US20170209561A1 - Vaccine composition against streptococcus suis infection - Google Patents

Vaccine composition against streptococcus suis infection Download PDF

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US20170209561A1
US20170209561A1 US15/314,597 US201515314597A US2017209561A1 US 20170209561 A1 US20170209561 A1 US 20170209561A1 US 201515314597 A US201515314597 A US 201515314597A US 2017209561 A1 US2017209561 A1 US 2017209561A1
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protein
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acid sequence
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Jana Seele
Christoph Baums
Peter Valentin-Weigand
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IDT Biologika GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K39/09—Lactobacillales, e.g. aerococcus, enterococcus, lactobacillus, lactococcus, streptococcus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K39/09—Lactobacillales, e.g. aerococcus, enterococcus, lactobacillus, lactococcus, streptococcus
    • A61K39/092—Streptococcus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/315—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Streptococcus (G), e.g. Enterococci
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/12—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria
    • C07K16/1267—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-positive bacteria
    • C07K16/1275—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-positive bacteria from Streptococcus (G)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/53—DNA (RNA) vaccination
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A61K2039/541—Mucosal route
    • A61K2039/543—Mucosal route intranasal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
    • A61K2039/552—Veterinary vaccine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A61K2039/575—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 humoral response

Definitions

  • the present invention relates to a vaccine composition and the use thereof for immunization and protection of mammals, in particular pigs and humans, against Streptococcus suis.
  • Streptococcus suis ( S. suis ) colonizes the respiratory, alimentary and genital tract of pigs. S. suis is also one of the most important porcine pathogens, causing different pathologies such as meningitis, septicaemia, arthritis and endocarditis.
  • S. suis infections account for high production losses in the swine industry worldwide. Antibiotics are commonly used to treat S. suis infections. But recurrent infections frequently occur as well as the ongoing discussions concerning the reduction of antibiotic usage underline the need for alternative control measures. In Europe, no licensed vaccine is available but autologous bacterins are commonly used. A major drawback is the fact that these vaccines protect only against the homologous serotype. But S. suis is a very diverse organism and different serotypes are responsible for morbidity in piglets. Especially serotype 2 strains play an important role for diseases in piglets worldwide.
  • S. suis serotype 2 has been identified to cause meningitis in adults in Asia, but to date no transmission of S. suis between humans has been detected.
  • IgM Immunoglobulin M
  • IgM is especially important as monomeric membrane IgM (mIgM) as it is the only B-cell receptor occurring since IgD is missing in pigs. Further, IgM synthesis in newborn piglets starts much earlier than IgG and IgA synthesis. IgM in colostrum is crucial for the protection against pathogens which is carried out by complement-mediated killing. Therefore IgM antibodies are important in the protection against different pathogens.
  • S. suis serotype 2 Various virulence or virulence-associated factors of S. suis serotype 2 have been identified, among the capsule which is so far the only known essential virulence factor protecting the pathogen against phagocytosis.
  • a variety of human or animal pathogens such as Streptococcus pyogenes, Streptococcus equi subspecies equi and Streptococcus equi subspecies zooepidemicus express specific IgG endopeptidases which are homologue to each other.
  • IdeSsuis A surface-associated or secreted factor with a function unique for S. suis has been firstly described by Seele et al. (“Identification of a Novel Host-specific IgM Protease in Streptococcus suis .” 2013; Journal of Bacteriology, 195: 930-940). Seele et al. showed that this IgM protease, designated IdeSsuis, does not function as an IgG endopeptidase. The IgM protease degrades opsonising IgM on the bacterial surface and therefore promotes the survival of S. suis in blood of bacterin-primed piglets. IdeSsuis is highly specific for IgM and does not cleave IgG or IgA.
  • IdeSsuis and related proteins may be used as the exclusive immunizing agent in a vaccine against S. suis infections.
  • Baums et al. disclose in Surface - associated and secreted factors of Streptococcus suis in epidemiology, pathogenesis and vaccine development, Animal Health Research Reviews , Volume 10, Issue 01, June 2009, pp 65-83 bacterial factors, both surface-associated and secreted ones, which are considered to contribute to S. suis interaction(s) with host factors and cells. Factors are presented with respect to (i) their identification and features, (ii) their distribution among S. suis and (iii) their significance for virulence, immune response and vaccination. This review emphasizes the numerous challenging questions remaining to be answered in the future.
