# US 8,147,850 B2 · Immunogenic constructs > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,147,850 B2 - Document ID: US8147850B2 - Status: Granted - Kind: B2 - Application number: 13/007,062 - Filed: 2011-01-14 - Published: 2011-06-02 - Granted: 2012-04-03 - Earliest claimed: 2005-08-09 - Assignees: HAV Vaccines Limited - Inventors: John Hermon-Taylor; Timothy John Bull - Web page: https://patentgrep.com/patent/US8147850B2 ## CPC - A61K 39/04: Mycobacterium, e.g. Mycobacterium tuberculosis - A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants - A61P 31/04: Antibacterial agents - C07K 14/35: from Mycobacteriaceae (F) - A61K 39/00: Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53) - A61K 2039/53: {DNA (RNA) vaccination} - A61K 2039/541: {Mucosal route} - A61K 2039/545: {characterised by the dose, timing or administration schedule} - C12N 2799/022: where the vector is derived from an adenovirus - C12N 2799/023: where the vector is derived from a poxvirus - Y10S 435/975: Kit - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00) - Y10S: TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS ## Abstract The present invention relates to molecules, which can be used to induce a therapeutic or prophylactic immune response against MAP. In particular, the present invention relates to polypeptides comprising an alipC polypeptide sequence, a gsd polypeptide sequence, a p12 polypeptide sequence and an mpa polypeptide sequence, wherein said ahpC polypeptide comprises the sequence of SEQ ID NO: 2, a variant thereof having more than 70% amino acid sequence identity to SEQ ID NO: 2 across the full length of SEQ ID NO: 2, or a fragment of at least 8 amino acids of SEQ ID NO: 2 which comprises an epitope; said gsd polypeptide comprises the sequence of SEQ ID NO: 6, a variant thereof having more than 70% amino acid sequence identity to SEQ ID NO: 6 across the full length of SEQ ID NO: 6, or a fragment of at least 8 amino acids of SEQ ID NO: 6 which comprises an epitope; said pi 2 polypeptide comprises the sequence of SEQ ID NO: 10, a variant thereof having more than 70% amino acid sequence identity to SEQ ID NO: 10 across the full length of SEQ ID NO: 10, or a fragment of at least 8 amino acids of SEQ ID NO: 10 which comprises an epitope; and said mpa polypeptide comprises the sequence of SEQ ID NO: 14, a variant thereof having more than 70% amino acid sequence identity to SEQ ID NO: 14 across the full length of SEQ ID NO: 14, or a fragment of at least 8 amino acids of SEQ ID NO: 14 which comprises an epitope. Preferably such a variant maintains the ability to generate an immune response against the unmodified polypeptide. ## Claims ### Claim 1 A polypeptide comprising an ahpC polypeptide sequence, a gsd polypeptide sequence, a p12 polypeptide sequence and an mpa polypeptide sequence, wherein said ahpC polypeptide comprises (ai) the sequence of SEQ ID NO: 2, (aii) a variant of SEQ ID NO: 2 having more than 70% amino acid sequence identity to SEQ ID NO: 2 across the full length of SEQ ID NO: 2 which comprises at least one amino acid sequence selected from the group consisting of amino acids 48 to 56 of SEQ ID NO: 4, amino acids 90 to 101 of SEQ ID NO: 4 and amino acids 161 to 169 of SEQ ID NO: 4, or (aiii) a fragment of SEQ ID NO: 2 which comprises at least one amino acid sequence selected from the group consisting of amino acids 48 to 56 of SEQ ID NO: 4, amino acids 90 to 101 of SEQ ID NO: 4 and amino acids 161 to 169 of SEQ ID NO: 4; said gsd polypeptide comprises (bi) the sequence of SEQ ID NO: 6, (bii) a variant of SEQ ID NO: 6 having more than 70% amino acid sequence identity to SEQ ID NO: 6 across the full length of SEQ ID NO: 6, which comprises at least one amino acid sequence selected from the