Compositions, methods and uses for dengue virus serotype-4 constructs
Embodiments herein report compositions, methods and uses for dengue-4 (DENV-4) virus constructs. Some embodiments concern a composition that includes, but is not limited to, DENV-4 virus constructs alone or in combination with other constructs, can be used in a vaccine composition to induce an immune response in a subject. In certain embodiments, compositions can include constructs of more than one serotypes of dengue virus, such as dengue-1 virus, dengue-2 virus, or dengue-3 virus in combination with DENV-4 virus constructs disclosed herein. In other embodiments, DENV-4 constructs disclosed herein can be combined in a composition with other flavivirus constructs to generate a vaccine against more than one flavivirus. Other embodiments provide methods and uses for DENV-4 virus constructs in vaccine compositions that when administered to a subject induce an immune response in the subject against DENV-4 that is improved by modified constructs compared to other vaccine compositions.
1. A nucleic acid molecule comprising a chimeric flavivirus construct comprising nucleic acid sequences encoding nonstructural proteins and one or more structural proteins from a live, attenuated dengue-2 virus and at least encoding one or more structural proteins from a second dengue virus, the second flavivirus is selected from the group dengue-1, dengue-3 or dengue-4 virus wherein the chimeric construct further comprises one or more mutations comprising, a mutation in an envelope (E) protein at an amino acid position synonymous of dengue 4 to amino acid 417 when the E protein is from the second flavivirus wherein the mutation in the envelope (E) protein at the position synonymous to amino acid 417 changes glutamic acid to a positively charged residue; a mutation in the capsid protein at an amino acid position synonymous to amino acid 107 in the attenuated dengue-2 wherein the mutation in the capsid (C) protein at the position synonymous to amino acid 107 changes cysteine to an aromatic amino acid residue in the attenuated dengue-2, and a mutation in NS4A at an amino acid position synonymous to amino acid position 17 in the attenuated dengue-2.
2. The nucleic acid molecule according to claim 1 , wherein the second flavivirus is dengue-4.
3. The nucleic acid molecule according to claim 1 , wherein the position synonymous to 417 is a lysine instead of the glutamic acid in the at least second flavivirus.
4. The nucleic acid molecule according to claim 1 , wherein the nucleic acid molecule comprises the mutation in the capsid (C) protein at a position synonymous to amino acid 107 changes cysteine to an aromatic amino acid residue; a mutation in the envelope (E) protein at the position synonymous to amino acid 417 changes glutamic acid to a positively charged residue; and a mutation in NS4A at an amino acid position synonymous to amino acid position 17 in the attenuated dengue-2.
5. The nucleic acid molecule according to claim 1 , wherein the aromatic amino acid at the position synonymous to amino acid 107 is a tyrosine.
6. The nucleic acid molecule according to claim 1 , wherein the mutation in the NS4A protein at the position synonymous to amino acid 17 changes methionine to a basic amino acid.
7. The nucleic acid molecule according to claim 1 , wherein the mutation in the NS4A protein at a position synonymous to amino acid 17 changes methionine to a leucine.
8. The nucleic acid molecule according to claim 1 , wherein the live, attenuated dengue-2 contains a mutation at position 57 in the 5′NCR, a mutation at position 53 of NS1 and a mutation at position 250 of NS3.
9. The nucleic acid molecule according to claim 1 , wherein the live, attenuated dengue-2 contains a mutation at position 53 of NS1 and a mutation at position 250 of NS3.
10. The nucleic acid molecule according to claim 2 , wherein amino acid positions 102-106 of attenuated dengue-2 are substituted with synonymous amino acids of a dengue-4 virus in these positions.
11. The nucleic acid molecule according to claim 1 , further comprising a structural protein from a third different flavivirus.
12. The nucleic acid molecule according to claim 11 , wherein the third different flavivirus is selected from the group consisting of West Nile virus, Japanese encephalitis virus, St. Louis encephalitis virus, tickborne encephalitis virus, and yellow fever virus.
13. A composition comprising one or more nucleic acid molecules according to claim 1 , and a pharmaceutically acceptable carrier.
14. The composition according to claim 13 , wherein the composition further comprises additional dengue-dengue chimeric constructs.
15. The composition according to claim 13 , wherein the composition is part of a divalent, trivalent or tetravalent dengue virus composition.
16. The composition according to claim 13 , wherein the composition further comprises other live, attenuated flaviviruses.
17. A method of inducing an immune response to dengue virus in a subject comprising administering the composition of claim 13 to the subject.
18. The method according to claim 17 , wherein an immune response to at least one of dengue-1, dengue-2, dengue-3 and dengue-4 is induced in the subject.
19. A kit comprising one or more compositions according to claim 13 and a container.
20. A live, attenuated virus comprising the nucleic acid molecule according to claim 1 .
21. A live, attenuated dengue-4 chimera comprising DENVax4e, DENVax4i or DENVax4h.
22. The chimera according to claim 21 , wherein the chimera comprises SEQ ID NO: 22, SEQ ID NO:9, or SEQ ID NO: 24.
23. A composition comprising one or more nucleic acid chimeras according to claim 21 , and a pharmaceutically acceptable carrier.
24. A method of inducing an immune response to dengue virus in a subject comprising administering the composition of claim 23 to the subject.
25. The nucleic acid molecule according to claim 2 , wherein dengue-4 is from strain 1036.
26. The nucleic acid molecule according to claim 1 , wherein the live, attenuated dengue-2 virus comprises a mutated PDK-53 backbone.
27. The live, attenuated virus of claim 20 , wherein the live, attenuated virus is part of an immunogenic composition against two or more dengue virus serotypes.