Vaccines for use in the prophylaxis and treatment of influenza virus disease
Provided herein are polypeptides comprising portions of the influenza virus hemagglutinin, compositions comprising such polypeptides that can be used as immunogens in vaccines and methods of their use to generate an immune response against multiple influenza subtypes in a subject.
1. An immunogenic composition capable of inducing antibodies that are cross-reactive among influenza hemagglutinin (HA) subtypes, the immunogenic composition comprising a flu polypeptide comprising an immunogenic core polypeptide, wherein the immunogenic core polypeptide is (a) directly or indirectly linked at its N- and/or C-terminus to one or more tags; (b) directly or indirectly linked at its N- and/or C-terminus to a T cell epitope; (c) directly or indirectly linked at its N- and/or C-terminus to a Toll Like Receptor ligand; or (d) directly or indirectly linked at its N- and/or C-terminus to a T4 foldon domain or a fragment thereof, wherein the immunogenic core polypeptide is less than 75 amino acids in length, and wherein the immunogenic core polypeptide comprises:
R-I-Q-D-L-E-K-Y-V-E-D-T-K-I-D-L-W-S-Y-N-A-E-L-L-V-A-L-E-N-Q-H-T-I-D-L-T-D-S-E-M-N-K-L-F-E-X 1 T-X 2 -X 3 -Q-L-R-E-N-A (SEQ ID NO: 15), wherein X 1 , X 2 , and X 3 are hydrophilic, basic amino acids.
2. The immunogenic composition of claim 1 , wherein the immunogenic core polypeptide comprises SEQ ID NO: 16, SEQ ID NO: 17, or SEQ ID NO: 18.
3. The immunogenic composition of claim 1 , wherein the immunogenic core polypeptide selectively binds neutralizing antiserum capable of binding an influenza hemagglutinin.
4. The immunogenic composition of claim 1 , wherein the immunogenic core polypeptide is further (a) acetylated at its N-terminus; or (b) linked to polyethylene glycol at its N- and/or C-terminus.
5. The immunogenic composition of claim 1 , wherein the immunogenic core polypeptide is further linked to a carrier protein.
6. The immunogenic composition of claim 1 , wherein the immunogenic core polypeptide has the amino acid sequence RIQDLEKYVEDTKIDLWSYNAELLVALENQHTIDLTDSEMNKLFEKTRRQLRENA (SEQ ID NO: 2), and wherein the immunogenic core polypeptide is linked at its C-terminus to a polypeptide having the amino acid sequence DYKDDDDKC (SEQ ID NO: 63).
7. The immunogenic composition of claim 1 , wherein X 1 is K or R, X 2 is K or R, and X 3 is K or R.
8. The immunogenic composition of claim 1 , wherein the immunogenic core polypeptide is directly or indirectly linked at its N- and/or C-terminus to one or more tags.
9. The immunogenic composition of claim 7 , wherein the immunogenic core polypeptide is directly or indirectly linked at its N- and/or C-terminus to one or more tags.
10. The immunogenic composition of claim 1 , wherein the immunogenic core polypeptide is directly or indirectly linked at its N- and/or C-terminus to a T cell epitope.
11. The immunogenic composition of claim 7 , wherein the immunogenic core polypeptide is directly or indirectly linked at its N- and/or C-terminus to a T cell epitope.
12. The immunogenic composition of claim 1 , wherein the immunogenic core polypeptide is directly or indirectly linked at its N- and/or C-terminus to a Toll Like Receptor ligand.
13. The immunogenic composition of claim 7 , wherein the immunogenic core polypeptide is directly or indirectly linked at its N- and/or C-terminus to a Toll Like Receptor ligand.
14. The immunogenic composition of claim 1 , wherein the immunogenic core polypeptide is directly or indirectly linked at its N- and/or C-terminus to a T4 foldon domain or a fragment thereof.
15. The immunogenic composition of claim 7 , wherein the immunogenic core polypeptide is directly or indirectly linked at its N- and/or C-terminus to a T4 foldon domain or a fragment thereof.
16. A method of inducing an immune response to an influenza virus in a subject, comprising administering to the subject an effective amount of the immunogenic composition of claim 1 .
17. A method of inducing an immune response to an influenza virus in a subject, comprising administering to the subject an effective amount of the immunogenic composition of claim 7 .
18. A method of preventing an influenza virus disease in a subject, comprising administering to the subject an effective amount of the immunogenic composition of claim 1 .
19. A method of preventing an influenza virus disease in a subject, comprising administering to the subject an effective amount of the immunogenic composition of claim 7 .
20. The method of claim 16 , wherein the subject is a human.
21. The method of claim 17 , wherein the subject is a human.
22. The method of claim 18 , wherein the subject is a human.
23. The method of claim 19 , wherein the subject is a human.