Immunogenic compositions containing inactivated influenza a virus and cpg oligonucleotide adjuvant and uses thereof

Abstract

Provided herein are immunogenic compositions comprising a chimeric influenza A virus HA and a CpG oligonucleotide adjuvant. Also provided herein are immunogenic compositions comprising an inactivated influenza A virus described herein or inactivated split influenza A virus described herein and a CpG oligonucleotide adjuvant described herein, wherein the inactivated influenza A virus or inactivated split influenza A virus comprises a chimeric hemagglutinin described herein. The immunogenic compositions may be used in a sequential immunization regimen. Also provided herein are methods of immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) using an immunogenic composition described herein. Further, provided herein are methods of preventing influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject using an immunogenic composition described herein.

Description

IMMUNOGENIC COMPOSITIONS CONTAINING INACTIVATED INFLUENZA A VIRUS AND CpG OLIGONUCLEOTIDE ADJUVANT AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 514,562, filed July 19, 2023, the disclosure of which is incorporated by reference herein in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with government support under award W81XWH-18-1- 0488 awarded by the Department of Defense grant, awards P01 AI097092, R01 AI145870, and R01 AI141226 awarded by the NIH, and the Collaborative Influenza Vaccine Innovation Centers (CIVIC) contract 75N93019C00051. The government has certain rights in this invention.SEQUENCE LISTING

[0003] This application contains an electronic Sequence Listing which has been submitted in XML file format with this application, the entire content of which is incorporated by reference herein in its entirety. The Sequence Listing XML file submitted with this application is entitled “06923-412-228_SEQ_LISTING.xml”, was created on July 18, 2024, and is 100,015 bytes in size.1. INTRODUCTION

[0004] Provided herein are immunogenic compositions comprising a chimeric influenza A virus HA and a CpG oligonucleotide adjuvant. Also provided herein are immunogenic compositions comprising an inactivated influenza A virus described herein or inactivated split influenza A virus described herein and a CpG oligonucleotide adjuvant described herein, wherein the inactivated influenza A virus or inactivated split influenza A virus comprises a chimeric hemagglutinin described herein. The immunogenic compositions may be used in a sequential immunization regimen. Also provided herein are methods of immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) using an immunogenic composition described herein. Further, provided herein are methods of preventing influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject using an immunogenic composition described herein.2. BACKGROUND

[0005] Seasonal influenza viruses represent a major public health burden every year. The vaccine effectiveness (VE) of commercially available influenza vaccines is in the range of 10-60%, being generally lower for H3N2 in comparison to H1N1 and influenza B viruses (1, 2). The rapid antigenic evolution of H3N2 viruses (FIG. 1) (3), the acquisition of TV-linked glycans in the immunodominant hemagglutinin (HA) head domain (4), and egg-adaptive mutations (5) may be the main reasons for the lower VE for these vaccines. Additionally, the risk of swine H3N2 influenza virus transmission to humans (6), the existence of other avian and mammalian animal reservoirs for viruses such as H3N8 (7), and sporadic inter-species transmission of other group 2 HA viruses like H7N9 (8) and H10NX (9, 10) pose a potential pandemic threat.

[0006] Current influenza virus vaccines are composed of the matched group 1, group 2, and influenza B virus circulating strains. The immune response elicited by these vaccines mainly targets the immunodominant head domain of the most abundant influenza virus glycoprotein, the HA. The head domain of the HA is subject to strong antigenic drift and can accommodate mutations that facilitate escape from pre-existing immunity, hence annual revaccinations are required. Moreover, seasonal influenza virus vaccines would offer little to no protection against pandemic influenza viruses. The development of broadly protective vaccines is therefore of high importance (11, 12).3. SUMMARY

[0007] In one aspect, provided herein are immunogenic compositions comprising a chimeric hemagglutinin (HA) described herein and a CpG oligonucleotide adjuvant. In some embodiments, provided herein is an immunogenic composition, comprising: (a) a chimeric hemagglutinin (HA) comprising an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0008] In some embodiments, provided herein are immunogenic compositions comprising an inactivated split influenza virus and a CpG oligonucleotide adjuvant, whereinthe inactivated influenza virus comprises a chimeric HA. In some embodiments, provided herein is an immunogenic composition, comprising: (a) an inactivated influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the inactivated influenza virus comprises neuraminidase of the group 2 influenza A virus of interest. In some embodiments, the inactivated influenza virus comprises one or more proteins encoded by one or more genes of influenza A virus A / Puerto Rico / 8 / 1934.

