Flavivirus vaccines
The invention provides flavivirus vaccines and methods of making and using these vaccines.
1. A method of reducing the viscerotropism and/or neurovirulence of a flavivirus which is a chimeric flavivirus comprising sequences encoding capsid and non-structural proteins of a first flavivirus and pre-membrane and envelope proteins of a dengue virus selected from a dengue-1 virus, a dengue-2 virus, a dengue-3 virus, and a dengue-4 virus, the method comprising substituting lysine at envelope protein position 202 (dengue-3) or 204 (dengue-1, dengue-2, or dengue-4) with arginine.
2. The method of claim 1 , wherein said sequences encoding said dengue pre-membrane and envelope proteins encode pre-membrane and envelope proteins of a dengue-1 virus.
3. The method of claim 1 , wherein said sequences encoding said dengue pre-membrane and envelope proteins encode pre-membrane and envelope proteins of a dengue-2 virus.
4. The method of claim 1 , wherein said sequences encoding said dengue pre-membrane and envelope proteins encode pre-membrane and envelope proteins of a dengue-3 virus.
5. The method of claim 1 , wherein said sequences encoding said dengue pre-membrane and envelope proteins encode pre-membrane and envelope proteins of a dengue-4 virus.
6. The method of claim 1 , wherein said first flavivirus is a yellow fever virus.
7. The method of claim 6 , wherein said substitution reduces the viscerotropism of said chimeric flavivirus.
8. A method of inducing an immune response to a flavivirus in a subject, said method comprising administering to said patient a flavivirus which is a chimeric flavivirus comprising sequences encoding capsid and non-structural proteins of a first flavivirus and pre-membrane and envelope proteins of a dengue virus selected from a dengue-1 virus, a dengue-2 virus, a dengue-3 virus and a dengue-4 virus, wherein the dengue virus envelope protein has a substitution of the lysine at amino acid position 202 (dengue-3) or 204 (dengue-1, dengue-2, or dengue-4) with arginine and wherein said method results in decreased viscerotropism and/or neurovirulence in said subject relative to a corresponding flavivirus lacking the substitution.
9. The method of claim 8 , wherein said sequences encoding said dengue pre-membrane and envelope proteins encode pre-membrane and envelope proteins of a dengue-1 virus.
10. The method of claim 8 , wherein said sequences encoding said dengue pre-membrane and envelope proteins encode pre-membrane and envelope proteins of a dengue-2 virus.
11. The method of claim 8 , wherein said sequences encoding said dengue pre-membrane and envelope proteins encode pre-membrane and envelope proteins of a dengue-3 virus.
12. The method of claim 8 , wherein said sequences encoding said dengue pre-membrane and envelope proteins encode pre-membrane and envelope proteins of a dengue-4 virus.
13. The method of claim 8 , wherein said first flavivirus is a yellow fever virus.
14. The method of claim 13 , wherein said substitution reduces the viscerotropism of said chimeric flavivirus.
15. The method of claim 8 , further comprising administering to said subject three additional chimeric flaviviruses that each comprise sequences encoding capsid and non-structural proteins of said first flavivirus and pre-membrane and envelope proteins of one of dengue-1, dengue-2, dengue-3, and dengue-4 viruses, wherein the dengue virus sequences of the three additional chimeric flaviviruses are of serotypes that are different from one another and different from that administered in the method of claim 8 , and optionally the dengue virus envelope protein of one or more of the three additional chimeras has a substitution of the lysine at amino acid position 202 (dengue-3) or 204 (dengue-1, dengue-2, or dengue-4) with arginine.
16. A method of reducing the viscerotropism and/or neurovirulence of a flavivirus which is a dengue virus selected from a dengue-1 virus, a dengue-2 virus, a dengue-3 virus, and a dengue-4 virus, the method comprising substituting lysine at envelope protein position 202 (dengue-3) or 204 (dengue-1, dengue-2, or dengue-4) with arginine, wherein when viscerotropism and/or neurovirulence of said dengue-3 virus is reduced, said substitution of lysine at envelope protein position 202 with arginine is the only mutation in said dengue-3 virus.
17. The method of claim 16 , wherein said dengue virus is a dengue-1 virus.
18. The method of claim 16 , wherein said dengue virus is a dengue-2 virus.
19. The method of claim 16 , wherein said dengue virus is a dengue-3 virus.
20. The method of claim 16 , wherein said dengue virus is a dengue-4 virus.
21. The method of claim 16 , wherein said substitution reduces the viscerotropism of said flavivirus.
22. A method of inducing an immune response to a flavivirus in a subject, said method comprising administering to said patient a flavivirus which is a dengue virus selected from a dengue-1 virus, a dengue-2 virus, a dengue-3 virus, and a dengue-4 virus, wherein the dengue virus envelope protein has a substitution of the lysine at amino acid position 202 (dengue-3) or 204 (dengue-1, dengue-2 or dengue-4) with arginine and wherein said method results in decreased viscerotropism and/or neurovirulence in said subject relative to a corresponding flavivirus lacking the substitution.
23. The method of claim 22 , wherein said dengue virus is a dengue-1 virus.
24. The method of claim 22 , wherein said dengue virus is a dengue-2 virus.
25. The method of claim 22 , wherein said dengue virus is a dengue-3 virus.
26. The method of claim 22 , wherein said dengue virus is a dengue-4 virus.
27. The method of claim 22 , wherein said substitution reduces the viscerotropism of said flavivirus.