Influenza virus vaccines and uses thereof

1. A chimeric influenza virus hemagglutinin (HA) polypeptide comprising:

(a) the stem domain of the HA from influenza virus A/California/4/2009 (H1N1) and the globular head domain of the HA from an A/Vietnam/1203/2004 (H5), A/Indonesia/5/2005 (H5), A/Anhui/1/2005 (H5), A/Bar headed goose/Quinghai/1A/2005 (H5), A/turkey/Turkey/1/2005 (H5), or A/Whooperswan/Mongolia/244/2005 (H5) influenza virus;

(b) the stem domain of the HA from influenza virus A/Victoria/361/2011 (H3N2), A/harbor seal/Massachusetts/1/2011 (H3N8), or A/Indiana/10/2011 (H3N2) and the globular head domain of the HA from an influenza virus of the H5 subtype;

(c) the stem domain of the HA from influenza virus A/Victoria/361/2011 (H3N2), A/harbor seal/Massachusetts/1/2011 (H3N8), or A/Indiana/10/2011 (H3N2) and the globular head domain of the HA from an influenza virus of the H7 subtype;

(d) the stem domain of the HA from influenza virus B/Malaysia/2506/2004, B/Florida/4/2006, B/Wisconsin/1/2010, or B/Brisbane/60/2008 and the globular head domain of the HA from an influenza virus of the H5 subtype;

(e) the stem domain of the HA from influenza virus B/Malaysia/2506/2004, B/Florida/4/2006, B/Wisconsin/1/2010, or B/Brisbane/60/2008 and the globular head domain of the HA from an influenza virus of the H7 subtype; or

(f) the stem domain of the HA from influenza virus B/Malaysia/2506/2004, B/Florida/4/2006, B/Wisconsin/1/2010, or B/Brisbane/60/2008 and the globular head domain of the HA from a different strain of influenza B virus.

2. The chimeric influenza virus hemagglutinin (HA) polypeptide of claim 1 (b), wherein the H5 subtype is influenza virus HA of A/Vietnam/1203/2004 (H5), A/Indonesia/5/2005 (H5), A/Anhui/1/2005 (H5), A/Bar headed goose/Quinghai/1A/2005 (H5), A/turkey/Turkey/1/2005 (H5), or A/Whooperswan/Mongolia/244/2005 (H5).

3. The chimeric influenza virus hemagglutinin (HA) polypeptide of claim 1 (c), wherein the H7 subtype is influenza virus A/Netherlands/219/03 (H7), A/Canada/504/04 (H7), A/Canada/444/04 (H7), A/chicken/Jalisco/CPA1/2012 (H7), A/mallard/Alberta/24/2001 (H7), A/Rhea/NC/39482/93 (H7), or A/mallard/Netherlands/12/2000 (H7).

4. The chimeric influenza virus hemagglutinin (HA) polypeptide of claim 1 (d), wherein the H5 subtype is influenza virus A/Vietnam/1203/2004 (H5), A/Indonesia/5/2005 (H5), A/Anhui/1/2005 (H5), A/Bar headed goose/Quinghai/1A/2005 (H5), A/turkey/Turkey/1/2005 (H5), or A/Whooperswan/Mongolia/244/2005 (H5).

5. The chimeric influenza virus hemagglutinin (HA) polypeptide of claim 1 (e), wherein the H7 subtype is influenza virus A/Netherlands/219/03 (H7), A/Canada/504/04 (H7), A/Canada/444/04 (H7), A/chicken/Jalisco/CPA1/2012 (H7), A/mallard/Alberta/24/2001 (H7), A/Rhea/NC/39482/93 (H7), or A/mallard/Netherlands/12/2000 (H7).

6. The chimeric influenza virus hemagglutinin (HA) polypeptide of claim 1 (f), wherein the different strain of influenza B virus is B/Lee/1940 or B/seal/Netherlands/1/99.