group consisting of amino acids 1 to 32 of SEQ ID NO: 8, amino acids 58 to 68 of SEQ ID NO: 8, amino acids 99 to 119 of SEQ ID NO: 8, amino acids 123 to 147 of SEQ ID NO: 8, amino acids 159 to 169 of SEQ ID NO: 8, amino acids 180 to 194 of SEQ ID NO: 8, amino acids 200 to 231 of SEQ ID NO: 8, amino acids 64 to 76 of SEQ ID NO: 8, amino acids 95 to 110 of SEQ ID NO: 8, amino acids 192 to 206 of SEQ ID NO: 8 and amino acids 223 to 240 of SEQ ID NO: 8, or (biii) a fragment of SEQ ID NO: 6 which comprises at least one amino acid sequence selected from the group consisting of amino acids 1 to 32 of SEQ ID NO: 8, amino acids 58 to 68 of SEQ ID NO: 8, amino acids 99 to 119 of SEQ ID NO: 8, amino acids 123 to 147 of SEQ ID NO: 8, amino acids 159 to 169 of SEQ ID NO: 8, amino acids 180 to 194 of SEQ ID NO: 8, amino acids 200 to 231 of SEQ ID NO: 8, amino acids 64 to 76 of SEQ ID NO: 8, amino acids 95 to 110 of SEQ ID NO: 8, amino acids 192 to 206 of SEQ ID NO: 8 and amino acids 223 to 240 of SEQ ID NO: 8; said p12 polypeptide comprises (ci) the sequence of SEQ ID NO: 10, (cii) a variant of SEQ ID NO: 10 having more than 70% amino acid sequence identity to SEQ ID NO: 10 across the full length of SEQ ID NO: 10 which comprises at least one amino acid sequence selected from the group consisting of amino acids 33 to 56 of SEQ ID NO: 12, amino acids 98 to 117 of SEQ ID NO: 12 and amino acids 3 to 10 of SEQ ID NO: 12, (ciii) a fragment of SEQ ID NO: 10 which comprises at least one amino acid sequence selected from the group consisting of amino acids 33 to 56 of SEQ ID NO: 12, amino acids 98 to 117 of SEQ ID NO: 12 and amino acids 3 to 10 of SEQ ID NO: 12; and said mpa polypeptide comprises (di) the sequence of SEQ ID NO: 14, (dii) a variant of SEQ ID NO: 14 having more than 70% amino acid sequence identity to SEQ ID NO: 14 across the full length of SEQ ID NO: 14 which comprises at least one amino acid sequence selected from the group consisting of amino acids 130 to 160 of SEQ ID NO: 16, amino acids 56 to 64 of SEQ ID NO: 16, amino acids 150 to 160 of SEQ ID NO: 16 and amino acids 177 to 185 of SEQ ID NO: 16, or (diii) a fragment of SEQ ID NO: 14 which comprises at least one amino acid sequence selected from the group consisting of amino acids 130 to 160 of SEQ ID NO: 16, amino acids 56 to 64 of SEQ ID NO: 16, amino acids 150 to 160 of SEQ ID NO: 16 and amino acids 177 to 185 of SEQ ID NO: 16. ### Claim 2 (depends on 1) A polypeptide according to claim 1 wherein said ahpC polypeptide has the amino acid sequence given in SEQ ID NO: 4. ### Claim 3 (depends on 1) A polypeptide according to claim 1 wherein said gsd polypeptide has the amino acid sequence given in SEQ ID NO: 8. ### Claim 4 (depends on 1) A polypeptide according to claim 1 wherein said p12 polypeptide has the amino acid sequence given in SEQ ID NO: 12. ### Claim 5 (depends on 1) A polypeptide according to claim 1 wherein said mpa polypeptide has the amino acid sequence given in SEQ ID NO: 16. ### Claim 6 (depends on 1) A polypeptide according to claim 1 wherein said mpa polypeptide comprises the amino acid sequence GFAEINPIA. ### Claim 7 (depends on 1) A polypeptide according to claim 1 which comprises the amino acid sequences of SEQ ID NOs: 4, 8, 12 and 16. ### Claim 8 (depends on 1) A polypeptide according to claim 1 which comprises the amino acid sequence given in SEQ ID NO: 24. ### Claim 9 (depends on 1) A composition comprising a polypeptide according to claim 1 and a pharmaceutically acceptable excipient or vehicle. ### Claim 10 (depends on 9) A composition according to claim 9 further comprising an adjuvant. ### Claim 11 (depends on 10) A kit for use in treating or preventing a condition or symptom associated with Mycobacterium avium subspecies paratuberculosis (MAP) infection, wherein said kit comprises (a) a composition according to claim 10 in combination with instructions for using said composition in a method for treating or preventing a condition or symptom associated with Mycobacterium avium subspecies paratuberculosis (MAP) infection; or (b) a composition comprising an ahpC polypeptide, a gsd polypeptide, a p12 polypeptide, an mpa polypeptide and an adjuvant in combination with instructions for using said composition in a method treating or preventing a condition or symptom associated with Mycobacterium avium subspecies paratuberculosis (MAP) infection, wherein said ahpC polypeptide comprises (ai) the sequence of SEQ ID NO: 2, (aii) a variant of SEQ ID NO: 2 having more than 70% amino acid sequence identity to SEQ ID NO: 2 across the full length of SEQ ID NO: 2 which comprises at least one amino acid sequence selected from the group consisting of amino acids 48 to 56 of SEQ ID NO: 4, amino acids 90 to 101 of SEQ ID NO: 4 and amino acids 161 to 169 of SEQ ID NO: 4, or (aiii) a fragment of SEQ ID NO: 2 which comprises at least one amino acid sequence selected from the group consisting of amino acids 48 to 56 of SEQ ID NO: 4, amino acids 90 to 101 of SEQ ID NO: 4 and amino acids 161 to 169 of SEQ ID NO: 4; said gsd polypeptide comprises (bi) the sequence of SEQ ID NO: 6, (bii) a variant of SEQ ID NO: 6 having more than 70% amino acid sequence identity to SEQ ID NO: 6 across the full length of SEQ ID NO: 6, which comprises at least one amino acid sequence selected from the group consisting of amino acids 1 to 32 of SEQ ID NO: 8, amino acids 58 to 68 of SEQ ID NO: 8, amino acids 99 to 119 of SEQ ID NO: 8, amino acids 123 to 147 of SEQ ID NO: 8, amino acids 159 to 169 of SEQ ID NO: 8, amino acids 180 to 194 of SEQ ID NO: 8, amino acids 200 to 231 of SEQ ID NO: 8, amino acids 64 to 76 of SEQ ID NO: 8, amino acids 95 to 110 of SEQ ID NO: 8, amino acids 192 to 206 of SEQ ID NO: 8 and amino acids 223 to 240 of SEQ ID NO: 8, or (biii) a fragment of SEQ ID NO: 6 which comprises at least one amino acid sequence selected from the group consisting of amino acids 1 to 32 of SEQ ID NO: 8, amino acids 58 to 68 of SEQ ID NO: 8, amino acids 99 to 119 of SEQ ID NO: 8, amino acids 123 to 147 of SEQ ID NO: 8, amino acids 159 to 169 of SEQ ID NO: 8, amino acids 180 to 194 of SEQ ID NO: 8, amino acids 200 to 231 of SEQ ID NO: 8, amino acids 64 to 76 of SEQ ID NO: 8, amino acids 95 to 110 of SEQ ID NO: 8, amino acids 192 to 206 of SEQ ID NO: 8 and amino acids 223 to 240 of SEQ ID NO: 8; said p12 polypeptide comprises (cii) the sequence of SEQ ID NO: 10, (cii) a variant of SEQ ID NO: 10 having more than 70% amino acid sequence identity to SEQ ID NO: 10 across the full length of SEQ ID NO: 10 which comprises at least one amino acid sequence selected from the group consisting of amino acids 33 to 56 of SEQ ID NO: 12, amino acids 98 to 117 of SEQ ID NO: 12 and amino acids 3 to 10 of SEQ ID NO: 12, (ciii) a fragment of SEQ ID NO: 10 which comprises at least one amino acid sequence selected from the group consisting of amino acids 33 to 56 of SEQ ID NO: 12, amino acids 98 to 117 of SEQ ID NO: 12 and amino acids 3 to 10 of SEQ ID NO: 12; said mpa polypeptide comprises (di) the sequence of SEQ ID NO: 14, (dii) a variant of SEQ ID NO: 14 having more than 70% amino acid sequence identity to SEQ ID NO: 14 across the full length of SEQ ID NO: 14 which comprises at least one amino acid sequence selected from the group consisting of amino acids 130 to 160 of SEQ ID NO: 16, amino acids 56 to 64 of SEQ ID NO: 16, amino acids 150 to 160 of SEQ ID NO: 16 and amino acids 177 to 185 of SEQ ID NO: 16, or (diii) a fragment of SEQ ID NO: 14 which comprises at least one amino acid sequence selected