Stabilized hemagglutinin (HA) trimer as an influenza vaccine antigen

Abstract

The present invention provides a vaccine composition comprising a novel engineered influenza hemagglutinin (HA) protein, an associated polynucleotide sequence, and a nanoparticle composition. Compared to the wild-type HA protein, the engineered HA protein is stabilized by the substitution of one or more conserved residues in the HA2 ectodomain with hydrophobic residues. The present invention also provides methods for using such vaccine compositions in various therapeutic applications, for example, to prevent or treat influenza virus infection.

Claims

1. An engineered influenza virus hemagglutinin (HA) protein comprising a modified HA2 ectodomain, wherein the modified HA2 ectodomain comprises a hydrophobic residue substitution at the 95th or 106th amino acid residue, and the amino acid numbering of HA2 is based on influenza A subtype H3.

2. The manipulated influenza virus hemagglutinin (HA) protein according to claim 1, further comprising intact HA1.

3. The manipulated influenza virus hemagglutinin (HA) protein according to claim 1, which does not contain the HA head domain.

4. The manipulated influenza virus hemagglutinin (HA) protein according to claim 1, wherein the HA protein is derived from influenza A virus and the substituted amino acid residue is N95.

5. The manipulated influenza virus hemagglutinin (HA) protein according to claim 1, wherein the HA protein is derived from influenza B virus and the substituted amino acid residue is Q95.

6. The manipulated influenza virus hemagglutinin (HA) protein according to claim 1, wherein the HA protein is derived from influenza C virus and the substituted amino acid residue is E95.

7. The manipulated influenza virus hemagglutinin (HA) protein according to claim 1, wherein the substituted residue is Ala, Val, Leu, Ile, Met, Phe, Tyr, or Trp.

8. The modified influenza virus hemagglutinin (HA) protein according to claim 1, wherein the modified HA2 ectodomain includes substitution of both amino acid residues at positions 95 and 106 with hydrophobic residues.

9. The manipulated influenza virus hemagglutinin (HA) protein according to claim 8, wherein (1) the HA protein is derived from influenza A virus of group 1 and the residue at position 106 is R106, (2) the HA protein is derived from influenza A virus of group 2 and the residue at position 106 is H106, or (3) the HA protein is derived from influenza B virus and the residue at position 106 is G106.

10. The manipulated influenza virus hemagglutinin (HA) protein according to claim 8, wherein each substitution is independently Ala, Val, Leu, Ile, Met, Phe, Tyr, or Trp.

11. The manipulated influenza virus hemagglutinin (HA) protein according to claim 1, comprising (1) the substitution at position 95, and (2) further amino acid substitution by a hydrophobic residue at either or both positions 51 and 103.

12. The manipulated influenza virus hemagglutinin (HA) protein according to claim 11, wherein the HA protein is derived from influenza A virus, and the additionally substituted amino acid residues are K51 and E103.

13. The manipulated influenza virus hemagglutinin (HA) protein according to claim 1, further comprising a subunit sequence of self-assembling nanoparticles fused to the C-terminus of the manipulated HA protein.

14. A pharmaceutical composition comprising the manipulated influenza virus hemagglutinin (HA) protein described in claim 1 and a pharmaceutically acceptable carrier.

15. The pharmaceutical composition according to claim 14, wherein the manipulated HA protein is presented on the surface of self-assembling nanoparticles.

16. A polynucleotide encoding the manipulated influenza virus hemagglutinin (HA) protein according to claim 1.

17. A vector comprising the polynucleotide described in claim 14.

18. A host cell having polynucleotides as described in claim 14.

19. An influenza virus vaccine composition comprising the manipulated HA protein according to claim 1, presented on the surface of self-assembling nanoparticles.

20. The vaccine composition according to claim 19, wherein the self-assembling nanoparticles comprise a trimer sequence, and the C-terminus of the manipulated HA protein is fused to the N-terminus of the subunit sequence of the nanoparticles.

21. The vaccine composition according to claim 19, wherein the self-assembling nanoparticles comprise I3-01, E2p, or ferritin.

22. The vaccine composition according to claim 19, further comprising a lock domain and / or a T cell epitope fused to the C-terminus of the nanoparticle subunit sequence.

23. A method for treating or preventing influenza virus infection in a subject, comprising administering the pharmaceutical composition described in claim 14 to the subject, thereby treating or preventing influenza virus infection in the subject.

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