, K78C, S99C and S110C corresponding to the sequence SEQ ID NO: 209 of ferritin from H. pylori , as determined by pairwise or structural alignment. 5. Antigenic polypeptide based on the OspA sequence according to any one of paragraphs. 1-4 containing one or more immunostimulatory moieties linked to ferritin via a surface exposed amino acid. 6. Antigenic polypeptide based on the OspA sequence according to any one of paragraphs. 1-5, wherein the ferritin contains a mutation replacing the surface-exposed asparagine with a non-asparagine amino acid, wherein optionally the surface-exposed asparagine is at a position corresponding to position 18 of the sequence SEQ ID NO: 209 of ferritin from H. pylori , as determined by pairwise or structural alignment. 7. Antigenic polypeptide based on the OspA sequence according to any one of paragraphs. 1-6, wherein the ferritin contains a mutation replacing the internal cysteine with a non-cysteine amino acid, wherein optionally the internal cysteine is at a position corresponding to position 30 of the sequence SEQ ID NO: 209 of ferritin from H. pylori , as determined by pairwise or structural alignment. 8. A ferritin particle for inducing an immune response against Borrelia or protecting a subject against Lyme disease, comprising an antigenic polypeptide based on the OspA sequence according to any one of claims. 1-7, and the ferritin particle contains a total of 24 ferritin subunits. 9. Antigenic polypeptide based on the OspA sequence according to any one of paragraphs. 1-7, wherein the OspA polypeptide is one of serotypes 1, 2, 3, 4, 5, 6 or 7. 10. A composition for inducing an immune response against Borrelia or protecting a subject from Lyme disease, comprising an antigenic polypeptide based on the OspA sequence or a ferritin particle according to any one of claims. 1-9, further containing a pharmaceutically acceptable carrier. 11. The composition of claim 10, further comprising an adjuvant, wherein optionally the adjuvant is AF03. 12. The composition of claim 10 or 11, which comprises a first and a second antigenic polypeptide based on the OspA sequence, wherein the first and second antigenic polypeptides based on the OspA sequence comprise OspA polypeptides of different serotypes. 13. The composition of claim 12, comprising one, two, three, four, five, six or seven OspA sequence-based antigenic polypeptides selected from an OspA sequence-based antigenic polypeptide comprising an OspA serotype 1 polypeptide; an antigenic polypeptide based on the OspA sequence containing a serotype 2 OspA polypeptide; an antigenic polypeptide based on the OspA sequence containing a serotype 3 OspA polypeptide; an antigenic polypeptide based on the OspA sequence containing a serotype 4 OspA polypeptide; an antigenic polypeptide based on the OspA sequence containing an OspA serotype 5 polypeptide; an antigenic polypeptide based on the OspA sequence containing a serotype 6 OspA polypeptide; and an antigenic polypeptide based on the OspA sequence containing a serotype 7 OspA polypeptide. 14. The composition according to claim 13, containing an antigenic polypeptide based on the OspA sequence, containing an OspA serotype 1 polypeptide; an antigenic polypeptide based on the OspA sequence containing a serotype 2 OspA polypeptide; an antigenic polypeptide based on the OspA sequence containing an OspA serotype 3 polypeptide; an antigenic polypeptide based on the OspA sequence containing a serotype 4 OspA polypeptide; an antigenic polypeptide based on the OspA sequence containing an OspA serotype 5 polypeptide; and an OspA sequence-based antigenic polypeptide comprising a serotype 7 OspA polypeptide. 15. Antigenic polypeptide based on the OspA sequence, ferritin particle or composition according to any one of paragraphs. 1-14 for use in a method of inducing an immune response against Borrelia or for protecting a subject from Lyme disease. 16. A method of inducing an immune response against Borrelia or protecting a subject from Lyme disease, comprising administering to the subject any one or more of an OspA sequence-based antigenic polypeptide, a ferritin particle, or a composition according to any one of claims. 1-14. 17. Antigenic polypeptide based on the OspA sequence, ferritin particle or composition according to any one of paragraphs. 1-14 or the method according to claim 16, where the subject is a human. 18. Nucleic acid encoding an antigenic polypeptide based on the OspA sequence according to any one of claims. 1-7 or 9. 19. Nucleic acid according to claim 18, wherein the nucleic acid is mRNA.

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