WO2005111066A2

WO2005111066A2 - Polypeptides from non-typeable haemophilus influenzae

Info

Publication number: WO2005111066A2
Application number: PCT/IB2005/001775
Authority: WO
Inventors: Vega Masignani; Maria Arico
Original assignee: Chiron Srl
Priority date: 2004-05-14
Filing date: 2005-05-16
Publication date: 2005-11-24
Also published as: EP2351774A1; CN1997663A; US9102729B2; US20140234363A1; US8124098B2; EP2351773A1; BRPI0511118A; RU2006144093A; EP1745067A2; WO2005111066A8; EP2343313A1; JP2012000112A; CA2566632A1; GB0410866D0; US20120148615A1; US20080267966A1; US7749518B2; US20100303822A1; EP2341069A1; WO2005111066A3

Abstract

Polypeptides comprising non-typeable Haemophilus influenzae (NTHi) amino acid sequences. Over 2500 specific NTHi proteins are disclosed. The invention also provides related polypeptides, nucleic acids, antibodies and methods. These can all be usedin medicine for treating or preventing disease and/or infection caused by H.influenzae, such as otitis media.

Description

POLYPEPTIDES FROM NON-TYPEABLE HAEMOPHILUS INFLUENZAE

All documents cited herein are incorporated by reference in their entirety.

TECHNICAL FIELD

This invention is in the field of Haemophilus influenzae immunology and vaccinology. BACKGROUND ART

Haemophilus influenzae is a small, non-motile, Gram-negative coccobacillus. It is a respiratory pathogen that causes a wide spectrum of human infections, including: asymptomatic colonization of the upper respiratory tract (i.e. carriage); infections that extend from colonized mucosal surfaces to cause otitis media (inflammation of the middle ear), bronchitis, conjunctivitis, sinusitis, urinary tract infections and pneumonia; and invasive infections, such as bacteremia, septic arthritis, epiglottitis, pneumonia, empyema, pericarditis, cellulitis, osteomyelitis and meningitis. H.influen∑ae was the first bacterium for which a complete genome sequence was published [1].

H. influenzae strains are either capsulated (typeable) or non-capsulated (non-typeable), and there are six major serological types of capsulated strains (a to f). 95% of Hinfluenzae-causnd invasive diseases are caused by H.influenzαe type b ('Hib') strains. The most serious manifestation of Hib disease is meningitis, but the introduction in the 1980s of vaccines based on conjugated Hib capsular saccharides has hugely reduced incidence of this disease.

Although Hib infections can now be controlled by vaccination, other pathogenic H.influenzαe strains remain a risk. For instance, non-typeable H.influenzαe (NTHi) is responsible for otitis media (OM), particularly chronic OM. While OM is rarely associated with mortality, it is associated with significant morbidity. Hearing loss is the most common complication of OM, with behavioral, educational and language development delays being additional consequences of early onset OM with effusion. Acute OM is the most common bacterial infection in children in the USA. The non-typeable H. influenzae biogroup aegyptius causes epidemic conjunctivitis and Brazilian purpuric fever (BPF) [2], with BPF having a mortality of up to 70%.

To date, antibiotics are the main tool against the spectrum of clinical entities known collectively as OM, but widespread use of antibiotics for OM has met with controversy due to the emergence of multiple-antibiotic resistant microorganisms. Progress towards a vaccine is slow due to an incomplete understanding of both the pathogenesis of OM and the immune response to it. The genome sequence of the serotype d strain KW20 [1,3] has been useful for understanding basic H.influenzae biology, but it has not been so useful in countering pathogenic H.influenzae strains, as serotype d strains are generally not pathogens.

It is an object of the invention to provide polypeptides for use in the development of vaccines for preventing and/or treating infections caused by non-typeable H.influenzae strains. In particular, it is an object to provide polypeptides for use in improved vaccines for preventing and/or treating otitis media. The polypeptides may also be useful for diagnostic purposes, and as targets for antibiotics. DISCLOSURE OF THE INVENTION

Polypeptides

The invention provides polypeptides comprising the H.influenzae amino acid sequences disclosed in the examples. These amino acid sequences are the even SEQ ID NOs between 2 and 5080. There are thus 2540 amino acid sequences, and these are referred to as NTHrørø?, where nnnn is a number between 0001 and 2832 (there are 292 ΗYΑnnnn numbers that have no sequence; see Table I). Further NTHi sequences of the invention are given as SEQ ID NOS: 5088 onwards.

The invention also provides polypeptides comprising amino acid sequences that have sequence identity to the H.influenzae amino acid sequences disclosed in the examples. Depending on the particular sequence, the degree of sequence identity is preferably greater than 50% (e.g. 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more). These polypeptides include homologs, orthologs, allelic variants and functional mutants. Typically, 50% identity or more between two polypeptide sequences is considered to be an indication of functional equivalence. Identity between polypeptides is preferably determined by the Smith-Waterman homology search algorithm as implemented in the MPSRCH program (Oxford Molecular), using an affine gap search with parameters gap open penalty =12 and gap extension penalty=l .

These polypeptide may, compared to the NTHi sequences of the examples, include one or more (e.g.

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) conservative amino acid replacements i.e. replacements of one amino acid with another which has a related side chain. Genetically-encoded amino acids are generally divided into four families: (1) acidic i.e. aspartate, glutamate; (2) basic i.e. lysine, arginine, histidine;

(3) non-polar i.e. alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan; and (4) uncharged polar i.e. glycine, asparagine, glutamine, cystine, serine, threonine, tyrosine.

Phenylalanine, tryptophan, and tyrosine are sometimes classified jointly as aromatic amino acids. In general, substitution of single amino acids within these families does not have a major effect on the biological activity. The polypeptides may also include one or more (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) single amino acid deletions relative to the NTHi sequences of the examples. The polypeptides may also include one or more (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) insertions (e.g. each of 1, 2, 3, 4 or

5 amino acids) relative to the NTHi sequences of the examples.

Preferred polypeptides of the invention are listed in Table II, including polypeptides that are lipidated, that are located in the outer membrane, that are located in the inner membrane, that are located in the periplasm, or that are not found in non-pathogenic H.influenzae strains. Particularly preferred polypeptides are those that fall into more than one of these categories e.g. polypeptides that are located in the outer membrane and are also not found in non-pathogenic H.influenzae strains.

A particularly preferred polypeptide is NTH0867. NTH0861, NTH0863 and NTH0865 are also preferred. As described below, these four proteins are embodied by SEQ ID NOS: 1566, 5095, 1570, 5094, 1574, 5903, 1578 and 5092. Within these eight SEQ ID NOS, 1566-1578 are preferred. The invention further provides polypeptides comprising fragments of the H.influenzae amino acid sequences disclosed in the examples. The fragments should comprise at least n consecutive amino acids from the sequences and, depending on the particular sequence, n is 7 or more (e.g. 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100 or more). The fragment may comprise at least one T-cell or, preferably, a B-cell epitope of the sequence. T- and B-cell epitopes can be identified empirically (e.g. using PEPSCAN [4,5] or similar methods), or they can be predicted (e.g. using the Jameson- Wolf antigenic index [6], matrix-based approaches [7], TEPITOPE [8], neural networks [9], OptiMer & EpiMer [10, 11], ADEPT [12], Tsites [13], hydrophilicity [14], antigenic index [15] or the methods disclosed in reference 16 etc.). Other preferred fragments are (a) the N-terminal signal peptides of the NTHi polypeptides of the invention, (b) the NTHi polypeptides, but without their N-terminal signal peptides, (c) the NTHi polypeptides, but without their N-terminal amino acid residue.

Polypeptides of the invention can be prepared in many ways e.g. by chemical synthesis (in whole or in part), by digesting longer polypeptides using proteases, by translation from RNA, by purification from cell culture (e.g. from recombinant expression), from the organism itself (e.g. after bacterial culture, or direct from patients), etc. A preferred method for production of peptides <40 amino acids long involves in vitro chemical synthesis [17,18]. Solid-phase peptide synthesis is particularly preferred, such as methods based on tBoc or Fmoc [19] chemistry. Enzymatic synthesis [20] may also be used in part or in full. As an alternative to chemical synthesis, biological synthesis may be used e.g. the polypeptides may be produced by translation. This may be carried out in vitro or in vivo. Biological methods are in general restricted to the production of polypeptides based on L-amino acids, but manipulation of translation machinery (e.g. of aminoacyl tRNA molecules) can be used to allow the introduction of D-amino acids (or of other non natural amino acids, such as iodotyrosine or methylphenylalanine, azidohomoalanine, etc.) [21]. Where D-amino acids are included, however, it is preferred to use chemical synthesis. Polypeptides of the invention may have covalent modifications at the C-terminus and/or N-terminus.

Polypeptides of the invention can take various forms (e.g. native, fusions, glycosylated, non-glycosylated, lipidated, non-lipidated, phosphorylated, non-phosphorylated, myristoylated, non-myristoylated, monomeric, multimeric, particulate, denatured, etc.). Polypeptides of the invention are preferably provided in purified or substantially purified form i.e. substantially free from other polypeptides (e.g. free from naturally-occurring polypeptides), particularly from other Haemophilus or host cell polypeptides, and are generally at least about 50% pure (by weight), and usually at least about 90% pure i.e. less than about 50%, and more preferably less than about 10% (e.g. 5%) of a composition is made up of other expressed polypeptides. Polypeptides of the invention are preferably H.influenzae polypeptides. Polypeptides of the invention preferably have the function indicated in Table III for the relevant sequence. Polypeptides of the invention may be attached to a solid support. Polypeptides of the invention may comprise a detectable label (e.g. a radioactive or fluorescent label, or a biotin label).

The term "polypeptide" refers to amino acid polymers of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. Also included within the definition are, for example, polypeptides containing one or more analogs of an amino acid (including, for example, unnatural amino acids, etc.), as well as other modifications known in the art. Polypeptides can occur as single chains or associated chains. Polypeptides of the invention can be naturally or non-naturally glycosylated (i.e. the polypeptide has a glycosylation pattern that differs from the glycosylation pattern found in the corresponding naturally occurring polypeptide).

The invention provides polypeptides comprising a sequence -X-Y- or -Y-X-, wherein: -X- is an amino acid sequence as defined above and -Y- is not a sequence as defined above i.e. the invention provides fusion proteins. Where the N-terminus codon of a polypeptide-coding sequence is not ATG then that codon will be translated as the standard amino acid for that codon rather than as a Met, which occurs when the codon is a start codon.

The invention provides a process for producing polypeptides of the invention, comprising the step of culturing a host cell of to the invention under conditions which induce polypeptide expression. The invention provides a process for producing a polypeptide of the invention, wherein the polypeptide is synthesised in part or in whole using chemical means.

The invention provides a composition comprising two or more polypeptides of the invention.

The invention also provides a hybrid polypeptide represented by the formula NH₂-A-[-X-L-]„-B- COOH, wherein X is a polypeptide of the invention as defined above, L is an optional linker amino acid sequence, A is an optional N-terminal amino acid sequence, B is an optional C-terminal amino acid sequence, and n is an integer greater than 1. The value of n is between 2 and x, and the value of x is typically 3, 4, 5, 6, 7, 8, 9 or 10. Preferably n is 2, 3 or 4; it is more preferably 2 or 3; most preferably, n = 2. For each n instances, -X- may be the same or different. For each n instances of [-X-L-], linker amino acid sequence -L- may be present or absent. For instance, when n=2 the hybrid may be NH₂-Xι-Lι-X₂-L₂-COOH, NH₂-Xι-X₂-COOH, NH₂-Xι-L,-X₂-COOH, NH₂-Xι-X₂-L₂- COOH, etc. Linker amino acid sequence(s) -L- will typically be short (e.g. 20 or fewer amino acids i.e. 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1). Examples include short peptide sequences which facilitate cloning, poly-glycine linkers (i.e. Gly,, where n = 2, 3, 4, 5, 6, 7, 8, 9, 10 or more), and histidine tags (i.e. His,, where n = 3, 4, 5, 6, 7, 8, 9, 10 or more). Other suitable linker amino acid sequences will be apparent to those skilled in the art. -A- and -B- are optional sequences which will typically be short (e.g. 40 or fewer amino acids i.e. 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1). Examples include leader sequences to direct polypeptide trafficking, or short peptide sequences which facilitate cloning or purification (e.g. histidine tags i.e. His„ where n = 3, 4, 5, 6, 7, 8, 9, 10 or more). Other suitable N-terminal and C-terminal amino acid sequences will be apparent to those skilled in the art.

Various tests can be used to assess the in vivo immunogenicity of polypeptides of the invention. For example, polypeptides can be expressed recombinantly and used to screen patient sera by immunoblot. A positive reaction between the polypeptide and patient serum indicates that the patient has previously mounted an immune response to the protein in question i.e. the protein is an immunogen. This method can also be used to identify immunodominant proteins.

Antibodies

The invention provides antibodies that bind to polypeptides of the invention. These may be polyclonal or monoclonal and may be produced by any suitable means (e.g. by recombinant expression). To increase compatibility with the human immune system, the antibodies may be chimeric or humanised [e.g. refs. 22 & 23], or fully human antibodies may be used. The antibodies may include a detectable label (e.g. for diagnostic assays). Antibodies of the invention may be attached to a solid support. Antibodies of the invention are preferably neutralising antibodies.

Monoclonal antibodies are particularly useful in identification and purification of the individual polypeptides against which they are directed. Monoclonal antibodies of the invention may also be employed as reagents in immunoassays, radioimmunoassays (RLA) or enzyme-linked immunosorbent assays (ELISA), etc.. In these applications, the antibodies can be labelled with an analytically- detectable reagent such as a radioisotope, a fluorescent molecule or an enzyme. The monoclonal antibodies produced by the above method may also be used for the molecular identification and characterization (epitope mapping) of polypeptides of the invention. Antibodies of the invention are preferably provided in purified or substantially purified form. Typically, the antibody will be present in a composition that is substantially free of other polypeptides e.g. where less than 90% (by weight), usually less than 60% and more usually less than 50% of the composition is made up of other polypeptides.

Antibodies of the invention can be of any isotype (e.g. IgA, IgG, IgM i.e. an α, γ or μ heavy chain), but will generally be IgG. Within the IgG isotype, antibodies may be IgGl, IgG2, IgG3 or IgG4 subclass. Antibodies of the invention may have a K or a λ light chain.

Antibodies of the invention can take various forms, including whole antibodies, antibody fragments such as F(ab')2 and F(ab) fragments, Fv fragments (non-covalent heterodimers), single-chain antibodies such as single chain Fv molecules (scFv), minibodies, oligobodies, etc. The term "antibody" does not imply any particular origin, and includes antibodies obtained through non-conventional processes, such as phage display. The invention provides a process for detecting polypeptides of the invention, comprising the steps of: (a) contacting an antibody of the invention with a biological sample under conditions suitable for the formation of an antibody-antigen complexes; and (b) detecting said complexes.

The invention provides a process for detecting antibodies of the invention, comprising the steps of: (a) contacting a polypeptide of the invention with a biological sample (e.g. a blood or serum sample) under conditions suitable for the formation of an antibody-antigen complexes; and (b) detecting said complexes.

Nucleic acids

The invention provides nucleic acid comprising the H. influenzae nucleotide sequences disclosed in the examples. These nucleic acid sequences are the odd SEQ ID NOs between 1 and 5080.

The invention also provides nucleic acid comprising nucleotide sequences having sequence identity to the H.influenzae nucleotide sequences disclosed in the examples. Identity between sequences is preferably determined by the Smith- Waterman homology search algorithm as described above.

The invention also provides nucleic acid which can hybridize to the H.influenzae nucleic acid disclosed in the examples. Hybridization reactions can be performed under conditions of different "stringency". Conditions that increase stringency of a hybridization reaction of widely known and published in the art [e.g. page 7.52 of reference 24]. Examples of relevant conditions include (in order of increasing stringency): incubation temperatures of 25°C, 37°C, 50°C, 55°C and 68°C; buffer concentrations of 10 x SSC, 6 x SSC, 1 x SSC, 0.1 x SSC (where SSC is 0.15 M NaCl and 15 mM citrate buffer) and their equivalents using other buffer systems; formamide concentrations of 0%, 25%, 50%, and 75%; incubation times from 5 minutes to 24 hours; 1, 2, or more washing steps; wash incubation times of 1, 2, or 15 minutes; and wash solutions of 6 x SSC, 1 x SSC, 0.1 x SSC, or de-ionized water. Hybridization techniques and their optimization are well known in the art [e.g. see references 24-27, etc.]. In some embodiments, nucleic acid of the invention hybridizes to a target of the invention under low stringency conditions; in other embodiments it hybridizes under intermediate stringency conditions; in preferred embodiments, it hybridizes under high stringency conditions. An exemplary set of low stringency hybridization conditions is 50°C and 10 x SSC. An exemplary set of intermediate stringency hybridization conditions is 55°C and 1 x SSC. An exemplary set of high stringency hybridization conditions is 68°C and 0.1 x SSC.

Nucleic acid comprising fragments of these sequences are also provided. These should comprise at least n consecutive nucleotides from the H.influenzae sequences and, depending on the particular sequence, n is 10 or more (e.g. 12, 14, 15, 18, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 150, 200 or more). The invention provides nucleic acid of formula 5'-X-Y-Z-3', wherein: -X- is a nucleotide sequence consisting of x nucleotides; -Z- is a nucleotide sequence consisting of z nucleotides; -Y- is a nucleotide sequence consisting of either (a) a fragment of one of the odd-numbered SEQ ID NOS: 1 to 5079, or (b) the complement of (a); and said nucleic acid 5'-X-Y-Z-3' is neither (i) a fragment of one of the odd-numbered SEQ ID NOS: 1 to 5079 nor (ii) the complement of (i). The -X- and/or -Z- moieties may comprise a promoter sequence (or its complement). The invention also provides nucleic acid encoding the polypeptides and polypeptide fragments of the invention.

The invention includes nucleic acid comprising sequences complementary to the sequences disclosed in the sequence listing (e.g. for antisense or probing, or for use as primers), as well as the sequences in the orientation actually shown. Nucleic acids of the invention can be used in hybridisation reactions (e.g. Northern or Southern blots, or in nucleic acid microarrays or 'gene chips') and amplification reactions (e.g. PCR, SDA, SSSR, LCR, TMA, NASBA, etc.) and other nucleic acid techniques.

Nucleic acid according to the invention can take various forms (e.g. single-stranded, double-stranded, vectors, primers, probes, labelled etc.). Nucleic acids of the invention may be circular or branched, but will generally be linear. Unless otherwise specified or required, any embodiment of the invention that utilizes a nucleic acid may utilize both the double-stranded form and each of two complementary single-stranded forms which make up the double-stranded form. Primers and probes are generally single-stranded, as are antisense nucleic acids.

Nucleic acids of the invention are preferably provided in purified or substantially purified form i.e. substantially free from other nucleic acids (e.g. free from naturally-occurring nucleic acids), particularly from other Haemophilus or host cell nucleic acids, generally being at least about 50% pure (by weight), and usually at least about 90% pure. Nucleic acids of the invention are preferably H.influenzae nucleic acids.

Nucleic acids of the invention may be prepared in many ways e.g. by chemical synthesis (e.g. phosphoramidite synthesis of DNA) in whole or in part, by digesting longer nucleic acids using nucleases (e.g. restriction enzymes), by joining shorter nucleic acids or nucleotides (e.g. using ligases or polymerases), from genomic or cDNA libraries, etc.

Nucleic acid of the invention may be attached to a solid support (e.g. a bead, plate, filter, film, slide, microarray support, resin, etc.). Nucleic acid of the invention may be labelled e.g. with a radioactive or fluorescent label, or a biotin label. This is particularly useful where the nucleic acid is to be used in detection techniques e.g. where the nucleic acid is a primer or as a probe.

The term "nucleic acid" includes in general means a polymeric form of nucleotides of any length, which contain deoxyribonucleotides, ribonucleotides, and/or their analogs. It includes DNA, RNA, DNA/RNA hybrids. It also includes DNA or RNA analogs, such as those containing modified backbones (e.g. peptide nucleic acids (PNAs) or phosphorothioates) or modified bases. Thus the invention includes mRNA, tRNA, rRNA, ribozymes, DNA, cDNA, recombinant nucleic acids, branched nucleic acids, plasmids, vectors, probes, primers, etc.. Where nucleic acid of the invention takes the form of RNA, it may or may not have a 5' cap.

Nucleic acids of the invention comprise NTHi sequences, but they may also comprise non-NTHi sequences (e.g. in nucleic acids of formula 5'-X-Y-Z-3', as defined above). This is particularly useful for primers, which may thus comprise a first sequence complementary to a PCAV nucleic acid target and a second sequence which is not complementary to the nucleic acid target. Any such non- complementary sequences in the primer are preferably 5' to the complementary sequences. Typical non-complementary sequences comprise restriction sites or promoter sequences.

Nucleic acids of the invention can be prepared in many ways e.g. by chemical synthesis (at least in part), by digesting longer nucleic acids using nucleases (e.g. restriction enzymes), by joining shorter nucleic acids (e.g. using ligases or polymerases), from genomic or cDNA libraries, etc.

Nucleic acids of the invention may be part of a vector i.e. part of a nucleic acid construct designed for transduction/transfection of one or more cell types. Vectors may be, for example, "cloning vectors" which are designed for isolation, propagation and replication of inserted nucleotides, "expression vectors" which are designed for expression of a nucleotide sequence in a host cell, "viral vectors" which is designed to result in the production of a recombinant virus or virus-like particle, or "shuttle vectors", which comprise the attributes of more than one type of vector. Preferred vectors are plasmids. A "host cell" includes an individual cell or cell culture which can be or has been a recipient of exogenous nucleic acid. Host cells include progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or in total DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation and/or change. Host cells include cells transfected or infected in vivo or in vitro with nucleic acid of the invention.

Where a nucleic acid is DNA, it will be appreciated that "U" in a RNA sequence will be replaced by "T" in the DNA. Similarly, where a nucleic acid is RNA, it will be appreciated that "T" in a DNA sequence will be replaced by "U" in the RNA.

The term "complement" or "complementary" when used in relation to nucleic acids refers to Watson- Crick base pairing. Thus the complement of C is G, the complement of G is C, the complement of A is T (or U), and the complement of T (or U) is A. It is also possible to use bases such as I (the purine inosine) e.g. to complement pyrimidines (C or T). The terms also imply a direction - the complement of 5'-ACAGT-3' is 5'-ACTGT-3' rather than 5'-TGTCA-3'.

Nucleic acids of the invention can be used, for example: to produce polypeptides; as hybridization probes for the detection of nucleic acid in biological samples; to generate additional copies of the nucleic acids; to generate ribozymes or antisense oligonucleotides; as single-stranded DNA primers or probes; or as triple-strand forming oligonucleotides. The invention provides a process for producing nucleic acid of the invention, wherein the nucleic acid is synthesised in part or in whole using chemical means. The invention provides vectors comprising nucleotide sequences of the invention (e.g. cloning or expression vectors) and host cells transformed with such vectors.

The invention also provides a kit comprising primers (e.g. PCR primers) for amplifying a template sequence contained within a Haemophilus bacterium (e.g. H.influenzae) nucleic acid sequence, the kit comprising a first primer and a second primer, wherein the first primer is substantially complementary to said template sequence and the second primer is substantially complementary to a complement of said template sequence, wherein the parts of said primers which have substantial complementarity define the termini of the template sequence to be amplified. The first primer and/or the second primer may include a detectable label (e.g. a fluorescent label). The invention also provides a kit comprising first and second single-stranded oligonucleotides which allow amplification of a Haemophilus template nucleic acid sequence contained in a single- or double-stranded nucleic acid (or mixture thereof), wherein: (a) the first oligonucleotide comprises a primer sequence which is substantially complementary to said template nucleic acid sequence; (b) the second oligonucleotide comprises a primer sequence which is substantially complementary to the complement of said template nucleic acid sequence; (c) the first oligonucleotide and/or the second oligonucleotide comprise(s) sequence which is not compementary to said template nucleic acid; and (d) said primer sequences define the termini of the template sequence to be amplified. The non-complementary sequence(s) of feature (c) are preferably upstream of (i.e. 5' to) the primer sequences. One or both of these (c) sequences may comprise a restriction site [e.g. ref.28] or a promoter sequence [e.g. 29]. The first oligonucleotide and/or the second oligonucleotide may include a detectable label (e.g. a fluorescent label).

The template sequence may be any part of a genome sequence.

The invention provides a process for detecting nucleic acid of the invention, comprising the steps of: (a) contacting a nucleic probe according to the invention with a biological sample under hybridising conditions to form duplexes; and (b) detecting said duplexes.

The invention provides a process for detecting H.influenzae in a biological sample (e.g. blood), comprising the step of contacting nucleic acid according to the invention with the biological sample under hybridising conditions. The process may involve nucleic acid amplification (e.g. PCR, SDA, SSSR, LCR, TMA, NASBA, etc.) or hybridisation (e.g. microarrays, blots, hybridisation with a probe in solution etc.). PCR detection of H.influenzae in clinical samples has been reported [e.g. see refs. 30 & 31]. Clinical assays based on nucleic acid are described in general in ref. 32.

The invention provides a process for preparing a fragment of a target sequence, wherein the fragment is prepared by extension of a nucleic acid primer. The target sequence and/or the primer are nucleic acids of the invention. The primer extension reaction may involve nucleic acid amplification (e g. PCR, SDA, SSSR, LCR, TMA, NASBA, etc.).

Nucleic acid amplification according to the invention may be quantitative and/or real-time. For certain embodiments of the invention, nucleic acids are preferably at least 7 nucleotides in length (e.g. 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 45, 50, 55, 60, 65, 70, 75, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300 nucleotides or longer). For certain embodiments of the invention, nucleic acids are preferably at most 500 nucleotides in length (e.g. 450, 400, 350, 300, 250, 200, 150, 140, 130, 120, 110, 100, 90, 80, 75, 70, 65, 60, 55, 50, 45, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15 nucleotides or shorter).

Primers and probes of the invention, and other nucleic acids used for hybridization, are preferably between 10 and 30 nucleotides in length (e.g. 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides).

Pharmaceutical compositions

The invention provides compositions comprising: (a) polypeptide, antibody, and/or nucleic acid of the invention; and (b) a pharmaceutically acceptable carrier. These compositions may be suitable as immunogenic compositions, for instance, or as diagnostic reagents, or as vaccines. Vaccines according to the invention may either be prophylactic (i.e. to prevent infection) or therapeutic (i.e. to treat infection), but will typically be prophylactic.

A 'pharmaceutically acceptable carriers' includes any carrier that does not itself induce the production of antibodies harmful to the individual receiving the composition. Suitable carriers are typically large, slowly metabolised macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, sucrose, trehalose, lactose, and lipid aggregates (such as oil droplets or liposomes). Such carriers are well known to those of ordinary skill in the art. The vaccines may also contain diluents, such as water, saline, glycerol, etc. Additionally, auxiliary substances, such as wetting or emulsifying agents, pH buffering substances, and the like, may be present. Sterile pyrogen-free, phosphate-buffered physiologic saline is a typical carrier. A thorough discussion of pharmaceutically acceptable excipients is available in ref. 138.

Compositions of the invention may include an antimicrobial, particularly if packaged in a multiple dose format.

Compositions of the invention may comprise detergent e.g. a Tween (polysorbate), such as Tween 80. Detergents are generally present at low levels e.g. <0.01%.

Compositions of the invention may include sodium salts (e.g. sodium chloride) to give tonicity. A concentration of 10+2mg/ml NaCl is typical.

Compositions of the invention will generally include a buffer. A phosphate buffer is typical.