7. A nucleic acid encoding the chimeric influenza virus hemagglutinin (HA) polypeptide of claim 1 .

8. A cell expressing the nucleic acid of claim 7 .

9. A virus comprising a genome engineered to express the nucleic acid of claim 7 .

10. A virus or virus-like particle comprising the polypeptide of claim 1 .

11. An immunogenic composition comprising the polypeptide of claim 1 .

12. An immunogenic composition comprising:

A (i) a first chimeric influenza virus hemagglutinin (HA) polypeptide, wherein the polypeptide comprises the stem domain of the HA of influenza virus A/California/4/2009 (H1N1) and the globular head domain of the HA of influenza virus /Vietnam/1203/2004 (H5), A/Indonesia/5/2005 (H5), A/Anhui/1/2005 (H5), A/Bar headed goose/Quinghai/1A/2005 (H5), A/turkey/Turkey/1/2005 (H5), or A/Whooperswan/Mongolia/244/2005 (H5); and

(ii) a second chimeric influenza virus hemagglutinin (HA) polypeptide, wherein the polypeptide comprises (a) the stem domain of the HA of influenza virus A/Victoria/361/2011 (H3N2), A/harbor seal/Massachusetts/1/2011 (H3N8), or A/Indiana/10/2011 (H3N2); and (b) the globular head domain of the HA of influenza virus A/Vietnam/1203/2004 (H5), A/Indonesia/5/2005 (H5), A/Anhui/1/2005 (H5), A/Bar headed goose/Quinghai/1A/2005 (H5), A/turkey/Turkey/1/2005 (H5), or A/Whooperswan/Mongolia/244/2005 (H5); or

B (i) a first chimeric influenza virus hemagglutinin (HA) polypeptide, wherein the polypeptide comprises the stem domain of the HA of influenza virus A/California/4/2009 (H1N1) and the globular head domain of the HA of influenza virus A/Vietnam/1203/2004 (H5), A/Indonesia/5/2005 (H5), A/Anhui/1/2005 (H5), A/Bar headed goose/Quinghai/1A/2005 (H5), A/turkey/Turkey/1/2005 (H5), or A/Whooperswan/Mongolia/244/2005 (H5); and

(ii) a second chimeric influenza virus hemagglutinin (HA) polypeptide, wherein the polypeptide comprises (a) the stem domain of the HA of influenza virus A/Victoria/361/2011 (H3N2), A/harbor seal/Massachusetts/1/2011 (H3N8), or A/Indiana/10/2011 (H3N2); and (b) the globular head domain of the HA of influenza virus B/Malaysia/2506/2004 and the globular head domain of the HA of influenza virus A/Netherlands/219/03 (H7), A/Canada/504/04 (H7), A/Canada/444/04 (H7), A/chicken/Jalisco/CPA1/2012 (H7), A/mallard/Alberta/24/2001 (H7), A/Rhea/NC/39482/93 (H7), or A/mallard/Netherlands/12/2000 (H7).

13. The immunogenic composition of claim 12 , further comprising a third chimeric influenza virus hemagglutinin (HA) polypeptide, wherein the polypeptide comprises (a) the stem domain of the HA of influenza virus B/Malaysia/2506/2004, B/Florida/4/2006, B/Wisconsin/1/2010; or B/Brisbane/60/2008; and (b) the globular head domain of the HA of influenza virus A/Vietnam/1203/2004 (H5), A/Indonesia/5/2005 (H5), A/Anhui/1/2005 (H5), A/Bar headed goose/Quinghai/1A/2005 (H5), A/turkey/Turkey/1/2005 (H5), A/Whooperswan/Mongolia/244/2005 (H5), B/Lee/1940, or B/Seal/Netherlands/1/99.

