Vaccine for treatment and prevention of herpes simplex virus infection
The present invention relates to methods and compositions for the prevention and treatment of herpes virus infections. The invention provides antigenic peptides, and pharmaceutical compositions comprising complexes of antigenic peptides and adjuvants that can activate an immune response against herpes viruses. The invention also provides methods of making the antigenic peptides and complexes of antigenic peptides and adjuvants. Methods of use of the pharmaceutical compositions are also provided.
1. A composition comprising at least ten different purified complexes of a stress protein noncovalently bound to an antigenic peptide, wherein said complexes each comprise a different antigenic peptide, and wherein each one of said different antigenic peptides comprises one or more HLA-binding epitopes of a different herpesvirus peptide selected from among herpesvirus peptides differing in amino acid sequence, wherein for ten of said complexes the amino acid sequence of each herpesvirus peptide is selected from the group consisting of SEQ ID NO: 3, 9, 21, 34, 35, 36, 37, 41, 42, and 44, wherein each one of said different antigenic peptides does not comprise the entire amino acid sequence of a herpes simplex virus protein.
2. The composition of claim 1 , wherein the stress protein is a member of the hsp60, hsp70, or hsp90 family of stress proteins.
3. The composition of claim 1 , wherein the stress protein is hsc70, Hsp70, hsp90, hsp110, grp170, gp96, calreticulin, or combinations of two or more thereof.
4. The composition of claim 1 , wherein the stress protein is a human stress protein.
5. The composition of claim 1 which further comprises one or more adjuvants.
6. The composition of claim 5 , wherein the adjuvant is a saponin or an immunostimulatory nucleic acid.
7. A kit comprising a first container comprising the composition of claim 1 , and at least one container comprising an adjuvant, a chemotherapeutic agent, an antibody, or a biological response modifier.
8. A method of eliciting an immune response against HSV-1 or HSV-2 in an individual, the method comprising administering to the individual an immunogenic amount of the composition of claim 1 .
9. The method of claim 8 , further comprising administering to the individual an adjuvant, an antibody, a biological response modifier, or a chemotherapeutic agent.
10. The method of claim 9 , wherein said chemotherapeutic agent is chosen from the group consisting of acyclovir, valacyclovir, pencyclovir, famcyclovir, cidofovir, and phosphonoformic acid, and combinations thereof.
11. The method of claim 9 , wherein said biological response modifier is IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IFNα, IFN-β, IFN-γ, TNFα, TNF β, G-CSF, GM-CSF, or TGF β.
12. The method of claim 8 , wherein the individual is a human.
13. The composition of claim 1 , wherein said different purified complexes are not obtained or purified from a cell.
14. The composition of claim 1 , wherein said different antigenic peptides do not include antigenic peptides comprising epitope(s) of HSV2 proteins other than those comprising the amino acid sequence of SEQ ID NO: 3, 9, 21, 34, 35, 36, 37, 41, 42, and 44, respectively.
15. The composition of claim 1 , wherein at least 50% of said at least ten plurality of different complexes comprise a herpesvirus peptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 9, 21, 34, 35, 36, 37, 41, 42, and 44.
16. The composition of claim 1 , wherein each of said different antigenic peptides do not comprise amino acid sequences that are adjacent to the amino acid sequence of each of the respective herpesvirus peptides.
17. The composition of claim 3 , wherein the stress protein is hsp70 or hsc70.
18. The composition of claim 17 , further comprising at least one other purified complex of a stress protein noncovalently bound to an antigenic peptide, wherein the antigenic peptide of the at least one other purified complex comprises one or more HLA-binding epitopes of a herpesvirus peptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 4-8, 16-18, 20, 23-25, 29, 33, 38, 39, 43, and 45-49.
19. The composition of claim 18 , further comprising QS-21.
20. The composition of claim 19 , wherein the amount of the stress protein in the composition is in a range of 10 μg to 600 μg.
21. The composition of claim 20 , wherein the amount of the QS-21 in the composition is 10 μg, 25 μg, or 50 μg.
22. The composition of claim 1 further comprising at least one other purified complex of a stress protein noncovalently bound to an antigenic peptide, wherein the antigenic peptide of the at least one other purified complex comprises one or more HLA-binding epitopes of a herpesvirus peptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 4-8, 16-18, 20, 23-25, 29, 33, 38, 39, 43, and 45-49.