Compositions of the invention may comprise a sugar alcohol (e g. mannitol) or a disaccharide (e.g. sucrose or trehalose) e.g. at around 15-30mg/ml (e.g. 25 mg/ml), particularly if they are to be lyophilised or if they include material which has been reconstituted from lyophilised material. The pH of a composition for lyophilisation may be adjusted to around 6.1 prior to lyophilisation.

Polypeptides of the invention may be administered in conjunction with other immunoregulatory agents. In particular, compositions will usually include a vaccine adjuvant. Adjuvants which may be used in compositions of the invention include, but are not limited to:

A. Mineral-containing compositions

Mineral containing compositions suitable for use as adjuvants in the invention include mineral salts, such as aluminium salts and calcium salts. The invention includes mineral salts such as hydroxides (e.g. oxyhydroxides), phosphates (e.g. hydroxyphosphates, orthophosphates), sulphates, etc. [e.g. see chapters 8 & 9 of ref. 33], or mixtures of different mineral compounds, with the compounds taking any suitable form (e.g. gel, crystalline, amorphous, etc.), and with adsorption being preferred. The mineral containing compositions may also be formulated as a particle of metal salt [34].

Aluminium phosphates are particularly preferred, particularly in compositions which include a H.influenzae saccharide antigen, and a typical adjuvant is amorphous aluminium hydroxyphosphate with P0 /A1 molar ratio between 0.84 and 0.92, included at 0.6mg Al³⁺/ml. Adsorption with a low dose of aluminium phosphate may be used e.g. between 50 and lOOμg Al³⁺ per conjugate per dose. Where there is more than one conjugate in a composition, not all conjugates need to be adsorbed.

B. Oil Emulsions

Oil emulsion compositions suitable for use as adjuvants in the invention include squalene-water emulsions, such as MF59 [Chapter 10 of ref. 33; see also ref. 35] (5% Squalene, 0.5% Tween 80, and 0.5% Span 85, formulated into submicron particles using a microfluidizer). Complete Freund's adjuvant (CFA) and incomplete Freund's adjuvant (IF A) may also be used.

C. Saponin formulations [chapter 22 of ref. 33]

Saponin formulations may also be used as adjuvants in the invention. Saponins are a heterologous group of sterol glycosides and triterpenoid glycosides that are found in the bark, leaves, stems, roots and even flowers of a wide range of plant species. Saponin from the bark of the Quillaia saponaria Molina tree have been widely studied as adjuvants. Saponin can also be commercially obtained from Smilax ornata (sarsaprilla), Gypsophilla paniculata (brides veil), and Saponaria officianalis (soap root). Saponin adjuvant formulations include purified formulations, such as QS21, as well as lipid formulations, such as ISCOMs. QS21 is marketed as Stimulon™.

Saponin compositions have been purified using HPLC and RP-HPLC. Specific purified fractions using these techniques have been identified, including QS7, QS17, QS18, QS21, QH-A, QH-B and QH-C. Preferably, the saponin is QS21. A method of production of QS21 is disclosed in ref. 36. Saponin formulations may also comprise a sterol, such as cholesterol [37]. Combinations of saponins and cholesterols can be used to form unique particles called immunostimulating complexs (ISCOMs) [chapter 23 of ref. 33], ISCOMs typically also include a phospholipid such as phosphatidylethanolamkie or phosphatidylcholine. Any known saponin can be used in ISCOMs. Preferably, the ISCOM includes one or more of QuilA, QHA & QHC. ISCOMs are further described in refs. 37-39. Optionally, the ISCOMS may be devoid of additional detergent [40].

A review of the development of saponin based adjuvants can be found in refs. 41 & 42.

D. Virosomes and virus-like particles

Virosomes and virus-like particles (VLPs) can also be used as adjuvants in the invention. These structures generally contain one or more proteins from a virus optionally combined or formulated with a phospholipid. They are generally non-pathogenic, non-replicating and generally do not contain any of the native viral genome. The viral proteins may be recombinantly produced or isolated from whole viruses. These viral proteins suitable for use in virosomes or VLPs include proteins derived from influenza virus (such as HA or NA), Hepatitis B virus (such as core or capsid proteins), Hepatitis E virus, measles virus, Sindbis virus, Rotavirus, Foot-and-Mouth Disease virus, Retrovirus, Norwalk virus, human Papilloma virus, HIV, RNA-phages, Qβ-phage (such as coat proteins), GA- phage, fr-phage, AP205 phage, and Ty (such as retrotransposon Ty protein pi). VLPs are discussed further in refs. 43-48. Virosomes are discussed further in, for example, ref. 49

E. Bacterial or microbial derivatives

Adjuvants suitable for use in the invention include bacterial or microbial derivatives such as non-toxic derivatives of enterobacterial lipopolysaccharide (LPS), Lipid A derivatives, immunostimulatory oligonucleotides and ADP-ribosylating toxins and detoxified derivatives thereof.

Non-toxic derivatives of LPS include monophosphoryl lipid A (MPL) and 3-O-deacylated MPL (3dMPL). 3dMPL is a mixture of 3 de-O-acylated monophosphoryl lipid A with 4, 5 or 6 acylated chains. A preferred "small particle" form of 3 De-O-acylated monophosphoryl lipid A is disclosed in ref. 50. Such "small particles" of 3dMPL are small enough to be sterile filtered through a 0.22μm membrane [50]. Other non-toxic LPS derivatives include monophosphoryl lipid A mimics, such as aminoalkyl glucosaminide phosphate derivatives e.g. RC-529 [51,52].

Lipid A derivatives include derivatives of lipid A from Escherichia coli such as OM-174. OM-174 is described for example in refs. 53 & 54. Immunostimulatory oligonucleotides suitable for use as adjuvants in the invention include nucleotide sequences containing a CpG motif (a dinucleotide sequence containing an unmethylated cytosine linked by a phosphate bond to a guanosine). Double-stranded RNAs and oligonucleotides containing palindromic or poly(dG) sequences have also been shown to be immunostimulatory.

The CpG's can include nucleotide modifications/analogs such as phosphorothioate modifications and can be double-stranded or single-stranded. References 55, 56 and 57 disclose possible analog substitutions e.g. replacement of guanosine with 2'-deoxy-7-deazaguanosine. The adjuvant effect of CpG oligonucleotides is further discussed in refs. 58-63.

The CpG sequence may be directed to TLR9, such as the motif GTCGTT or TTCGTT [64]. The CpG sequence may be specific for inducing a Thl immune response, such as a CpG-A ODN, or it may be more specific for inducing a B cell response, such a CpG-B ODN. CpG-A and CpG-B ODNs are discussed in refs. 65-67. Preferably, the CpG is a CpG-A ODN.

Preferably, the CpG oligonucleotide is constructed so that the 5' end is accessible for receptor recognition. Optionally, two CpG oligonucleotide sequences may be attached at their 3' ends to form "immunomers". See, for example, refs. 64 & 68-70. Bacterial ADP-ribosylating toxins and detoxified derivatives thereof may be used as adjuvants in the invention. Preferably, the protein is derived from E.coli (E.coli heat labile enterotoxin "LT"), cholera ("CT"), or pertussis ("PT"). The use of detoxified ADP-ribosylating toxins as mucosal adjuvants is described in ref. 71 and as parenteral adjuvants in ref. 72. The toxin or toxoid is preferably in the form of a holotoxin, comprising both A and B subunits. Preferably, the A subunit contains a detoxifying mutation; preferably the B subunit is not mutated. Preferably, the adjuvant is a detoxified LT mutant such as LT-K63, LT-R72, and LT-G192. The use of ADP-ribosylating toxins and detoxified derivaties thereof, particularly LT-K63 and LT-R72, as adjuvants can be found in refs. 73- 80. Numerical reference for amino acid substitutions is preferably based on the alignments of the A and B subunits of ADP-ribosylating toxins set forth in ref. 81, specifically incorporated herein by reference in its entirety.

F. Human immunomodulators

Human immunomodulators suitable for use as adjuvants in the invention include cytokines, such as interleukins (e.g. IL-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL-12 [82], etc.) [83], interferons (e.g. interferon-γ), macrophage colony stimulating factor, and tumor necrosis factor. G. Bioadhesives and Mucoadhesives

Bioadhesives and mucoadhesives may also be used as adjuvants in the invention. Suitable bioadhesives include esterified hyaluronic acid microspheres [84] or mucoadhesives such as cross-linked derivatives of poly(acrylic acid), polyvinyl alcohol, polyvinyl pyrollidone, polysaccharides and carboxymethylcellulose. Chitosan and derivatives thereof may also be used as adjuvants in the invention [85].

H. Microparticles

Microparticles may also be used as adjuvants in the invention. Microparticles (i.e. a particle of -lOOnm to ~150μm in diameter, more preferably ~200nm to ~30μm in diameter, and most preferably ~500nm to ~10μm in diameter) formed from materials that are biodegradable and non-toxic (e.g. a poly(α-hydroxy acid), a polyhydroxybutyric acid, a polyorthoester, a polyanhydride, a polycaprolactone, etc.), with poly(lactide-co-glycolide) are preferred, optionally treated to have a negatively-charged surface (e.g. with SDS) or a positively-charged surface (e.g. with a cationic detergent, such as CTAB).

I. Liposomes (Chapters 13 & 14 of ref. 33)

Examples of liposome formulations suitable for use as adjuvants are described in refs. 86-88. J. Polyoxyethylene ether and polyoxyethylene ester formulations

Adjuvants suitable for use in the invention include polyoxyethylene ethers and polyoxyethylene esters [89]. Such formulations further include polyoxyethylene sorbitan ester surfactants in combination with an octoxynol [90] as well as polyoxyethylene alkyl ethers or ester surfactants in combination with at least one additional non-ionic surfactant such as an octoxynol [91]. Preferred polyoxyethylene ethers are selected from the following group: polyoxyethylene-9-lauryl ether (laureth 9), polyoxyethylene-9-steoryl ether, polyoxytheylene-8-steoryl ether, polyoxyethylene-4- lauryl ether, polyoxyethylene-35-lauryl ether, and polyoxyethylene-23-lauryl ether.

K. Polyphosphazene (PCPP)

PCPP formulations are described, for example, in refs. 92 and 93. L. Muramyl peptides

Examples of muramyl peptides suitable for use as adjuvants in the invention include N-acetyl- muramyl-L-threonyl-D-isoglutamine (thr-MDP), N-acetyl-normuramyl-L-alanyl-D-isoglutamine (nor- MDP), and N-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-( 1 '-2'-dipalmitoyl-s7i-glycero-3- hydroxyphosphoryloxy)-ethylamine MTP-PE) . M. Imidazoquinolone Compounds.

Examples of imidazoquinolone compounds suitable for use adjuvants in the invention include Imiquamod and its homologues (e,g. "Resiquimod 3M"), described further in refs. 94 and 95.

The invention may also comprise combinations of aspects of one or more of the adjuvants identified above. For example, the following adjuvant compositions may be used in the invention: (1) a saponin and an oil-in-water emulsion [96]; (2) a saponin (e.g. QS21) + a non-toxic LPS derivative (e.g. 3dMPL) [97]; (3) a saponin (e.g. QS21) + a non-toxic LPS derivative (e.g. 3dMPL) + a cholesterol; (4) a saponin (e.g. QS21) + 3dMPL + IL-12 (optionally + a sterol) [98]; (5) combinations of 3dMPL with, for example, QS21 and/or oil-in-water emulsions [99]; (6) SAF, containing 10% squalane, 0.4% Tween 80™, 5% pluronic-block polymer L121, and thr-MDP, either microfluidized into a submicron emulsion or vortexed to generate a larger particle size emulsion. (7) Ribi™ adjuvant system (RAS), (Ribi Immunochem) containing 2% squalene, 0.2% Tween 80, and one or more bacterial cell wall components from the group consisting of monophosphorylipid A (MPL), trehalose dimycolate (TDM), and cell wall skeleton (CWS), preferably MPL + CWS (Detox™); and (8) one or more mineral salts (such as an aluminum salt) + a non-toxic derivative of LPS (such as 3dMPL). Other substances that act as immunostimulating agents are disclosed in chapter 7 of ref. 33. The use of an aluminium hydroxide or aluminium phosphate adjuvant is particularly preferred, and antigens are generally adsorbed to these salts. Calcium phosphate is another preferred adjuvant.

The pH of compositions of the invention is preferably between 6 and 8, preferably about 7. Stable pH may be maintained by the use of a buffer. Where a composition comprises an aluminium hydroxide salt, it is preferred to use a histidine buffer [100]. The composition may be sterile and/or pyrogen-free. Compositions of the invention may be isotonic with respect to humans.

Compositions may be presented in vials, or they may be presented in ready-filled syringes. The syringes may be supplied with or without needles. A syringe will include a single dose of the composition, whereas a vial may include a single dose or multiple doses. Injectable compositions will usually be liquid solutions or suspensions. Alternatively, they may be presented in solid form (e.g. freeze-dried) for solution or suspension in liquid vehicles prior to injection.

Compositions of the invention may be packaged in unit dose form or in multiple dose form. For multiple dose forms, vials are preferred to pre-filled syringes. Effective dosage volumes can be routinely established, but a typical human dose of the composition for injection has a volume of 0.5ml.

Where a composition of the invention is to be prepared extemporaneously prior to use (e.g. where a component is presented in lyophilised form) and is presented as a kit, the kit may comprise two vials, or it may comprise one ready-filled syringe and one vial, with the contents of the syringe being used to reactivate the contents of the vial prior to injection. Immunogenic compositions used as vaccines comprise an immunologically effective amount of antigen(s), as well as any other components, as needed. By 'immunologically effective amount', it is meant that the administration of that amount to an individual, either in a single dose or as part of a series, is effective for treatment or prevention. This amount varies depending upon the health and physical condition of the individual to be treated, age, the taxonomic group of individual to be treated (e.g. non-human primate, primate, etc.), the capacity of the individual's immune system to synthesise antibodies, the degree of protection desired, the formulation of the vaccine, the treating doctor's assessment of the medical situation, and other relevant factors. It is expected that the amount will fall in a relatively broad range that can be determined through routine trials, and a typical quantity of each meningococcal saccharide antigen per dose is between lμg and lOmg per antigen. Pharmaceutical uses

The invention also provides a method of treating a patient, comprising administering to the patient a therapeutically effective amount of a composition of the invention. The patient may either be at risk from the disease themselves or may be a pregnant woman ('maternal immunisation').

The invention provides nucleic acid, polypeptide, or antibody of the invention for use as medicaments (e.g. as immunogenic compositions or as vaccines) or as diagnostic reagents. It also provides the use of nucleic acid, polypeptide, or antibody of the invention in the manufacture of: (i) a medicament for treating or preventing disease and/or infection caused by H.influenzae; (ii) a diagnostic reagent for detecting the presence of H.influenzae or of antibodies raised against H.influenzae; and/or (iii) a reagent which can raise antibodies against H.influenzae. Said H.influenzae serotype or strain, but is preferably a non-typeable H. influenzae. Said disease may be, for instance, otitis media (including acute otitis media), bronchitis, conjunctivitis, sinusitis, a urinary tract infection, pneumonia, bacteremia, septic arthritis, epiglottitis, pneumonia, empyema, pericarditis, cellulitis, osteomyelitis, lower respiratory tract infection or meningitis. The invention is particularly useful for preventing inflammation of the middle ear, by eliciting an immune response that prevents bacteria from moving from the throat to the middle ear via the eustachian tube, where the middle ear is then colonised.

The patient is preferably a human. Where the vaccine is for prophylactic use, the human is preferably a child (e.g. a toddler or infant); where the vaccine is for therapeutic use, the human is preferably an adult. A vaccine intended for children may also be administered to adults e.g. to assess safety, dosage, immunogenicity, etc. One way of checking efficacy of therapeutic treatment involves monitoring NTΗi infection after administration of the composition of the invention. One way of checking efficacy of prophylactic treatment involves monitoring immune responses against an administered polypeptide after administration. Immunogenicity of compositions of the invention can be determined by administering them to test subjects (e.g. children 12-16 months age, or animal models [e.g. a chinchilla model [146]) and then determining standard parameters including ELISA titres (GMT) of IgG. These immune responses will generally be determined around 4 weeks after administration of the composition, and compared to values determined before administration of the composition. Where more than one dose of the composition is administered, more than one post-administration determination may be made. Administration of polypeptide antigens is a preferred method of treatment for inducing immunity. Administration of antibodies of the invention is another preferred method of treatment. This method of passive immunisation is particularly useful for newborn children or for pregnant women. This method will typically use monoclonal antibodies, which will be humanised or fully human.

Compositions of the invention will generally be administered directly to a patient. Direct delivery may be accomplished by parenteral injection (e.g. subcutaneously, intraperitoneally, intravenously, intramuscularly, or to the interstitial space of a tissue), or by rectal, oral, vaginal, topical, transdermal, intranasal, ocular, aural, pulmonary or other mucosal administration. Intramuscular administration to the thigh or the upper arm is preferred. Injection may be via a needle (e.g. a hypodermic needle), but needle-free injection may alternatively be used. A typical intramuscular dose is 0.5 ml.

The invention may be used to elicit systemic and/or mucosal immunity. Dosage treatment can be a single dose schedule or a multiple dose schedule. Multiple doses may be used in a primary immunisation schedule and/or in a booster immunisation schedule. A primary dose schedule may be followed by a booster dose schedule. Suitable timing between priming doses (e.g. between 4-16 weeks), and between priming and boosting, can be routinely determined. Bacterial infections affect various areas of the body and so compositions may be prepared in various forms. For example, the compositions may be prepared as injectables, either as liquid solutions or suspensions. Solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection can also be prepared (e.g. a lyophilised composition). The composition may be prepared for topical administration e.g. as an ointment, cream or powder. The composition be prepared for oral administration e.g. as a tablet or capsule, or as a syrup (optionally flavoured). The composition may be prepared for pulmonary administration e.g. as an inhaler, using a fine powder or a spray. The composition may be prepared as a suppository or pessary. The composition may be prepared for nasal, aural or ocular administration e.g. as spray, drops, gel or powder [e.g. refs 101 & 102].

Combinations Within the >2500 proteins described in the examples, NTH0861, NTH0863, NTH0865 and NTH0867 are particularly preferred for use with the invention (particularly in vaccines), and these four proteins can be used in combinations. Thus the invention provides a composition comprising: (a) a NTH0861 protein; and (b) at least one further NTHi protein. The invention also provides a composition comprising: (a) a NTH0863 protein; and (b) at least one further NTHi protein. The invention also provides a composition comprising: (a) a NTH0865 protein; and (b) at least one further NTHi protein. The invention also provides a composition comprising: (a) a NTH0867 protein; and (b) at least one further NTHi protein. The further NTHi protein can be selected from proteins of the invention as described above.

The combinations are preferably selected within these four proteins, and so the invention provides a composition comprising two or more (i.e. 2, 3 or 4) of NTH0861, NTH0863, NTH0865 and/or NTH0867. Preferred compositions comprise: (1) NTH0861 and NTH0863; (2) NTH0861 and NTH0865; (3) NTH0861 and NTH0867; (4) NTH0863 and NTH0865; (5) NTH0863 and NTH0867; (6) NTH0865 and NTH0867; (7) NTH0861, NTH0863 and NTH0865; (8) NTH0861, NTH0863 and NTH0867; (9) NTH0863, NTH0865 and NTH0867; (10) NTH0861, NTH0865 and NTH0867; (11) NTH0861, NTH0863 , NTH0865 and NTH0867.

The NTH0861 protein preferably comprises SEQ ID NO: 1566, SEQ ID NO: 5095, or an amino acid sequence having sequence identity (as described above) to SEQ ID NO: 1566 and/or to SEQ ID NO: 5095. The NTH0863 protein preferably comprises SEQ ID NO: 1570, SEQ ID NO: 5094, or an amino acid sequence having sequence identity (as described above) to SEQ ID NO: 1570 and/or to SEQ ID NO: 5094. The NTH0865 protein preferably comprises SEQ ID NO: 1574, SEQ ID NO: 5093, or an amino acid sequence having sequence identity (as described above) to SEQ ID NO: 1574 and/or to SEQ ID NO: 5093. The NTH0867 protein preferably comprises SEQ ID NO: 1578, SEQ ID NO: 5092, or an amino acid sequence having sequence identity (as described above) to SEQ ID NO: 1578 and/or to SEQ ID NO: 5092.

Further antigenic components of compositions of the invention

The invention also provides a composition comprising a polypeptide or the invention and one or more of the following further antigens:

- a saccharide antigen from N.meningitidis serogroup A, C, W135 and/or Y (preferably all four), such as the oligosaccharide disclosed in ref. 103 from serogroup C [see also ref. 104] or the oligosaccharides of ref. 105.

- a saccharide antigen from Streptococcus pneumoniae [e.g. 106, 107, 108]. - an antigen from hepatitis A virus, such as inactivated virus [e.g. 109, 110].

- an antigen from hepatitis B virus, such as the surface and/or core antigens [e.g. 110, 111].

- a diphtheria antigen, such as a diphtheria toxoid [e.g. chapter 3 of ref. 112] e.g. the CRM₁97 mutant [e.g. 113].

- a tetanus antigen, such as a tetanus toxoid [e.g. chapter 4 of ref. 112]. - an antigen from Bordetella pertussis, such as pertussis holotoxin (PT) and filamentous haemagglutinin (FHA) from B.pertussis, optionally also in combination with pertactin and/or agglutinogens 2 and 3 [e.g. refs. 114 & 115].

- a saccharide antigen from Haemophilus influenzae B [e.g. 104].

- polio antigen(s) [e.g. 116, 117] such as IPV. - measles, mumps and/or rubella antigens [e.g. chapters 9, 10 & 11 of ref. 112].

- influenza antigen(s) [e.g. chapter 19 of ref. 112], such as the haemagglutinin and/or neuraminidase surface proteins.

- an antigen from Moraxella catarrhalis [e.g. 118].

- an protein antigen from Streptococcus agalactiae (group B streptococcus) [e.g. 119, 120]. - a saccharide antigen from Streptococcus agalactiae (group B streptococcus).

- an antigen from Streptococcus pyogenes (group A streptococcus) [e.g. 120, 121, 122].

- an antigen from Staphylococcus aureus [e.g. 123].

The composition may comprise one or more of these further antigens.

Toxic protein antigens may be detoxified where necessary (e.g. detoxification of pertussis toxin by chemical and/or genetic means [115]).

Where a diphtheria antigen is included in the composition it is preferred also to include tetanus antigen and pertussis antigens. Similarly, where a tetanus antigen is included it is preferred also to include diphtheria and pertussis antigens. Similarly, where a pertussis antigen is included it is preferred also to include diphtheria and tetanus antigens. DTP combinations are thus preferred. Saccharide antigens are preferably in the form of conjugates. Carrier proteins for the conjugates include diphtheria toxin, tetanus toxin, the N.meningitidis outer membrane protein [124], synthetic peptides [125,126], heat shock proteins [127,128], pertussis proteins [129,130], protein D from H.influenzae [131], cytokines [132], lymphokines [132], streptococcal proteins, hormones [132], growth factors [132], toxin A or B from C.difficϊle [133], iron-uptake proteins [134], etc. A preferred carrier protein is the CRM197 diphtheria toxoid [135].

Antigens in the composition will typically be present at a concentration of at least 1 μg/ml each. In general, the concentration of any given antigen will be sufficient to elicit an immune response against that antigen.

As an alternative to using proteins antigens in the immunogenic compositions of the invention, nucleic acid (preferably DNA e.g. in the form of a plasmid) encoding the antigen may be used.

Antigens are preferably adsorbed to an aluminium salt. Screening methods

The invention provides a process for determining whether a test compound binds to a polypeptide of the invention. If a test compound binds to a polypeptide of the invention and this binding inhibits the life cycle of the H. influenzae bacterium, then the test compound can be used as an antibiotic or as a lead compound for the design of antibiotics. The process will typically comprise the steps of contacting a test compound with a polypeptide of the invention, and determining whether the test compound binds to said polypeptide. Preferred polypeptides of the invention for use in these processes are enzymes (e.g. tRNA synthetases), membrane transporters and ribosomal polypeptides. Suitable test compounds include polypeptides, polypeptides, carbohydrates, lipids, nucleic acids (e.g. DNA, RNA, and modified forms thereof), as well as small organic compounds (e.g. MW between 200 and 2000 Da). The test compounds may be provided individually, but will typically be part of a library (e.g. a combinatorial library). Methods for detecting a binding interaction include NMR, filter-binding assays, gel-retardation assays, displacement assays, surface plasmon resonance, reverse two-hybrid etc. A compound which binds to a polypeptide of the invention can be tested for antibiotic activity by contacting the compound with GBS bacteria and then monitoring for inhibition of growth. The invention also provides a compound identified using these methods.

Preferably, the process comprises the steps of: (a) contacting a polypeptide of the invention with one or more candidate compounds to give a mixture; (b) incubating the mixture to allow polypeptide and the candidate compound(s) to interact; and (c) assessing whether the candidate compound binds to the polypeptide or modulates its activity. Once a candidate compound has been identified in vitro as a compound that binds to a polypeptide of the invention then it may be desirable to perform further experiments to confirm the in vivo function of the compound in inhibiting bacterial growth and/or survival. Thus the method comprise the further step of contacting the compound with a NTΗi bacterium and assessing its effect.

The polypeptide used in the screening process may be free in solution, affixed to a solid support, located on a cell surface or located intracellularly. Preferably, the binding of a candidate compound to the polypeptide is detected by means of a label directly or indirectly associated with the candidate compound. The label may be a fluorophore, radioisotope, or other detectable label.

General

The invention provides a computer-readable medium (e.g. a floppy disk, a hard disk, a CD-ROM, a DVD etc.) and/or a computer memory and/or a computer database containing one or more of the sequences in the sequence listing.

The term "comprising" encompasses "including" as well as "consisting" e.g. a composition "comprising" X may consist exclusively of X or may include something additional e.g. X + Y.

The term "about" in relation to a numerical value x means, for example, x+10%. The word "substantially" does not exclude "completely" e.g. a composition which is "substantially free" from Y may be completely free from Y. Where necessary, the word "substantially" may be omitted from the definition of the invention.

The N-terminus residues in the amino acid sequences in the sequence listing are given as the amino acid encoded by the first codon in the corresponding nucleotide sequence. Where the first codon is not ATG, it will be understood that it will be translated as methionine when the codon is a start codon, but will be translated as the indicated non-Met amino acid when the sequence is at the C-terminus of a fusion partner. The invention specifically discloses and encompasses each of the amino acid sequences of the sequence listing having a N-terminus methionine residue (e.g. a formyl-methionine residue) in place of any indicated non-Met residue. Alternative start codons can be used in biology. The amino acid sequences in the sequence listing are based on particular start codons, but downstream start codons may alternatively be used. Thus the invention specifically discloses and encompasses each of the amino acid sequences of the sequence listing, starting at any methionine residue from the sequence that is downstream of the N-terminal residue shown in the sequence listing (e.g. SEQ ID NOS: 5088, 5089 & 5090). As indicated in the above text, nucleic acids and polypeptides of the invention may include sequences that: (a) are identical (i.e. 100% identical) to the sequences disclosed in the sequence listing; (b) share sequence identity with the sequences disclosed in the sequence listing; (c) have 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 single nucleotide or amino acid alterations (deletions, insertions, substitutions), which may be at separate locations or may be contiguous, as compared to the sequences of (a) or (b); and (d) when aligned with a particular sequence from the sequence listing using a pairwise alignment algorithm, a moving window of x monomers (amino acids or nucleotides) moving from start (N-terminus or 5') to end (C-terminus of 3'), such that for an alignment that extends to p monomers (where p>x) there are p-x+1 such windows, each window has at least x identical aligned monomers, where: x is selected from 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200; y is selected from 0.50, 0.60, 0.70, 0.75, 0.80, 0.85, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99; and if x-y is is not an integer then it is rounded up to the nearest integer. The preferred pairwise alignment algorithm is the Needleman-Wunsch global alignment algorithm [136], using default parameters (e.g. with Gap opening penalty = 10.0, and with Gap extension penalty = 0.5, using the EBLOSUM62 scoring matrix). This algorithm is conveniently implemented in the needle tool in the EMBOSS package [137].