14. An immunogenic composition comprising:

A (i) a first virus comprising a genome engineered to express a first nucleic acid that encodes a chimeric influenza virus hemagglutinin (HA) polypeptide, wherein the polypeptide comprises the stem domain of the HA of influenza virus A/California/4/2009 (H1N1) and the globular head domain of the HA of influenza virus A/Vietnam/1203/2004 (H5), A/Indonesia/5/2005 (H5), A/Anhui/1/2005 (H5), A/Bar headed goose/Quinghai/1A/2005 (H5), A/turkey/Turkey/1/2005 (H5), or A/Whooperswan/Mongolia/244/2005 (H5); and

(ii) a second virus comprising a genome engineered to express a second nucleic acid that encodes a chimeric influenza virus hemagglutinin (HA) polypeptide, wherein the polypeptide comprises (a) the stem domain of the HA of influenza virus A/Victoria/361/2011 (H3N2), A/harbor seal/Massachusetts/1/2011 (H3N8), or A/Indiana/10/2011 (H3N2); and (b) the globular head domain of the HA of influenza virus A/Vietnam/1203/2004 (H5), A/Indonesia/5/2005 (H5), A/Anhui/1/2005 (H5), A/Bar headed goose/Quinghai/1A/2005 (H5), A/turkey/Turkey/1/2005 (H5), or A/Whooperswan/Mongolia/244/2005 (H5); or

B (i) a first virus comprising a genome engineered to express a first nucleic acid that encodes a chimeric influenza virus hemagglutinin (HA) polypeptide, wherein the polypeptide comprises the stem domain of the HA of influenza virus A/California/4/2009 (H1N1) and the globular head domain of the HA of influenza virus A/Vietnam/1203/2004 (H5), A/Indonesia/5/2005 (H5), A/Anhui/1/2005 (H5), A/Bar headed goose/Quinghai/1A/2005 (H5), A/turkey/Turkey/1/2005 (H5), or A/Whooperswan/Mongolia/244/2005 (H5); and

(ii) a second virus comprising a genome engineered to express a second nucleic acid that encodes a chimeric influenza virus hemagglutinin (HA) polypeptide, wherein the polypeptide comprises (a) the stem domain of the HA of influenza virus A/Victoria/361/2011 (H3N2), A/harbor seal/Massachusetts/1/2011 (H3N8), or A/Indiana/10/2011 (H3N2); and (b) the globular head domain of the HA of influenza virus B/Malaysia/2506/2004 and the globular head domain of the HA of A/Netherlands/219/03 (H7), A/Canada/504/04 (H7), A/Canada/444/04 (H7), A/chicken/Jalisco/CPA1/2012 (H7), A/mallard/Alberta/24/2001 (H7), A/Rhea/NC/39482/93 (H7), or A/mallard/Netherlands/12/2000 (H7).

15. The immunogenic composition of claim 14 , further comprising a third virus comprising a genome engineered to express a third nucleic acid that encodes a chimeric influenza virus hemagglutinin (HA) polypeptide, wherein the polypeptide comprises (a) the stem domain of the HA of influenza virus B/Malaysia/2506/2004, B/Florida/4/2006, B/Wisconsin/1/2010; or B/Brisbane/60/2008; and (b) the globular head domain of the HA of influenza virus A/Vietnam/1203/2004 (H5), A/Indonesia/5/2005 (H5), A/Anhui/1/2005 (H5), A/Bar headed goose/Quinghai/1A/2005 (H5), A/turkey/Turkey/1/2005 (H5), A/Whooperswan/Mongolia/244/2005 (H5), B/Lee/1940, or B/Seal/Netherlands/1/99.

16. An immunogenic composition comprising:

A (i) a first virus comprising a first chimeric influenza virus hemagglutinin (HA) polypeptide, wherein the polypeptide comprises the stem domain of the HA of influenza virus A/California/4/2009 (H1N1) and the globular head domain of the HA of influenza virus A/Vietnam/1203/2004 (H5), A/Indonesia/5/2005 (H5), A/Anhui/1/2005 (H5), A/Bar headed goose/Quinghai/1A/2005 (H5), A/turkey/Turkey/1/2005 (H5), or A/Whooperswan/Mongolia/244/2005 (H5); and

(ii) a second virus comprising a second chimeric influenza virus hemagglutinin (HA) polypeptide, wherein the polypeptide comprises (a) the stem domain of the HA of influenza virus A/Victoria/361/2011 (H3N2), A/harbor seal/Massachusetts/1/2011 (H3N8), or A/Indiana/10/2011 (H3N2); and (b) the globular head domain of the HA of influenza virus A/Vietnam/1203/2004 (H5), A/Indonesia/5/2005 (H5), A/Anhui/1/2005 (H5), A/Bar headed goose/Quinghai/1A/2005 (H5), A/turkey/Turkey/1/2005 (H5), or A/Whooperswan/Mongolia/244/2005 (H5); or