23. The composition of claim 1 further comprising at least one other purified complex of a stress protein noncovalently bound to an antigenic peptide, wherein the antigenic peptide of the at least one other purified complex comprises one or more HLA-binding epitopes of a herpesvirus peptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 1-2, 4-8, 10-20, 22-33, 38-40, 43, and 45-49.
24. The composition of claim 2 further comprising at least one other purified complex of a stress protein noncovalently bound to an antigenic peptide, wherein the antigenic peptide of the at least one other purified complex comprises one or more HLA-binding epitopes of a herpesvirus peptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 1-2, 4-8, 10-20, 22-33, 38-40, 43, and 45-102.
25. The method of claim 8 , wherein the composition is administered to the individual biweekly.
26. The method of claim 8 , wherein the composition is administered to the individual by intradermal, subcutaneous, or mucosal administration.
27. The method of claim 8 , wherein the stress protein is a member of the hsp60, hsp70, or hsp90 family of stress proteins.
28. The method of claim 27 , wherein the stress protein is hsp70 or hsc70.
29. The method of claim 28 , wherein the composition further comprises at least one other purified complex of a stress protein noncovalently bound to an antigenic peptide, wherein the antigenic peptide of the at least one other purified complex comprises one or more HLA-binding epitopes of a herpesvirus peptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 4-8, 16-18, 20, 23-25, 29, 33, 38, 39, 43, and 45-49.
30. The method of claim 29 , wherein the composition further comprises QS-21.
31. The method of claim 30 , wherein the amount of the stress protein in the composition is in a range of 10 μg to 600 μg.
32. The method of claim 31 , wherein the amount of the QS-21 in the composition is 10 μg, 25 μg, or 50 μg.
33. The method of claim 21 , wherein the composition further comprises at least one other purified complex of a stress protein noncovalently bound to an antigenic peptide, wherein the antigenic peptide of the at least one other purified complex comprises one or more HLA-binding epitopes of a herpesvirus peptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 4-8, 16-18, 20, 23-25, 29, 33, 38, 39, 43, and 45-49.
34. The method of claim 8 , wherein, prior to administering the immunogenic amount of the composition of claim 1 , antibodies against an HSV antigen are detectable in serum from the individual.
35. The method of claim 8 , wherein, prior to administering the immunogenic amount of the composition of claim 1 , antibodies against an HSV antigen are not detectable in serum from the individual.
36. A composition, comprising a plurality of different purified complexes of a stress protein noncovalently bound to an antigenic peptide, wherein said plurality of different complexes each comprise a different antigenic peptide, and wherein each one of said different antigenic peptides comprises one or more HLA-binding epitopes of a different herpesvirus peptide selected from among herpesvirus peptides differing in amino acid sequence, the amino acid sequence of each herpesvirus peptide selected from the group consisting of SEQ ID NO: 3, 9, 21, 34, 35, 36, 37, 41, 42, and 44, wherein each one of said different antigenic peptides is in a range of 8 amino acids to 45 amino acids in length.
37. The composition of claim 36 , wherein each one of said different antigenic peptides is in a range of 30 amino acids to 40 amino acids in length.
38. The composition of claim 1 , wherein the composition comprises at least 20 different purified complexes of a stress protein noncovalently bound to an antigenic peptide.
39. The composition of claim 1 , wherein the composition comprises at least 30 different purified complexes of a stress protein noncovalently bound to an antigenic peptide.
40. The composition of claim 15 , wherein each of said at least ten different complexes comprise a herpesvirus peptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 9, 21, 34, 35, 36, 37, 41, 42, and 44.
41. The composition of claim 36 , further comprising at least one other purified complex of a stress protein noncovalently bound to an antigenic peptide, wherein the antigenic peptide of the at least one other purified complex comprises one or more HLA-binding epitopes of a herpesvirus peptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 4-8, 16-18, 20, 23-25, 29, 33, 38, 39, 43, and 45-49.
42. The composition of claim 41 , wherein the antigenic peptide in the at least one other purified complex is in a range of 8 amino acids to 45 amino acids in length.
43. The composition of claim 41 , wherein the antigenic peptide in the at least one other purified complex is in a range of 30 amino acids to 40 amino acids in length.