The nucleic acids and polypeptides of the invention may additionally have further sequences to the N-terminus/5' and/or C-terminus/3' of these sequences (a) to (d). The practice of the present invention will employ, unless otherwise indicated, conventional methods of chemistry, biochemistry, molecular biology, immunology and pharmacology, within the skill of the art. Such techniques are explained fully in the literature. See, e.g., references 138-145, etc.

MODES FOR CARRYING OUT THE INVENTION

Genome sequencing has been carried out on a low-passage clinical NTHi isolate (strain 86-028NP [146]). A total of 2540 coding sequences were identified in the genome, and these are given in the sequence listing together with their inferred translation products. Annotation of 1489 of the polypeptide sequences is given in Table III. From the sequenced material, polypeptide-coding sequences of particular interest were selected for further work, with particular attention to immunogenic proteins for vaccine development. Lipoproteins

Of the 2540 coding sequences, the following 39 were identified as lipoproteins: NTH0094, NTH0163, NTH0167, NTH0255, NTH0289, NTH0838, NTH0909, NTH0997, NTH1000, NTH1016, NTHI 174, NTH1298, NTH1313, NTH1413, NTH1416, NTH1552, NTH1623, NTH1675, NTH1680, NTH1739, NTH1873, NTH1922, NTH1942, NTH1974, NTH2142, NTH2169, TH2251, NTH2349, NTH2356, NTH2358, NTH2524, NTH2588, NTH2595, NTH2641, NTH2673, NTH2715, NTH2754, NTH2758, and NTH2769. Lipoproteins are surface-exposed and, as such, they represent accessible immunological targets e.g. for diagnostic and for immunisation purposes. Moreover, it has been found in B.burgdorferi [147] that OspA protein is immunogenic in a lipidated form but is non-immunogenic in a non-lipidated form, and the authors concluded that post-translational lipid attachment is a critical determinant of OspA immunogenicity.

Outer membrane

As H.influenzae is a Gram-negative bacterium, its cell wall includes an outer membrane. Of the 2540 coding sequences, the following 48 were identified as being located in this outer membrane: NTH0017, NTH0193, NTH0227, NTH0241, NTH0252, NTH0270, NTH0283, NTH0432, NTH0498, NTH0502, NTH0504, NTH0512, NTH0539, NTH0638, NTH0647, NTH0648, NTH0788, NTH0839, NTH0867, NTH0914, NTH1054, NTH1075, NTH1082, NTH1200, NTH1203, NTH1214, NTH1290, NTH1390, NTH1582, NTH1652, NTH1666, NTH1744, NTH1819, NTH1845, NTH1900, NTH1953, NTH1956, NTH1958, NTH1962, NTH2039, NTH2232, NTH2234, NTH2235, NTH2269, NTH2448, NTH2484, NTH2493, and NTH2727. Outer membrane proteins (OMPs) are surface-exposed and, as such, they represent accessible immunological targets e.g. for diagnostic and for immunisation purposes. OMPs are often invasins, adhesins, etc. which, if blocked, offers a means of preventing bacterial infection. NTHI 845 is an Aida-like autotransporter ('Lav') and is a preferred protein of the invention. It is conserved between NTHi strains, including one known to cause meningitis, but there is no corresponding gene in the Rd sequence or in strain R2846.. It lies between the tmk and holb genes. A preferred form of NTH1845 starts at Met-22 (i.e. SEQ ID NO: 5090).

Periplasm As H.influenzae is a Gram-negative bacterium, it has a periplasm between its cell cytoplasmic membrane and its outer membrane. Of the 2540 coding sequences, the following 105 were identified as being located in the periplasm: NTH0014, NTH0049, NTH0057, NTH0059, NTH0106, NTH0119, NTH0120,

NTH0132, NTH0174, NTH0190, NTH0206, NTH0244, NTH0346, NTH0405, NTH0421, NTH0468, NTH0485, NTH0513, NTH0547, NTH0619. NTH0643, NTH0661, NTH0691, NTH0738, NTH0820, NTH0835, NTH0848, NTH0849, NTH0856, NTH0861, NTH0863, NTH0865, NTH0910, NTH0926, NTH0961, NTH1015, NTH1018, NTH1121, NTH1164, NTH1185, NTHI 190, NTH1261, NTH1268, NTH1301, NTH1311, NTH1388, NTH1394, NTH1406, NTH1407, NTH1414, NTH1435, NTH1468, NTH1541, NTH1570, NTH1600, NTH1601, NTH1619, NTH1622, NTH1724, NTH1745, NTH1773, NTH1781, NTH1798, NTH1807, NTH1829, NTH1865, NTHI 871, NTH1892, NTH1897, NTH1916, NTH1917, NTH1965, NTH1999, NTH2116, NTH2119, NTH2133, NTH2135, NTH2149, NTH2150, NTH2187, NTH2217, NTH2227, NTH2256, NTH2258, NTH2277, NTH2291, NTH2316, NTH2342, NTH2344, NTH2369, NTH2394, NTH2432, NTH2434, NTH2451, NTH2496, NTH2508, NTH2537, NTH2541, NTH2572, NTH2575, NTH2610, NTH2705, NTH2726, NTH2738, and NTH2778. Periplasmic proteins represent useful immunological targets e.g. for diagnostic and for immunisation purposes.

Inner membrane As H.influenzae is a Gram-negative bacterium, it has an inner membrane. Of the 2540 coding sequences, the following 740 were identified as being located in the inner membrane: NTH0002, NTH0015, NTH0019, NTH0020, NTH0021, NTH0025, NTH0032, NTH0034, NTH0035, NTH0041, NTH0043, NTH0045, NTH0048, NTH0050, NTH0052, NTH0060, NTH0061, NTH0067, NTH0073, NTH0076, NTH0085, NTH0089, NTH0091, NTH0097, NTH0107, NTH0110, NTH0116, NTH0118, NTH0121, NTH0128, NTH0134, NTH0135, NTH0151, NTH0155, NTH0157, NTH0158, NTH0180, NTH0184, NTH0185, NTH0186, NTH0189, NTH0199, NTH0203, NTH0208, NTH0209, NTH0223, NTH0224, NTH0228, NTH0232, NTH0237, NTH0238, NTH0242, NTH0247, NTH0248, NTH0251, NTH0253, NTH0254, NTH0256, NTH0263, NTH0269, NTH0278, NTH0279, NTH0280, NTH0290, NTH0295, NTH0297, NTH0302, NTH0307, NTH0311, NTH0317, NTH0320, NTH0321, NTH0325, NTH0326, NTH0333, NTH0334, NTH0341, NTH0347, NTH0351, NTH0352, NTH0353, NTH0356, NTH0358, NTH0366, NTH0371, NTH0372, NTH0388, NTH0397, NTH0400, NTH0401 , NTH0402, NTH0407, NTH0411 , NTH0412, NTH0417, NTH0418, NTH0420, NTH0426, NTH0427, NTH0434, NTH0435, NTH0437, NTH0444, NTH0453, NTH0455, NTH0457, NTH0459, NTH0460, NTH0461, NTH0462, NTH0463, NTH0465, NTH0469, NTH0473, NTH0475, NTH0478, NTH0484, NTH0489, NTH0490, NTH0493, NTH0496, NTH0507, NTH0509, NTH0518, NTH0524, NTH0526, NTH0528, NTH0529, NTH0544, NTH0545, NTH0549, NTH0565, NTH0566, NTH0574, NTH0580, NTH0581, NTH0584, NTH0585, NTH0586, NTH0587, NTH0590, NTH0617, NTH0618, NTH0622 NTH0624, NTH0626, NTH0630, NTH0636, NTH0637, NTH0642, NTH0644, NTH0646, NTH0654, NTH0656, NTH065& NTH0673, NTH0675, NTH0676, NTH0677, NTH0678, NTH0680, NTH0694, NTH0696, NTH0702, NTH0703, NTH0706, NTH0709, NTH0710, NTH0712, NTH0715, NTH0718, NTH0728, NTH0730, NTH0740, NTH0744, NTH0745, NTH0749 NTH0750, NTH0755, NTH0762, NTH0764, NTH0765, NTH0771, NTH0774, NTH0794, NTH0795, NTH0796, NTH0797 NTH0798, NTH0802, NTH0803, NTH0804, NTH0813, NTH0814, NTH0815, NTH0821, NTH0822, NTH0827, NTH0829, NTH0834, NTH0836, NTH0850, NTH0851, NTH0852, NTH0858, NTH0872, NTH0874, NTH0875, NTH0880, NTH0887_; NTH0888, NTH0894, NTH0904, NTH0913, NTH0927, NTH0928, NTH0941, NTH0948, NTH0949, NTH0950, NTH0952 NTH0953, NTH0955, NTH0964, NTH0968, NTH0973, NTH0986, NTH0987, NTH0989, NTH0994, NTH0996, NTH1002 NTH1003, NTH1004, NTH1005, NTH1009, NTH1010, NTH1012, NTH1020, NTH1021, NTH1026, NTH1028, NTH1031 NTH1032, NTH1037, NTH1039, NTH1042, NTH1043, NTH1048, NTH1052, NTH1058, NTH1063, NTH1064, NTH1069 NTH1073, NTH1080, NTH1083, NTH1084, NTH1085, NTH1086, NTH1087, NTH1089, NTH1090, NTH1091, NTH1092 NTH 1098, NTH 1102, NTHI 103, NTH 1104, NTHI 106, NTHI 123, NTHI 124, NTH! 125, NTHI 130. NTHI 138, NTHI 141 NTH1150, NTH1151, NTHI 178, NTHI 181, NTHI 184, NTHI 188, NTHI 189, NTHI 191, NTH1192, NTHI 193, NTH1201 NTH1205, NTH1216, NTH1220, NTH1221, NTH1224, NTH1225, NTH1226, NTH1229, NTH1230, NTH1231, NTH1233 NTH1234, NTH1236, NTH1238, NTH1240, NTH1241, NTH1250, NTH1252, NTH1254, NTH1255, NTH1256, NTH1262 NTH1273, NTH1275, NTH1279, NTH1280, NTH1281, NTH1282, NTH1283, NTH1286, NTH1287, NTH1293, NTH1295 NTH1297, NTH1300, NTH1302, NTH1305, NTH1306, NTH1307, NTH1308, NTH1309, NTH1315, NTH1319, NTH1321 NTH1327, NTH1332, NTH1334, NTH1336, NTH1337, NTH1341, NTH1346, NTH1348, NTH1354, NTH1357, NTH1359_; NTH1363, NTH1365, NTH1368, NTH1374, NTH1376, NTH1379, NTH1380, NTH1383, NTH1391, NTH1393, NTH1398_: NTH1400, NTH1411, NTH1412, NTH1420, NTH1421, NTH1425, NTH1427, NTH1428, NTH1429, NTH1430, NTH1431 NTH1434, NTH1437, NTH1438, NTH1439, NTH1447, NTH1448, NTH1450, NTH1454, NTH1455, NTH1464, NTH146 NTH1470, NTH1471, NTH1472, NTH1473, NTH1474, NTH1479, NTH1491, NTH1492, NTH1493, NTH1495, NTH1500_; NTH 1503, NTH 1506, NTH1510, NTH1515, NTHI525, NTH1526, NTH1527, NTH1528, NTH1531, NTH1532, NTH1537, NTH1538, NTH1540, NTH1548, NTH1559, NTH1562, NTH1567, NTHI569, NTH1573, NTH1575, NTH1581, NTH1584 NTHI 586, NTH1587, NTH1588, NTH1590, NTH1594, NTH1597, NTH1599, NTH1602, NTHI 605, NTHI 606, NTH1608_; NTH1609, NTH1617, NTH1618, NTHI 620, NTH1621, NTH1625, NTH1629, NTH1631, NTH1634, NTH1637, NTH1638 NTH1653, NTH1654, NTH1657, NTH1662, NTH1664, NTH1668, NTH1671, NTH1686, NTH1687, NTH1688, NTH1689, NTH1690, NTH1692, NTH1693, NTH1698, NTH1701, NTH1707, NTH1712, NTH1718, NTH1719, NTH1722, NTH1725 NTH1729, NTH1732, NTH1735, NTH1760, NTH1767, NTH1770, NTH1778, NTH1779, NTH1782, NTH1783, NTH1788_; NTHI 793, NTHI 795, NTH1796, NTH1799, NTH1803, NTH1805, NTH1806, NTH1813, NTHI 815, NTHI 820, NTHI 824 NTHI 828, NTHI 835, NTH1836, NTH1842, NTH1849, NTH1850, NTH1859, NTH1861, NTH1870, NTH1872, NTH1881 NTHI 882, NTHI 885, NTH1888, NTH1889, NTH1891, NTH1896, NTH1898, NTH1899, NTH1906, NTH1908, NTH1919 NTHI 923, NTHI 925, NTH1927, NTH1935, NTH1939, NTH 1941, NTH1951, NTH1960, NTH1963, NTH1966, NTH1967, NTH1968, NTH1978, NTH1981, NTH1986, NTH1992, NTH1993, NTH1995, NTH1996, NTH1997, NTH1998, NTH2001 NTH2005, NTH2008, NTH2009, NTH2010, NTH2024, NTH2025, NTH2038, NTH2040, NTH204I, NTH2043, NTH2050_; NTH2052, NTH2055, NTH2060, NTH2062, NTH2064, NTH2065, NTH2070, NTH2071, NTH2073, NTH2078, NTH2079 NTH2081, NTH2083, NTH2089, NTH2091, NTH2092, NTH2093, NTH2094, NTH2095, NTH2096, NTH2097, NTH2099, NTH2101, NTH2112, NTH2115, NTH2118, NTH2120, NTH2122, NTH2126, NTH2128, NTH2129, NTH2130, NTH2131, NTH2136, NTH2138, NTH2145, NTH2146, NTH2162, NTH2163, NTH2166, NTH2169, NTH2170, NTH2173, NTH2181, NTH2183, NTH2191, NTH2193, NTH2195, NTH2196, NTH2200, NTH2204, NTH2205, NTH2209, NTH2213, NTH2226, NTH2228, NTH2231, NTH2242, NTH2243, NTH2247, NTH2250, NTH2253, NTH2257, NTH2259, NTH2262, NTH2263, NTH2266, NTH2273, NTH2274, NTH2282, NTH2284, NTH2285, NTH2288, NTH2292, NTH2296, NTH2299, NTH2318, NTH2323, NTH2324, NTH2326, NTH2327, NTH2333, NTH2343, NTH2346, NTH2347, NTH2352, NTH2361, NTH2364, NTH2365, NTH2368, NTH2370, NTH2371, NTH2376, NTH2377, NTH2381, NTH2382, NTH2388, NTH2398, NTH2402, NTH2405, NTH2406, NTH2407, NTH2408, NTH2414, NTH2422, NTH2430, NTH2433, NTH2438, NTH2447, NTH2455, NTH2457, NTH2458, NTH2472, NTH2478, NTH2481, NTH2486, NTH2495, NTH2497, NTH2498, NTH2499, NTH2501, NTH2505, NTH2525, NTH2531, NTH2532, NTH2533, NTH2534, NTH2542, NTH2543, NTH2545, NTH2546, NTH2548, NTH2549, NTH2550, NTH2552, NTH2554, NTH2556, NTH2557, NTH2558, NTH2562, NTH2566, NTH2567, NTH2568, NTH2569, NTH2570, NTH2573, NTH2577, NTH2578, NTH2587, NTH2591, NTH2593, NTH2597, NTH2600, NTH2602, NTH2603, NTH2604, NTH2605, NTH2612, NTH2613, NTH2615, NTH2616, NTH2618, NTH2626, NTH2633, NTH2640, NTH2647, NTH2648, NTH2649, NTH2650, NTH2661, NTH2663, NTH2664, NTH2667, NTH2668, NTH2674, NTH2675, NTH2680, NTH2690, NTH2701, NTH2702, NTH2703, NTH2708, NTH2711, NTH2724, NTH2725, NTH2732, NTH2735, NTH2740, NTH2743, NTH2749, NTH2750, NTH2755, NTH2756, NTH2757, NTH2764, NTH2765, NTH2774, NTH2777, NTH2779, NTH2781, NTH2793, NTH2794, NTH2796, NTH2797, NTH2798, NTH2806, NTH2807, NTH2813, NTH2814, NTH2823, and NTH2824. Inner membrane proteins represent useful immunological targets e.g. for diagnostic and for immunisation purposes.

Of these proteins, NTH1069 in particular has been identified as a virulence-associated protein. A preferred form of this protein starts at Met-27 (i.e. SEQ ID NO: 5088). Another preferred form starts at Met-19 (SEQ ID NO: 5089).

Adhesin An adhesin having amino acid sequence SEQ ID NO: 5091 has been identified in a NTHi strain isolated from a patient with meningitis. It is homologous to the Hia adhesin from N.meningitidis.

H.influenzae Rd

The genome sequence of the serotype d strain KW20 [1,3] was published in 1995. As serotype d strains are generally not pathogens, but the sequenced NTHi strain is from a clinical infection, expressed NTHi sequences that are not seen in serotype d are likely to be the proteins that are involved in pathogenic mechanisms. Blocking these proteins, either by antibiotic treatment or by antibody binding, thus has therapeutic potential. Of the 2540 coding sequences, the following 613 are not seen in the Rd genome: NTH0001, NTH0002, NTH0004, NTH0005, NTH0012, NTH0016, NTH0021, NTH0022, NTH0024, NTH0032, NTH0033, NTH0034, NTH0035, NTH0036, NTH0037, NTH0038, NTH0040, NTH0045, NTH0050, NTH0051, NTH0052, NTH0053, NTH0064, NTH0089, NTH0092, NTH0097, NTH0101, NTH0104, NTH0110, NTH0114, NTH0122, NTH0123, NTH0124, NTH0125, NTH0129, NTH0135, NTH0136, NTH0138, NTH0140, NTH0146, NTH0148, NTH0151, NTH0153, NTH0154, NTH0159, NTH0161, NTH0164, NTH0169, NTH0173, NTH0176, NTH0177, NTH0187, NTH0191, NTH0192, NTH0193, NTH0194, NTH0195, NTH0197, NTH0198, NTH0199, NTH0226, NTH0235, NTH0236, NTH0238, NTH0250, NTH0251, NTH0254, NTH0255, NTH0256, NTH0264, NTH0265, NTH0278, NTH0279, NTH0280, NTH0282, NTH0283, NTH0284, NTH0285, NTH0289, NTH0297, NTH0298, NTH0299, NTH0300, NTH0302, NTH0307, NTH0308, NTH0310, NTH0312, NTH0313, NTH0319, NTH0327, NTH0328, NTH0331, NTH0334, NTH0335, NTH0339, NTH0341, NTH0348, NTH0363, NTH0371, NTH0375, NTH0378, NTH0379, NTH0384, NTH0385, NTH0396, NTH0407, NTH0408, NTH0411, NTH0417, NTH0419, NTH0420, NTH0424, NTH0429, NTH0430, NTH0431, NTH0432, NTH0433, NTH0434, NTH0435, NTH0438, NTH0455, NTH0478, NTH0484, NTH0485, NTH0486, NTH0487, NTH0488, NTH0489, NTH0498, NTH0500, NTH0501, NTH0506, NTH0509, NTH0510, NTH0511, NTH0520, NTH0523, NTH0526, NTH0527, NTH0531, NTH0534, NTH0536, NTH0539, NTH0559, NTH0561, NTH0573, NTH0577, NTH0579, NTH0580, NTH0581, NTH0582, NTH0583, NTH0584, NTH0585, NTH0586, NTH0588, NTH0599, NTH0603, NTH0604, NTH0606, NTH0615, NTH0617, NTH0631, NTH0637, NTH0644, NTH0645, NTH0653, NTH0662, NTH0663, NTH0664, NTH0667, NTH0668, NTH0673, NTH0677, NTH0680, NTH0681, NTH0683, NTH0687, NTH0690, NTH0691, NTH0692, NTH0694, NTH0695, NTH0696, NTH0706, NTH0707, NTH0711, NTH0715, NTH0716, NTH0717, NTH0721, NTH0724, NTH0725, NTH0726, NTH0728, NTH0729, NTH0730, NTH0749, NTH0752, NTH0756, NTH0768, NTH0776, NTH0792, NTH0797, NTH0818, NTH0827, NTH0832, NTH0839, NTH0841 , NTH0843, NTH0844, NTH0862, NTH0864, NTH0866, NTH0867, NTH0877, NTH0879, NTH0885, NTH0886, NTH0892, NTH0895, NTH0896, NTH0900, NTH0901, NTH0904, NTH0906, NTH0921, NTH0924, NTH0928, NTH0929, NTH0930, NTH0931, NTH0932, NTH0933, NTH0937, NTH0938, NTH0942, NTH0949, NTH0953, NTH0955, NTH0961, NTH0964, NTH0970, NTH0971, NTH0972, NTH0973, NTH0985, NTH0987, NTH0991, NTH0992, NTH0993, NTH0994, NTH0995, NTH0996, NTH1007, NTH1016, NTH1017, NTH1020, NTH1025, NTH1026, NTH1027, NTH1028, NTH1029, NTH1037, NTH1040, NTH1049, NTH1067, NTH1069, NTH1070, NTH1073, NTH1082, NTH1086, NTH1089, NTH1090, NTHI 108, NTHI 111, NTHI 112, NTHI 114, NTHI 115, NTHI 116, NTHI 122, NTHI 129, NTH1131; NTHI 142, NTHI 149, NTH1150, NTH1153, NTH1157, NTH1159, NTH1161, NTH1162, NTH1176, NTH1178, NTHI 179, NTHI 193, NTHI 195, NTHI 196, NTH1204, NTH1205, NTH1207, NTH1208, NTH1209, NTH1210, NTH1211, NTH1214, NTH1216, NTH1220, NTH1225, NTH1234, NTH1235, NTH1237, NTH1241, NTH1244, NTH1245, NTH1246, NTH1247, NTH1248, NTH1249, NTH1250, NTH1251, NTH1252, NTH1253, NTH1270, NTH1271, NTH1294, NTH1299, NTH1313, NTH1315, NTH1316, NTH1325, NTH1330, NTH1333, NTH1337, NTH1339, NTH1342, NTH1353, NTH1361, NTH1367, NTH1374, NTH1375, NTH1381, NTH1382, NTH1390, NTH1391, NTH1395, NTH1396, NTH1399, NTH1414, NTH1415, NTH1418, NTH1419, NTH1437, NTH1441, NTH1454, NTH1456, NTH1471, NTH1474, NTH1487, NTH1489, NTH1490, NTH1491, NTH1492, NTH1493, NTH1494, NTH1495, NTH1496, NTH1497, NTH1504, NTH1516, NTH1540, NTH1543, NTH1555, NTH1563, NTH1564, NTH1567, NTHI 571, NTH1573, NTH1574, NTH1580, NTH1587, NTH1598, NTH1599, NTH1600, NTH1601, NTH1602, NTH1603, NTH1605, NTH1606, NTH1607, NTH1611, NTH1612, NTH1615, NTH1616, NTH1626, NTH1627, NTH1628, NTH1647, NTH1656, NTH1657, NTH1658, NTH1676, NTH1677, NTH1687, NTH1697, NTH1702, NTH1703, NTH1713, NTH1734, NTH1740, NTH1742, NTH1744, NTH1745, NTH1748, NTH1749, NTH1751, NTH1752, NTH1753, NTH1754, NTH1755, NTH1756, NTH1757, NTH1758, NTH1759, NTH1760, NTH1765, NTH1769, NTH1770, NTH1778, NTH1798, NTH1804, NTH1811, NTH1812, NTH1815, NTH1816, NTH1817, NTH1818, NTH1820, NTH1821, NTH1822, NTH1829, NTH1832, NTH1833, NTH1837, NTH1842, NTH1845, NTH1854, NTH1857, NTH1904, NTH1910, NTH1914, NTH1916, NTH1920, NTH1921, NTH1922, NTH1945, NTH1946, NTH1947, NTH1948, NTH1956, NTH1962, NTH1964, NTH1968, NTH1989, NTH1994, NTH2019, NTH2031, NTH2035, NTH2043, NTH2056, NTH2060, NTH2069, NTH2075, NTH2093, NTH2096, NTH2109, NTH2110, NTH2112, NTH2113, NTH2114, NTH2117, NTH2156, NTH2159, NTH2170, NTH2197, NTH2198, NTH2199, NTH2206, NTH2207, NTH2216, NTH2217, NTH2219, NTH2220, NTH2221, NTH2222, NTH2223, NTH2226, NTH2229, NTH2245, NTH2273, NTH2284, NTH2287, NTH2305, NTH2309, NTH2315, NTH2316, NTH2323, NTH2326, NTH2330, NTH2332, NTH2343, NTH2349, NTH2353, NTH2362, NTH2363, NTH2364, NTH2386, NTH2414, NTH2442, NTH2451, NTH2455, NTH2456, NTH2457, NTH2458, NTH2460, NTH2461, NTH2463, NTH2464, NTH2466, NTH2467, NTH2468, NTH2471, NTH2480, NTH2481, NTH2482, NTH2483, NTH2484, NTH2485, NTH2486, NTH2487, NTH2488, NTH2500, NTH2510, NTH2524, NTH2525, NTH2527, NTH2528, NTH2536, NTH2537, NTH2549, NTH2562, NTH2563, NTH2572, NTH2573, NTH2575, NTH2584, NTH2585, NTH2590, NTH2604, NTH2607, NTH2608, NTH2609, NTH2635, NTH2647, NTH2648, NTH2650, NTH2655, NTH2664, NTH2668, NTH2679, NTH2684, NTH2693, NTH2694, NTH2696, NTH2697, NTH2703, NTH2704, NTΗ2706, NTH2707, NTH2708, NTH2709, NTH2710, NTH2711, NTH2712, NTH2713, NTH2715, NTH2716, NTH2718, NTH2719, NTH2720, NTH2721, NTH2723, NTH2724, NTH2725, NTH2726, NTH2727, NTH2729, NTH2730, NTH2731, NTH2737, NTH2744, NTH2753, NTH2778, NTH2781, NTH2783, NTH2784, NTH2785, NTH2791, NTH2804, NTH2806, NTH2809, NTH2810, and NTH2816. NTH0861 to NTH0867

Protein NMB0419 from Neisseria meningitidis has been found to participate in the meningococcal invasion mechanism [2]. The protein was shown to modulate bacterial interaction with monolayers of human repiratory epithelial cells, promoting invasion. A homologous protein BPF001 is seen in H.influenzae biogroup aegyptius, but study of this protein was not possible. The NTHi genome includes a region (SEQ ID NO: 5081) encoding a string of four polypeptides (NTH0861, NTH0863, NTH0865 and NTH0867) with strong similarity to NMB0419. This region and the four polypeptides are shown below: GCCAGCTTGCTGCCTGCGGTCGACTCTANGAGACCCCTACAACAAAACATAATGCTAAAC