from the group consisting of amino acids 130 to 160 of SEQ ID NO: 16, amino acids 56 to 64 of SEQ ID NO: 16, amino acids 150 to 160 of SEQ ID NO: 16 and amino acids 177 to 185 of SEQ ID NO: 16. ### Claim 12 (depends on 11) A kit according to claim 11 which further comprises at least one other therapeutic agent, for simultaneous, sequential or separate use. ### Claim 13 (depends on 12) A kit according to claim 12 wherein said other therapeutic agent is a polynucleotide which encodes a polypeptide comprising an ahpC polypeptide sequence, a gsd polypeptide sequence, a p12 polypeptide sequence and an mpa polypeptide sequence, wherein said ahpC polypeptide comprises: (ai) the sequence of SEQ ID NO: 2, (aii) a variant of SEQ ID NO: 2 having more than 70% amino acid sequence identity to SEQ ID NO: 2 across the full length of SEQ ID NO: 2 which comprises at least one amino acid sequence selected from the group consisting of amino acids 48 to 56 of SEQ ID NO: 4, amino acids 90 to 101 of SEQ ID NO: 4 and amino acids 161 to 169 of SEQ ID NO: 4; or (aiii) a fragment of SEQ ID NO: 2 which comprises at least one amino acid sequence selected from the group consisting of amino acids 48 to 56 of SEQ ID NO: 4, amino acids 90 to 101 of SEQ ID NO:4 and amino acids 161 to 169 of SEQ ID NO: 4; said gsd polypeptide comprises: (bi) the sequence of SEQ ID NO: 6, (bii) a variant of SEQ ID NO: 6 having more than 70% amino acid sequence identity to SEQ ID NO: 6 across the full length of SEQ ID NO: 6 which comprises at least one amino acid sequence selected from the group consisting of amino acids 1 to 32 of SEQ ID NO: 8, amino acids 58 to 68 of SEQ ID NO: 8, amino acids 99 to 119 of SEQ ID NO: 8, amino acids 123 to 147 of SEQ ID NO: 8, amino acids 159 to 169 of SEQ ID NO: 8, amino acids 180 to 194 of SEQ ID NO: 8, amino acids 200 to 231 of SEQ ID NO: 8, amino acids 64 to 76 of SEQ ID NO: 8, amino acids 95 to 110 of SEQ ID NO: 8, amino acids 192 to 206 of SEQ ID NO: 8 and amino acids 223 to 240 of SEQ ID NO: 8; or (biii) a fragment of SEQ ID NO: 6 which comprises at least one amino acid sequence selected from the group consisting of amino acids 1 to 32 of SEQ ID NO: 8, amino acids 58 to 68 of SEQ ID NO: 8, amino acids 99 to 119 of SEQ ID NO: 8, amino acids 123 to 147 of SEQ ID NO: 8, amino acids 159 to 169 of SEQ ID NO: 8, amino acids 180 to 194 of SEQ ID NO: 8, amino acids 200 to 231 of SEQ ID NO: 8, amino acids 64 to 76 of SEQ ID NO: 8, amino acids 95 to 110 of SEQ ID NO: 8, amino acids 192 to 206 of SEQ ID NO: 8 and amino acids 223 to 240 of SEQ ID NO: 8; said p12 polypeptide comprises: (ci) the sequence of SEQ ID NO: 10, (cii) a variant of SEQ ID NO: 10 having more than 70% amino acid sequence identity to SEQ ID NO: 10 across the full length of SEQ ID NO: 10 which comprises at least one amino acid sequence selected from the group consisting of amino acids 33 to 56 of SEQ ID NO: 12, amino acids 98 to 117 of SEQ ID NO: 12 and amino acids 3 to 10 of SEQ ID NO: 12; or (ciii) a fragment of SEQ ID NO: 10 which comprises at least one amino acid sequence selected from the group consisting of amino acids 33 to 56 of SEQ ID NO: 12, amino acids 98 to 117 of SEQ ID NO: 12 and amino acids 3 to 10 of SEQ ID NO: 12; and said mpa polypeptide comprises: (di) the sequence of SEQ ID NO: 14, (dii) a variant of SEQ ID NO: 14 having more than 70% amino acid sequence identity to SEQ ID NO: 14 across the full length of SEQ ID NO: 14 which comprises at least one amino acid sequence selected from the group consisting of amino acids 130 to 160 of SEQ ID NO:16, amino acids 56 to 64 of SEQ ID NO:16, amino acids 150 to 160 of SEQ ID NO: 16 and amino acids 177 to 185 of SEQ ID NO: 16; or (diii) a fragment of SEQ ID NO: 14 which comprises at least one amino acid