  • the problem to be solved according to the invention is to overcome the problems described in the art and to provide a new vaccine composition to immunize and protect mammals, in particular pigs and humans, against S. suis infections.
  • a vaccine composition which comprises an effective amount of at least one polypeptide or at least one vector selected from the group of
  • At least a pharmaceutical carrier at least a pharmaceutical carrier, a diluent or an adjuvant.
  • the vaccine composition used in the present invention contains at least one sole polypeptide defined by (a) or (b) together with a pharmaceutical carrier or a diluent or an adjuvant or a mixture thereof. Further the vaccine may also comprise at least one sole vector defined by (c) or (d) with a pharmaceutical carrier, a diluent or an adjuvant or a mixture thereof.
  • IdeSsuis of (a) comprises
  • rIdeSsuis of (b) comprises or consists of
  • SEQ ID NO: 2 represents the sequence of SEQ ID NO: 1, however lacking amino acids 1-34 (signal peptide) but adding a HIS tag. It is noted that SEQ ID NO: 1 was derived from the serotype 2 strain of S. suis.
  • amino acid sequence of SEQ ID NO: 6 represents the N terminal sequence of SEQ ID NO: 2.
  • SEQ ID NO: 7 (also called antigen rIdeSsuisB2) contains the complete amino acid sequence of the mature IdeSsuis protein of a S. suis serotype7 strain but adding a N terminal HIS tag.
  • IdeSsuis protein of a S. suis serotype7 strain differs in the C terminal half of the protein since it lacks a sequence of 114 amino acids compared to SEQ ID NO: 1.
  • Amino acids 80 to 414 of SEQ ID NO: 7 (highly conserved part of the so-called Mac-1 domain) correspond in 97.9% to the sequence of SEQ ID NO: 5.
  • the overall identity between SEQ ID NO: 7 and 1 is 96.4% (not considering the N terminal HIS tag and the gap of 114 amino acids).
  • fragment or analogue as used herein is defined as follows:
  • an “analogue” can be regarded as an amino acid sequence similar to the ones disclosed above and showing a level of homology of at least 60%, preferably 70% and most preferably 85% to the original amino acid sequence (e.g. SEQ ID NO: 1, 2, 6 or 7). Also higher degrees of homology, such as 95%, are contemplated herein.
  • Homology means identity. As such, the sequences might differ from each other based on substitution, deletion or insertion.
  • the degree of identity can be determined with the protein blast program using the blastp algorithm with default parameters which are, for example, Expect threshold: 10, Word size: 3, Matrix: BLOMSUM62, Gap Costs: Existence: 11 Extension: 1 and Compositional adjustments: Conditional compositional score matrix adjustment (BLAST is a registered trademark of the National Library of Medicine).
  • the program can be used to search a protein database using a protein query. Identity reports the exact matches between aligned query and database sequences.
  • amino acid “substitutions” are the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, i.e., conservative amino acid replacements.
  • Nonpolar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan, and methionine
  • polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine
  • positively charged (basic) amino acids include arginine, lysine, and histidine
  • negatively charged (acidic) amino acids include aspartic acid and glutamic acid.
  • “Insertions” or “deletions” are typically in the range of about 1, 2 or 3 amino acids. The variation allowed may be experimentally determined by systematically making insertions or deletions of amino acids in a protein using recombinant DNA techniques and assaying the resulting recombinant variants for activity. This does not require more than routine experiments for a skilled person.
  • an “analogue” may alternatively or in addition be defined as an amino acid sequence similar to the ones disclosed above and comprising the highly conserved part of the Mac-1 domain (SEQ ID NO: 5) or an amino acid sequence which is at least 95% homologous thereto.
  • This domain is mainly responsible for the unexpected immunogenic activity of IdeSsuis proteins and, for itself, is sufficient to provide immune protection to the vaccinated animal.
  • Different serotypes of S. suis are existing which partially show large variations in their amino acid sequence thus leading to a level of homology down to about 60%.