AAAAAATGTTTGGTTGTTTCAATTGTTGATTAATAAATGGACGATTTCTATGCGATTCΆC (SEQ ID NO: 1578) NTH0867 M R F T AAAAACACTTTTTACCACCGCACTTTTAGGTGCTTCTATCTTTTCTTTTCAATCCACCGC K T L F T T A L L G A S I F S F Q S T A TTGGGCGGATACGCTGGAACAGCAATTCCAACAAGGTTCTGAAGCCACTACGAGAGGCGA W A D T L E Q Q F Q Q G S E A T T K G D TTATCAAACCACCTTTAAATTTTTGTTACCTCTGGCGGAGCAGGGAAATGCAGAGGCTCA Y Q T T F K F L P A E Q G N A E A Q ATTGATGTTGGGCGTGATGTATGCAAGAGGAATAGGCGTCAAACAAGATGair2^,2?TGAAGC L M L G V M Y A R G I G V K Q D D F E A GGTGAAGTGGTATCGCCAAGCGGCGGAGCAGGGATATGCAAATGCTCAAGCTATATTGGG V K Y R Q A A E Q G Y A N A Q A I L G ATTCTCATATCTTTTAGGACAAAGCGGTGTTCAAGTAAATAAATCTTTAGCCAAAGAATG F S Y G Q S G V Q V N K S L A K E GTTTGGTAAGGCTTGTGATAATGGTGATCAAAATGGTTGCGAATATTATGGCAAGTTAAA F G K A D N G D Q N G E Y Y G K L N TAGAGGGGAGCTCTAATGCCAACTTTACAATGCGAATTTTGGAATGTAGGGCAAGGGTTA R G E L * TTTTCAAGTGGGCGTATTCAAATGGGAGACGCCCCAGCCTTTCATTGGGTTTATGGTTTG

CAAGTTCCTCΆTCATGGTTCAAAGCCAATTTTAGTGAATAAAAATAAAAGATTATCCATT

CATTCAATTTAATAGGAAAACΆAATGAAACTCACAΆAAACACTTCTTACCACCGCACTTT (SEQ ID NO: 1574) NTH0865... K L T K T L L T T A L F TCGGTGCTTCTATTTTTTCTTTTCAATCCACCGCTTGGGCGGATACGCCGGAACAGCAAT G A S I F S F Q S T A W A D T P E Q Q F TCCAACAAGGTTTAACCGCTTATGAGCAAAGCAACTATCAAACCGCCTTTAAACTTTGGT Q Q G L T A Y E Q S N Y Q T A F K L TACCTCTGGCGGAGCAGGGAGATGCACAGGCTCAAGGTGGTTTGGGCATGATGTATGAAA P L A E Q G D A Q A Q G G L G M M Y E R GAGGACTTGGCGTAAAACAAGATSarTTCAAAGCAGTGAACTGGTATCGCAAAGCGGCGG G L G V K Q D D F K A V N W Y R K A A E AGCAGGGGGATGCAGATGCTCAATTAAATTTGGGTGCGATGTATGCAATCGGACGTGGCG Q G D A D A Q L N L G A M Y A I G R G V TAAAACAAGATGGTGTgGAaGCGGTGAAGTGGTTTCGCAAAGCGGCAGAGCAGGGAAATG ff Q D G V E A V K F R K A A E Q G N A CAAAGGCTCAAAATGGTTTGGGCATGATGTATGACGGAGGACTTGGCATAAAACAAGATT K A Q N G L G M Y D G G L G I K Q D Y ATTTCAAAGCGGTGAAATGGCATCGCAAAGCGGCGGAGCAGGGATATGGAGGTGCTCAAG F K A V K W H R K A A E Q G Y G G A Q V TTATGTTGGGATTCTCATATCTTTCGGGAAAAGGTGTTCAAGTAAATAAATCTTTAGCCA M L G F S Y L S G K G V Q V N K S A K AAGAATGGTTTGGTAAGGCTTGTGATAATGGTGAACAAGTGGGTTGTGAATATTATGGCA E W F G K A D N G E Q V G E Y Y G K AGCTAAATAGAGGGGAACGCTAATGCCAACTTTACAATGCGAATTTTGGAATGTAGGGCA L N R G E R * AGGGTTATTTTCAAGTGGGCGTATTCAAATGGGAGACGCCCAAGCCTTTCATTGGGTTTA TGGTTTGCAAGTTCCTCATCATGGTTCAAAGCCAATTTTAGTGAATAAAAATAAAAGATT

ATCCATTCATTCAATTTAATAGGAAAACAAAATGAAACTCACAAAAACACTTCTTACCAC (SEQ ID NO: 1570) NTH0863 M K T K T L L T T CGCACTTTTCGGTGCTTCTGTATTTTCTTTTCAATCCACCGCTTGGGCGGATACGCTGGA A L F G A S V F S F Q S T A A D T L E ACAGCAATTCCAACAAGGTTTAACCGCTTATGAGCAAAGCAACTATCAAACCGCCTTTAA Q Q F Q Q G L T A Y E Q S N Y Q T A F K ACTTTGGTTACCTATGGCAGAGCAGGGATATGCAAAGGCTCAATTTAATTTGGGCGTGAT L W L P M A E Q G Y A K A Q F N L G V M GTATGCTAAGGGGCAAGGCGTCAAACAAGATGΛΓΓΓTGAAGCGGTGAAGTGGTTTCGCAA Y A K G Q G V K Q D D F E A V K W F R K AGCGGCGGAGCAGGGATATGCAGAGGCTAAATTTAATTTGGGCCATATGTATTCTAAGGG A A E Q G Y A E A K F N G H Y S K G ACGAGGCGTCAAACAAGATGATTTTGAAGCAGTGAACTGGTATCGCAAAGCGGCGGAGCA R G V K Q D D F E A V N Y R K A A E Q GGGAGATGCAGATGCTCAAGCTATATTGGGATTCTTATATCTTTTAGGAGAAAGAGGTGT G D A D A Q A I L G F L Y L L G E R G V CAAGTAAATAATTCTTTAGCCAAGNAATGGTNTGGTAAGGCTTGTGATAATGGTAATCAA K * AATGGCTGCGAATATTATGGCAAGCTAAATAGAGGGGAGCTCTAATGCCCACTTTTACAA

TGCGAATTNTGGAATGTAGGGCAAGGGTTATTTTCAAGTGGGCGTATTCAAGTGGAGACG CNNCCAAGCCTTTCATTGGGTTTATGGTTTGCAAGTTCCTCATCATGGTTCANAGCCCAA TTTAGTGNAATAAAAATAAAAGATTATCCATTCATTCAATTTAATAGGAAAACAAAATGA (SEQ ID NO: 1566) NTH0861 M K AACTCACAAAAACACTTCTTACCACCGCACTTTTAGGTGCTTCTGTATTATCTTTTCAAT L T K T L L T T A L L G A S V L S F Q S CCACCGCTTGGGCGGATACGCTGGAACAGCAATTCCAACAAGGTTTAACCGCTTATGAGC T A W A D T L E Q Q F Q Q G L T A Y E Q AAAGCAACTATCAAACCGCCTTTAAACTTTGGTTACCTCTGGCGGAGCAGGGAGATGCAA S N Y Q T A F K L W P L A E Q G D A N ATGTTCAATTTAATTTGGGCGTGATGTATGCTGAGGGGCAAGGCGTCAAACAAGATGJS.ΪT V Q F N L G V M Y A E G Q G V K Q D D F ΓTGAAGCGGTGAAATGGTATCGCAAAGCGGCGGAGCAGGGAGATGCAAATGCTCAGGCTT E A V K Y R K A A E Q G D A N A Q A Y ATTTAGGTTTGGCTTATACTGAAGGGCGTGGTGTAAGACAAGATTATACCGAAGCGGTGA L G L A Y T E G R G V R Q D Y T E A V K AGTGGTTTCGCAAAGCGGCGGAGCAGGGACATGCAAATGCTCAΆGCTATATGGGATCTCT W F R K A A E Q G H A N A Q A I D 1 F TTCTTTAGGGTACCGAGCCGAATCGATCCA L *

The four coding sequences are aligned (ClustalW) below: NTH0863 ATGAAACTCACAAAAACACTTCTTACCACCGCACTTTTCGGTGCTTCTGTATTTTCTTTT NTH0867 ATGCGATTCACAAAAACACTTTTTACCACCGCACTTTTAGGTGCTTCTATCTTTTCTTTT NTH0865 ATGAAACTCACAAAAACACTTCTTACCACCGCACTTTTCGGTGCTTCTATTTTTTCTTTT NTH0861 ATGAAACTCACAAAAACACTTCTTACCACCGCACTTTTAGGTGCTTCTGTATTATCTTTT *** * ************** **************** ********* * ** ****** NTH0863 CAATCCACCGCTTGGGCGGATACGCTGGAACAGCAATTCCAACAAGGTTTAACCGCTTAT NTH0867 CAATCCACCGCTTGGGCGGATACGCTGGAACAGCAATTCCAACAAGGTTCTGAAGCCACT NTH0865 CAATCCACCGCTTGGGCGGATACGCCGGAACAGCAATTCCAACAAGGTTTAACCGCTTAT NTH0861 CAATCCACCGCTTGGGCGGATACGCTGGAACAGCAATTCCAACAAGGTTTAACCGCTTAT ************************* *********************** ** * NTH0863 GAGCAAAGCAACTATCAAACCGCCTTTAAACTTTGGTTACCTATGGCAGAGCAGGGATAT NTH0867 ACGAGAGGCGATTATCAAACCACCTTTAAATTTTTGTTACCTCTGGCGGAGCAGGGAAAT NTH0865 GAGCAAAGCAACTATCAAACCGCCTTTAAACTTTGGTTACCTCTGGCGGAGCAGGGAGAT NTH0861 GAGCAAAGCAACTATCAAACCGCCTTTAAACTTTGGTTACCTCTGGCGGAGCAGGGAGAT * * ** * ********* ******** *** ******* **** ********* **

NTH0863 GCAAAGGCTCAATTTAATTTGGGCGTGATGTATGCTAAGGGGCAAGGCGTCAAACAAGAT

NTHO867 GCAGAGGCTCAATTGATGTTGGGCGTGATGTATGCAAGAGGAATAGGCGTCAAACAAGAT

NTHO865 GCACAGGCTCAAGGTGGTTTGGGCATGATGTATGAAAGAGGACTTGGCGTAAAACAAGAT

NTHO861 GCAAATGTTCAATTTAATTTGGGCGTGATGTATGCTGAGGGGCAAGGCGTCAAACAAGAT *** * * **** ****** ********* ** ***** *********

NTH0863 GATTT NTH0867 GATTT NTH0865 GATTTCAAAGCAGTGAACTGGTATCGCAAAGCGGCGGAGCAGGGGGATGCAGATGCTCAA NTH0861 GATTT

NTH0863 TGAAGCG NTH0867 TGAAGCG NTH0865 TTAAATTTGGGTGCGATGTATGCAATCGGACGTGGCGTAAAACAAGATGGTGTTGAAGCG NTH0861 TGAAGCG *******

NTHO863 GTGAAGTGGTTTCGCAAAGCGGCGGAGCAGGGATATGCAGAGGCTAAATTTAATTTGGGC

NTH0867 GTGAAGTGGTATCGCCAAGCGGCGGAGCAGGGATATGCAAA

NTHO865 GTGAAGTGGTTTCGCAAAGCGGCAGAGCAGGGAAATGCAAAGGCTCAAAATGGTTTGGGC

NTH0861 GTGAAATGGTATCGCAAAGCGGCGGAGCAGGGAGATGCAAA

NTH0863 CATATGTATTCTAAGGGACGAGGCGTCAAACAAGATGATTTTGAAGCAGTGAACTGGTAT NTH0867 NTH0865 ATGATGTATGACGGAGGACTTGGCATAAAACAAGATTATTTCAAAGCGGTGAAATGGCAT NTH0861

NTHO863 CGCAAAGCGGCGGAGCAGGGAGATGCAGATGCTCAAGCTATATTGGGATTCTTATATCTT

NTH0867 TGCTCAAGCTATATTGGGATTCTCATATCTT NTHO865 CGCAAAGCGGCGGAGCAGGGATATGGAGGTGCTCAAGTTATGTTGGGATTCTCATATCTT

NTH0861 TGCTCAGGCTTATTTAGGTTTGGCTTATACT ****** * * ** ** ** *** *

NTHO863 TTAGGAGAAAGAGGTGT-CAAGTAAATAATTCTTTAGCCAAGNAATGGTNTGGTAAGGCT NTHO867 TTAGGACAAAGCGGTGTTCAAGTAAATAAATCTTTAGCCAAAGAATGGTTTGGTAAGGCT

NTHO865 TCGGGAAAA GGTGTTCAAGTAAATAAATCTTTAGCCAAAGAATGGTTTGGTAAGGCT

NTH0861 GAAGGGCGT GGTGTAAGACAAGATTATACCGAAGCGGTGAAGTGGTTTCGCAAAGC- ** ***** * * ** * * *** * **** * * ** **

NTH0863 TGTGATAATGGTAATCAAAATGGCTGCGAATATTATGGCAAGCTAAATAGAGGGGAGCTC NTH0867 TGTGATAATGGTGATCAAAATGGTTGCGAATATTATGGCAAGTTAAATAGAGGGGAGCTC NTH0865 TGTGATAATGGTGAACAAGTGGGTTGTGAATATTATGGCAAGCTAAATAGAGGGGAACGC NTH0861 GGCGGAGCAGGGACATGCAAATGCT CAAGCTATAT GGGATCTC

NTH0863 TAATGCCCACTTTTACAATGCGAATTNTGGAATGTAGGGCAAGGGTTATTTTCAAGTGGG NTH0867 TAATGCCAACTTT-ACAATGCGAATTTTGGAATGTAGGGCAAGGGTTATTTTCAAGTGGG NTH0865 TAATGCCAACTTT-ACAATGCGAATTTTGGAATGTAGGGCAAGGGTTATTTTCAAGTGGG NTH0861 TTTCTTTAGGGTA-CCGAGCCGAATC GATCCA

NTH0863 CGTATTCAAGTGGAGACGCNNCCAAGCCTTTCATTGGGTTTATGGTTTGCAAGTTCCTCA NTH0867 CGTATTCAAATGG-GAGACGCCCCAGCCTTTCATTGGGTTTATGGTTTGCAAGTTCCTCA NTH0865 CGTATTCAAATGG-GAGACGCCCAAGCCTTTCATTGGGTTTATGGTTTGCAAGTTCCTCA NTH0861

NTH0863 TCATGGTTCANAGCCCAATTTAGTGNAATAAAAATAAAAGATTATCCATTCATTCAATTT NTH0867 TCATGGTTCAAAGCCAATTTTAGTGAA-TAAAAATAAAAGATTATCCATTCATTCAATTT NTH0865 TCATGGTTCAAAGCCAATTTTAGTGAA-TAAAAATAAAAGATTATCCATTCATTCAATTT NTH0861

NTH0863 AATAGGAAAACAAA SEQ ID NO: 5083 NTH0867 AATAGGAAAACAA- SEQ ID NO: 5085 NTH0865 AATAGGAAAACAAA SEQ ID NO: 5084 NTH0861 SEQ ID NO: 5082

The encoded polypeptides are aligned below, together with the bpfOOl and NMB0419 sequences: NTH0861 -MKLTKTLLTTALLG- -ASV SFQS TAWADTLEQQFQQG NTH0863 -MKLTKTLLTTALFG ASVFSFQS TAWADTLEQQFQQG NTH0865 -MKLTKTLLTTALFG ASIFSFQS TAWADTPEQQFQQG NTH0867 -MRFTKTLFTTALLG ASIFSFQS TAWADTLEQQFQQG BPF001 -MKLTKTLFTSALLG ASILSFHP TVAAMDFGT—QVG NMB0419 -MKQTVKWLAAALIALGLNRAVWADDVSDFRENLQAAAQGNAAAQYNLG NTHO861 LTAYE QSNYQTAFKLWLPLAEQ-GDANVQFNLGVMYAEGQGVKQDDFEAVKWYRKA NTHO863 LTAYE QSNYQTAFKLWLPMAEQ-GYAKAQFNLGVMYAKGQGVKQDDFEAVKWFRKA NTHO865 LTAYE QSNYQTAFKLWLPLAEQ-GDAQAQGGLG MYERGLGVKQDDFKAVNWYRKA NTH0867 SEATT RGDYQTTFKFLLPLAEQ-GNAEAQLMLGVMYARGIGVKQDDFEAVKWYRQA BPF001 IDAYR KNDFAQAAEQFKDAGIVRGDPTAQLFLGRMYYNGEFFKQDYVEAAKWYRKA NMBO419 AMYYKGRGVRRDDAEAVRWYRQAAEQ-GLAQAQYNLGWMYANGRGVRQDDTEAVRWYRQA

NTH0861 AEQG NTH0863 AEQG NTH0865 AEQGDADAQLNLGAMYAIGRGVKQDGVEAVKWFRKAAEQGNAKAQNGLGMMYDGGLGIKQ NTH0867 AEQG BPF001 AEQGEEFGLLFLG ETYEDGEGVEK NMB0419 AAQGVVQAQYNLG VIYAEGRGVRQ

NTH0861 DANAQAYLGLAYTEGR-GVRQDYTEAVKWFRKAAEQGHANAQAl NTH0863 YAEAKFNLGHMYSKGR-GVKQDDFEAVNWYRKAAEQGDADAQAI NTH0865 DYFKAVKWHRKAAEQGYGGAQVMLGFSYLSGK-GVQVNKSLAKEWFGKACDNGEQVGCEY NTH0867 YANAQAILGFSYLLGQSGVQVNKSLAKEWFGKACDNGDQNGCEY BPF001 DYAEAAKLYRKAAEQGSAEGQ ALGK YRFGN-GVEKDYAEAIKLYRKSAEQGNFTALFF N B0419 DDVEAVRWFRQAAAQGVAQAQNNLGVMYAERR-GVRQDRALAQEWFGKACQNGDQDGCDN ** * ** . * . . *. ..* NTH0861 WDLFL SEQ ID NO: 1566 NTH0863 LGFLYLLGERGVK SEQ ID NO: 1570 NTH0865 YGKLNR-GER SEQ ID NO: 1574 NTH0867 YGKLNR-GEL SEQ ID NO: 1578 BPF001 LGEMYDNGVGVKQNKAESQRII SEQ ID NO: 5086 NMB0419 DQRLKAGY SEQ ID NO: 5087

The serial repeats of four closely-related genes that are also related to genes involved in bacterial invasion is noteworthy, and NTH0861, NTH0863, NTH0865 and NTH0867 are of particular interest for immunisation purposes. NTH0867 in particular is an outer-membrane protein that is not seen in the Rd genome, and is of special interest.

Moreover, as well as being caused by NTHi, acute otitis media is often caused by Moraxella catarrhalis and Streptococcus pneumoniae. Four proteins have been identified that in the NTHi genome that have homologs in the Mxatarrhalis genome, namely NTH0861 (SEQ ID NO: 1566), NTH0863 (SEQ ID NO: 1570), NTH0865 (SEQ ID NO: 1574) and NTH0867 (SEQ ID NO: 1578). . These proteins can thus be used as antigens for a general AOM vaccine. The corresponding M.catarrhalis antigens can also be used, either on their own or in combination with the NTHi 5 antigens. A variant of SEQ ID NO: 1566 is given as SEQ ID NO: 5095: 10 20 30 40 50 60 70 80 I I 1 I I I I I 1566 MKLTKTLLTTA LGASVLSFQSTAWADTLEQQFQQGLTAYEQSNYQTAFK WLP AEQGDANVQFN GVMYAEGQGVKQD

10 5095 MKLTKTLLTTA LGASVFΞFQSTA ADTPEQQFQQGSTAYEQSDYQTAFKL LPMAEQGDANVQFN GVMYAKGQGVKQD _{*****************}._{********** ******* ******}._**********._{*****************}._******* 90 100 110 120 130 140 150 160 1 I I I I I I I

15 1566 DFEAVKWYRKAAEQ GDANAQAYLG AYTEGRGVRQDYTEAVKWF 5095 DFEAVKWYRKAAEQGHAKAQFN GVMYAKGQGVKQDDFKAVKWYRKAAEQGYADAQAN GSAYSAGRGVRQDYIEAVKWF _{************** * *}._{*** ** **}. _{******** ******} 170 180 190 200 210 20 I I I I I 1566 RKAAEQGHANAQAIWDLFL 5095 KKAAENGSADGQFKLGLVYLIGQSIQKDRTLAKEWFGKACDNGEQRGCEYYGKLNRGEL ._****._{* *};._* ,_*.

25 A variant of SEQ ID NO: 1570 is given as SEQ ID NO: 5094: 10 20 30 40 50 60 70 80 1 I I I I I I 1 1570 MKLTKTL TTA FGASVFSFQSTAADTLEQQFQQGLTAYEQSNYQTAFKLWLPMAEQGYAKAQFNLGVMYAKGQGVKQD 5094 MKLTKTLLTTA GASVFSFQSTA ADTPEQQFQQGSTAYEQSDYQTAFK WLPMAEQGDANVQFNLGV YAKGQGVKQD

30 _************._{*************** ******* ******}._{*************** *}. _{*****************} 90 100 110 120 130 140 150 I I I I I I I 1570 DFEAVKWFRKAAEQGYAEAKFNLGHMYSKG-RGVKQDDFEAVNWYRKAAEQGDADAQAILGFLYLLGERGVK

35 5094 DFEAVKWFRKAAEQGHAKAQAILGFSY LGERGVQVNKS AKEWFGKACDNGNQDGCEYYG K NRGGF- _{***************}._*._*. _**_ _{* * ***}. ._ _* ._*. _**.;_{:*: *}. _{* *}.. _*. A variant of SEQ ID NO: 1574 is given as SEQ ID NO: 5093: 10 20 30 40 50 60 70 80

40 I I I 1 I I I I 1574 MKLTKT LTTA FGASIFSFQSTAWADTPEQQFQQGLTAYEQSNYQTAFKLWLPLAEQGDAQAQGGLGMMYERG GVKQD 5093 MK TKTLLTTA FGASIFSFQΞTA ADTPEQQFQQGLTAYEQSDYQTAFK WLPMAEQGYAQAQGG GMMYERG GVKQD *******************************************.**********.**** ********************

45 90 100 110 120 130 140 150 160 I I I I I I I I 157 DFKAVNWYRKAAEQGDADAQ N GAMYAIGRGVKQDGVEAVKWFRKAAEQGNAKAQNGLGMMYDGGLGIKQDYFKAVK H 5093 DFKAVN YRKAAEQGDAD QLNLGAMY IGHGVKQDGVEAVKWFRK AEQGN KAQ GLGMYRGRLGIKQDYFKAVK _{******************************}._{******************************** * **************}

50 170 180 190 200 210 I I I I I 1574 RKAAEQGYGGAQV GFSY SGKGVQVNKS AKE FGKACDNGEQVGCEYYGKLNRGER 5093 RKAAEQGYGGAQVM GFSY SGKGVQVNKSLAKEWFGKACDNGEQVGCEYYSKLNRGER

55 _{*************************************************** ^ *******} A variant of SEQ ID NO: 1578 is given as SEQ ID NO: 5092: 10 20 30 40 50 60 70 80 I I I I I I I I

OU 5092 MRFTKT FTTA GAΞVFSFQSTAWADTLEQQFQQGSEATTRGDYQTTFKF LP AEQGNALAQMM GVMYA GQGVKQD 1578 MRFTKTLFTTA GASIFSFQSTAWADTLEQQFQQGSEATTRGDYQTTFKFL PLAEQGNAEAQLMLGVMYARGIGVKQD _{****************};_{******************************************** **} . _******* •_{* *****} 90 100 110 120 130 140

65 I I l l l l 5092 DVEAVKWYRKAAEQGYADAQAMLGFΞY LGQSGVQVNKSLAKEWFGKACDNGDQNGCEYYGKLNRGE 1578 DFEAVKWYRQAAEQGYANAQAILGFSYLLGQSGVQVNKSLAKEWFGKACDNGDQNGCEYYGKLNRGE * *_****** . *_***_*** . _*** • _*********_{***********************}*_*****_**_*****_**_**_***

Preferred NTH0861 proteins have identity to both of SEQ ID NOS: 1566 and 5095. Preferred NTH0863 proteins have identity to both of SEQ ID NOS: 1570 and 5094. Preferred NTH0865 proteins have identity to both of SEQ ID NOS: 1574 and 5093. Preferred NTH0867 proteins have identity to both of SEQ ID NOS: 1578 and 5092.

It will be understood that the invention has been described by way of example only and modifications may be made whilst remaining within the scope and spirit of the invention.

