Methods of modulating an immune response using immunostimulatory sequences and compositions for use therein
The invention provides methods of modulating an immune response to a second antigen which entail administration of a first antigen and an immunostimulatory polynucleotide. Modulation of the immune response is generally manifested as stimulation of a Th1 response.
1. A method of modulating an immune response to a second antigen in an individual, comprising co-administering to the individual
(i) a complex comprising an immunomodulatory polynucleotide covalently conjugated to a first antigen and
(ii) a second antigen
wherein the polynucleotide comprises an immunostimulatory sequence (ISS), wherein the ISS comprises the sequence 5′-cytosine, guanine-3′, wherein the complex and the second antigen are administered at the same site in the individual and wherein the complex is administered in an amount sufficient to modulate an immune response in the individual to the second antigen.
2. The method of claim 1 , wherein the first antigen is an allergen.
3. The method of claim 1 , wherein the first antigen is a conserved polypeptide of a virus.
4. The method of claim 3 , wherein the conserved viral polypeptide is influenza nucleocapsid protein.
5. The method of claim 3 , wherein the conserved viral polypeptide is human immunodeficiency virus (HIV) gag protein.
6. The method of claim 1 , wherein the first antigen is a carrier molecule.
7. The method of claim 6 , wherein the carrier molecule is diphtheria toxin mutant (CRM 197).
8. The method of claim 6 , wherein the carrier molecule is diphtheria toxoid.
9. The method of claim 1 , wherein the first antigen is associated with a carrier molecule.
10. The method of claim 1 , wherein the immune response is modulated by stimulating a Th1 response to the second antigen.
11. The method of claim 10 , wherein production of second antigen-specific Th1-associated antibodies is stimulated.
12. The method of 10 , wherein interferon gamma production is stimulated.
13. The method of claim 1 , wherein the ISS comprises the sequence 5′-TCG-3′.
14. The method of claim 1 , wherein the ISS comprises the sequence 5′-purine, purine, C, G, pyrimidine, pyrimidine-3′.
15. The method of claim 14 , wherein the ISS comprises the sequence 5′-AACGTT-3′.
16. The method of claim 14 , wherein the ISS comprises the sequence 5′-purine, purine, C, G, pyrimidine, pyrimidine, C, C-3′.
17. The method of claim 14 , wherein the ISS comprises the sequence 5′-purine, purine, C, G, pyrimidine, pyrimidine, C, G-3′.
18. The method of claim 14 , wherein the ISS comprises a sequence selected from the group consisting of AACGTTCC, AACGTTCG, GACGTTCC, and GACGTTCG.
19. The method of claim 17 , wherein the ISS comprises the sequence TGACTGTGAACGTTCGAGATGA (SEQ ID NO:1).
20. The method of claim 1 , wherein the individual is a mammal.
21. The method of claim 20 , wherein the mammal is human.
22. A composition comprising
(i) a complex comprising an immunomodulatory polynucleotide covalently conjugated to a first antigen and
(ii) a second antigen,
wherein the polynucleotide comprises an immunostimulatory sequence (ISS), wherein the ISS comprises the sequence 5′-cytosine, guanine-3′, and wherein the first antigen is a viral conserved polypeptide and the second antigen is a viral variable polypeptide.
23. The composition of claim 22 , wherein the first antigen is influenza nucleocapsid protein.
24. The composition of claim 22 , wherein the first antigen is human immunodeficiency virus (HIV) gag protein.
25. A composition comprising
(i) a complex comprising an immunomodulatory polynucleotide covalently conjugated to a first antigen and
(ii) a second antigen,
wherein the polynucleotide comprises an immunostimulatory sequence (ISS), wherein the ISS comprises the sequence 5′-cytosine, guanine-3′, and wherein the first antigen is an allergen.
26. The composition of claim 25 , wherein the allergen is Amb a I.
27. The method of claim 2 , wherein the allergen is Amb a I.