  • the highly conserved Mac-1 domain shows only small variations between the different serotypes, for example 97.9% between serotype strains 2 and 7.
  • amino acids of the present invention show a higher level of variation outside the Mac-1 domain than inside.
  • fragment can be defined in a similar way (see above). It describes a shorter amino acid sequence than an analogue (less than about 400 amino acids). It contains or consists of the highly conserved part of the Mac-1 domain (SEQ ID NO: 5) or an amino acid sequence which is at least 95% homologous thereto.
  • a fragment can be defined as having an IgM protease activity, although this is not an essential requirement. These fragments may be used as the exclusive active ingredient in a vaccine according to the present invention.
  • the vaccine composition of the present invention in a preferred embodiment comprises, essentially consists of or consists of a protein comprising or consisting of the amino acid sequence of SEQ ID NO: 5 or an amino acid sequence which is at least 95% homologous thereto.
  • the protein or vector encoding the same
  • the protein is the only active or immunogenic ingredient.
  • composition means that further active or immunogenic components can be present.
  • Consisting of means that no further components are present and “essentially consisting of” means that specific further components can be present, namely those not materially affecting the essential characteristics of the vaccine (i.e. inactive or not immunogenic ingredients).
  • the present invention provides a vaccine composition essentially consisting of an rIdeSsuis protein which is at least 60%, 70%, 85% or 95% homologous to the amino acid sequence of the protein IdeSsuis of SEQ ID NO: 1 and/or comprises or consists of the amino acid sequence of SEQ ID NO: 5 or an amino acid sequence which is at least 95% homologous thereto.
  • a vaccine composition according to the present invention wherein a fragment of the effective amount of said polypeptide of (a) or (b) is part of a fusion protein with at least one other protein.
  • polynucleotide of (c) comprises a sequence encoding a protein defined as IdeSsuis, namely
  • a vaccine composition according to the present invention, which is characterized in that the polynucleotide comprises
  • (c.c) a fragment of the sequence of (c.a) which encodes a protein having IgM protease activity.
  • the polynucleotide of (d) comprises a sequence encoding a protein defined as rIdeSsuis, namely
  • a vaccine composition according to the present invention, which is characterized in that the polynucleotide comprises
  • nucleic acid sequence refers to a heteropolymer of nucleotides or the sequence of these nucleotides.
  • nucleic acid and polynucleotide are used interchangeably herein to refer to a heteropolymer of nucleotides.
  • a vaccine composition is further characterized by the polynucleotide integrated into a vector, wherein the polynucleotide is operably linked to an expression control region of the vector.
  • This expression vector preferably comprises one or more regulatory sequences.
  • expression vector generally refers to a plasmid or phage or virus or vector, for expressing a polypeptide from a DNA (RNA) sequence.
  • An expression vector can comprise a transcriptional unit comprising an assembly of (1) a genetic element or elements having a regulatory role in gene expression, for example, promoters or enhancers, (2) a structural or coding sequence which is transcribed into mRNA and translated into protein, and (3) appropriate transcription initiation and termination sequences.
  • Structural units intended for use in yeast or eukaryotic expression systems preferably include a leader sequence enabling extracellular secretion of translated protein by a host cell.
  • recombinant protein when expressed without a leader or transport sequence, it may include an N-terminal methionine residue. This residue may or may not be subsequently cleaved from the expressed recombinant protein to provide a final product.
  • a vaccine composition is provided in a physiologically administrable form and is suitable for intramuscular, intravenous, subcutaneous or dermal injection or mucosal application. It is noted that an intravenous administration is less preferred.
  • the present invention is directed to a fragment of IdeSsuis having the amino acid sequence of SEQ ID NO: 5, or an amino acid sequence which is at least 95% homologous thereto.
  • SEQ ID NO: 5 corresponds to the highly conserved part of the Mac-1 domain. Although this domain shows an IgM protease activity, the immunogenic effect is not necessarily linked to this activity.
  • analogues of SEQ ID NO: 5 where the active center of the protease has been inactivated by mutagenesis of the Cys-residue. Also in this case, the analogue will be effective as a vaccine for eliciting an immune response.