TABLE I — MISSING ISΥΪbtnnn VALUES between NTHOOOl and NTH2832

TABLE II — Preferred polypeptides NTHOOOl NTH0002 NTH0004 NTH0005 NTH0012 NTH0014 NTH0015 NTH0016 NTH0017 NTH0019 NTH0020 NTH0021 NTH0022 NTH0024 NTH0025 NTH0032 NTH0033 NTH0034 NTH0035 NTH0036 NTH0037 NTH0038 NTH0040 NTH0041 NTH0043 NTH0045 NTH0048 NTH0049 NTH0050 NTH0051 NTH0052 NTH0053 NTH0057 NTH0059 NTH0060 NTH0061 NTH0064 NTH0067 NTH0073 NTH0076 NTH0085 NTH0089 NTH0091 NTH0092 NTH0094 NTH0097 NTH0101 NTHO 104 NTH0106 NTH0107 NTH0110 NTH0114 NTH0116 NTH0118 NTH01 19 NTH0120 NTH0121 NTH0122 NTH0123 NTH0124 NTH0125 NTH0128 NTH0129 NTH0132 NTH0134 NTH0135 NTH0136 NTH0138 NTH0140 NTH0146 NTH0148 NTH0151 NTH0153 NTH0154 NTH0155 NTH0157 NTH0158 NTH0159 NTH0161 NTH0163 NTHO 164 NTHO 167 NTHO 169 NTHO 173 NTHO 174 NTHO 176 NTHO 177 NTHO 180 NTH0184 NTH0185 NTH0186 NTH0187 NTH0189 NTH0190 NTH0191 NTH0192 NTH0193 NTH0194 NTH0195 NTH0197 NTH0198 NTH0199 NTH0203 NTH0206

NTH0208 NTH0209 NTH0223 NTH0224 NTH0226 NTH0227 NTH0228 NTH0232

NTH0235 NTH0236 NTH0237 NTH0238 NTH0241 NTH0242 NTH0244 NTH0247

NTH0248 NTH0250 NTH0251 NTH0252 NTH0253 NTH0254 NTH0255 NTH0256 NTH0263 NTH0264 NTH0265 NTH0269 NTH0270 NTH0278 NTH0279 NTH0280

NTH0282 NTH0283 NTH0284 NTH0285 NTH0289 NTH0290 NTH0295 NTH0297

NTH0298 NTH0299 NTH0300 NTH0302 NTH0307 NTH0308 NTH0310 NTH0311

NTH0312 NTH0313 NTH0317 NTH0319 NTH0320 NTH0321 NTH0325 NTH0326

NTH0327 NTH0328 NTH0331 NTH0333 NTH0334 NTH0335 NTH0339 NTH0341 NTH0346 NTH0347 NTH0348 NTH0351 NTH0352 NTH0353 NTH0356 NTH0358

NTH0363 NTH0366 NTH0371 NTH0372 NTH0375 NTH0378 NTH0379 NTH0384

NTH0385 NTH0388 NTH0396 NTH0397 NTH0400 NTH0401 NTH0402 NTH0405

NTH0407 NTH0408 NTH0411 NTH0412 NTH0417 NTH0418 NTH0419 NTH0420

NTH0421 NTH0424 NTH0426 NTH0427 NTH0429 NTH0430 NTH0431 NTH0432 NTH0433 NTH0434 NTH0435 NTH0437 NTH0438 NTH0444 NTH0453 NTH0455

NTH0457 NTH0459 NTΗ0460 NTH0461 NTH0462 NTH0463 NTH0465 NTH0468

NTH0469 NTH0473 NTH0475 NTH0478 NTH0484 NTH0485 NTH0486 NTH0487

NTH0488 NTH0489 NTH0490 NTH0493 NTH0496 NTH0498 NTH0500 NTH0501

NTH0502 NTH0504 NTH0506 NTΗ0507 NTH0509 NTH0510 NTH0511 NTH0512 NTH0513 NTH0518 NTH0520 NTH0523 NTH0524 NTH0526 NTH0527 NTH0528

NTH0529 NTH0531 NTH0534 NTH0536 NTH0539 NTH0544 NTH0545 NTH0547

NTH0549 NTH0559 NTH0561 NTH0565 NTH0566 NTH0573 NTH0574 NTH0577

NTH0579 NTH0580 NTH0581 NTH0582 NTH0583 NTH0584 NTH0585 NTH0586

NTH0587 NTH0588 NTH0590 NTH0599 NTH0603 NTH0604 NTH0606 NTH0615 NTH0617 NTH0618 NTH0619 NTH0622 NTH0624 NTH0626 NTH0630 NTH0631

NTH0636 NTH0637 NTH0638 NTH0642 NTH0643 NTH0644 NTH0645 NTH0646

NTH0647 NTH0648 NTH0653 NTH0654 NTH0656 NTH0658 NTH0661 NTH0662

NTH0663 NTH0664 NTH0667 NTH0668 NTH0673 NTH0675 NTH0676 NTH0677

NTH0678 NTH0680 NTH0681 NTH0683 NTH0687 NTH0690 NTH0691 NTH0692 NTH0694 NTH0695 NTH0696 NTH0702 NTH0703 NTH0706 NTH0707 NTH0709

NTH0710 NTH0711 NTH0712 NTH0715 NTH0716 NTH0717 NTH0718 NTH0721

NTH0724 NTH0725 NTH0726 NTH0728 NTH0729 NTH0730 NTH0738 NTH0740

NTH0744 NTH0745 NTH0749 NTH0750 NTH0752 NTH0755 NTH0756 NTH0762

NTH0764 NTH0765 NTH0768 NTH0771 NTH0774 NTH0776 NTH0788 NTH0792 NTH0794 NTH0795 NTH0796 NTH0797 NTH0798 NTH0802 NTH0803 NTH0804

NTH0813 NTH0814 NTH0815 NTH0818 NTH0820 NTH0821 NTH0822 NTH0827

NTH0829 NTH0832 NTH0834 NTH0835 NTH0836 NTH0838 NTH0839 NTH0841

NTH0843 NTH0844 NTH0848 NTH0849 NTH0850 NTH0851 NTH0852 NTH0856 NTH0858 NTH0861 NTH0862 NTH0863 NTH0864 NTH0865 NTH0866 NTH0867

NTH0872 NTH0874 NTH0875 NTH0877 NTH0879 NTH0880 NTH0885 NTH0886

NTH0887 NTH0888 NTΗ0892 NTH0894 NTH0895 NTH0896 NTH0900 NTH0901

NTH0904 NTH0906 NTΗ0909 NTH0910 NTH0913 NTH0914 NTH0921 NTH0924 NTH0926 NTH0927 NTH0928 NTH0929 NTH0930 NTH0931 NTH0932 NTH0933

NTH0937 NTH0938 NTH0941 NTΗ0942 NTH0948 NTH0949 NTH0950 NTH0952

NTH0953 NTH0955 NTH0961 NTH0964 NTH0968 NTH0970 NTH0971 NTH0972

NTH0973 NTH0985 NTH0986 NTH0987 NTH0989 NTH0991 NTH0992 NTH0993

NTH0994 NTH0995 NTH0996 NTH0997 NTH1000 NTH1002 NTH1003 NTH1004 NTH1005 NTH1007 NTH1009 NTHIOIO NTH1012 NTH1015 NTH1016 NTH1017

NTH1018 NTH1020 NTH1021 NTH1025 NTH1026 NTH1027 NTH1028 NTH1029

NTH1031 NTH1032 NTH1037 NTH1039 NTH1040 NTH1042 NTH1043 NTH1048

NTH1049 NTH1052 NTH1054 NTH1058 NTH1063 NTH1064 NTH1067 NTH1069

NTH1070 NTH1073 NTH1075 NTH1080 NTH1082 NTH1083 NTH1084 NTH1085 NTH1086 NTH1087 NTH1089 NTH1090 NTH1091 NTH1092 NTH1098 NTHI 102

NTHI 103 NTHI 104 NTHI 106 NTHI 108 NTH11U NTHI 112 NTHI 114 NTHI 115

NTH1116 NTH1121 NTH1122 NTH1123 NTH1124 NTH1125 NTH1129 NTH1130

NTH1131 NTH1138 NTH1141 NTH1142 NTH1149 NTH1150 NTH1151 NTH1153

NTHI 157 NTHI 159 NTHI 161 NTHI 162 NTHI 164 NTΗ1174 NTHI 176 NTHI 178 NTH1179 NTH1181 NTH1184 NTH1185 NTH1188 NTH1189 NTH1190 NTH1191

NTHI 192 NTHI 193 NTHI 195 NTHI 196 NTH1200 NTH1201 NTH1203 NTH1204

NTH1205 NTH1207 NTH1208 NTH1209 NTH1210 NTH1211 NTH1214 NTH1216

NTH1220 NTH1221 NTH1224 NTH1225 NTH1226 NTH1229 NTH1230 NTH1231

NTH1233 NTH1234 NTH1235 NTH1236 NTH1237 NTH1238 NTH1240 NTH1241 NTH1244 NTH1245 NTH1246 NTH1247 NTH1248 NTH1249 NTH1250 NTH1251

NTH1252 NTH1253 NTH1254 NTH1255 NTH1256 NTH1261 NTH1262 NTH1268

NTH1270 NTH1271 NTH1273 NTH1275 NTH1279 NTH1280 NTH1281 NTH1282

NTH1283 NTH1286 NTH1287 NTH1290 NTH1293 NTH1294 NTH1295 NTH1297

NTH1298 NTH1299 NTH1300 NTH1301 NTH1302 NTH1305 NTH1306 NTH1307 NTH1308 NTH1309 NTH1311 NTH1313 NTH1315 NTH1316 NTH1319 NTH1321

NTH1325 NTH1327 NTH1330 NTH1332 NTH1333 NTH1334 NTH1336 NTH1337

NTH1339 NTH1341 NTH1342 NTH1346 NTH1348 NTH1353 NTH1354 NTH1357

NTH1359 NTH1361 NTH1363 NTH1365 NTH1367 NTH1368 NTH1374 NTH1375

NTH1376 NTH1379 NTH1380 NTH1381 NTH1382 NTH1383 NTH1388 NTH1390 NTH1391 NTH1393 NTH1394 NTH1395 NTH1396 NTH1398 NTH1399 NTH1400

NTH1406 NTH1407 NTH1411 NTH1412 NTH1413 NTH1414 NTH1415 NTH1416

NTH1418 NTH1419 NTH1420 NTH1421 NTH1425 NTH1427 NTH1428 NTH1429

NTH1430 NTH1431 NTH1434 NTH1435 NTH1437 NTH1438 NTH1439 NTH1441 NTH1447 NTH1448 NTH1450 NTH1454 NTH1455 NTH1456 NTH1464 NTH1467

NTH1468 NTH1470 NTH1471 NTH1472 NTH1473 NTH1474 NTH1479 NTH1487

NTH1489 NTH1490 NTH1491 NTH1492 NTH1493 NTH1494 NTH1495 NTH1496

NTH1497 NTH1500 NTH1503 NTH1504 NTH1506 NTH1510 NTH1515 NTH1516 NTH1525 NTH1526 NTH1527 NTH1528 NTH1531 NTH1532 NTH1537 NTH1538

NTH1540 NTH1541 NTH1543 NTH1548 NTH1552 NTH1555 NTH1559 NTH1562

NTH1563 NTH1564 NTH1567 NTH1569 NTH1570 NTH1571 NTH1573 NTH1574

NTH1575 NTH1580 NTΗ1581 NTH1582 NTH1584 NTH1586 NTH1587 NTH1588

NTH1590 NTH1594 NTH1597 NTH1598 NTH1599 NTH1600 NTH1601 NTH1602 NTH1603 NTH1605 NTH1606 NTH1607 NTH1608 NTH1609 NTHI 611 NTH1612

NTH1615 NTH1616 NTH1617 NTH1618 NTH1619 NTH1620 NTH1621 NTH1622

NTH1623 NTH1625 NTH1626 NTH1627 NTH1628 NTH1629 NTH1631 NTH1634

NTH1637 NTH1638 NTH1647 NTH1652 NTH1653 NTH1654 NTH1656 NTH1657

NTH1658 NTH1662 NTH1664 NTH1666 NTH1668 NTH1671 NTHI 675 NTH1676 NTH1677 NTH1680 NTH1686 NTH1687 NTH1688 NTH1689 NTH1690 NTH1692

NTH1693 NTH1697 NTH1698 NTH1701 NTH1702 NTH1703 NTH1707 NTH1712

NTH1713 NTH1718 NTH1719 NTH1722 NTH1724 NTH1725 NTH1729 NTH1732

NTH1734 NTH1735 NTH1739 NTH1740 NTH1742 NTH1744 NTH1745 NTH1748

NTH1749 NTH1751 NTH1752 NTH1753 NTH1754 NTH1755 NTH1756 NTH1757 NTH1758 NTH1759 NTH1760 NTH1765 NTH1767 NTH1769 NTH1770 NTH1773

NTH1778 NTH1779 NTH1781 NTH1782 NTΗ1783 NTH1788 NTH1793 NTH1795

NTH1796 NTH1798 NTH1799 NTHI 803 NTHI 804 NTHI 805 NTHI 806 NTHI 807

NTH1811 NTH1812 NTH1813 NTH1815 NTH1816 NTH1817 NTH1818 NTH1819

NTH1820 NTH1821 NTH1822 NTH1824 NTH1828 NTH1829 NTH1832 NTH1833 NTH1835 NTH1836 NTH1837 NTH1842 NTH1845 NTH1849 NTH1850 NTH1854

NTH1857 NTH1859 NTH1861 NTH1865 NTH1870 NTH1871 NTH1872 NTH1873

NTHI 881 NTHI 882 NTHI 885 NTHI 888 NTHI 889 NTHI 891 NTHI 892 NTHI 896

NTH1897 NTH1898 NTH1899 NTH1900 NTH1904 NTH1906 NTH1908 NTH1910

NTH1914 NTH1916 NTH1917 NTH1919 NTH1920 NTH1921 NTH1922 NTH1923 NTH1925 NTH1927 NTH1935 NTH1939 NTH1941 NTH1942 NTH1945 NTH1946

NTH1947 NTH1948 NTH1951 NTH1953 NTH1956 NTH1958 NTH1960 NTH1962

NTH1963 NTH1964 NTH1965 NTH1966 NTH1967 NTH1968 NTH1974 NTH1978

NTH1981 NTH1986 NTH1989 NTH1992 NTH1993 NTH1994 NTH1995 NTH1996

NTH1997 NTH1998 NTH1999 NTH2001 NTH2005 NTH2008 NTH2009 NTH2010 NTH2019 NTH2024 NTH2025 NTH2031 NTH2035 NTH2038 NTH2039 NTH2040

NTH2041 NTH2043 NTH2050 NTH2052 NTH2055 NTH2056 NTH2060 NTH2062

NTH2064 NTH2065 NTH2069 NTH2070 NTH2071 NTH2073 NTH2075 NTH2078

NTH2079 NTH2081 NTH2083 NTH2089 NTH2091 NTH2092 NTH2093 NTH2094 NTH2095 NTH2096 NTH2097 NTH2099 NTH2101 NTH2109 NTH2110 NTH2112

NTH2113 NTH2114 NTH2115 NTH2116 NTH2117 NTH2118 NTH2119 NTH2120

NTH2122 NTH2126 NTH2128 NTH2129 NTH2130 NTH2131 NTH2133 NTH2135

NTH2136 NTH2138 NTH2142 NTH2145 NTH2146 NTH2149 NTH2150 NTH2156 NTH2159 NTH2162 NTH2163 NTH2166 NTH2169 NTH2170 NTH2173 NTH2181

NTH2183 NTH2187 NTH2191 NTH2193 NTH2195 NTH2196 NTH2197 NTH2198

NTH2199 NTH2200 NTH2204 NTH2205 NTH2206 NTH2207 NTH2209 NTH2213

NTH2216 NTH2217 NTH2219 NTH2220 NTH2221 NTH2222 NTH2223 NTH2226

NTH2227 NTH2228 NTH2229 NTH2231 NTH2232 NTH2234 NTH2235 NTH2242 NTH2243 NTH2245 NTH2247 NTH2250 NTH2251 NTH2253 NTH2256 NTH2257

NTH2258 NTH2259 NTH2262 NTH2263 NTH2266 NTH2269 NTH2273 NTH2274

NTH2277 NTΗ2282 NTH2284 NTH2285 NTH2287 NTH2288 NTH2291 NTH2292

NTH2296 NTH2299 NTH2305 NTH2309 NTH2315 NTH2316 NTH2318 NTH2323

NTH2324 NTH2326 NTH2327 NTH2330 NTH2332 NTH2333 NTH2342 NTH2343 NTH2344 NTH2346 NTH2347 NTH2349 NTH2352 NTH2353 NTH2356 NTH2358

NTH2361 NTH2362 NTH2363 NTH2364 NTH2365 NTH2368 NTH2369 NTH2370

NTH2371 NTH2376 NTH2377 NTH2381 NTH2382 NTH2386 NTH2388 NTH2394

NTH2398 NTH2402 NTH2405 NTH2406 NTH2407 NTH2408 NTH2414 NTH2414

NTH2422 NTH2430 NTH2432 NTH2433 NTH2434 NTH2438 NTH2442 NTH2447 NTH2448 NTH2451 NTH2455 NTH2456 NTH2457 NTH2458 NTH2460 NTH2461

NTH2463 NTH2464 NTH2466 NTH2467 NTH2468 NTH2471 NTH2472 NTH2478

NTH2480 NTH2481 NTH2482 NTH2483 NTH2484 NTH2485 NTH2486 NTH2487

NTH2488 NTH2493 NTH2495 NTH2496 NTH2497 NTH2498 NTH2499 NTH2500

NTH2501 NTH2505 NTH2508 NTH2510 NTH2524 NTH2525 NTH2527 NTH2528 NTH2531 NTH2532 NTH2533 NTH2534 NTH2536 NTH2537 NTH2541 NTH2542

NTH2543 NTH2545 NTH2546 NTH2548 NTH2549 NTH2550 NTH2552 NTH2554

NTH2556 NTH2557 NTH2558 NTH2562 NTH2563 NTH2566 NTH2567 NTH2568

NTH2569 NTH2570 NTH2572 NTH2573 NTH2575 NTH2577 NTH2578 NTH2584

NTH2585 NTH2587 NTH2588 NTH2590 NTH2591 NTH2593 NTH2595 NTH2597 NTH2600 NTH2602 NTH2603 NTH2604 NTH2605 NTH2607 NTH2608 NTH2609

NTH2610 NTH2612 NTH2613 NTH2615 NTH2616 NTH2618 NTH2626 NTH2633

NTH2635 NTH2640 NTH2641 NTH2647 NTH2648 NTH2649 NTH2650 NTH2655

NTH2661 NTH2663 NTH2664 NTH2667 NTH2668 NTH2673 NTH2674 NTH2675

NTH2679 NTH2680 NTH2684 NTH2690 NTH2693 NTH2694 NTH2696 NTH2697 NTH2701 NTH2702 NTH2703 NTH2704 NTH2705 NTH2706 NTH2707 NTH2708

NTH2709 NTH2710 NTH2711 NTH2712 NTH2713 NTH2715 NTH2716 NTH2718

NTH2719 NTH2720 NTH2721 NTH2723 NTH2724 NTH2725 NTH2726 NTH2727

NTH2729 NTH2730 NTH2731 NTH2732 NTH2735 NTH2737 NTH2738 NTH2740 NTH2743 NTH2744 NTH2749 NTH2750 NTH2753 NTH2754 NTH2755 NTH2756 NTH2757 NTH2758 NTH2764 NTH2765 NTH2769 NTH2774 NTH2777 NTH2778 NTH2779 NTH2781 NTH2783 NTH2784 NTH2785 NTH2791 NTH2793 NTH2794 NTH2796 NTH2797 NTH2798 NTH2804 NTH2806 NTH2807 NTH2809 NTH2810 NTH2813 NTH2814 NTH2816 NTH2823

TABLE III — Annotations aa = length of polypeptide PSORT = cellular location of polypeptide, according to PSORT algorithm

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Claims

1. A polypeptide comprising an amino acid sequence that has at least 75% sequence identity to one or more of SEQ ID NOS: 1566, 5095, 1570, 5094, 1574, 5903, 1578, 5092, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342 344, 346, 348, 350, 352354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 384, 386, 388, 390, 392, 394, 396, 398, 400, 402, 404, 406, 408, 410, 412, 414, 416, 418, 420, 422, 424, 426, 428, 430, 432, 434, 436, 438, 440, 442, 444, 446, 448_: 450, 452, 454, 456, 458, 460, 462, 464, 466, 468, 470, 472, 474, 476, 478, 480, 482, 484, 486, 488, 490, 492, 494, 96, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, 540, 542, 544.546, 548, 550, 552, 554, 556, 558, 560, 562, 564, 566, 568, 570, 572, 574, 576, 578, 580, 582, 584, 586, 588, 590, 592594, 596, 598, 600, 602, 604, 606, 608, 610, 612, 614, 616, 618, 620, 622, 624, 626, 628, 630, 632, 634, 636, 638, 640, 642, 644, 646, 648, 650, 652, 654, 656, 658, 660, 662, 664, 666, 668, 670, 672, 674, 676, 678, 680, 682, 684, 686, 688690, 692, 694, 696, 698, 700, 702, 704, 706, 708, 710, 712, 714, 716, 718, 720, 722, 724, 726, 728, 730, 732, 734, 736738, 740, 742, 744, 746, 748, 750, 752, 754, 756, 758, 760, 762, 764, 766, 768, 770, 772, 774, 776, 778, 780, 782, 784, 786, 788, 790, 792, 794, 796, 798, 800, 802, 804, 806, 808, 810, 812, 814, 816, 818, 820, 822, 824, 826, 828, 830, 832834, 836, 838, 840, 842, 844, 846, 848, 850, 852, 854, 856, 858, 860, 862, 864, 866, 868, 870, 872, 874, 876, 878, 880882, 884, 886, 888, 890, 892, 894, 896, 898, 900, 902, 904, 906, 908, 910, 912, 914, 916, 918, 920, 922, 924, 926, 928, 930, 932, 934, 936, 938, 940, 942, 944, 946, 948, 950, 952, 954, 956, 958, 960, 962, 964, 966, 968, 970, 972, 974, 976978, 980, 982, 984, 986, 988, 990, 992, 994, 996, 998, 1000, 1002, 1004, 1006, 1008, 1010, 1012, 1014, 1016, 1018 1020, 1022, 1024, 1026, 1028, 1030, 1032, 1034, 1036, 1038 1040, 1042, 1044, 1046, 1048, 1050, 1052, 1054 1056 1058 1060, 1062, 1064, 1066, 1068. 1070, 1072, 1074, 1076, 1078, 1080, 1082, 1084.1086, 1088, 1090, 1092, 10941096, 1098, 1100, 1102, 1104, 1106, 1108, 1110, 1112, 1114, 1116, 1118, 1120, 11221124, 1126, 1128, 1130, 1132, 1134.1136, 1138, 1140, 1142, 1144, 1146, 1148, 1150, 1152, 1154, 1156, 1158, 1160, 1162, 1164,11661168, 11701172, 1174, 1176, 1178, 11 1182, 1184, 1186, 1188, 1190, 1192,1194, 1196, 11981200, 1202, 1204, 1206, 1208, 1210, 1212, 1214, 1216, 1218, 1220, 1222, 1224, 1226, 1228, 1230, 1232, 1234.1236, 1238, 1240, 1242, 1244, 1246, 1248, 1250, 1252, 1254, 1256, 1258, 1260, 12621264, 1266, 1268, 1270, 12721274, 1276, 1278, 1280, 1282, 1284, 12861288, 1290, 1292, 1294, 1296, 1298, 13001302, 1304, 1306, 1308, 1310, 13121314, 1316, 1318, 1320, 1322, 1324, 1326, 1328, 1330, 1332, 13341336, 1338, 1340, 13421344, 1346, 134813501352, 1354, 13561358, 1360, 1362, 1364, 1366, 1368, 13701372, 1374, 13761378, 1380, 1382, 1384, 13861388, 1390, 1392, 1394, 13961398, 1400, 1402, 1404, 1406, 1408, 1410, 1412, 14141416, 1418, 1420, 1422, 14241426, 1428, 1430, 1432, 143414361438.1440, 1442, 1444, 1446 1448, 1450, 1452, 1454, 1456, 1458, 1460, 1462, 1464, 1466, 1468, 1470, 14721474, 14761478, 1480, 1482, 14841486, 1488, 1490, 1492, 1494, 1496, 1498, 1500, 1502, 1504, 1506, 1508 1510, 1512, 1514, 1516, 1518, 1520, 1522, 1524, 1526, 1528, 1530, 1532, 1534, 1536, 1538 1540, 1542, 1544, 1546, 1548, 1550, 1552, 1554, 1556, 1558, 1560, 1562.1564.1566, 1568, 1570, 1572, 1574, 1576, 1578, 1580, 1582, 1584, 1586, 1588, 1590, 1592, 1594, 1596, 1598, 1600, 1602.1604, 1606, 1608, 1610, 1612, 1614, 1616, 1618, 1620, 16221624, 1626, 1628, 1630, 1632, 1634, 16361638 1640.1642.1644, 1646.1648, 1650, 1652, 1654.1656,

3178, 3180, 3182, 3184, 3186, 3188, 3190, 3192, 3194, 3196, 3198, 3200, 3202, 3204, 3206, 3208, 3210, 3212, 3214, 3216, 3218, 3220, 3222, 3224, 3226, 3228, 3230, 3232, 3234, 3236, 3238, 3240, 3242, 3244, 3246, 3248, 3250, 3252, 3254, 3256, 3258, 3260, 3262, 3264, 3266, 3268, 3270, 3272.3274, 3276, 3278, 3280, 3282, 3284, 3286, 3288, 3290, 3292, 3294, 3296, 3298, 3300, 3302, 3304, 3306, 3308, 3310, 3312, 3314, 3316, 3318, 3320, 3322, 3324, 3326, 3328, 3330, 3332, 3334, 3336, 3338, 3340, 3342, 3344, 3346, 3348, 3350, 3352, 3354, 3356, 3358, 3360, 3362, 3364, 3366, 3368, 3370, 3372, 3374, 3376, 3378, 3380, 3382, 3384, 33863388, 3390, 3392, 3394, 3396, 3398, 3400, 3402, 3404, 3406, 3408, 3410, 3412, 3414, 3416, 3418, 3420, 3422, 34243426, 3428, 3430, 3432, 3434, 3436, 3438, 3440, 3442, 3444, 3446, 3448, 3450, 3452, 3454, 3456, 3458, 3460, 3462, 3464, 3466, 3468, 3470, 3472, 3474, 3476, 3478, 3480, 3482, 3484, 3486, 3488, 3490, 3492, 3494, 3496, 3498, 3500, 3502, 3504, 3506, 3508, 3510, 3512, 3514, 3516, 3518, 3520, 3522, 3524, 3526, 3528, 3530, 3532, 3534, 3536, 3538, 3540, 3542, 3544, 3546, 3548, 3550, 3552, 3554, 3556, 3558, 3560, 3562, 3564, 3566, 3568, 3570, 3572, 3574, 3576, 3578, 3580, 3582, 3584, 3586, 3588, 3590, 3592, 3594, 3596, 3598, 3600, 3602, 3604, 3606, 3608, 3610, 3612, 36143616, 3618, 3620, 3622, 3624, 3626, 3628, 3630, 3632, 3634, 3636, 3638, 3640, 3642, 3644, 3646, 3648, 3650, 3652, 3654, 3656, 3658, 3660, 3662, 3664, 3666, 3668, 3670, 3672, 3674, 3676, 3678, 3680, 3682, 3684, 3686, 3688, 3690, 3692, 3694, 3696, 3698, 3700, 3702, 3704, 3706, 3708, 3710, 3712, 3714, 3716, 3718, 3720, 3722, 3724, 3726, 3728, 3730, 3732, 3734, 3736, 3738, 3740, 3742, 3744, 3746, 3748, 3750, 3752, 3754, 3756, 3758, 3760, 3762, 3764, 3766, 3768, 3770, 3772, 3774, 3776, 3778, 3780, 3782, 3784, 3786, 3788, 3790, 3792, 3794, 3796, 3798, 3800, 3802, 3804, 3806, 3808, 3810, 3812, 3814, 38163818, 3820, 3822, 3824, 3826, 3828, 3830, 3832, 3834, 3836, 3838, 3840, 3842.3844, 3846, 3848, 3850, 3852, 3854, 3856, 3858, 3860, 3862, 3864, 3866, 3868, 3870, 3872, 3874, 3876, 3878, 3880, 3882, 3884, 3886, 3888, 3890, 3892, 3894, 3896, 3898, 3900, 3902, 3904, 3906, 3908, 3910, 3912, 3914, 3916, 3918, 3920, 3922, 3924, 3926, 3928, 3930, 3932, 3934, 3936, 3938, 3940, 3942, 3944, 3946, 3948, 3950, 3952, 3954, 3956, 3958, 3960, 3962, 3964, 3966, 3968, 3970, 3972, 3974, 3976, 3978, 3980, 3982, 3984, 3986, 3988, 3990, 3992, 3994, 3996, 3998, 4000, 4002, 4004, 4006, 4008, 4010, 4012, 4014, 4016, 4018, 4020, 4022, 4024, 4026, 4028, 4030, 40324034, 4036, 4038, 4040, 4042, 4044, 4046, 4048, 4050, 4052, 4054, 4056, 4058, 4060, 4062, 4064, 4066, 4068, 4070, 4072, 4074, 4076, 4078, 4080, 4082, 4084, 4086, 4088, 4090, 4092, 4094, 4096, 4098, 4100, 4102, 4104, 4106, 4108, 4110,4112, 4114,4116, 4118,4120, 4122, 4124, 4126 4128, 4130, 4132, 4134, 4136, 4138, 4140, 4142, 4144, 41464148, 4150, 4152, 4154, 4156, 4158, 4160, 4162, 4164, 4166, 4168, 4170, 4172, 4174, 4176, 4178, 4180, 4182, 4184, 4186, 4188, 4190, 4192, 4194, 4196, 4198, 4200, 4202, 4204, 4206, 4208, 4210, 4212, 4214, 4216, 4218, 4220, 4222, 4224, 4226, 4228, 4230, 4232, 4234, 4236, 4238, 4240, 4242, 4244, 4246, 4248, 4250, 4252, 4254, 4256, 4258, 4260, 4262, 4264, 4266, 4268, 4270, 4272, 4274, 4276, 4278, 4280, 4282, 4284, 4286, 4288, 4290, 4292, 4294, 4296, 4298, 4300, 4302, 4304, 4306, 4308, 4310, 4312,4314,4316, 4318, 4320, 4322, 4324, 4326, 4328, 4330, 4332, 4334, 4336, 4338, 4340, 4342, 4344, 4346, 43484350, 4352, 4354, 4356, 4358, 4360, 4362, 4364, 4366, 4368, 4370, 4372, 4374, 4376, 4378, 4380, 4382, 4384, 43864388, 4390, 4392, 4394, 4396, 4398, 4400, 4402, 4404, 4406, 4408, 4410, 4412, 4414, 4416, 4418, 4420, 4422, 4424, 4426, 4428, 4430, 4432, 4434, 4436, 4438, 4440, 4442, 4444, 4446, 4448, 4450, 4452, 4454, 4456, 4458, 4460, 4462, 4464, 4466, 4468, 4470, 4472, 4474, 4476, 4478, 4480, 4482, 4484, 4486, 44884490, 4492, 4494, 4496, 4498, 4500, 4502, 4504, 4506 4508, 4510, 4512, 4514, 4516, 4518, 4520, 4522, 4524, 4526, 4528, 4530, 4532, 4534, 4536, 4538, 4540, 4542, 4544, 4546, 4548, 4550, 4552, 4554, 4556, 4558, 4560, 4562, 4564, 4566, 4568, 4570, 4572, 4574, 4576, 4578, 4580, 4582, 4584, 4586, 4588, 4590, 4592, 4594, 4596, 4598, 4600, 4602.4604, 4606, 4608, 4610, 4612, 46144616, 4618, 4620, 4622, 4624, 4626, 4628, 4630, 4632, 4634, 4636, 4638, 4640, 4642, 4644, 4646, 4648, 4650, 4652, 4654, 4656, 4658, 4660, 4662, 4664, 4666, 4668, 4670, 4672, 4674, 4676, 46784680, 4682, 4684, 4686, 4688, 4690, 4692, 4694, 4696, 4698, 4700, 4702, 4704, 4706, 4708, 4710, 4712, 4714, 4716, 4718, 4720, 4722, 4724, 4726, 4728, 4730, 4732, 4734, 4736, 4738, 4740, 4742, 4744, 4746, 4748, 4750, 4752, 4754, 4756, 4758, 4760, 4762, 4764, 4766, 4768, 4770, 4772, 4774, 4776, 4778, 4780, 4782, 4784, 4786, 4788, 4790, 4792, 4794, 4796, 4798, 4800, 4802, 4804, 4806, 4808, 4810, 4812, 4814, 4816, 4818, 4820, 4822, 4824, 4826, 4828, 4830, 4832, 4834, 4836, 4838, 4840, 4842, 4844, 4846, 4848, 4850, 4852, 4854, 4856, 4858, 4860, 4862, 4864, 4866, 4868, 4870, 4872, 4874, 4876, 4878, 4880, 4882, 4884, 4886, 4888, 4890, 4892, 4894, 4896, 4898, 4900, 4902, 4904, 4906, 4908, 4910, 4912, 4914, 4916, 4918, 4920, 4922, 4924, 4926, 4928, 4930, 4932, 4934, 4936, 4938, 4940, 4942, 4944, 4946, 4948, 4950, 4952, 4954, 4956, 4958, 4960, 4962, 4964, 4966, 4968, 4970, 4972, 4974, 4976, 4978, 4980, 4982, 4984, 4986, 4988, 4990, 4992, 4994, 4996, 4998, 5000, 5002, 5004, 5006, 5008, 5010, 5012, 5014, 5016, 5018, 5020, 5022, 5024, 5026, 5028, 5030, 5032, 5034, 5036, 5038, 5040, 5042, 5044, 5046, 5048, 5050, 5052, 5054, 5056, 5058, 5060, 5062, 5064, 5066, 5068, 5070, 5072, 5074, 5076, 5078, 5080, 5088, 5089, 5090, 5091, 5092, 5093, 5094 & 5095.