[0009] In some embodiments, provided herein are immunogenic compositions comprising an inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the inactivated split influenza virus comprises a chimeric HA. In some embodiments, provided herein is an immunogenic composition, comprising: (a) an inactivated split influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the inactivated split influenza virus comprises neuraminidase of the group 2 influenza A virus of interest. In some embodiments, the inactivated split influenza virus comprises one or more proteins encoded by one or more genes of influenza A virus A / Puerto Rico / 8 / 1934.

[0010] In some embodiments, the group 2 influenza A virus HA of interest is of subtype H3. In some embodiments, the group 2 influenza A virus HA of interest is A / Hong Kong / 4801 / 2014, NYMC X-263 HA or A / Hong Kong / 4801 / 2014-like HA.

[0011] In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is a group 1 influenza A virus HA. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is of subtype H2, H5, H6, H8, H9, Hl 1, H12, H13, H16, H17, or H18. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is of subtype H4, H7, H10, H14, or H15. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is the HA of an avian influenza virus subtype which does not circulate in humans (e.g., an avian influenza A virus subtype H4 or Hl 5). In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is A / wedge-tailed shearwater / Western Australia / 2576 / 1979 HA or A / wedge-tailed shearwater / We stern Australia / 2576 / 1979-like HA. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is A / Duck / Czechoslovakia / 1956 HA or A / Duck / Czechoslovakia / 1956-like HA.

[0012] In some embodiments, provided herein is an immunogenic composition, comprising: (a) an inactivated influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:5, 6, 7 or 8, or the amino acid sequence of SEQ ID NO:5, 6, 7, or 8; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, provided herein is an immunogenic composition, comprising: (a) an inactivated split influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:5, 6, 7 or 8, or the amino acid sequence of SEQ ID NO:5, 6, 7, or 8; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0013] In some embodiments, the oligonucleotide comprises the nucleotide sequence of 5’-TGACTGTGAACGTTCGAGATGA-3’ (SEQ ID NO:4). In some embodiments, the oligonucleotide is 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 nucleotides in length. In some embodiments, the oligonucleotide is a single stranded oligodeoxynucleotide. In some embodiments, the oligonucleotide comprises only phosphorothioate linkages, or a combination of one or more phosphodiester linkages and one or more phosphorothioatelinkages. In some embodiments, the oligonucleotide is fully RNA or is an RNA / DNA chimera.

[0014] In some embodiments, the immunogenic composition further comprises an aluminum salt. In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate. In some embodiments, the aluminum salt comprises aluminum hydroxide or aluminum phosphate.

[0015] In another aspect, provided herein are methods for preventing influenza virus disease in a subject, comprising administering to the subject the immunogenic composition described herein. In another aspect, provided herein are methods of immunizing a subject against influenza virus disease, comprising administering to the subject the immunogenic composition described herein. In another aspect, provided herein are methods of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising administering to the subject the immunogenic composition described herein. In some embodiments, the immunogenic composition is administered intramuscularly to the subject. In some embodiments, the immunogenic composition is administered intranasally to the subject.

[0016] In another aspect, provided herein are methods for preventing influenza virus disease in a subject, comprising administering to the subject two or more immunogenic compositions described herein. In another aspect, provided herein are methods of immunizing a subject against influenza virus disease, comprising administering to the subject two or more immunogenic compositions described herein. In another aspect, provided herein are methods of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising administering to the subject two or more immunogenic compositions described herein. In some embodiments, the two or more immunogenic compositions are administered intramuscularly to the subject. In some embodiments, the two or more immunogenic compositions are administered intranasally to the subject.

[0017] In some embodiments, provided herein is a method for preventing influenza virus disease in a subject, comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, andwherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the third inactivated influenza virus comprises a third chimeric HA, wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain.

[0018] In some embodiments, provided herein is a method of immunizing a subject against influenza virus disease, comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpGoligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the third inactivated influenza virus comprises a third chimeric HA, wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virusHA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain.

[0019] In some embodiments, provided herein is a method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the third inactivated influenza virus comprises a third chimeric HA, wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virusHA of interest, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain.

[0020] In some embodiments, the first inactivated influenza virus and the second inactivated influenza virus each comprise neuraminidase of the group 2 influenza A virus of interest. In some embodiments, the group 2 influenza A virus of interest is an H3. In some embodiment, the group 2 influenza A virus of interest is A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263. In some embodiments, the first inactivated influenza virus and the second inactivated influenza virus each comprise one or more proteins encoded by one or more genes of influenza A virus A / Puerto Rico / 8 / 1934.