  • amino acid sequences may be effective as a vaccine against S. suis infections if they maintain a homology of at least 95% to SEQ ID NO: 5. This includes substitution, insertion or deletion of single amino acids. It turned out that natural occurring Mac-1 domains, although showing some variations, do not differ by more than 5%, or in other words, share an identity of 95% or more in this domain.
  • Exemplary Streptococcus suis sequences were obtained from strains isolated in different geographic regions (America, Asia, Europe) and were derived from different host organisms (humans, pigs). These strains belong to different serotypes (1 to 4, 7 to 9, 14 and 16 or which were non-typeable). This is summarized in the enclosed table 1:
  • SEQ ID NO: 10 The sequence information on the Mac-1 domain of proteins WP_044671938, WP_002935529, WP_015647040, WP_023370787 and WP_044678723 is disclosed in SEQ ID NO: 10 to SEQ ID NO: 14. Since their homology to SEQ ID NO: 5 is higher than 95% they are falling within the definition of a fragment or homologue of the present invention.
  • a still further aspect is an rIdeSsuis protein comprising the amino acid sequence of SEQ ID NO: 6 or 7, or an amino acid sequence which is at least 60%, preferably 70%, 85% or 95% homologous to the amino acid sequence of the protein IdeSsuis of SEQ ID NO: 6 or 7.
  • Another object of the present invention is a host cell which is transfected with the vector.
  • a further object of the present invention is a method for producing a protein defined as rIdeSsuis as a guest antigen in a vector or a different organism, respectively a host cell transfected under condition suitable for expression of said recombinant protein.
  • a further aspect of the present invention is an antibody which recognizes an IdeSsuis or rIdeSsuis protein, analogue or fragment has defined above.
  • the antibody is preferably selected from a group, which consists of polyclonal antibodies, monoclonal antibodies, humanized antibodies, chimeric antibodies and synthetic antibodies.
  • antibody is used herein for intact antibodies as well as antibody fragments, which have a certain ability to selectively bind to an epitop. Such fragments include, without limitations, Fab, F(ab′) 2 und Fv antibody fragments.
  • epitop means any antigen determinant of an antigen, to which the paratop of an antibody can bind. Epitop determinants usually consist of chemically active surface groups of molecules (e.g. amino acid or sugar residues) and usually display a three-dimensional structure as well as specific physical properties.
  • the antibodies according to the invention can be produced according to any known procedure.
  • the pure complete IdeSsuis or rIdeSsuis protein according to the invention or a fragment/analogue of it can be produced and used as immunogen, to immunize an animal and to produce specific antibodies.
  • polyclonal antibodies The production of polyclonal antibodies is commonly known. Detailed protocols can be found for example in Green et al, Production of Polyclonal Antisera, in Immunochemical Protocols (Manson, editor), pages 1-5 (Humana Press 1992) and Coligan et al, Production of Polyclonal Antisera in Rabbits, Rats, Mice and Hamsters, in Current Protocols In Immunology , section 2.4.1 (1992). In addition, the expert is familiar with several techniques regarding the purification and concentration of polyclonal antibodies, as well as of monoclonal antibodies (Coligan et al, Unit 9, Current Protocols in Immunology , Wiley Interscience, 1994).
  • monoclonal antibodies are as well commonly known. Examples include the hybridoma method (Kohler and Milstein, 1975, Nature, 256:495-497, Coligan et al., section 2.5.1-2.6.7; and Harlow et al., Antibodies: A Laboratory Manual , page 726 (Cold Spring Harbor Pub. 1988).), the trioma technique, the human B-cell hybridoma technique (Kozbor et al., 1983, Immunology Today 4:72), and the EBV-hybridoma technique to produce human monoclonal antibodies (Cole, et al., 1985, in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96).
  • monoclonal antibodies can be attained by injecting a mixture which contains the protein according to the invention into mice.
  • the antibody production in the mice is checked via a serum probe.
  • the mouse is sacrificed and the spleen is removed to isolate B-cells.
  • the B cells are fused with myeloma cells resulting in hybridomas.
  • the hybridomas are cloned and the clones are analyzed. Positive clones which contain a monoclonal antibody against the protein are selected and the antibodies are isolated from the hybridoma cultures. There are many well established techniques to isolate and purify monoclonal antibodies.