2. Thepolypeptide ofclaim 1, comprising one or more ofamino acid sequences SEQ IDNOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88.90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 384, 386, 388, 390, 392, 394, 396, 398, 400, 402, 404, 406, 408, 410, 412, 414, 416, 418, 420, 422, 424, 426, 428, 430, 432, 434, 436, 438, 440, 442, 444, 446, 448, 450, 452, 454, 456, 458, 460, 462, 464, 466, 468, 470, 472, 474, 476, 478, 480, 482, 484, 486, 488, 490, 492, 494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564, 566, 568, 570, 572, 574, 576, 578, 580, 582, 584, 586, 588, 590, 592, 594, 596, 598, 600, 602, 604, 606, 608, 610, 612, 614, 616, 618, 620, 622, 624, 626, 628, 630, 632, 634, 636, 638, 640, 642, 644, 646, 648, 650, 652, 654, 656, 658, 660, 662, 664, 666, 668, 670, 672, 674, 676, 678, 680, 682, 684, 686, 688, 690, 692, 694, 696, 698, 700, 702, 704, 706, 708, 710, 712, 714, 716, 718, 720, 722, 724, 726, 728, 730, 732, 734, 736, 738, 740, 742, 744, 746, 748, 750, 752, 754, 756, 758, 760, 762, 764, 766, 768, 770, 772, 774, 776, 778, 780, 782, 784, 786, 788, 790, 792, 794, 796, 798, 800, 802, 804, 806, 808, 810, 812, 814, 816, 818, 820, 822, 824, 826, 828, 830, 832, 834, 836, 838, 840, 842, 844, 846, 848, 850, 852, 854, 856, 858, 860, 862, 864, 866, 868, 870, 872, 874, 876, 878, 880, 882, 884, 886, 888, 890, 892, 894, 896, 898, 900, 902, 904, 906, 908, 910, 912, 914, 916, 918, 920, 922, 924, 926, 928, 930, 932, 934, 936, 938, 940, 942, 944, 946, 948, 950, 952, 954, 956, 958, 960, 962, 964, 966, 968, 970, 972, 974, 976, 978, 980, 982, 984, 986, 988, 990, 992, 994, 996, 998, 1000, 1002, 1004, 1006, 1008, 1010, 1012, 1014, 1016, 1018, 1020, 1022, 1024, 1026, 1028, 1030, 1032, 1034, 1036, 1038, 1040, 1042, 1044, 1046, 1048, 1050, 1052, 1054, 1056, 1058, 1060, 1062, 1064, 1066, 1068, 1070, 1072, 1074, 1076, 1078, 1080, 1082, 1084, 1086, 1088, 1090, 1092, 1094, 1096, 1098, 1100, 1102, 1104, 1106, 1108, 1110, 1112, 1114, 1116, 1118, 1120, 1122, 1124, 1126, 1128, 1130, 1132, 1134, 1136, 1138, 1140, 1142, 1144, 1146, 1148, 1150, 1152, 1154, 1156, 1158, 1160, 1162, 1164, 1166, 1168, 1170, 1172, 1174, 1176, 1178, 1180, 1182, 1184, 1186, 1188, 1190, 1192, 1194, 1196, 1198, 1200, 1202, 1204, 1206, 1208, 1210, 1212, 1214, 1216, 1218, 1220, 1222, 1224, 1226, 1228, 1230, 1232, 1234, 1236, 1238, 1240, 1242, 1244, 1246, 1248, 1250, 1252, 1254, 1256, 1258, 1260, 1262, 1264, 1266, 1268, 1270, 1272, 1274, 1276, 1278, 1280, 1282, 1284, 1286, 1288, 1290, 1292, 1294, 1296, 1298, 1300, 1302, 1340, 1378, 1416, 1454, 1492, 1530, 1568, 1606, 1644, 1682, 1720, 1758, 1796, 1834, 1872, 1910, 1948, 1986, 2024, 2062, 2100, 2138, 2176, 2214, 2252, 2290, 2328, 2366, 2404, 2442, 2480, 2518, 2556, 2594, 2632, 2670, 2708, 2746, 2784,

2822, 2824, 2826, 2828, 2830, 2832, 2834, 2836, 2838, 2840, 2842, 2844, 2846, 2848, 2850, 2852, 2854, 2856, 2858, 2860, 2862, 2864, 2866, 2868, 2870, 2872, 2874, 2876, 2878, 2880, 2882, 2884, 2886, 2888, 2890, 2892, 2894, 2896, 2898, 2900, 2902, 2904, 2906, 2908, 2910, 2912, 2914, 2916, 2918, 2920, 2922, 2924, 2926, 2928, 2930, 2932, 2934, 2936, 2938, 2940, 2942, 2944, 2946, 2948, 2950, 2952, 2954, 2956, 2958, 2960, 2962, 2964, 2966, 2968, 2970, 2972, 2974, 2976, 2978, 2980, 2982, 2984, 2986, 2988, 2990, 2992, 2994, 2996, 2998, 3000, 3002, 3004, 3006, 3008, 3010, 3012, 3014, 3016, 3018, 3020, 3022, 3024, 3026, 3028, 3030, 3032, 3034, 3036, 3038, 3040, 3042, 3044, 3046, 3048, 3050, 3052, 3054, 3056, 3058, 3060, 3062, 3064, 3066, 3068, 3070, 3072, 3074, 3076, 3078, 3080, 3082, 3084, 3086, 3088, 3090, 3092, 3094, 3096, 3098, 3100, 3102, 3104, 3106, 3108, 3110, 3112, 3114, 3116, 3118, 3120, 3122, 3124, 3126, 3128, 3130, 3132, 3134, 3136, 3138, 3140, 3142, 3144, 3146, 3148, 3150, 3152, 3154, 3156, 3158, 3160, 3162, 3164, 3166, 3168, 3170, 3172, 3174, 3176, 3178, 3180, 3182, 3184, 3186, 3188, 3190, 3192, 3194, 3196, 3198, 3200, 3202, 3204, 3206, 3208, 3210, 3212, 3214, 3216, 3218, 3220, 3222, 3224, 3226, 3228, 3230, 3232, 3234, 3236, 3238, 3240, 3242, 3244, 3246, 3248, 3250, 3252, 3254, 3256, 3258, 3260, 3262, 3264, 3266, 3268, 3270, 3272, 3274, 3276, 3278, 3280, 3282, 3284, 3286, 3288, 3290, 3292, 3294, 3296, 3298, 3300, 3302, 3304, 3306, 3308, 3310, 3312, 3314, 3316, 3318, 3320, 3322, 3324, 3326, 3328, 3330, 3332, 3334, 3336, 3338, 3340, 3342, 3344, 3346, 3348, 3350, 3352, 3354, 3356, 3358, 3360, 3362, 3364, 3366, 3368, 3370, 3372, 3374, 3376, 3378, 3380, 3382, 3384, 3386, 3388, 3390, 3392, 3394, 3396, 3398, 3400, 3402, 3404, 3406, 3408, 3410, 3412, 3414, 3416, 3418, 3420, 3422, 3424, 3426, 3428, 3430, 3432, 3434, 3436, 3438, 3440, 3442, 3444, 3446, 3448, 3450, 3452, 3454, 3456, 3458, 3460, 3462, 3464, 3466, 3468, 3470, 3472, 3474, 3476, 3478, 3480, 3482, 3484, 3486, 3488, 3490, 3492, 3494, 3496, 3498, 3500, 3502, 3504, 3506, 3508, 3510, 3512, 3514, 3516, 3518, 3520, 3522, 3524, 3526, 3528, 3530, 3532, 3534, 3536, 3538, 3540, 3542, 3544, 3546, 3548, 3550, 3552, 3554, 3556, 3558, 3560, 3562, 3564, 3566, 3568, 3570, 3572, 3574, 3576, 3578, 3580, 3582, 3584, 3586, 3588, 3590, 3592, 3594, 3596, 3598, 3600, 3602, 3604, 3606, 3608, 3610, 3612, 3614, 3616, 3618, 3620, 3622, 3624, 3626, 3628, 3630, 3632, 3634, 3636, 3638, 3640, 3642, 3644, 3646, 3648, 3650, 3652, 3654, 3656, 3658, 3660, 3662, 3664, 3666, 3668, 3670, 3672, 3674, 3676, 3678, 3680, 3682, 3684, 3686, 3688, 3690, 3692, 3694, 3696, 3698, 3700, 3702, 3704, 3706, 3708, 3710, 3712, 3714, 3716, 3718, 3720, 3722, 3724, 3726, 3728, 3730, 3732, 3734, 3736, 3738, 3740, 3742, 3744, 3746, 3748, 3750, 3752, 3754, 3756, 3758, 3760, 3762, 3764, 3766, 3768, 3770, 3772, 3774, 3776, 3778, 3780, 3782, 3784, 3786, 3788, 3790, 3792, 3794, 3796, 3798, 3800, 3802, 3804, 3806, 3808, 3810, 3812, 3814, 3816, 3818, 3820, 3822, 3824, 3826, 3828, 3830, 3832, 3834, 3836, 3838, 3840, 3842, 3844, 3846, 3848, 3850, 3852, 3854, 3856, 3858, 3860, 3862, 3864, 3866, 3868, 3870, 3872, 3874, 3876, 3878, 3880, 3882, 3884, 3886, 3888, 3890, 3892, 3894, 3896, 3898, 3900, 3902, 3904, 3906, 3908, 3910, 3912, 3914, 3916, 3918, 3920, 3922, 3924, 3926, 3928, 3930, 3932, 3934, 3936, 3938, 3940, 3942, 3944, 3946, 3948, 3950, 3952, 3954, 3956, 3958, 3960, 3962, 3964, 3966, 3968, 3970, 3972, 3974, 3976, 3978, 3980, 3982, 3984, 3986, 3988, 3990, 3992, 3994, 3996, 3998, 4000, 4002, 4004, 4006, 4008, 4010, 4012, 4014, 4016, 4018, 4020, 4022, 4024, 4026, 4028, 4030, 4032, 4034, 4036, 4038, 4040, 4042, 4044, 4046, 4048, 4050, 4052, 4054, 4056, 4058, 4060, 4062, 4064, 4066, 4068, 4070, 4072, 4074, 4076, 4078, 4080, 4082, 4084, 4086, 4088, 4090, 4092, 4094, 4096, 4098, 4100, 4102, 4104, 4106, 4108, 4110, 4112, 4114, 4116, 4118, 4120, 4122, 4124, 4126, 4128, 4130, 4132, 4134, 4136, 4138, 4140, 4142, 4144, 4146, 4148, 4150, 4152, 4154, 4156, 4158, 4160, 4162, 4164, 4166, 4168, 4170, 4172, 4174, 4176, 4178, 4180, 4182, 4184, 4186, 4188, 4190, 4192, 4194, 4196, 4198, 4200, 4202, 4204, 4206, 4208, 4210, 4212, 4214, 4216, 4218, 4220, 4222, 4224, 4226, 4228, 4230, 4232, 4234, 4236, 4238, 4240, 4242, 4244, 4246, 4248, 4250, 4252, 4254, 4256, 4258, 4260, 4262, 4264, 4266, 4268, 4270, 4272, 4274, 4276, 4278, 4280, 4282, 4284, 4286, 4288, 4290, 4292, 4294, 4296, 4298, 4300, 4302, 4304, 4306, 4308, 4310, 4312, 4314, 4316, 4318, 4320, 4322, 4324, 4326, 4328, 4330, 4332, 4334, 4336, 4338, 4340, 4342, 4344, 4346, 4348, 4350, 4352, 4354, 4356, 4358, 4360, 4362, 4364, 4366, 4368, 4370, 4372, 4374, 4376, 4378, 4380, 4382, 4384, 4386, 4388, 4390, 4392, 4394, 4396, 4398, 4400, 4402, 4404, 4406, 4408, 4410, 4412, 4414, 4416, 4418, 4420, 4422, 4424, 4426, 4428, 4430, 4432, 4434, 4436, 4438, 4440, 4442, 4444, 4446, 4448, 4450, 4452, 4454, 4456, 4458, 4460, 4462, 4464, 4466, 4468, 4470, 4472, 4474, 4476, 4478, 4480, 4482, 4484, 4486, 4488, 4490, 4492, 4494, 4496, 4498, 4500, 4502, 4504, 4506, 4508, 4510, 4512, 4514, 4516, 4518, 4520, 4522, 4524, 4526, 4528, 4530, 4532, 4534, 4536, 4538, 4540, 4542, 4544, 4546, 4548, 4550, 4552, 4554, 4556, 4558, 4560, 4562, 4564, 4566, 4568, 4570, 4572, 4574, 4576, 4578, 4580, 4582, 4584, 4586, 4588, 4590, 4592, 4594, 4596, 4598, 4600, 4602, 4604, 4606, 4608, 4610, 4612, 4614, 4616, 4618, 4620, 4622, 4624, 4626, 4628, 4630, 4632, 4634, 4636, 4638, 4640, 4642, 4644, 4646, 4648, 4650, 4652, 4654, 4656, 4658, 4660, 4662, 4664, 4666, 4668, 4670, 4672, 4674, 4676, 4678, 4680, 4682, 4684, 4686, 4688, 4690, 4692, 4694, 4696, 4698, 4700, 4702, 4704, 4706, 4708, 4710, 4712, 4714, 4716, 4718, 4720, 4722 4724, 4726, 4728, 4730, 4732, 4734, 4736, 4738, 4740, 4742, 4744, 4746, 4748, 4750, 4752, 4754, 4756, 4758, 4760, 4762, 4764, 4766, 4768, 4770, 4772, 4774, 4776, 4778, 4780, 4782, 4784, 4786, 4788, 4790, 4792, 4794, 4796, 4798, 4800, 4802, 4804, 4806, 4808, 4810, 4812, 4814, 4816, 4818, 4820, 4822, 4824, 4826, 4828, 4830, 4832, 4834, 4836, 4838, 4840, 4842, 4844, 4846, 4848, 4850, 4852, 4854, 4856, 4858, 4860, 4862, 4864, 4866, 4868, 4870, 4872, 4874. 4876, 4878, 4880, 4882, 4884, 4886, 4888, 4890, 4892, 4894, 4896, 4898, 4900, 4902, 4904, 4906, 4908, 4910, 4912, 4914, 4916, 4918, 4920, 4922, 4924, 4926, 4928, 4930, 4932, 4934, 4936, 4938, 4940, 4942, 4944, 4946, 4948, 4950, 4952, 4954, 4956, 4958, 4960, 4962, 4964, 4966, 4968, 4970, 4972, 4974, 4976, 4978, 4980, 4982, 4984, 4986, 4988, 4990, 4992, 4994, 4996, 4998, 5000, 5002, 5004, 5006, 5008, 5010, 5012, 5014, 5016, 5018, 5020, 5022, 5024, 5026, 5028, 5030, 5032, 5034, 5036, 5038, 5040, 5042, 5044, 5046, 5048, 5050, 5052, 5054, 5056, 5058, 5060, 5062, 5064, 5066, 5068, 5070, 5072, 5074, 5076, 5078, 5080, 5088, 5089, 5090, 5091, 5092, 5093, 5094 & 5095.

3. A polypeptide comprising a fragment of at least 7 consecutive amino acids from one or more of SEQ ID NOS: 1566, 5095, 1570, 5094, 1574, 5903, 1578, 5092, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 384, 386, 388, 390, 392, 394, 396, 398, 400, 402, 404, 406, 408, 410, 412, 414, 416, 418, 420, 422, 424, 426, 428, 430, 432, 434, 436, 438, 440, 442, 444, 446, 448, 450, 452, 454, 456, 458, 460, 462, 464, 466, 468, 470, 472, 474, 476, 478, 480, 482, 484, 486, 488, 490, 492, 494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564, 566, 568, 570, 572, 574, 576, 578, 580, 582, 584, 586 588, 590, 592, 594, 596, 598, 600, 602, 604, 606, 608, 610, 612, 614, 616, 618, 620, 622, 624, 626, 628, 630, 632, 634, 636, 638, 640, 642, 644, 646, 648, 650, 652, 654, 656, 658, 660, 662, 664, 666, 668, 670, 672, 674, 676, 678, 680, 682, 684, 686, 688, 690, 692, 694, 696, 698, 700, 702, 704, 706, 708, 710, 712, 714, 716, 718, 720, 722, 724, 726, 728, 730, 732, 734, 736, 738, 740, 742, 744, 746, 748, 750, 752, 754, 756, 758, 760, 762, 764, 766, 768, 770, 772, 774, 776, 778, 780, 782, 784, 786, 788, 790, 792, 794, 796, 798, 800, 802, 804, 806, 808, 810, 812, 814, 816, 818, 820, 822, 824, 826, 828, 830, 832, 834, 836, 838, 840, 842, 844, 846, 848, 850, 852, 854, 856, 858, 860, 862, 864, 866, 868, 870, 872, 874, 876, 878, 880, 882, 884, 886, 888, 890, 892, 894, 896, 898, 900, 902, 904, 906, 908, 910, 912, 914, 916, 918, 920, 922, 924, 926, 928, 930, 932, 934, 936, 938, 940, 942, 944, 946, 948, 950, 952, 954, 956, 958, 960, 962, 964, 966, 968, 970,

972, 974, 976, 978, 980, 982, 984, 986, 988, 990, 992, 994, 996, 998, 1000, 1002, 1004, 1006, 1008, 1010, 1012, 1014,

1016, 1018, 1020, 1022, 1024, 1026, 1028, 1030, 1032, 1034, 1036, 1038, 1040, 1042, 1044, 1046, 1048, 1050, 1052,

1054, 1056, 1058, 1060, 1062, 1064, 1066, 1068, 1070, 1072, 1074, 1076, 1078, 1080, 1082, 1084, 1086, 1088, 1090,

1092, 1094, 1096, 1098, 1100, 1102, 1104, 1106, 1108, 1110, 1112, 1114, 1116, 1118, 1120, 1122, 1124, 1126, 1128,

1130, 1132, 1134, 1136, 1138, 1140, 1142, 1144, 1146, 1148, 1150, 1152, 1154, 1156, 1158, 1160, 1162, 1164, 1166,

1168, 1170, 1172, 1174, 1176, 1178, 1180, 1182, 1184, 1186, 1188, 1190, 1192, 1194, 1196, 1198, 1200, 1202, 1204,

1206, 1208, 1210, 1212, 1214, 1216, 1218, 1220, 1222, 1224, 1226, 1228, 1230, 1232, 1234, 1236, 1238, 1240, 1242,

1244, 1246, 1248, 1250, 1252, 1254, 1256, 1258, 1260, 1262, 1264, 1266, 1268, 1270, 1272, 1274, 1276, 1278, 1280,

1282, 1284, 1286, 1288, 1290, 1292, 1294, 1296, 1298, 1300, 1302, 1304, 1306, 1308, 1310, 1312, 1314, 1316, 1318,

1320, 1322, 1324, 1326, 1328, 1330, 1332, 1334, 1336, 1338, 1340, 1342, 1344, 1346, 1348, 1350, 1352, 1354, 1356,

1358, 1360, 1362, 1364, 1366, 1368, 1370, 1372, 1374, 1376, 1378, 1380, 1382, 1384, 1386, 1388, 1390, 1392, 1394,

1396, 1398, 1400, 1402, 1404, 1406, 1408, 1410, 1412, 1414, 1416, 1418, 1420, 1422, 1424, 1426, 1428, 1430, 1432,

1434, 1436, 1438, 1440, 1442, 1444, 1446, 1448, 1450, 1452, 1454, 1456, 1458, 1460, 1462, 1464, 1466, 1468, 1470,

1472, 1474, 1476, 1478, 1480, 1482, 1484, 1486, 1488, 1490, 1492, 1494, 1496, 1498, 1500, 1502, 1504, 1506, 1508,

1510, 1512, 1514, 1516, 1518, 1520, 1522, 1524, 1526, 1528, 1530, 1532, 1534, 1536, 1538, 1540, 1542, 1544, 1546,

1548, 1550, 1552, 1554, 1556, 1558, 1560, 1562, 1564, 1566, 1568, 1570, 1572, 1574, 1576, 1578, 1580, 1582, 1584,

1586, 1588, 1590, 1592, 1594, 1596, 1598, 1600, 1602, 1604, 1606, 1608, 1610, 1612, 1614, 1616, 1618, 1620, 1622,

1624, 1626, 1628, 1630, 1632, 1634, 1636, 1638, 1640, 1642, 1644, 1646, 1648, 1650, 1652, 1654, 1656, 1658, 1660,

1662, 1664, 1666, 1668, 1670, 1672, 1674, 1676, 1678, 1680, 1682, 1684, 1686, 1688, 1690, 1692, 1694, 1696, 1698,

1700, 1702, 1704, 1706, 1708, 1710, 1712, 1714, 1716, 1718, 1720, 1722, 1724, 1726, 1728, 1730, 1732, 1734, 1736,

1738, 1740, 1742, 1744, 1746, 1748, 1750, 1752, 1754, 1756, 1758, 1760, 1762, 1764, 1766, 1768, 1770, 1772, 1774,

1776, 1778, 1780, 1782, 1784, 1786, 1788, 1790, 1792, 1794, 1796, 1798, 1800, 1802, 1804, 1806, 1808, 1810, 1812,

1814, 1816, 1818, 1820, 1822, 1824, 1826, 1828, 1830, 1832, 1834, 1836, 1838, 1840, 1842, 1844, 1846, 1848, 1850,

1852, 1854, 1856, 1858, 1860, 1862, 1864, 1866, 1868, 1870, 1872, 1874, 1876, 1878, 1880, 1882, 1884, 1886, 1888,

1890, 1892, 1894, 1896, 1898, 1900, 1902, 1904, 1906, 1908, 1910, 1912, 1914, 1916, 1918, 1920, 1922, 1924, 1926,

1928, 1930, 1932, 1934, 1936, 1938, 1940, 1942, 1944, 1946, 1948, 1950, 1952, 1954, 1956, 1958, 1960, 1962, 1964,

1966, 1968, 1970, 1972, 1974, 1976, 1978, 1980, 1982, 1984, 1986, 1988, 1990, 1992, 1994, 1996, 1998, 2000, 2002,

2004, 2006, 2008, 2010, 2012, 2014, 2016, 2018, 2020, 2022, 2024, 2026, 2028, 2030, 2032, 2034, 2036, 2038, 2040,

2042, 2044, 2046, 2048, 2050, 2052, 2054, 2056, 2058, 2060, 2062, 2064, 2066, 2068, 2070, 2072, 2074, 2076, 2078,

2080, 2082, 2084, 2086, 2088, 2090, 2092, 2094, 2096, 2098, 2100, 2102, 2104, 2106, 2108, 2110, 2112, 2114, 2116,

2118, 2120, 2122, 2124, 2126, 2128, 2130, 2132, 2134, 2136, 2138, 2140, 2142, 2144, 2146, 2148, 2150, 2152, 2154,

2156, 2158, 2160, 2162, 2164, 2166, 2168, 2170, 2172, 2174, 2176, 2178, 2180, 2182, 2184, 2186, 2188,2190,2192,

2194, 2196, 2198, 2200, 2202, 2204, 2206, 2208, 2210, 2212, 2214, 2216, 2218, 2220, 2222, 2224, 2226, 2228, 2230,

2232, 2234, 2236, 2238, 2240, 2242, 2244, 2246, 2248, 2250, 2252, 2254, 2256, 2258, 2260, 2262, 2264, 2266, 2268,

2270, 2272, 2274, 2276, 2278, 2280, 2282, 2284, 2286, 2288, 2290, 2292, 2294, 2296, 2298, 2300, 2302, 2304, 2306,

2308, 2310, 2312, 2314, 2316, 2318, 2320, 2322, 2324, 2326, 2328, 2330, 2332, 2334, 2336, 2338, 2340, 2342, 2344,

2346, 2348, 2350, 2352, 2354, 2356, 2358, 2360, 2362, 2364, 2366, 2368, 2370, 2372, 2374, 2376, 2378, 2380, 2382,

2384, 2386, 2388, 2390, 2392, 2394, 2396, 2398, 2400, 2402, 2404, 2406, 2408, 2410, 2412, 2414, 2416, 2418, 2420,