[0021] In some embodiments, provided herein is a method of preventing influenza virus disease in a subject, comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group thanthe influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the third inactivated split influenza virus comprises a third chimeric HA, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain.

[0022] In some embodiments, provided herein is a method of immunizing a subject against influenza virus disease, comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globularhead domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the third inactivated split influenza virus comprises a third chimeric HA, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain.

[0023] In some embodiments, provided herein is a method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein thesecond inactivated split influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the third inactivated split influenza virus comprises a third chimeric HA, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain.

[0024] In some embodiments, the first inactivated split influenza virus and the second inactivated split influenza virus each comprise neuraminidase of the group 2 influenza A virus of interest. In some embodiments, the group 2 influenza A virus of interest is an H3. In some embodiment, the group 2 influenza A virus of interest is A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263. In some embodiments, the first inactivated split influenza virus and the second inactivated split influenza virus each comprise one or more proteins encoded by one or more genes of influenza A virus A / Puerto Rico / 8 / 1934.

[0025] In some embodiments, provided herein is a method of preventing influenza virus disease in a subject, comprising: (a) administering to the subject a first immunogeniccomposition comprising a first chimeric hemagglutinin (HA) and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first globular head comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0026] In some embodiments, provided herein is a method of immunizing a subject against influenza virus disease, comprising: (a) administering to the subject a first immunogenic composition comprising a first chimeric hemagglutinin (HA) and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence ofthe HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0027] In some embodiments, provided herein is a method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: (a) administering to the subject a first immunogenic composition comprising a first chimeric hemagglutinin (HA) and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0028] In some embodiments, the group 2 influenza A virus HA of interest is of subtype H3. In some embodiments, the group 2 influenza A virus HA of interest is A / Hong Kong / 4801 / 2014, NYMC X-263 HA, or A / Hong Kong / 4801 / 2014-like HA.

[0029] In some embodiments, the first HA globular head domain or the second HA globular head domain is the HA globular head domain of a group 1 influenza A virus HA. In some embodiments, the first HA globular head domain and the second HA globular head domain are the HA globular head domain of group 1 influenza A virus HAs. In some embodiments, provided herein is the first HA globular head domain or the second HA globular head domain is the HA globular head domain of an HA of subtype H2, H5, H6, H8, H9, Hl 1, H12, H13, H16, H17, or H18. In some embodiments, the first HA globular head domain and the second HA globular head domain are the HA globular head domain of an HA of subtype H2, H5, H6, H8, H9, Hl l, H12, H13, H16, H17, or H18. In some embodiments, the first HA globular head domain and the second HA globular head domain are the HA globular head domain of subtype H4, H7, H10, H14, or H15. In some embodiments, the first HA globular head domain and the second HA globular head domain are the HA globular head domains of HAs of avian influenza viruses which do not circulate in humans (e.g., an avian influenza A virus subtype H4 or Hl 5). In some embodiments, the first HA globular head domain is the HA globular head domain of A / wedge-tailed shearwater / We stern Australia / 2576 / 1979 HA or A / wedge-tailed shearwater / Westem Australia / 2576 / 1979-like HA. In some embodiments, the second HA globular head domain is the HA globular head domain of A / Duck / Czechoslovakia / 1956 HA or A / Duck / Czechoslovakia / 1956-like HA.

[0030] In some embodiments, the first HA globular head domain is the HA globular head domain of A / wedge-tailed shearwater / Westem Australia / 2576 / 1979 HA or A / wedge-tailed shearwater / Westem Australia / 2576 / 1979-like HA and the first HA stalk domain is the HA stalk domain of A / Hong Kong / 4801 / 2014, NYMC X-263 HA, or A / Hong Kong / 4801 / 2014- like HA. In some embodiments, the second HA globular head domain is the HA globular head domain of A / Duck / Czechoslovakia / 1956 HA or A / Duck / Czechoslovakia / 1956-like HA and the second HA stalk domain is the HA stalk domain of A / Hong Kong / 4801 / 2014, NYMC X-263 HA, or A / Hong Kong / 4801 / 2014-like HA.

[0031] In some embodiments, provided herein is a method of preventing influenza vims disease in a subject, comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated influenza vims and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza vims comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or8; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein (i) the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8; or (ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the CpG oligonucleotide adjuvant comprises the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant.