  • Such techniques include affinity chromatography with protein A sepharose, size-exclusion chromatography and ion exchange chromatography. Also see for example, Coligan et al., section 2.7.1-2.7.12 and section “Immunglobulin G (IgG)”, in Methods In Molecular Biology , volume 10, pages 79-104 (Humana Press 1992).
  • the present invention provides humanized IdeSsuis or rIdeSsuis specific mouse antibodies.
  • the above antibodies may form part of a parenteral composition for therapeutic treatment of a human or animal (pig) patient suffering from a S. suis infection. However, it might be used for prophylactic purposes as well.
  • the present invention is directed to the use of the proteins as disclosed hereinabove for producing the above described antibodies.
  • Another object of the present invention is the use of the vaccine or parenteral composition, according to the present invention, to perform a prophylactic or metaphylactic or therapeutic treatment of a Streptococcus suis infection in pigs. It is further contemplated herein to use the vaccine or the parenteral composition of the present invention for prophylactic or metaphylactic or therapeutic treating an S. suis infection in a human patient.
  • the vaccine composition according to the present invention, wherein the treatment causes an immunological response in pigs whereas the immunological response is the activation of a humoral and cellular response against the protein IdeSsuis produced by Streptococcus suis.
  • the treatment involves at least one or two immunizations.
  • the overall dosage administered per pig/human is about 0.05-2.0 mg of protein.
  • diluents or adjuvants which can be used which comprise but are not limited to the following: mineral salt adjuvants (e.g., alum-, calcium-, iron-, zirconium-based), tensoactive adjuvants (e.g., Quil A, QS-21, other saponins), bacteria-derived adjuvants (e.g., N-acetyl muramyl-L-alanyl-D-isoglutamine (MDP), lipopolysaccharides (LPS), monophosphoryl lipid A, trehalose dimycolate (TDM), DNA, CpGs, bacterial toxins), adjuvant emulsions (e.g., FIA, Montanide, Adjuvant 65, Lipovant), liposome adjuvants,
  • mineral salt adjuvants e.g., alum-, calcium-, iron-, zirconium-based
  • tensoactive adjuvants e.g.
  • the present invention is directed to a vaccine composition
  • a vaccine composition comprising a protein designated as IdeSsuis or rIdeSsuis or a fragment of either thereof; or a polynucleotide either expressing the protein IdeSsuis or rIdeSsuis or a fragment either thereof which is integrated into an expression vector, whereas the recombinant protein is preferred.
  • the inventors showed, that the vaccination of pigs using the protein rIdeSsuis alone as the sole antigen provides a protection for pigs infected by S. suis .
  • vaccination with rIdeSsuis prevents the cleavage of IgMs by the IdeSsuis IgM protease of S. suis by inducing neutralizing antibodies.
  • the inventors showed, that the vaccination of pigs with the recombinant protein rIdeSsuis or an analogue or fragment thereof reduces the survival of S. suis in the blood.
  • rIdeSsuis (SEQ ID NO: 2) provides immune protection across different serotyps of S. suis,
  • a protein at least containing the highly conserved Mac-1 domain (SEQ ID NO: 5) is sufficient to provide immune protection
  • IdeSsuis proteins of other serotypes at least containing the highly conserved Mac-1 domain (SEQ ID NO: 5) induce protection, even if their overall sequence outside this domain differs from that of the serotype 2 strains (even if certain sequence segments are entirely absent).
  • the proteins IdeSsuis or rIdeSsuis or analogues/fragments thereof can also be used in fusion proteins.
  • Fusion proteins are created by joining two or more genes which are originally coded for separate proteins. The translation of this fusion gene results in a single or multiple polypeptide with functions derived each from the originally proteins.
  • fusion proteins are often used to simplify specific applications, such as detection, integration or transport of the protein of interest.
  • a prominent member for detection by fluorescent microscopy is the green fluorescent protein (GFP) fused to the protein of interest.
  • proteins which could be fused to IdeSsuis to improve the delivery and immunogenicity of the antigen are immunoglobulin FC-fragment, non-toxic cholera toxin CTA subunit, mutated heat-labile toxins, Bacillus subtilis spore coat protein or bacterial flagellins .