2422, 2424, 2426, 2428, 2430, 2432, 2434, 2436, 2438, 2440, 2442, 2444, 2446, 2448, 2450, 2452, 2454, 2456, 2458, 2464, 2466, 2468, 2470, 2472, 2474, 2476:,, 2478, 2480, 2482, 2484, 2486, 2488, 2490, 2492, 2494, 2496, 2502, 2504, 2506, 2508, 2510, 2512, 2514,, 2516, 2518, 2520, 2522, 2524, 2526, 2528, 2530, 2532, 2534, 2540, 2542, 2544, 2546, 2548, 2550, 2552,,, 2554, 2556, 2558, 2560, 2562, 2564, 2566, 2568, 2570, 2572, 2578, 2580, 25822584, 2586, 2588, 2590,, 2592, 2594, 2596, 2598, 2600, 2602, 2604, 2606, 2608, 2610, 2616, 2618, 2620, 2622, 2624, 2626, 2628;,, 2630, 2632, 2634, 2636, 2638, 2640, 2642, 2644, 2646, 2648, 2654, 2656, 2658, 2660, 2662, 2664, 2666i,, 2668, 2670, 2672, 2674, 2676, 2678, 2680, 2682, 2684, 2686, 2692, 2694, 2696, 2698, 2700, 2702, 2704•,, 2706, 2708, 2710, 2712, 2714, 2716, 2718, 2720, 2722, 2724, 2730, 2732, 2734, 2736, 2738, 2740, 2742,, 2744, 2746, 2748, 2750, 2752, 2754, 2756, 2758, 2760, 2762, 2768, 2770, 2772, 2774, 2776, 2778, 2780,, 2782, 2784, 2786, 2788, 2790, 2792, 2794, 2796, 2798, 2800, 2806, 2808, 2810, 2812, 2814, 2816, 2818,,, 2820, 2822, 2824, 2826, 2828, 2830, 2832, 2834, 2836, 2838, 2844, 2846, 2848, 2850, 2852, 2854, 2856i,, 2858, 2860, 2862, 2864, 2866, 2868, 2870, 2872, 2874, 2876, 2882, 2884, 28862888, 2890, 2892, 2894,, 2896, 2898, 2900, 2902, 2904, 2906, 2908, 2910, 2912, 2914, 2920, 2922, 2924, 2926, 2928, 2930, 2932:,, 2934, 2936, 2938, 2940, 2942, 2944, 2946, 2948, 2950, 2952, 2958, 2960, 2962, 2964, 2966, 2968, 2970,, 2972, 2974, 2976, 2978, 2980, 2982, 2984, 2986, 2988, 2990, 2996, 2998, 3000, 3002, 3004, 3006, 3008,, 3010, 3012, 3014, 3016, 3018, 3020, 3022, 3024, 3026, 3028, 3034, 3036, 3038, 3040, 3042, 3044, 3046s, 3048, 3050, 3052, 3054, 3056, 3058, 3060, 3062, 3064, 3066, 3072, 3074, 3076, 3078, 3080, 3082, 3084,, 3086, 3088, 3090, 3092, 3094, 3096, 3098, 3100, 3102, 3104, 3110, 3112, 3114, 3116,3118, 3120, 3122,, 3124, 3126, 3128, 3130, 3132, 3134, 3136, 3138, 3140, 3142, 3148, 3150, 3152, 3154, 3156, 3158, 3160i,, 3162, 3164, 3166, 3168, 3170, 3172, 3174, 3176, 3178, 3180, 3186, 3188, 3190, 3192, 3194, 3196, 3198:,, 3200, 3202, 3204, 3206, 3208, 3210, 3212, 3214, 3216, 3218, 3224, 3226, 3228, 3230, 3232, 3234, 3236,, 3238, 3240, 3242, 3244, 3246, 3248, 3250, 3252, 3254, 3256, 3262, 3264, 3266, 3268, 3270, 3272, 3274,, 3276, 3278, 3280, 3282, 3284, 3286, 3288, 3290, 3292, 3294, 3300, 3302, 3304, 3306, 3308, 3310, 3312,, 3314, 3316, 3318, 3320, 3322, 3324, 3326, 3328, 3330, 3332, 3338, 3340, 3342, 3344, 3346, 3348, 3350,, 3352, 3354, 3356, 3358, 3360, 3362, 3364, 3366, 3368, 3370, 3376, 3378, 3380, 3382, 3384, 3386, 3388:,, 3390, 3392, 3394, 3396, 3398, 3400, 3402, 3404, 3406, 3408, 3414, 3416, 3418, 3420, 3422, 3424, 3426i,, 3428, 3430, 3432, 3434, 3436, 3438, 3440, 3442, 3444, 3446, 3452, 3454, 34563458, 3460, 3462, 3464,, 3466, 3468, 3470, 3472, 3474, 3476, 3478, 3480, 3482, 3484, 3490, 3492, 34943496, 3498, 3500, 3502,, 3504, 3506, 3508, 3510, 3512, 3514, 3516, 3518, 3520, 3522, 3528, 3530, 35323534, 3536, 3538, 3540,, 3542, 3544, 3546, 3548, 3550, 3552, 3554, 3556, 3558, 3560, 3566, 3568, 35703572, 3574, 3576, 3578,, 3580, 3582, 3584, 3586, 3588, 3590, 3592, 3594, 3596, 3598, 3604, 3606, 3608, 3610, 3612, 3614, 3616,, 3618, 3620, 3622, 3624, 3626, 3628, 3630, 3632, 3634, 3636, 3642, 3644, 3646, 3648, 3650, 3652, 3654,, 3656, 3658, 3660, 3662, 3664, 3666, 3668, 3670, 3672, 3674, 3680, 3682, 3684, 3686, 3688, 3690, 3692:,, 3694, 3696, 3698, 3700, 3702, 3704, 3706, 3708, 3710, 3712, 3718, 3720, 3722, 3724, 3726, 3728, 3730,, 3732, 3734, 3736, 3738, 3740, 3742, 3744, 3746, 3748, 3750, 3756, 3758, 3760, 3762, 3764, 3766, 3768,,, 3770, 3772, 3774, 3776, 3778, 3780, 3782, 3784, 3786, 3788, 3794, 3796, 3798, 3800, 3802, 3804, 3806,, 3808, 3810, 3812, 3814, 3816, 3818, 3820, 3822, 3824, 3826, 3832, 3834, 38363838, 3840, 3842, 3844,, 3846, 3848, 3850, 3852, 3854, 3856, 3858, 3860, 3862, 3864, 3870, 3872, 3874, 3876, 3878, 3880, 3882,, 3884, 3886, 3888, 3890, 3892, 3894, 3896, 3898, 3900, 3902, 3908, 3910, 39123914, 3916, 3918, 3920,, 3922, 3924, 3926, 3928, 3930, 3932, 3934, 3936, 3938, 3940,

3946, 3948, 39503952, 3954, 3956, 3958,, 3960, 3962, 3964, 3966, 3968, 3970, 3972, 3974, 3976, 3978, 3980, 3982, 3984, 3986, 3988, 3990, 3992, 3994, 3996, 3998, 4000, 4002, 4004, 4006, 4008, 4010, 4012, 4014, 4016, 4018, 4020, 4022, 4024, 4026, 4028, 4030, 4032, 4034, 4036, 4038, 4040, 4042, 4044, 4046, 4048, 4050, 4052, 4054, 4056, 4058, 4060, 4062, 4064, 4066, 4068, 4070, 4072, 4074, 4076, 4078, 4080, 4082, 4084, 4086, 4088, 4090, 4092, 4094, 4096, 4098, 4100, 4102, 4104, 4106, 4108, 4110, 4112, 4114, 4116, 4118, 4120, 4122, 4124, 4126, 4128, 4130, 4132, 4134, 4136, 4138, 4140, 4142, 4144, 4146, 4148, 4150, 4152, 4154, 4156, 4158, 4160, 4162, 4164, 4166, 4168, 4170, 4172, 4174, 4176, 4178, 4180, 4182, 4184, 4186, 4188, 4190, 4192, 4194, 4196, 4198, 4200, 4202, 4204, 4206, 4208, 4210, 4212, 4214, 4216, 4218, 4220, 4222, 4224, 4226, 4228, 4230, 4232, 4234, 4236, 4238, 4240, 4242, 4244, 4246, 4248, 4250, 4252, 4254, 4256, 4258, 4260, 4262, 4264, 4266, 4268, 4270, 4272, 4274, 4276, 4278, 4280, 4282, 4284, 4286, 4288, 4290, 4292, 4294, 4296, 4298, 4300, 4302, 4304, 4306, 4308, 4310, 4312, 4314, 4316, 4318, 4320, 4322, 4324, 4326, 4328, 4330, 4332, 4334, 4336, 4338, 4340, 4342, 4344, 4346, 4348, 4350, 4352, 4354, 4356, 4358, 4360, 4362, 4364, 4366, 4368, 4370, 4372, 4374, 4376, 4378, 4380, 4382, 4384, 4386, 4388, 4390, 4392, 4394, 4396, 4398, 4400, 4402, 4404, 4406, 4408, 4410, 4412, 4414, 4416, 4418, 4420, 4422, 4424, 4426, 4428, 4430, 4432, 4434, 4436, 4438, 4440, 4442, 4444, 4446, 4448, 4450, 4452, 4454, 4456, 4458, 4460, 4462, 4464, 4466, 4468, 4470, 4472, 4474, 4476, 4478, 4480, 4482, 4484, 4486, 4488, 4490, 4492, 4494, 4496, 4498, 4500, 4502, 4504, 4506, 4508, 4510, 4512, 4514, 4516, 4518, 4520, 4522, 4524, 4526, 4528, 4530, 4532, 4534, 4536, 4538, 4540, 4542, 4544, 4546, 4548, 4550, 4552, 4554, 4556, 4558, 4560, 4562, 4564, 4566, 4568, 4570, 4572, 4574, 4576, 4578, 4580, 4582, 4584, 4586 4588, 4590, 4592, 4594, 4596, 4598, 4600, 4602, 4604, 4606, 4608, 4610, 4612, 4614, 4616, 4618, 4620, 4622, 4624, 4626, 4628, 4630, 4632, 4634, 4636, 4638, 4640, 4642, 4644, 4646, 4648, 4650, 4652, 4654, 4656, 4658, 4660, 4662, 4664, 4666, 4668, 4670, 4672, 4674, 4676, 4678, 4680, 4682, 4684, 4686, 4688, 4690, 4692, 4694, 4696, 4698, 4700, 4702, 4704, 4706, 4708, 4710, 4712, 4714, 4716, 4718, 4720, 4722, 4724, 4726, 4728, 4730, 4732, 4734, 4736, 4738, 4740, 4742, 4744, 4746, 4748, 4750, 4752, 4754, 4756, 4758, 4760, 4762, 4764, 4766, 4768, 4770, 4772, 4774, 4776, 4778, 4780, 4782, 4784, 4786, 4788, 4790, 4792, 4794, 4796, 4798, 4800, 4802, 4804, 4806, 4808, 4810, 4812, 4814, 4816, 4818, 4820, 4822, 4824, 4826, 4828, 4830, 4832, 4834, 4836, 4838, 4840, 4842, 4844, 4846, 4848, 4850, 4852, 4854, 4856, 4858, 4860, 4862, 4864, 4866, 4868, 4870, 4872, 4874, 4876, 4878, 4880, 4882, 4884, 4886, 4888, 4890, 4892, 4894, 4896, 4898, 4900, 4902, 4904, 4906, 4908, 4910, 4912, 4914, 4916, 4918, 4920, 4922, 4924, 4926, 4928, 4930, 4932, 4934, 4936, 4938, 4940, 4942, 4944, 4946, 4948, 4950, 4952, 4954, 4956, 4958, 4960, 4962, 4964, 4966, 4968, 4970, 4972, 4974, 4976, 4978, 4980, 4982, 4984, 4986, 4988, 4990, 4992, 4994, 4996, 4998, 5000, 5002, 5004, 5006, 5008, 5010, 5012, 5014, 5016, 5018, 5020, 5022, 5024, 5026, 5028, 5030, 5032, 5034, 5036, 5038, 5040, 5042, 5044, 5046, 5048, 5050, 5052, 5054, 5056, 5058, 5060, 5062, 5064, 5066, 5068, 5070, 5072, 5074, 5076, 5078, 5080, 5088, 5089, 5090, 5091, 5092, 5093, 5094 & 5095.

4. The polypeptide ofclaim 3, whereinthe fragment comprises aT-cell or aB-cell epitope fromthe SEQ ID NO: amino acid sequence.

5. Antibody thatbinds to the polypeptide ofany preceding claim.

6. Antibody ofclaim 5, wherein the antibody is amonoclonal antibody. 7. Nucleic acid comprising an nucleotide sequence that has at least 75% sequence identity to one or more ofSEQ ID NOS: 1565, 1569, 1573, 1577, 1, 3, 5,

7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239, 241243, 245, 247249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 295, 297, 299, 301, 303, 305 307, 309, 311, 313, 315, 317,319,321,323,325, 327, 329, 331, 333, 335, 337, 339, 341, 343, 345, 347, 349, 351, 353, 355, 357, 359, 361, 363365, 367, 369, 371, 373, 375, 377, 379, 381, 383, 385, 387, 389, 391 393, 395, 397, 399, 401 403, 405, 407, 409, 411 413, 415, 417, 419, 421423, 425, 427, 429, 431, 433435, 437, 439, 441, 443, 445, 447, 449, 451, 453, 455, 457, 459, 461, 463, 465, 467, 469, 471, 473, 475, 477, 479, 481483, 485, 487, 489, 491, 493, 495, 497, 499, 501, 503, 505, 507, 509,511,513,515,517, 519, 521, 523, 525, 527, 529, 531, 533, 535537, 539, 541, 543, 545, 547, 549, 551, 553, 555, 557, 559, 561, 563, 565, 567, 569, 571, 573, 575, 577, 579, 581, 583585, 587, 589, 591, 593 595, 597, 599, 601, 603605,607,609,611,613615, 617, 619, 621, 623, 625, 627, 629, 631633, 635, 637, 639, 641 643, 645, 647, 649, 651 653, 655, 657, 659, 661663, 665, 667, 669, 671, 673, 675, 677, 679, 681, 683, 685, 687, 689, 691, 693, 695, 697, 699, 701, 703, 705, 707, 709, 711,713, 715, 717, 719, 721723, 725, 727, 729, 731, 733, 735, 737 739, 741, 743, 745, 747, 749,751,753,755,757, 759, 761, 763, 765, 767, 769, 771, 773, 775, 777, 779, 781, 783, 785 787, 789, 791, 793, 795797, 799, 801, 803, 805807, 809, 811,813, 815, 817819, 821, 823, 825, 827, 829, 831, 833 835, 837, 839, 841, 843 845, 847, 849, 851, 853855, 857, 859, 861, 863, 865, 867, 869, 871, 873, 875, 877, 879, 881 883, 885, 887, 889, 891, 893, 895, 897, 899, 901 903, 905, 907, 909, 911,913915, 917, 919, 921, 923, 925, 927, 929, 931, 933, 935, 937, 939, 941, 943, 945, 947, 949, 951, 953, 955, 957, 959, 961963, 965, 967, 969, 971, 973, 975, 977, 979, 981, 983, 985, 987^',, 989, 991, 993, 995, 997, 999, 1001 1003, 1005, 1007, 1009, 1011, 1013, 1015, 1017, 1019, 1035 1037 1039 1041 1043, 1045 1047, 1049, 1051, 1053, 1055, 1057 1073, 1075 1077 1079, 1081, 1083 1085 1087, 1089, 1091, 1093, 1095 1111 1113 1115 1117, 1119, 1121 1123 1125, 1127, 1129, 1131, 1133, 1149, 1151 1153 11551157, 1159, 1161 1163, 1165, 1167, 1169, 1171 1187, 1189 1191 1193, 1195, 1197, 1199, 1201, 1203, 1205, 1207, 1209. 1225, 1227 1229 1231 1233, 1235, 1237, 1239, 1241, 1243, 1245, 1247, 1263 1265 1267 1269, 1271, 1273 1275, 1277, 1279, 1281, 1283, 1285, 1301 1303 1305 1307, 1309, 1311 1313 1315, 1317, 1319, 1321, 1323 1339, 1341 1343 1345, 1347, 1349, 1351 1353, 1355, 1357, 1359, 1361, 1377. 1379 1381 1383 1385, 1387, 1389, 1391, 1393, 1395, 1397, 1399. 1415 1417 1419 1421 1423, 1425 1427, 1429, 1431, 1433, 1435, 1437. 1453, 1455 1457 1459, 1461, 1463 1465 1467, 1469, 1471, 1473, 1475, 1491 1493 1495 1497, 1499, 1501 1503 1505, 1507, 1509, 1511, 1513, 1529, 1531 1533 1535 1537, 1539, 1541 1543, 1545, 1547, 1549, 1551 1567, 1569 1571 1573, 1575, 1577, 1579, 1581, 1583, 1585, 1587, 1589. 1605 1607 1609 1611 1613, 1615, 1617, 1619, 1621, 1623, 1625, 1627, 1643 1645 1647 1649, 1651, 1653 1655 1657, 1659, 1661, 1663, 1665, 1681 1683 1685, 1687, 1689, 1691 1693 1695, 1697, 1699, 1701, 1703, 1719, 1721 1723, 1725 1727, 1729, 1731 1733, 1735, 1737, 1739, 1741, 1757, 1759 1761, 1763 1765, 1767. 1769, 1771, 1773, 1775, 1777, 1779, 1795, 1797 1799, 1801 1803, 1805 1807, 1809, 1811, 1813, 1815, 1817. 1833 1835 1837, 1839, 1841, 1843, 1845 1847, 1849, 1851, 1853, 1855

1871 1873 1875, 1877.1879, 1881 1883 1885, 1887, 1889, 1891, 1893, 1895, 1897, 1899,, 1901, 1903, 1905, 1907, 1909, 1911, 1913, 1915, 1917,, 1919,, 1921, 1923, 1925, 1927, 1929, 1931, 1933, 1935, 1937, 1939, 1941, 1943, 1945, 1947, 1949, 1951, 1953, 1955 , 1957., 1959, 1961, 1963, 1965, 1967, 1969, 1971, 1973, 1975, 1977, 1979, 1981, 1983, 1985, 1987, 1989, 1991 1993,, 1995i,, 1997, 1999, 2001, 2003, 2005, 2007, 2009, 2011, 2013, 2015, 2017, 2019, 2021, 2023, 2025, 2027, 2029, 2031, 2033,, 2035, 2037, 2039, 2041, 2043, 2045, 2047, 2049, 2051, 2053, 2055, 2057, 2059, 2061, 2063, 2065, 2067, 2069,,2071, 2073, 2075, 2077, 2079, 2081, 2083, 2085, 2087, 2089,, 2091, 2093, 2095, 2097, 2099, 2101, 2103, 2105 2107,, 2109',,2111,2113, 2115,2117, 2119,2121, 2123, 2125, 2127,, 2129, 2131, 2133, 2135, 2137, 2139, 2141, 2143, 2145, 2147^',, 2149, 2151, 2153, 2155, 2157, 2159, 2161, 2163, 2165,, 2167, 2169, 2171, 2173, 2175, 2177, 2179, 2181 2183,2185, 2187, 2189, 2191, 2193, 2195, 2197, 2199, 2201, 2203,, 2205, 2207, 2209,2211, 2213, 2215, 2217, 2219, 2221,2223, 2225, 2227, 2229, 2231, 2233, 2235, 2237, 2239, 2241, 2243, 2245, 2247, 2249, 2251, 2253, 2255, 2257, 2259,,2261, 2263, 2265, 2267, 2269, 2271, 2273, 2275, 2277, 2279',, 2281, 2283, 2285, 2287, 2289, 2291, 2293, 2295, 2297,, 2299,, 2301, 2303, 2305, 2307, 2309,2311, 2313, 2315, 2317',, 2319, 2321, 2323, 2325, 2327, 2329, 2331, 2333 2335,, 2337,, 2339, 2341, 2343, 2345, 2347, 2349, 2351, 2353, 2355,, 2357, 2359, 2361, 2363, 2365, 2367, 2369, 2371 2373, 2375, 2377, 2379, 2381, 2383, 2385, 2387, 2389, 2391, 2393, 2395, 2397, 2399, 2401, 2403, 2405, 2407, 2409, 2411,2413, 2415, 2417, 2419, 2421, 2423, 2425, 2427, 2429, 2431, 2433, 2435, 2437, 2439, 2441, 2443, 2445, 2447, 2449,,2451, 2453, 2455, 2457, 2459, 2461, 2463, 2465, 2467, 2469',, 2471, 2473, 2475, 2477, 2479, 2481, 2483, 2485, 2487,, 2489,, 2491, 2493, 2495, 2497, 2499, 2501, 2503, 2505, 2507,,2509,2511, 2513, 2515, 2517,2519,2521,2523 2525,, 2527,,2529,2531, 2533, 2535, 2537, 2539, 2541, 2543, 2545:,, 2547, 2549, 2551, 2553, 2555, 2557, 2559, 2561, 2563, 2565,, 2567, 2569, 2571, 2573, 2575, 2577, 2579, 2581, 2583,, 2585, 2587, 2589, 2591, 2593, 2595, 2597, 2599, 2601,2603, 2605, 2607, 2609,2611, 2613, 2615, 2617, 2619, 2621, 2623, 2625, 2627, 2629, 2631,2633,2635,2637, 2639.,2641, 2643, 2645, 2647, 2649, 2651,2653, 2655, 2657, 2659i,, 2661, 2663, 2665, 2667, 2669, 2671, 2673, 2675, 2677,, 2679,, 2681, 2683, 2685, 2687, 2689, 2691, 2693, 2695, 2697',, 2699, 2701, 2703, 2705, 2707,2709,2711,2713, 2715,, 2717,, 2719, 2721, 2723, 2725, 2727, 2729, 2731, 2733, 2735,, 2737, 2739, 2741, 2743, 2745,2747,2749,2751 2753, 2755,, 2757, 2759, 2761, 2763, 2765, 2767, 2769, 2771, 2773, 2775, 2777, 2779, 2781, 2783, 2785, 2787, 2789, 2791,2793, 2795, 2797, 2799, 2801, 2803, 2805, 2807,2809,2811, 2813, 2815, 2817, 2819, 2821, 2823, 2825, 2827, 2829,,283 , 2833, 2835, 2837, 2839, 2841, 2843, 2845, 2847, 2849,,2851,2853, 2855, 2857, 2859, 2861, 2863, 2865, 2867, 2869',, 2871, 2873, 2875, 2877, 2879, 2881, 2883, 2885, 2887,, 2889, 2891, 2893, 2895, 2897, 2899, 2901, 2903 2905, 2907,,2909,2911, 2913, 2915, 2917, 2919, 2921, 2923, 2925,, 2927, 2929, 2931,2933, 2935, 2937, 2939, 2941 2943,, 2945,, 2947, 2949, 2951, 2953, 2955, 2957, 2959, 2961, 2963,, 2965, 2967, 2969, 2971, 2973, 2975, 2977, 2979, 2981,2983, 2985, 2987, 2989, 2991, 2993, 2995, 2997, 2999, 3001, 3003, 3005, 3007, 3009, 3011,3013,3015,3017, 3019,,3021, 3023, 3025, 3027, 3029, 3031,3033, 3035, 3037, 3039',, 3041, 3043, 3045, 3047, 3049, 3051, 3053, 3055, 3057,, 3059,, 3061, 3063, 3065, 3067, 3069, 3071, 3073, 3075, 3077,, 3079, 3081, 3083, 3085, 3087, 3089, 3091, 3093 3095,, 3097,, 3099, 3101, 3103,3105, 3107,3109, 3111,3113,3115,3117,3119, 3121,3123, 3125,3127,3129,313 3133,3135i, 3137, 3139, 3141,3143, 3145,3147, 3149,3151,3153,3155,3157, 3159,3161, 3163,3165,3167,3169, 3171,3173, 3175, 3177, 3179,3181, 3183,3185, 3187,3189,3191,3193,3195, 3197, 3199, 3201, 3203, 3205, 3207, 3209,,321 ,3213,3215, 3217, 3219, 3221, 3223, 3225, 3227, 3229,,3231,3233, 3235, 3237, 3239, 3241, 3243, 3245, 3247., 3249',, 3251, 3253, 3255, 3257, 3259, 3261, 3263, 3265, 3267, 3269, 3271, 3273, 3275, 3277, 3279, 3281, 3283 3285, 3287,, 3289, 3291, 3293, 3295, 3297, 3299, 3301, 3303, 3305, 3307, 3309, 3311,3313, 3315,3317,3319,3321 3323,3325, 3327, 3329, 3331, 3333, 3335, 3337, 3339, 3341, 3343, 3345, 3347, 3349,3351, 3353, 3355, 3357, 3359, 3361,3363, 3365, 3367, 3369, 3371, 3373, 3375, 3377, 3379, 3381, 3383, 3385, 3387, 3389, 3391, 3393, 3395, 3397, 3399,3401, 3403, 3405, 3407, 3409, 3411,3413,

4935, 4937, 4939, 4941, 4943, 4945, 4947, 4949, 4951, 4953, 4955, 4957, 4959, 4961, 4963, 4965, 4967, 4969, 4971 4973, 4975, 4977, 4979, 4981, 4983, 4985, 4987, 4989, 4991, 4993, 4995, 4997, 4999, 5001, 5003, 5005, 5007, 5009, 5011, 5013, 5015, 5017, 5019, 5021, 5023, 5025, 5027, 5029, 5031, 5033, 5035, 5037, 5039, 5041, 5043, 5045, 5047, 5049, 5051, 5053, 5055, 5057, 5059, 5061, 5063, 5065, 5067, 5069, 5071, 5073, 5075, 5077 and 5079.

8. Nucleic acid of claim 7, comprising an nucleotide sequence selected from SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83 85, 87, 89, 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145 147, 149, 151, 153, 155 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183 185, 187, 189, 191, 193, 195, 197, 199, 201, 203205,207,209,211, 213, 215, 217, 219, 221, 223, 225, 227, 229, 231 233, 235, 237, 239, 241243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 295, 297, 299, 301, 303, 305, 307, 309,311,313,315,317, 319, 321, 323, 325, 327, 329, 331, 333, 335, 337, 339, 341, 343, 345, 347, 349, 351, 353, 355, 357, 359, 361, 363, 365, 367, 369, 371, 373, 375 377, 379, 381, 383, 385, 387, 389, 391, 393, 395397, 399, 401, 403, 405,407,409,411,413, 415, 417, 419, 421, 423 425, 427, 429, 431, 433435,437,439,441,443, 445,447,449,451, 453,455,457,459,461, 463, 465, 467, 469, 471 473, 475, 477, 479, 481, 483, 485, 487, 489, 491 493, 495, 497, 499, 501, 503, 505, 507, 509, 511,513,515,517,519, 521, 523, 525, 527, 529, 531,533,535,537,539, 541, 543, 545, 547, 549, 551, 553, 555, 557, 559, 561, 563, 565, 567, 569, 571, 573, 575, 577, 579, 581, 583, 585, 587, 589, 591, 593, 595, 597, 599, 601, 603, 605, 607,609,611,613,615 617, 619, 621, 623, 625627, 629, 631, 633, 635637, 639, 641, 643, 645, 647, 649, 651, 653, 655, 657, 659, 661, 663 665, 667, 669, 671, 673, 675,677,679,681,683685, 687, 689, 691, 693, 695, 697, 699, 701, 703,705,707,709,711 713, 715, 717, 719, 721, 723,725,727,729,731 733, 735, 737, 739, 741, 743, 745, 747, 749, 751, 753, 755, 757, 759, 761, 763, 765, 767, 769, 771, 773, 775, 777, 779, 781, 783, 785, 787, 789, 791, 793, 795, 797, 799, 801, 803, 805, 807, 809, 811, 813, 815, 817, 819, 821, 823, 825, 827, 829,831,833,835, 837, 839, 841, 843, 845, 847, 849, 851, 853, 855, 857, 859, 861, 863, 865, 867, 869, 871, 873, 875877, 879, 881, 883, 885, 887, 889, 891, 893, 895, 897, 899, 901, 903, 905, 907, 909, 911, 913915, 917, 919, 921, 923925,927,929,931, 933, 935, 937, 939, 941, 943, 945, 947, 949, 951 953, 955, 957, 959, 961 963, 965, 967, 969, 971 973, 975, 977, 979, 981, 983, 985, 987, 989, 991, 993, 995, 997, 999, 1001, 1003, 1005, 1007, 10151017, 1019, 1021, 1023, 1025, 1027, 1029, 1031, 1033, 1035, 1037, 1039, 1041 1043 1045, 1053 „, 1057, 1059, 1061 1063 1065, 1067, 1069, 1071 1073, 1075, 1077, 1079, 1081 1083 1091 3, 1095, 1097, 1099, 1101 1103, 1105, 1107, 1109, 1111,1113 1115, 1117, 1119, 1121 1129, 1, 1133, 1135, 1137, 1139, 1141, 1143, 1145 11471149,1151 1153, 1155, 1157.1159, 1167, 9, 1171, 1173, 11751177, 1179, 1181, 1183 1185 1187, 1189, 1191, 1193 1195 1197, 1205, 7, 1209, 1211, 1213 1215 1217, 1219, 1221 1223 1225, 1227, 1229, 1231 1233 1235, 1243 5, 1247, 1249, 1251 1253 1255, 1257, 1259, 1261 1263, 1265, 1267, 1269, 1271 1273, 1281, 3, 1285, 1287, 1289, 1291 1293, 1295, 1297, 1299, 1301, 1303 1305, 1307, 1309, 1311 1319, ., 1323, 1325, 1327, 1329, 1331, 1333, 1335, 13371339, 1341 1343, 1345 1347, 1349, 1357. 9, 1361, 1363, 1365 1367, 1369, 1371, 1373, 1375, 1377, 1379, 1381, 1383 13851387, 1395 7, 1399, 1401, 1403 1405, 1407, 1409, 1411, 1413 1415, 1417, 1419, 1421 1423 1425 1433 „ 1437, 1439, 1441 1443, 1445, 1447, 1449, 1451 1453, 1455 1457, 1459, 1461 1463 1471 3, 1475, 1477, 1479, 1481 1483, 1485, 1487 1489, 1491, 1493 1495, 14971499, 1501 1509, 1, 1513, 1515, 1517, 1519, 1521, 1523, 1525 1527, 1529, 1531, 1533, 1535 1537, 1539.