sequence selected from the group consisting of amino acids 130 to 160 of SEQ ID NO:16, amino acids 56 to 64 of SEQ ID NO: 16, amino acids 150 to 160 of SEQ ID NO: 16 and amino acids 177 to 185 of SEQ ID NO: 16. ### Claim 14 (depends on 10) A method of generating an immune response against MAP comprising administering to an individual in need thereof (a) a composition according to claim 10; or (b) a composition comprising an ahpC polypeptide, a gsd polypeptide, a p12 polypeptide, an mpa polypeptide and an adjuvant, wherein said ahpC polypeptide comprises (ai) the sequence of SEQ ID NO: 2, (aii) a variant of SEQ ID NO: 2 having more than 70% amino acid sequence identity to SEQ ID NO: 2 across the full length of SEQ ID NO: 2 which comprises at least one amino acid sequence selected from the group consisting of amino acids 48 to 56 of SEQ ID NO: 4, amino acids 90 to 101 of SEQ ID NO: 4 and amino acids 161 to 169 of SEQ ID NO: 4, or (aiii) a fragment of SEQ ID NO: 2 which comprises at least one amino acid sequence selected from the group consisting of amino acids 48 to 56 of SEQ ID NO: 4, amino acids 90 to 101 of SEQ ID NO: 4 and amino acids 161 to 169 of SEQ ID NO: 4; said gsd polypeptide comprises (bi) the sequence of SEQ ID NO: 6, (bii) a variant of SEQ ID NO: 6 having more than 70% amino acid sequence identity to SEQ ID NO: 6 across the full length of SEQ ID NO: 6, which comprises at least one amino acid sequence selected from the group consisting of amino acids 1 to 32 of SEQ ID NO: 8, amino acids 58 to 68 of SEQ ID NO: 8, amino acids 99 to 119 of SEQ ID NO: 8, amino acids 123 to 147 of SEQ ID NO: 8, amino acids 159 to 169 of SEQ ID NO: 8, amino acids 180 to 194 of SEQ ID NO: 8, amino acids 200 to 231 of SEQ ID NO: 8, amino acids 64 to 76 of SEQ ID NO: 8, amino acids 95 to 110 of SEQ ID NO: 8, amino acids 192 to 206 of SEQ ID NO: 8 and amino acids 223 to 240 of SEQ ID NO: 8, or (biii) a fragment of SEQ ID NO: 6 which comprises at least one amino acid sequence selected from the group consisting of amino acids 1 to 32 of SEQ ID NO: 8, amino acids 58 to 68 of SEQ ID NO: 8, amino acids 99 to 119 of SEQ ID NO: 8, amino acids 123 to 147 of SEQ ID NO: 8, amino acids 159 to 169 of SEQ ID NO: 8, amino acids 180 to 194 of SEQ ID NO: 8, amino acids 200 to 231 of SEQ ID NO: 8, amino acids 64 to 76 of SEQ ID NO: 8, amino acids 95 to 110 of SEQ ID NO: 8, amino acids 192 to 206 of SEQ ID NO: 8 and amino acids 223 to 240 of SEQ ID NO: 8; said p12 polypeptide comprises (ci) the sequence of SEQ ID NO: 10, (cii) a variant of SEQ ID NO: 10 having more than 70% amino acid sequence identity to SEQ ID NO: 10 across the full length of SEQ ID NO: 10 which comprises at least one amino acid sequence selected from the group consisting of amino acids 33 to 56 of SEQ ID NO: 12, amino acids 98 to 117 of SEQ ID NO: 12 and amino acids 3 to 10 of SEQ ID NO: 12, (ciii) a fragment of SEQ ID NO: 10 which comprises at least one amino acid sequence selected from the group consisting of amino acids 33 to 56 of SEQ ID NO: 12, amino acids 98 to 117 of SEQ ID NO: 12 and amino acids 3 to 10 of SEQ ID NO: 12; said mpa polypeptide comprises (di) the sequence of SEQ ID NO: 14, (dii) a variant of SEQ ID NO: 14 having more than 70% amino acid sequence identity to SEQ ID NO: 14 across the full length of SEQ ID NO: 14 which comprises at least one amino acid sequence selected from the group consisting of amino acids 130 to 160 of SEQ ID NO: 16, amino acids 56 to 64 of SEQ ID NO: 16, amino acids 150 to 160 of SEQ ID NO: 16 and amino acids 177 to 185 of SEQ ID NO: 16, or (diii) a fragment of SEQ ID NO: 14 which comprises at least one amino acid sequence selected from the group consisting of amino acids 130 to 160 of SEQ ID NO: 16, amino acids 56 to 64 of SEQ ID NO: 16, amino acids 150 to 160 of SEQ ID NO: 16 and amino acids 177 to 185 of SEQ ID NO: 16. ### Claim 15 (depends on 14) A method according to claim 14 wherein said individual is also administered a polynucleotide which encodes a polypeptide comprising an ahpC polypeptide sequence, a gsd polypeptide sequence, a p12 polypeptide sequence and an mpa polypeptide sequence prior to administration of said composition, wherein said ahpC polypeptide comprises: (ai) the sequence of SEQ ID NO: 2, (aii) a variant of SEQ ID NO: 2 having more than 70% amino acid sequence identity to SEQ ID NO: 2 across the full length of SEQ ID NO: 2 which comprises at least one amino acid sequence selected from the group consisting of amino acids 48 to 56 of SEQ ID NO: 4, amino acids 90 to 101 of SEQ ID NO: 4 and amino acids 161 to 169 of SEQ ID NO: 4; or (aiii) a fragment of SEQ ID NO: 2 which comprises at least one amino acid sequence selected from the group consisting of amino acids 48 to 56 of SEQ ID NO: 4, amino acids 90 to 101 of SEQ ID NO:4 and amino acids 161 to 169 of SEQ ID NO: 4; said gsd polypeptide comprises: (bi) the sequence of SEQ ID NO: 6, (bii) a variant of SEQ ID NO: 6 having more than 70% amino acid sequence identity to SEQ ID NO: 6 across the full length of SEQ ID NO: 6 which comprises at least one amino acid sequence selected from the group consisting of amino acids 1 to 32 of SEQ ID NO: 8, amino acids 58 to 68 of SEQ ID NO: 8, amino acids 99 to 119 of SEQ ID NO: 8, amino acids 123 to 147 of SEQ ID NO: 8, amino acids 159 to 169 of SEQ ID NO: 8, amino acids 180 to 194 of SEQ ID NO: 8, amino acids 200 to 231 of SEQ ID NO: 8, amino acids 64 to 76 of SEQ ID NO: 8, amino acids 95 to 110 of SEQ ID NO: 8, amino acids 192 to 206 of SEQ ID NO: 8 and amino acids 223 to 240 of SEQ ID NO: 8; or (biii) a fragment of SEQ ID NO: 6 which comprises at least one amino acid sequence selected from the group consisting of amino acids 1 to 32 of SEQ ID NO: 8, amino acids 58 to 68 of SEQ ID NO: 8, amino acids 99 to 119 of SEQ ID NO: 8, amino acids 123 to 147 of SEQ ID NO: 8, amino acids 159 to 169 of SEQ ID NO: 8, amino acids 180 to 194 of SEQ ID NO: 8, amino acids 200 to 231 of SEQ ID NO: 8, amino acids 64 to 76 of SEQ ID NO: 8, amino acids 95 to 110 of SEQ ID NO: 8, amino acids 192 to 206 of SEQ ID NO: 8 and amino acids 223 to 240 of SEQ ID NO: 8; said p12 polypeptide comprises: (ci) the sequence of SEQ ID NO: 10, (cii) a variant of SEQ ID NO: 10 having more than 70% amino acid sequence identity to SEQ ID NO: 10 across the full length of SEQ ID NO: 10 which comprises at least one amino acid sequence selected from the group consisting of amino acids 33 to 56 of SEQ ID NO: 12, amino acids 98 to 117 of SEQ ID NO: 12 and amino acids 3 to 10 of SEQ ID NO: 12; or (ciii) a fragment of SEQ ID NO: 10 which comprises at least one amino acid sequence selected from the group consisting of amino acids 33 to 56 of SEQ ID NO: 12, amino acids 98 to 117 of SEQ ID NO: 12 and amino acids 3 to 10 of SEQ ID NO: 12; and said mpa polypeptide comprises: (di) the sequence of SEQ ID NO: 14, (dii) a variant of SEQ ID NO: 14 having more than 70% amino acid sequence identity to SEQ ID NO: 14 across the full length of SEQ ID NO: 14 which comprises at least one amino acid sequence selected from the group consisting of amino acids 130 to 160 of SEQ ID NO:16, amino acids 56 to 64 of SEQ ID NO:16, amino acids 150 to 160 of SEQ ID NO: 16 and amino acids 177 to 185 of SEQ ID NO: 16; or (diii) a fragment of SEQ ID NO: 14 which comprises at least one amino acid sequence selected from the group consisting of amino acids 130 to 160 of SEQ ID NO:16, amino acids 56 to 64 of SEQ ID NO: 16, amino acids 150 to 160 of SEQ ID NO: 16 and amino acids 177 to 185 of SEQ ID NO: 16.