[0032] In some embodiments, provided herein is a method of immunizing a subject against influenza virus disease, comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition, wherein the second immunogenic composition comprises a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein (i) the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8; or (ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the CpG oligonucleotide adjuvant comprises the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant.

[0033] In some embodiments, provided herein is a method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivatedinfluenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition, wherein the second immunogenic composition comprises a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein (i) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8; or (ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the CpG oligonucleotide adjuvant comprises the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant.

[0034] In some embodiments, provided herein is a method of preventing influenza virus disease in a subject, comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein (i) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8; or (ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the CpG oligonucleotide adjuvant comprises the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant.

[0035] In some embodiments, provided herein is a method of immunizing a subject against influenza virus disease, comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein (i) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8; or (ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the CpG oligonucleotide adjuvant comprises the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant.

[0036] In some embodiments, provided herein is a method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: (a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein (i) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8; or (ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequenceof 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the CpG oligonucleotide adjuvant comprises the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant.

[0037] In some embodiments, provided herein is a method of preventing influenza virus disease in a subject, comprising: (a) administering to the subject a first immunogenic composition comprising a first chimeric HA and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein (i) the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8; or (ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the CpG oligonucleotide adjuvant comprises the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant.

[0038] In some embodiments, provided herein is a method of immunizing a subject against influenza virus disease, comprising: (a) administering to the subject a first immunogenic composition comprising a first chimeric HA and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein (i) the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8; or (ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the CpG oligonucleotide adjuvant comprises the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant.

[0039] In some embodiments, provided herein is a method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: (a) administering to the subject a first immunogenic composition comprising a first chimeric HA and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and (b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein (i) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8; or (ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the CpG oligonucleotide adjuvant comprises the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant.

[0040] In some embodiments, the second immunogenic composition is administered to the subject about 21 days to about 6 months after the administration of the first immunogenic composition to the subject.

[0041] In some embodiments, the oligonucleotide comprises the nucleotide sequence of 5’-TGACTGTGAACGTTCGAGATGA-3’ (SEQ ID NO:4). In some embodiments, the oligonucleotide is 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 nucleotides in length. In some embodiments, the oligonucleotide is a single stranded oligodeoxynucleotide. In some embodiments, the oligonucleotide comprises only phosphorothioate linkages, or a combination of one or more phosphodiester linkages and one or more phosphorothioate linkages. In some embodiments, the oligonucleotide is fully RNA or is an RNA / DNA chimera.

[0042] In some embodiments, the composition further comprises an aluminum salt. In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate. In some embodiments, the aluminum salt comprises aluminum hydroxide or aluminum phosphate.

[0043] In some embodiments, the first immunogenic composition or second immunogenic is administered to the subject intramuscularly or intranasally. In someembodiments, the first immunogenic composition and second immunogenic are administered to the subject intramuscularly or intranasally.

[0044] In some embodiments, the subject is human.

[0045] In another aspect, provided herein are methods for preventing an influenza virus disease in a subject, comprising administering to the subject an immunogenic composition comprising a chimeric HA described herein, and administering to the subject a CpG oligonucleotide adjuvant described herein. In another aspect, provided herein are methods of immunizing a subject against influenza virus disease, comprising administering to the subject an immunogenic composition comprising a chimeric HA described herein, and administering to the subject a CpG oligonucleotide adjuvant described herein. In another aspect, provided herein are methods of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising administering to the subject an immunogenic composition comprising a chimeric HA described herein, and administering to the subject a CpG oligonucleotide adjuvant described herein. In some embodiments, the CpG oligonucleotide adjuvant is administered to the subject first. In some embodiments, the immunogenic composition is administered to the subject first.

[0046] In some embodiments, provided herein is a method of preventing an influenza virus disease in a subject, comprising: (a) administering to the subject an immunogenic composition comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA is from an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0047] In some embodiments, provided herein is a method of immunizing a subject against influenza virus disease, comprising: (a) administering to the subject an immunogenic composition comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globularhead domain of the chimeric HA is heterologous to the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA is from an influenza A virus HA of a different strain, subtype, or group than the globular head domain of the group 2 influenza A virus HA of interest; and (b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0048] In some embodiments, provided herein is a method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: (a) administering to the subject an immunogenic composition comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA is from an influenza A virus HA of a different strain, subtype, or group than the globular head domain of the group 2 influenza A virus HA of interest; and (b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0049] In some embodiments, the group 2 influenza A virus HA of interest is of subtype H3. In some embodiments, the group 2 influenza A virus HA of interest is A / Hong Kong / 4801 / 2014, NYMC X-263 HA or A / Hong Kong / 4801 / 2014-like HA.