1547, 1551, 1553, 1555 1557, 1559, 1561, 1563 1565 1567, 1569,

3091, 3093, 3095, 3097, 3099, 3101, 3103, 3105, 3107, 3109',, 3111, 3113, 3115, 3117, 3119, 3121, 3123, 3125, 3127, 3129, 3131, 3133, 3135, 3137, 3139, 3141, 3143, 3145, 3147^',, 3149, 3151, 3153, 3155, 3157, 3159, 3161, 3163, 3165, 3167, 3169, 3171, 3173, 3175, 3177, 3179, 3181, 3183, 3185,, 3187, 3189, 3191, 3193, 3195, 3197, 3199, 3201, 3203, 3205, 3207, 3209, 3211, 3213, 3215, 3217, 3219, 3221, 3223,, 3225, 3227, 3229, 3231, 3233, 3235, 3237, 3239, 3241, 3243, 3245, 3247, 3249, 3251, 3253, 3255, 3257, 3259, 3261, 3263, 3265, 3267, 3269, 3271, 3273, 3275, 3277, 3279, 3281, 3283, 3285, 3287, 3289, 3291, 3293, 3295, 3297, 3299>, 3301, 3303, 3305, 3307, 3309, 3311, 3313, 3315, 3317, 3319, 3321, 3323, 3325, 3327, 3329, 3331, 3333, 3335, 3337,, 3339, 3341, 3343, 3345, 3347, 3349, 3351, 3353, 3355, 3357, 3359, 3361, 3363, 3365, 3367, 3369, 3371, 3373, 3375,, 3377, 3379, 3381, 3383, 3385, 3387, 3389, 3391, 3393, 3395, 3397, 3399, 3401, 3403, 3405, 3407, 3409, 3411, 3413,, 3415, 3417, 3419, 3421, 3423, 3425, 3427, 3429, 3431, 3433, 3435, 3437, 3439, 3441, 3443, 3445, 3447, 3449, 3451, 3453, 3455, 3457, 3459, 3461, 3463, 3465, 3467, 3469, 3471, 3473, 3475, 3477, 3479, 3481, 3483, 3485, 3487, 3489',, 3491, 3493, 3495, 3497, 3499, 3501, 3503, 3505, 3507, 3509, 3511, 3513, 3515, 3517, 3519, 3521, 3523, 3525, 3527',, 3529, 3531, 3533, 3535, 3537, 3539, 3541, 3543, 3545, 3547, 3549, 3551, 3553, 3555, 3557, 3559, 3561, 3563, 3565, 3567, 3569, 3571, 3573, 3575, 3577, 3579, 3581, 3583, 3585, 3587, 3589, 3591, 3593, 3595, 3597, 3599, 3601, 3603, 3605, 3607, 3609, 3611, 3613, 3615, 3617, 3619, 3621, 3623, 3625, 3627, 3629, 3631, 3633, 3635, 3637, 3639, 3641, 3643, 3645, 3647, 3649, 3651, 3653, 3655, 3657, 3659, 3661, 3663, 3665, 3667, 3669, 3671, 3673, 3675, 3677, 3679>,, 3681, 3683, 3685, 3687, 3689, 3691, 3693, 3695, 3697, 3699, 3701, 3703, 3705, 3707, 3709, 3711, 3713, 3715, 3717,, 3719, 3721, 3723, 3725, 3727, 3729, 3731, 3733, 3735, 3737, 3739, 3741, 3743, 3745, 3747, 3749, 3751, 3753, 3755,, 3757, 3759, 3761, 3763, 3765, 3767, 3769, 3771, 3773, 3775, 3777, 3779, 3781, 3783, 3785, 3787, 3789, 3791, 3793, 3795, 3797, 3799, 3801, 3803, 3805, 3807, 3809, 3811, 3813, 3815, 3817, 3819, 3821, 3823, 3825, 3827, 3829, 3831, 3833, 3835, 3837, 3839, 3841, 3843, 3845, 3847, 3849, 3851, 3853, 3855, 3857, 3859, 3861, 3863, 3865, 3867, 3869,, 3871, 3873, 3875, 3877, 3879, 3881, 3883, 3885, 3887, 3889, 3891, 3893, 3895, 3897, 3899, 3901, 3903, 3905, 3907,, 3909, 3911, 3913, 3915, 3917, 3919, 3921, 3923, 3925, 3927, 3929, 3931, 3933, 3935, 3937, 3939, 3941, 3943, 3945,, 3947, 3949, 3951, 3953, 3955, 3957, 3959, 3961, 3963, 3965, 3967, 3969, 3971, 3973, 3975, 3977, 3979, 3981, 3983,, 3985, 3987, 3989, 3991, 3993, 3995, 3997, 3999, 4001, 4003, 4005, 4007, 4009, 4011, 4013, 4015, 4017, 4019, 4021, 4023, 4025, 4027, 4029, 4031, 4033, 4035, 4037, 4039, 4041, 4043, 4045, 4047, 4049, 4051, 4053, 4055, 4057, 4059',, 4061, 4063, 4065, 4067, 4069, 4071, 4073, 4075, 4077, 4079, 4081, 4083, 4085, 4087, 4089, 4091, 4093, 4095, 4097',, 4099, 4101, 4103, 4105, 4107, 4109, 4111, 4113, 4115, 4117, 4119, 4121, 4123, 4125, 4127, 4129, 4131, 4133, 4135i,, 4137, 4139, 4141, 4143, 4145, 4147, 4149, 4151, 4153, 4155, 4157, 4159, 4161, 4163, 4165, 4167, 4169, 4171, 4173, 4175, 4177, 4179, 4181, 4183, 4185, 4187, 4189, 4191, 4193, 4195, 4197, 4199, 4201, 4203, 4205, 4207, 4209, 421 , 4213, 4215, 4217, 4219, 4221, 4223, 4225, 4227, 4229, 4231, 4233, 4235, 4237, 4239, 4241, 4243, 4245, 4247, 4249I, 4251, 4253, 4255, 4257, 4259, 4261, 4263, 4265, 4267, 4269, 4271, 4273, 4275, 4277, 4279, 4281, 4283, 4285, 4287,, 4289, 4291, 4293, 4295, 4297, 4299, 4301, 4303, 4305, 4307, 4309, 4311, 4313, 4315, 4317, 4319, 4321, 4323, 4325,, 4327, 4329, 4331, 4333, 4335, 4337, 4339, 4341, 4343, 4345, 4347, 4349, 4351, 4353, 4355, 4357, 4359, 4361, 4363,, 4365, 4367, 4369, 4371, 4373, 4375, 4377, 4379, 4381, 4383, 4385, 4387, 4389, 4391, 4393, 4395, 4397, 4399, 4401, 4403, 4405, 4407, 4409, 4411, 4413, 4415, 4417, 4419, 4421, 4423, 4425, 4427, 4429, 4431, 4433, 4435, 4437, 4439>,, 4441, 4443, 4445, 4447, 4449, 4451, 4453, 4455, 4457, 4459, 4461, 4463, 4465, 4467, 4469, 4471, 4473, 4475, 4477^',, 4479, 4481, 4483, 4485, 4487, 4489, 4491, 4493, 4495, 4497, 4499, 4501, 4503, 4505, 4507, 4509, 4511, 4513, 4515:,, 4517, 4519, 4521, 4523, 4525, 4527, 4529, 4531, 4533, 4535, 4537, 4539, 4541, 4543, 4545, 4547, 4549, 4551, 4553,, 4555, 4557, 4559, 4561, 4563, 4565, 4567, 4569, 4571, 4573, 4575, 4577, 4579, 4581, 4583, 4585, 4587, 4589, 4591, 4593, 4595, 4597, 4599, 4601, 4603, 4605, 4607, 4609, 4611, 4613, 4615, 4617, 4619, 4621, 4623, 4625, 4627, 4629, 4631, 4633, 4635, 4637, 4639, 4641, 4643, 4645, 4647, 4649, 4651, 4653, 4655, 4657, 4659, 4661, 4663, 4665, 4667, 4669, 4671, 4673, 4675, 4677, 4679, 4681, 4683, 4685, 4687, 4689, 4691, 4693, 4695, 4697, 4699, 4701, 4703, 4705, 4707, 4709, 4711, 4713, 4715, 4717, 4719, 4721, 4723, 4725, 4727, 4729, 4731, 4733, 4735, 4737, 4739, 4741, 4743, 4745, 4747, 4749, 4751, 4753, 4755, 4757, 4759, 4761 4763, 4765, 4767, 4769, 4771, 4773, 4775, 4777, 4779, 4781, 4783, 4785, 4787, 4789, 4791, 4793, 4795, 4797, 4799, 4801, 4803, 4805, 4807, 4809, 4811, 4813, 4815, 4817, 4819, 4821, 4823, 4825, 4827, 4829, 4831, 4833, 4835, 4837, 4839, 4841, 4843, 4845, 4847, 4849, 4851, 4853, 4855, 4857, 4859, 4861, 4863, 4865, 4867, 4869, 4871, 4873, 4875, 4877, 4879, 4881, 4883, 4885, 4887, 4889, 4891, 4893, 4895, 4897, 4899, 4901, 4903, 4905, 4907, 4909, 4911, 4913, 4915, 4917, 4919, 4921, 4923, 4925, 4927, 4929, 4931, 4933, 4935, 4937, 4939, 4941, 4943, 4945, 4947, 4949, 4951 4953, 4955, 4957, 4959, 4961, 4963, 4965, 4967, 4969, 4971, 4973, 4975, 4977, 4979, 4981, 4983, 4985, 4987, 4989, 4991, 4993, 4995, 4997, 4999, 5001, 5003, 5005, 5007, 5009, 5011, 5013, 5015, 5017, 5019, 5021, 5023, 5025, 5027, 5029, 5031, 5033, 5035, 5037, 5039, 5041, 5043, 5045, 5047, 5049, 5051, 5053, 5055, 5057, 5059, 5061, 5063, 5065 5067, 5069, 5071, 5073, 5075, 5077 and 5079.

9. Nucleic acid that can hybridize to the nucleic acid ofclaim 8 under high stringency conditions.

10. Nucleic acid comprising a fragments of 10 or more consecutive nucleotides from one or more of SEQ ID NOS: 1565, 1569, 1573, 1577, 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 295, 297, 299, 301, 303, 305, 307, 309, 311, 313, 315, 317, 319, 321, 323, 325, 327, 329, 331, 333, 335, 337, 339, 341, 343, 345, 347, 349, 351, 353, 355, 357, 359, 361, 363, 365, 367, 369, 371, 373, 375, 377, 379, 381, 383, 385, 387, 389, 391, 393, 395, 397, 399, 401, 403, 405, 407, 409, 411, 413, 415, 417, 419, 421, 423, 425, 427, 429, 431, 433, 435, 437, 439, 441, 443, 445, 447, 449, 451, 453, 455, 457, 459, 461, 463, 465, 467, 469, 471, 473, 475, 477, 479, 481, 483, 485, 487, 489, 491, 493, 495, 497, 499, 501, 503, 505, 507, 509, 511, 513, 515, 517, 519, 521, 523, 525, 527, 529, 531, 533, 535, 537, 539, 541, 543, 545, 547, 549, 551, 553, 555, 557, 559, 561, 563, 565, 567, 569, 571, 573, 575, 577, 579, 581, 583, 585, 587, 589, 591, 593, 595, 597, 599, 601, 603, 605, 607, 609, 611, 613, 615, 617, 619, 621, 623, 625, 627, 629, 631, 633, 635, 637, 639, 641, 643, 645, 647, 649, 651, 653, 655, 657, 659, 661, 663, 665, 667, 669, 671, 673, 675, 677, 679, 681, 683, 685, 687, 689, 691, 693, 695, 697, 699, 701, 703, 705, 707, 709, 711, 713, 715, 717, 719, 721, 723, 725, 727, 729, 731, 733, 735, 737, 739, 741, 743, 745, 747, 749, 751, 753, 755, 757, 759, 761, 763, 765, 767, 769, 771, 773, 775, 777, 779, 781, 783, 785, 787, 789, 791, 793, 795, 797, 799, 801, 803, 805, 807, 809, 811, 813, 815, 817, 819, 821, 823, 825, 827, 829, 831, 833, 835, 837, 839, 841, 843, 845, 847, 849, 851, 853, 855, 857, 859, 861, 863, 865, 867, 869, 871, 873, 875, 877, 879, 881, 883, 885, 887, 889, 891, 893, 895, 897, 899, 901, 903, 905, 907, 909, 911, 913, 915, 917, 919, 921, 923, 925, 927, 929, 931, 933, 935, 937, 939, 941, 943, 945, 947, 949, 951, 953, 955, 957, 959, 961, 963, 965, 967, 969, 971, 973, 975, 977, 979, 981, 983, 985, 987, 989, 991, 993, 995, 997, 999, 1001, 1003, 1005, 1007, 1009, 1011, 1013, 1015, 1017, 1019, 1021, 1023, 1025, 1027, 1029, 1031, 1033, 1035, 1037, 1039, 1041, 1043.1045, 1047, 1049, 1051, 1053, 1055, 1057, 1059, 1061, 1063, 1065, 1067, 1069, 1071, 1073, 1075, 1077, 1079, 1081, 1083, 1085, 1087, 1089, 1091, 1093, 1095, 1097, 1099, 1101, 1103, 1105, 1107, 1109, 1111, 1113, 1115, 1117, 1119, 1121, 1123, 1125, 1127, 1129, 1131, 1133, 1135, 1137, 1139, 1141, 1143, 1145, 1147, 1149, 1151, 1153, 1155, 1157, 1159, 1161, 1163, 1165, 1167, 1169, 1171, 1173,

1175, 1177, 1179, 1181, 1183, 1185, 1187, 1189, 1191 1193, 1195, 1197, 1199 , 1201, 1203, 1205, 1207, 1209, 1211,

1213, 1215, 1217, 1219, 1221, 1223, 1225, 1227, 1229 , 1231, 1233, 1235, 1237 , 1239, 1241, 1243, 1245, 1247, 1249,

1251, 1253, 1255, 1257, 1259, 1261, 1263, 1265, 1267 1269, 1271, 1273, 1275 , 1277, 1279, 1281, 1283, 1285, 1287,

1289, 1291, 1293, 1295, 1297, 1299, 1301, 1303, 1305 1307, 1309, 1311, 1313 , 1315, 1317, 1319, 1321, 1323, 1325,

1327, 1329, 1331, 1333, 1335, 1337, 1339, 1341, 1343 1345, 1347, 1349, 1351 , 1353, 1355, 1357, 1359, 1361, 1363,

1365, 1367, 1369, 1371, 1373, 1375, 1377, 1379, 1381 1383, 1385, 1387, 1389 , 1391, 1393, 1395, 1397, 1399, 1401,

1403, 1405, 1407, 1409, 1411, 1413, 1415, 1417, 1419 1421, 1423, 1425, 1427 , 1429, 1431, 1433, 1435, 1437, 1439,

1441, 1443, 1445, 1447, 1449, 1451, 1453, 1455, 1457 1459, 1461, 1463, 1465 1467, 1469, 1471, 1473, 1475, 1477,

1479, 1481, 1483, 1485, 1487, 1489, 1491, 1493, 1495 1497, 1499, 1501, 1503 1505, 1507, 1509, 1511, 1513, 1515,

1517, 1519, 1521, 1523, 1525, 1527, 1529, 1531, 1533 1535, 1537, 1539, 1541 1543, 1545, 1547, 1549, 1551, 1553,

1555, 1557, 1559, 1561, 1563, 1565, 1567, 1569, 1571 1573, 1575, 1577, 1579 1581, 1583, 1585, 1587, 1589, 1591,

1593, 1595, 1597, 1599, 1601, 1603, 1605, 1607, 1609 1611, 1613, 1615, 1617 1619, 1621, 1623, 1625, 1627, 1629,

1631, 1633, 1635, 1637, 1639, 1641, 1643, 1645, 1647 1649, 1651, 1653, 1655 1657, 1659, 1661, 1663, 1665, 1667,

1669, 1671, 1673, 1675, 1677, 1679, 1681, 1683, 1685 1687, 1689, 1691, 1693 1695, 1697, 1699, 1701, 1703, 1705,

1707, 1709, 1711, 1713, 1715, 1717, 1719, 1721, 1723 1725, 1727, 1729, 1731 1733, 1735, 1737, 1739, 1741, 1743,

1745, 1747, 1749, 1751, 1753, 1755, 1757, 1759, 1761 1763, 1765, 1767, 1769 1771, 1773, 1775, 1777, 1779, 1781,

1783, 1785, 1787, 1789, 1791, 1793, 1795, 1797, 1799 1801, 1803, 1805, 1807 1809,1811,1813,1815,1817,1819,

1821, 1823, 1825, 1827, 1829, 1831, 1833, 1835, 1837 1839, 1841, 1843, 1845 1847, 1849, 1851, 1853, 1855, 1857,

1859, 1861, 1863, 1865, 1867, 1869, 1871, 1873, 1875 1877, 1879, 1881, 1883 1885, 1887, 1889, 1891, 1893, 1895,

1897, 1899, 1901, 1903, 1905, 1907, 1909, 1911, 1913 1915, 1917, 1919, 1921 1923, 1925, 1927, 1929, 1931, 1933,

1935, 1937, 1939, 1941, 1943, 1945, 1947, 1949, 1951 1953, 1955, 1957, 1959 1961, 1963, 1965, 1967, 1969, 1971,

1973, 1975, 1977, 1979, 1981, 1983, 1985, 1987, 1989 1991, 1993, 1995, 1997 1999, 2001, 2003, 2005, 2007, 2009,

2011, 2013, 2015, 2017, 2019, 2021, 2023, 2025, 2027 2029, 2031, 2033, 2035 2037, 2039, 2041, 2043, 2045, 2047,

2049, 2051, 2053, 2055, 2057, 2059, 2061, 2063, 2065 2067, 2069, 2071, 2073 2075, 2077, 2079, 2081, 2083, 2085,

2087, 2089, 2091, 2093, 2095, 2097, 2099, 2101, 2103 2105,2107,2109,2111 2113,2115,2117,2119,2121,2123,

2125, 2127, 2129, 2131, 2133, 2135, 2137, 2139, 2141 2143, 2145, 2147, 2149 2151,2153,2155,2157,2159,2161,

2163, 2165, 2167, 2169, 2171, 2173, 2175, 2177, 2179 2181, 2183, 2185, 2187 2189, 2191, 2193, 2195, 2197, 2199,

2201, 2203, 2205, 2207, 2209, 2211, 2213, 2215, 2217 2219, 2221, 2223, 2225 2227, 2229, 2231, 2233, 2235, 2237,

2239, 2241, 2243, 2245, 2247, 2249, 2251, 2253, 2255 2257, 2259, 2261, 2263 2265, 2267, 2269, 2271, 2273, 2275,

2277, 2279, 2281, 2283, 2285, 2287, 2289, 2291, 2293 2295, 2297, 2299, 2301 2303,2305,2307,2309,2311,2313,

2315, 2317, 2319, 2321, 2323, 2325, 2327, 2329, 2331 2333, 2335, 2337, 2339 2341, 2343, 2345, 2347, 2349, 2351,

2353, 2355, 2357, 2359, 2361, 2363, 2365, 2367, 2369 2371, 2373, 2375, 2377 2379, 2381, 2383, 2385, 2387, 2389,

2391, 2393, 2395, 2397, 2399, 2401, 2403, 2405, 2407 2409,2411,2413,2415 2417,2419,2421,2423,2425,2427,

2429, 2431, 2433, 2435, 2437, 2439, 2441, 2443, 2445 2447, 2449, 2451, 2453 2455, 2457, 2459, 2461, 2463, 2465,

2467, 2469, 2471, 2473, 2475, 2477, 2479, 2481, 2483 2485, 2487, 2489, 2491 2493, 2495, 2497, 2499, 2501, 2503,

2505, 2507, 2509, 2511, 2513, 2515, 2517, 2519, 2521 2523, 2525, 2527, 2529 2531,2533,2535,2537,2539,2541,

2543, 2545, 2547, 2549, 2551, 2553, 2555, 2557, 2559, 2561, 2563, 2565, 2567, 2569, 2571, 2573, 2575, 2577, 2579,

2581, 2583, 2585, 2587, 2589, 2591, 2593, 2595, 2597 2599, 2601, 2603, 2605, 2607,2609,2611,2613,2615,2617,

2619, 2621, 2623, 2625, 2627, 2629, 2631, 2633, 2635 2637, 2639, 2641, 2643 2645, 2647, 2649, 2651, 2653, 2655,

4177, 4179, 4181, 4183, 4185, 4187, 4189, 4191, 4193, 4195, 4197, 4199, 4201, 4203, 4205, 4207, 4209, 4211, 4213, 4215, 4217, 4219, 4221, 4223, 4225, 4227, 4229, 4231, 4233, 4235, 4237, 4239, 4241, 4243, 4245, 4247, 4249, 4251 4253, 4255, 4257, 4259, 4261, 4263, 4265, 4267, 4269, 4271, 4273, 4275, 4277, 4279, 4281, 4283, 4285, 4287, 4289, 4291, 4293, 4295, 4297, 4299, 4301, 4303, 4305, 4307, 4309, 4311, 4313, 4315, 4317, 4319, 4321, 4323, 4325, 4327, 4329, 4331, 4333, 4335, 4337, 4339, 4341, 4343, 4345, 4347, 4349, 4351, 4353, 4355, 4357, 4359, 4361, 4363, 4365, 4367, 4369, 4371, 4373, 4375, 4377, 4379, 4381, 4383, 4385, 4387, 4389, 4391, 4393, 4395, 4397, 4399, 4401, 4403 4405, 4407, 4409, 4411, 4413, 4415, 4417, 4419, 4421, 4423, 4425, 4427, 4429, 4431, 4433, 4435, 4437, 4439, 4441, 4443, 4445, 4447, 4449, 4451, 4453, 4455, 4457, 4459, 4461, 4463, 4465, 4467, 4469, 4471, 4473, 4475, 4477, 4479, 4481, 4483, 4485, 4487, 4489, 4491, 4493, 4495, 4497, 4499, 4501, 4503, 4505, 4507, 4509, 4511, 4513, 4515, 4517, 4519, 4521, 4523, 4525, 4527, 4529, 4531, 4533, 4535, 4537, 4539, 4541, 4543, 4545, 4547, 4549, 4551, 4553, 4555, 4557, 4559, 4561, 4563, 4565, 4567, 4569, 4571, 4573, 4575, 4577, 4579, 4581, 4583, 4585, 4587, 4589, 4591, 4593, 4595, 4597, 4599, 4601, 4603, 4605, 4607, 4609, 4611, 4613, 4615, 4617, 4619, 4621, 4623, 4625, 4627, 4629, 4631 4633, 4635, 4637, 4639, 4641, 4643, 4645, 4647, 4649, 4651, 4653, 4655, 4657, 4659, 4661, 4663, 4665, 4667, 4669, 4671, 4673, 4675, 4677, 4679, 4681, 4683, 4685, 4687, 4689, 4691, 4693, 4695, 4697, 4699, 4701, 4703, 4705, 4707, 4709, 4711, 4713, 4715, 4717, 4719, 4721, 4723, 4725, 4727, 4729, 4731, 4733, 4735, 4737, 4739, 4741, 4743, 4745 4747, 4749, 4751, 4753, 4755, 4757, 4759, 4761, 4763, 4765, 4767, 4769, 4771, 4773, 4775, 4777, 4779, 4781, 4783, 4785, 4787, 4789, 4791, 4793, 4795, 4797, 4799, 4801, 4803, 4805, 4807, 4809, 4811, 4813, 4815, 4817, 4819, 4821 4823, 4825, 4827, 4829, 4831, 4833, 4835, 4837, 4839, 4841, 4843, 4845, 4847, 4849, 4851, 4853, 4855, 4857, 4859, 4861, 4863, 4865, 4867, 4869, 4871, 4873, 4875, 4877, 4879, 4881, 4883, 4885, 4887, 4889, 4891, 4893, 4895, 4897, 4899, 4901, 4903, 4905, 4907, 4909, 4911, 4913, 4915, 4917, 4919, 4921, 4923, 4925, 4927, 4929, 4931, 4933, 4935, 4937, 4939, 4941, 4943, 4945, 4947, 4949, 4951, 4953, 4955, 4957, 4959, 4961, 4963, 4965, 4967, 4969, 4971, 4973 4975, 4977, 4979, 4981, 4983, 4985, 4987, 4989, 4991, 4993, 4995, 4997, 4999, 5001, 5003, 5005, 5007, 5009, 5011 5013, 5015, 5017, 5019, 5021, 5023, 5025, 5027, 5029, 5031, 5033, 5035, 5037, 5039, 5041, 5043, 5045, 5047, 5049, 5051, 5053, 5055, 5057, 5059, 5061, 5063, 5065, 5067, 5069, 5071, 5073, 5075, 5077 and 5079. 11. Nucleic acid encoding the polypeptide of any one of claims 1 to 4.

12. A composition comprising: (a) polypeptide, antibody, and/or nucleic acid of any preceding claim; and (b) a pharmaceutically acceptable carrier.

13. The composition of claim 12, further comprising a vaccine adjuvant.

14. Nucleic acid, polypeptide, or antibody of any one of claims 1 to 11 for use as a medicament.

15. A method of treating a patient, comprising administering to the patient a therapeutically effective amount of the composition of claim 12.

16. The use of nucleic acid, polypeptide, or antibody of any one of claims 1 to 11 in the manufacture of a medicament for treating or preventing disease and/or infection caused by H.influenzae.

17. The method of claim 15, or the use of claim 16, for preventing otitis media, bronchitis, conjunctivitis, sinusitis, a urinary tract infection, pneumonia, bacteremia, septic arthritis, epiglottitis, pneumonia, empyema, pericarditis, cellulitis, osteomyelitis or meningitis.