West nile virus vaccine
The invention provides chimeric flavivirus vaccines against West Nile virus and methods of using these vaccines to prevent or treat West Nile virus infection.
1. A nucleic acid molecule comprising sequences encoding the pre-membrane and envelope proteins of a West Nile virus and the capsid and non-structural proteins of a Yellow Fever virus, wherein said envelope protein comprises attenuating amino acid substitutions in position 316 and position 440, or the complement of said nucleic acid molecule.
2. The nucleic acid molecule of claim 1 , wherein the sequence encoded by said nucleic acid molecule further comprises an amino acid substitution in amino acid position 107.
3. The nucleic acid molecule of claim 2 , wherein said amino acid substitution at position 107 is leucine to phenylalanine, or a conservative amino acid of phenylalanine.
4. The nucleic acid molecule of claim 1 , wherein said amino acid substitution at position 316 is alanine to valine, or a conservative amino acid of valine.
5. The nucleic acid molecule of claim 1 , wherein said amino acid substitution at position 440 is lysine to arginine, or a conservative amino acid of arginine.
6. A chimeric flavivirus encoded by the nucleic acid molecule of claim 1 .
7. A method of inducing an immune response to West Nile virus in a subject, said method comprising administering to the subject the chimeric flavivirus of claim 6 .
8. The method of claim 7 , wherein said subject is at risk of developing, but does not have, West Nile virus infection.
9. The method of claim 7 , wherein said subject is infected with West Nile virus.
10. A method of making a chimeric flavivirus vaccine, comprising introducing the nucleic acid molecule of claim 1 , into cells.
11. The nucleic acid molecule of claim 1 , wherein said nucleic acid molecule comprises the genome of a chimeric flavivirus comprising the pre-membrane and envelope proteins of West Nile virus and the capsid and non-structural proteins of Yellow Fever virus, wherein said envelope protein comprises attenuating amino acid substitutions in position 316 and position 440.
12. The chimeric flavivirus of claim 6 , wherein the envelope protein of said chimeric flavivirus further comprises an amino acid substitution in amino acid position 107.
13. The chimeric flavivirus of claim 12 , wherein said amino acid substitution at position 107 is leucine to phenylalanine, or a conservative amino acid of phenylalanine.
14. The chimeric flavivirus of claim 6 , wherein said amino acid substitution at position 316 is alanine to valine, or a conservative amino acid of valine.
15. The chimeric flavivirus of claim 6 , wherein said amino acid substitution at position 440 is lysine to arginine, or a conservative amino acid of arginine.
16. The method of claim 7 , wherein the envelope protein of said chimeric flavivirus further comprises an amino acid substitution in amino acid position 107.
17. The method of claim 16 , wherein said amino acid substitution at position 107 is leucine to phenylalanine, or a conservative amino acid of phenylalanine.
18. The method of claim 7 , wherein said amino acid substitution at position 316 is alanine to valine, or a conservative amino acid of valine.
19. The method of claim 7 , wherein said amino acid substitution at position 440 is lysine to arginine, or a conservative amino acid of arginine.
20. The method of claim 10 , wherein the envelope protein of said chimeric flavivirus further comprises an amino acid substitution in amino acid position 107.
21. The method of claim 20 , wherein said amino acid substitution at position 107 is leucine to phenylalanine, or a conservative amino acid of phenylalanine.
22. The method of claim 10 , wherein said amino acid substitution at position 316 is alanine to valine, or a conservative amino acid of valine.
23. The method of claim 10 , wherein said amino acid substitution at position 440 is lysine to arginine, or a conservative amino acid of arginine.
24. A vaccine composition comprising the flavivirus of claim 6 .
25. The vaccine composition of claim 24 , wherein the envelope protein of said chimeric flavivirus further comprises an amino acid substitution in amino acid position 107.
26. The vaccine composition of claim 25 , wherein said amino acid substitution at position 107 is leucine to phenylalanine, or a conservative amino acid of phenylalanine.
27. The vaccine composition of claim 24 , wherein said amino acid substitution at position 316 is alanine to valine, or a conservative amino acid of valine.
28. The vaccine composition of claim 24 , wherein said amino acid substitution at position 440 is lysine to arginine, or a conservative amino acid of arginine.