[0050] In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is a group 1 influenza A virus HA. In some embodiments, the influenza A virus HA of a different strain, subtype, or group is subtype than the group 2 influenza A virus HA of interest is HA of subtype H2, H5, H6, H8, H9, Hl 1, H12, H13, H16, H17, or H18. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is HA of subtype H4, H7, H10, H14, or H15. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is the HA of an avian influenza virus which does not circulate in humans. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is A / wedge-tailed shearwater / Westem Australia / 2576 / 1979 HA orA / wedge-tailed shearwater / We stern Australia / 2576 / 1979-like HA. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is A / Duck / Czechoslovakia / 1956 HA or A / Duck / Czechoslovakia / 1956- like HA.

[0051] In some embodiments, the HA globular head domain is the HA globular head domain of A / wedge-tailed shearwater / Westem Australia / 2576 / 1979 HA or A / wedge-tailed shearwater / Westem Australia / 2576 / 1979-like HA and the HA stalk domain is the HA stalk domain of A / Hong Kong / 4801 / 2014, NYMC X-263 HA, or A / Hong Kong / 4801 / 2014-like HA. The term “ A / shearwater / West Australia / 2576 / 1979” is used interchangeably herein for the term “A / wedge-tailed shearwater / We stern Australia / 2576 / 1979”. In some embodiments, the HA globular head domain is the HA globular head domain of A / Duck / Czechoslovakia / 1956 HA or A / Duck / Czechoslovakia / 1956-like HA and the HA stalk domain is the HA stalk domain of A / Hong Kong / 4801 / 2014, NYMC X-263 HA, or A / Hong Kong / 4801 / 2014-like HA.

[0052] In some embodiments, the oligonucleotide comprises the nucleotide sequence of 5’-TGACTGTGAACGTTCGAGATGA-3’ (SEQ ID NO:4). In some embodiments, the oligonucleotide is 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 nucleotides in length. In some embodiments, the oligonucleotide is a single stranded oligodeoxynucleotide. In some embodiments, the oligonucleotide comprises only phosphorothioate linkages, or a combination of one or more phosphodiester linkages and one or more phosphorothioate linkages. In some embodiments, the oligonucleotide is fully RNA or is an RNA / DNA chimera.

[0053] In some embodiments, the immunogenic composition, the CpG oligonucleotide adjuvant, or both are administered intramuscularly to the subject. In some embodiments, the immunogenic composition, the CpG oligonucleotide adjuvant, or both are administered intranasally to the subject.

[0054] In some embodiments, the immunogenic composition further comprises an aluminum salt. In some embodiments, the CpG oligonucleotide adjuvant further comprises an aluminum salt. In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate. In some embodiments, the aluminum salt comprises aluminum hydroxide or aluminum phosphate.

[0055] In some embodiments, the subject is human.

[0056] In some embodiments, the immunogenic composition and CpG oligonucleotide adjuvant are administered concurrently to the subject. In some embodiments, the immunogenic composition and CpG oligonucleotide adjuvant are administered to the subject within 30 minutes of each other. In some embodiments, the immunogenic composition and CpG oligonucleotide adjuvant are administered to the subject within 15 minutes of each other.

[0057] In another aspect, provided herein are methods for preventing an influenza virus disease in a subject, comprising administering to the subject an immunogenic composition comprising an inactivated influenza virus, wherein the inactivated influenza virus comprises a chimeric HA described herein, and administering to the subject a CpG oligonucleotide adjuvant described herein. In another aspect, provided herein are methods of immunizing a subject against influenza virus disease, comprising administering to the subject an immunogenic composition comprising an inactivated influenza virus, wherein the inactivated influenza virus comprises a chimeric HA described herein, and administering to the subject a CpG oligonucleotide adjuvant described herein. In another aspect, provided herein are methods of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising administering to the subject an immunogenic composition comprising an inactivated influenza virus, wherein the inactivated influenza virus comprises a chimeric HA described herein, and administering to the subject a CpG oligonucleotide adjuvant described herein. In some embodiments, the CpG oligonucleotide adjuvant is administered to the subject first. In some embodiments, the immunogenic composition is administered to the subject first.