  • fusion proteins with proteins of viruses or phages e.g. modified vaccinia virus Ankara (MVA), Hepatitis B virus , Lambda phage or filamentous bacteriophages like fd, M13 or fl
  • viruses or phages e.g. modified vaccinia virus Ankara (MVA), Hepatitis B virus , Lambda phage or filamentous bacteriophages like fd, M13 or fl
  • viruses or phages e.g. modified vaccinia virus Ankara (MVA), Hepatitis B virus , Lambda phage or filamentous bacteriophages like fd
  • Protein tags are commonly short amino acid sequences for example HIS-Tag, myc-Tag, HA-Tag, Step-Tag, GST-Tag, maltose binding protein-Tag or Thioredoxin-Tag.
  • host cells are used for being transfected with a vector encoding the protein of interest for production of a recombinant protein.
  • those host cells may be bacteria (e.g E.coli, Bacillus or Lactococcus strains), human (e.g. 293-T, HEK-293), mouse cell lines, insect cell lines, yeast cells or plant based systems.
  • plasmids e.g pET, pQE
  • viruses and phages e.g. baculovirus, Lambda phage or filamentous bacteriophages
  • vaccine or parenteral compositions are prepared as injectables, either as liquid solutions or suspensions.
  • the subject of the present invention is also a vaccine or parenteral composition for subcutaneous, intravenous, intramuscular, dermal or mucosal application.
  • the present vaccines are used to perform a prophylactic or metaphylactic or therapeutic treatment of a Streptococcus suis infection in pigs or humans.
  • the treatment involves at least one, preferably two immunizations.
  • a standard immunization usually comprises a prime-boost regimen, i.e. 2 distinct vaccinations.
  • the boost vaccination usually is given in a time frame of 1-3, preferably about 2 weeks after the prime vaccination.
  • the dosage of the individual vaccinations might be the same or different, although it is preferred that the vaccine dosage of both is identical.
  • the overall dosage which has to be administered to the animal or human patient is about 0.05-2.0 mg of IdeSsuis or rIdeSsuis protein, analogues or fragments as defined hereinabove.
  • Preferred dosages include 0.1-1.0, more preferably about 0.5 mg. This dosage is administered in one dosage should one single vaccination be sufficient. If more than one vaccination is applied, the overall dosage is split in several equal sub-dosages, for example, if two vaccinations are used, the individual dosage of the vaccination is about 0.025-1.0 mg of protein.
  • FIG. 1 shows a time table representing the vaccination challenge experiments with S. suis in pigs
  • FIG. 2 shows a graph representing the results gained with the vaccination challenge experiments of FIG. 1 ,
  • FIG. 3 shows a diagram of a bactericidal assay involving vaccination with placebo vs. rIdeSsuis
  • FIG. 4 depicts a diagram of a bactericidal assay involving vaccination with rIdeSsuis or rIdeSsuis analogues vs. a control group.
  • SEQ ID NO: 1 shows the amino acid sequence of the protein IdeSsuis
  • SEQ ID NO: 2 shows the amino acid sequence of the recombinant protein rIdeSsuis without the signal peptide
  • SEQ ID NO: 3 shows the nucleotide sequence coding for IdeSsuis
  • SEQ ID NO: 4 shows the nucleotide sequence coding for rIdeSsuis.
  • SEQ ID NO: 5 shows the amino acid sequence of the highly conserved part of the Mac-1 domain of IdeSsuis.
  • SEQ ID NO: 6 shows the amino acid sequence of the rIdeSsuis analogue rIdeSsuis_homologue.
  • SEQ ID NO: 7 shows the amino acid sequence of the rIdeSsuis analogue rIdeSsuisB2.
  • SEQ ID NO: 8 shows the nucleotide sequence coding for rIdeSsuis analogue rIdeSsuis_homologue.
  • SEQ ID NO: 9 shows the nucleotide sequence coding for rIdeSsuis analogue rIdeSsuisB2.
  • SEQ ID NO: 10 shows amino acid sequence of amino acids 91 to 425 of WP_044671938.
  • SEQ ID NO: 11 shows amino acid sequence of amino acids 91 to 425 of WP_002935529.
