Patent
This invention is directed to composition, vaccines, tools and methods in the treatment and prevention of Bordetella pertussis . In particular, the invention is directed to a three-pronged approach that involves removal of the nonessential vaccine components, use of a nondenatured, genetically detoxified mutant, and adding virulence factors.
1. An immunogenic B. pertussis vaccine composition comprising a genetically detoxified pertussis toxin (PT); a genetically detoxified pertussis adenylate cyclase toxin (ACT) containing the amino acid sequence of SEQ ID NO 1; an immunogenic oligosaccharide or fragment thereof derived from the lipooligosaccharide of B. pertussis having one or more of the antigenic determinants of the endotoxin to a carrier protein or peptide; a TLR agonist to induce a protective cell-mediated response against B. pertussis wherein when provided to a mammal said composition:
produces neutralizing anti toxin antibodies against B. pertussis;
produces direct bactericidal antibodies against B. pertussis;
elicits a pertussis toxin-specific Th1/Th17 cell response;
generates IFN-δ and IL-17 cytokines wherein said cytokines permit recruitment of neutrophils; and
reduces nasopharyngeal colonization and carriage of B. pertussis in the vaccine recipient.
2. The vaccine of claim 1 , wherein the genetically detoxified pertussis toxin is produced in E. coli, B. pertussis or B. bronchiseptica.
3. The vaccine of claim 1 , wherein the genetically detoxified pertussis toxin comprises a mutation of pertussis toxin that is produced in B. pertussis, B. bronchiseptica or E. coli.
4. The vaccine of claim 1 , wherein the genetically detoxified AC toxin is produced in E. coli, B. pertussis or B. bronchiseptica.
5. The vaccine of claim 1 , which induces the production of anti-PT and anti-ACT neutralizing and bactericidal antibodies against B. pertussis.
6. An oligosaccharide conjugate comprising a genetically detoxified pertussis toxin (PT); a genetically detoxified pertussis adenylate cyclase toxin (ACT) containing the amino acid sequence of SEQ ID NO 1; an immunogenic oligosaccharide or fragment thereof derived from the lipooligosaccharide of B. pertussis having one or more of the antigenic determinants of the endotoxin to a carrier protein or peptide; a TLR agonist to induce a protective cell-mediated response against B. pertussis.
7. The conjugate of claim 6 , wherein the oligosaccharide is selected from the group consisting of the structure of the dodecasaccharide core of B. bronseptica LOS, the structure of the pentasaccharide hapten obtained by deamination of the LOS of B. pertussis strain 186, and the structure of a synthetic B. pertussis epitope distal LOS trisaccharide with a spacer and a terminal aldehyde.
8. The conjugate of claim 7 , wherein the structure of the synthetic B. pertussis epitope distal LOS trisaccharide with a spacer and a terminal aldehyde is synthetic or a deamination product of the B. pertussis LOS.
9. The conjugate of claim 6 , wherein the oligosaccharide comprises a B. pertussis LOS-derived oligosaccharide (OS) or a fragment thereof, and the B. pertussis derived detoxified toxin (dPT).
10. The conjugate of claim 6 , wherein the oligosaccharide comprises a B. pertussis LOS-derived oligosaccharide (OS) or its fragment and the pertussis derived detoxified toxin (dACT).
11. The conjugate of claim 6 , wherein the TLR agonist is a TLR-2, a TLR-4 or a TLR-8.
12. An oligosaccharide conjugate comprising a genetically detoxified pertussis toxin (PT); a genetically detoxified pertussis adenylate cyclase toxin (ACT); an immunogenic oligosaccharide or fragment thereof derived from the lipooligosaccharide of B. pertussis having one or more of the antigenic determinants of the endotoxin to a carrier protein or peptide; a TLR agonist to induce a protective cell-mediated response against B. pertussis , wherein the oligosaccharide comprises one or more of the oligosaccharides of the structure of the dodecasaccharide core of B. bronseptica LOS, the structure of the pentasaccharide hapten obtained by deamination of the LOS of B. pertussis strain 186, or the structure of a synthetic B. pertussis epitope distal LOS trisaccharide comprising a spacer and a terminal aldehyde.
13. The conjugate of claim 12 , wherein the genetically detoxified pertussis adenylate cyclase toxin (ACT) comprises the amino acid sequence of SEQ ID NO 1.
14. The conjugate of claim 12 , wherein the structure of the synthetic B. pertussis epitope distal LOS trisaccharide comprises a spacer and a terminal aldehyde.
15. The conjugate of claim 14 , wherein the synthetic B. pertussis epitope distal LOS trisaccharide is a deamination product of the B. pertussis LOS.
16. The conjugate of claim 12 , wherein the oligosaccharide comprises a B. pertussis LOS-derived oligosaccharide (OS) or its fragment and the B. pertussis derived detoxified toxin (dPT).
17. The conjugate of claim 12 , wherein the oligosaccharide comprises a B. pertussis LOS-derived oligosaccharide (OS), or a fragment thereof, and the pertussis derived detoxified toxin (dACT).
18. The conjugate of claim 12 , wherein the TLR agonist is a TLR-2, a TLR-4 or a TLR-8.
19. The conjugate of claim 12 , wherein the genetically detoxified pertussis toxin is produced in E. coli, B. pertussis or B. bronchiseptica.
20. The conjugate of claim 12 , wherein the genetically detoxified pertussis toxin comprises a mutation of pertussis toxin that is produced in B. pertussis, B. bronchiseptica or E. coli.
21. The conjugate of claim 12 , wherein the genetically detoxified AC toxin is produced in E. coli, B. pertussis or B. bronchiseptica.
22. A vaccine comprising the oligosaccharide conjugate of claim 6 .
23. A vaccine comprising the oligosaccharide conjugate of claim 12 .