B (i) a first virus comprising a first chimeric influenza virus hemagglutinin (HA) polypeptide, wherein the polypeptide comprises the stem domain of the HA of influenza virus A/California/4/2009 (H1N1) and the globular head domain of the HA of influenza virus A/Vietnam/1203/2004 (H5), A/Indonesia/5/2005 (H5), A/Anhui/1/2005 (H5), A/Bar headed goose/Quinghai/1A/2005 (H5), A/turkey/Turkey/1/2005 (H5), or A/Whooperswan/Mongolia/244/2005 (H5); and

(ii) a second virus comprising a second chimeric influenza virus hemagglutinin (HA) polypeptide, wherein the polypeptide comprises (a) the stem domain of the HA of influenza virus A/Victoria/361/2011 (H3N2), A/harbor seal/Massachusetts/1/2011 (H3N8), or A/Indiana/10/2011 (H3N2); and (b) the globular head domain of the HA of influenza virus A/Netherlands/219/03 (H7), A/Canada/504/04 (H7), A/Canada/444/04 (H7), A/chicken/Jalisco/CPA1/2012 (H7), A/mallard/Alberta/24/2001 (H7), A/Rhea/NC/39482/93 (H7), or A/mallard/Netherlands/12/2000 (H7).

17. The immunogenic composition of claim 16 , further comprising a third virus comprising a third chimeric influenza virus hemagglutinin (HA) polypeptide, wherein the polypeptide comprises (a) the stem domain of the HA of influenza virus B/Malaysia/2506/2004, B/Florida/4/2006, B/Wisconsin/1/2010; or B/Brisbane/60/2008; and (b) the globular head domain of the HA of influenza virus A/Vietnam/1203/2004 (H5), A/Indonesia/5/2005 (H5), A/Anhui/1/2005 (H5), A/Bar headed goose/Quinghai/1A/2005 (H5), A/turkey/Turkey/1/2005 (H5), A/Whooperswan/Mongolia/244/2005 (H5), B/Lee/1940, or B/Seal/Netherlands/1/99.

18. A method of immunizing a subject against influenza virus comprising administering to the subject an effective amount of the immunogenic composition of claim 11 .

19. A method of immunizing a subject against influenza virus comprising administering to the subject a first dose of an effective amount of an immunogenic composition and administering to the subject a second dose of an effective amount of the immunogenic composition 30 days to 6 months after the subject has received the first dose, wherein the immunogenic composition is the composition of claim 11 .

20. A method of immunizing a subject against influenza virus comprising administering to the subject a first dose of an effective amount of a first immunogenic composition and administering to the subject a second dose of an effective amount of a second immunogenic composition 30 days to 6 months after the subject has received the first dose, wherein the immunogenic compositions are the compositions of claim 11 , and wherein the globular head domain of the chimeric influenza virus hemagglutinin (HA) polypeptide present in the first immunogenic composition is different than the globular head domain of the chimeric influenza virus hemagglutinin (HA) polypeptide present in the second immunogenic composition.

21. A method of preventing an influenza virus disease or treating an influenza virus infection or an influenza virus disease comprising administering to a subject an effective amount of the immunogenic composition of claim 11 .

22. The chimeric influenza virus hemagglutinin (HA) polypeptide of claim 1 , wherein the polypeptide is soluble.

23. The chimeric influenza virus HA polypeptide of claim 22 , wherein the polypeptide does not comprise a transmembrane domain or an endodomain of an influenza virus HA.

24. The chimeric influenza virus HA polypeptide of claim 23 , wherein the polypeptide further comprises a thrombin cleavage site and a T4 trimerization domain.

25. The chimeric influenza virus HA polypeptide of claim 23 , wherein the polypeptide further comprises a HIS tag.

26. The chimeric influenza virus HA polypeptide of claim 23 , wherein the polypeptide further comprises a HIS tag.