  • SEQ ID NO: 12 shows amino acid sequence of amino acids 92 to 426 of WP_015647040.
  • SEQ ID NO: 13 shows amino acid sequence of amino acids 92 to 426 of WP_023370787.
  • SEQ ID NO: 14 shows amino acid sequence of amino acids 92 to 426 of WP_044678723.
  • the following example provides experimental data after performing vaccination challenge experiments in piglets infected by S. suis.
  • piglets at an age of five weeks were prime vaccinated with a rIdeSsuis vaccine.
  • these piglets were boostered with rIdeSsuis and in one group also prime vaccinated with a bacterin by intramuscular injection (given in the table in FIG. 1 ).
  • One group of piglets was only prime vaccinated with a bacterin at an age of 7 weeks and a last group of animals was vaccinated twice with a placebo consisting of buffer and adjuvant.
  • the piglets were challenged two weeks after the second immunizations intranasally. Animals were further monitored every eight hours. For reasons of animal welfare, animals were euthanized in any case in which a piglet exhibits high fever in combination with apathy and anorexia as well as in the case of clinical signs of acute polyarthritis or severe meningitis.
  • the bactericidial assay has been used to evaluate the effectiveness of a given vaccine.
  • This test involves the determination of the survival of S. suis bacteria of a certain serotype after adding the same to the blood of a test animal. If antibodies protective against a certain serotype are present in the blood of this test animal, the bacteria will be killed during an incubation time of 2 hours efficiently.
  • the extent of protection is designated as “survival factor” (SF) and is the ratio of the colony count after 120 min. and the colony count directly after adding the bacteria to the blood of the test animal.
  • SF survival factor
  • a low survival factor means an efficient killing of the bacteria in the blood and, therefore, an effective protection of the test animal.
  • Piglets were prime and booster vaccinated with 1.5 ml vaccine containing 0.25 mg rIdeSsuis or 0.25 mg rIdeSsuisB2 or 0.5 mg rIdeSsuis_homologue containing 20% [vol/vol] Emulsigen as an adjuvant.
  • immu- bactericidal group pigs nization nization assay 1 9 Placebo (PBS Placebo (PBS Serotype 2 Serotype 9 plus adjuvant) plus adjuvant) (St. 10) (A3286/94) 2 9 rldeSsuis rldeSsuis Serotype 2 Serotype 9 (0.25 mg/ (0.25 mg/ (St. 10) (A3286/94) piglet) piglet)
  • FIG. 3 shows the results which were achieved.
  • the control group showed a much higher survival factor than the vaccinated group.
  • the recombinant antigen rIdeSsuis (group vaccinated), containing the complete sequence of IdeSsuis proteins of serotype 2 strain (SEQ ID NO: 2) induces antibodies effecting an efficient killing of S. suis bacteria of strain 2 as well as of strain 9.
  • FIG. 4 shows the results which were achieved.
  • the result of group 2 can be compared with those obtained for group 4.
  • antigen rIdeSsuis containing the complete amino acid sequence of mature IdeSsuis protein of a S. suis serotype2 strain induces antibodies which reduce the survival of S. suis serotype9 strain in the blood considerably.
  • the survival of serotype9 strain is even more compromised by antibodies which have been induced by antigen rIdeSsuisB2 (group 3).
  • rIdeSsuisB2 contains the complete amino acid sequence of the mature IdeSsuis protein of a S. suis serotype7 strain and differs in the C terminal half of the protein since it lacks a sequence of 114 aa compared to SEQ ID NO: 1.
  • Aa 80 to 414 of SEQ ID NO: 7 correspond in 97.9% to the sequence of SEQ ID NO: 5.
  • the identity between remaining C-terminal part of SEQ ID NO: 7 and 1 is 96.4%.
  • rIdeSsuis (SEQ ID NO: 2) provides immune protection across different serotypes of S. suis,
  • An amino acid at least containing the highly conserved Mac-1 domain is sufficient to provide immune protection
  • IdeSsuis proteins of other serotypes at least containing the highly conserved Mac-1 domain induce protection, even if their overall sequence outside this domain differs from that of the serotype 2 strains (even if certain sequence segments are entirely absent).

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