[0058] In some embodiments, provided herein is a method of preventing an influenza virus disease in a subject, comprising: (a) administering to the subject an immunogenic composition comprising an inactivated influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) administering to the subject a CpG oligonucleotide adjuvant comprising anoligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0059] In some embodiments, provided herein is a method of immunizing a subject against influenza virus disease, comprising: (a) administering to the subject an immunogenic composition comprising an inactivated influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0060] In some embodiments, provided herein is a method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: (a) administering to the subject an immunogenic composition comprising an inactivated influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0061] In some embodiments, the inactivated influenza virus comprises neuraminidase of the group 2 influenza A virus of interest. In some embodiments, the group 2 influenza A virus of interest is of subtype H3. In some embodiments, the group 2 influenza A virus of interest is A / Hong Kong / 4801 / 2014, NYMC X-263 HA or A / Hong Kong / 4801 / 2014-like HA.

[0062] In some embodiments, the inactivated influenza virus comprises one or more proteins encoded by one or more genes of influenza A virus A / Puerto Rico / 8 / 1934.

[0063] In some embodiments, the group 2 influenza A virus HA of interest is of subtype H3. In some embodiments, the group 2 influenza A virus HA of interest is A / Hong Kong / 4801 / 2014, NYMC X-263 HA or A / Hong Kong / 4801 / 2014-like HA.

[0064] In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is a group 1 influenza A virus HA. In some embodiments, the influenza A virus HA of a different strain, subtype, or group is subtype than the group 2 influenza A virus HA of interest is HA of subtype H2, H5, H6, H8, H9, Hl 1, H12, H13, H16, H17, or H18. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is HA of subtype H4, H7, H10, H14, or H15. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is the HA of an avian influenza virus which does not circulate in humans. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is A / wedge-tailed shearwater / Westem Australia / 2576 / 1979 HA or A / wedge-tailed shearwater / We stern Australia / 2576 / 1979-like HA. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is A / Duck / Czechoslovakia / 1956 HA or A / Duck / Czechoslovakia / 1956- like HA.

[0065] In some embodiments, the HA globular head domain is the HA globular head domain of A / wedge-tailed shearwater / Westem Australia / 2576 / 1979 HA or A / wedge-tailed shearwater / Westem Australia / 2576 / 1979-like HA and the HA stalk domain is the HA stalk domain of A / Hong Kong / 4801 / 2014, NYMC X-263 HA, or A / Hong Kong / 4801 / 2014-like HA. In some embodiments, the HA globular head domain is the HA globular head domain of A / Duck / Czechoslovakia / 1956 HA or A / Duck / Czechoslovakia / 1956-like HA and the HA stalk domain is the HA stalk domain of A / Hong Kong / 4801 / 2014, NYMC X-263 HA, or A / Hong Kong / 4801 / 2014-like HA.

[0066] In some embodiments, the oligonucleotide comprises the nucleotide sequence of 5’-TGACTGTGAACGTTCGAGATGA-3’ (SEQ ID NO:4). In some embodiments, the oligonucleotide is 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 nucleotides in length. In some embodiments, the oligonucleotide is a single stranded oligodeoxynucleotide. In some embodiments, the oligonucleotide comprises only phosphorothioate linkages, or a combination of one or more phosphodiester linkages and one or more phosphorothioatelinkages. In some embodiments, the oligonucleotide is fully RNA or is an RNA / DNA chimera.

[0067] In some embodiments, the immunogenic composition, the CpG oligonucleotide adjuvant, or both are administered intramuscularly to the subject. In some embodiments, the immunogenic composition, the CpG oligonucleotide adjuvant, or both are administered intranasally to the subject.

[0068] In some embodiments, the immunogenic composition further comprises an aluminum salt. In some embodiments, the CpG oligonucleotide adjuvant further comprises an aluminum salt. In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate. In some embodiments, the aluminum salt comprises aluminum hydroxide or aluminum phosphate.

[0069] In some embodiments, the subject is human.

[0070] In some embodiments, the immunogenic composition and CpG oligonucleotide adjuvant are administered concurrently to the subject. In some embodiments, the immunogenic composition and CpG oligonucleotide adjuvant are administered to the subject within 30 minutes of each other. In some embodiments, the immunogenic composition and CpG oligonucleotide adjuvant are administered to the subject within 15 minutes of each other.

[0071] In another aspect, provided herein are methods for preventing an influenza virus disease in a subject, comprising administering to the subject an immunogenic composition comprising an inactivated split influenza virus, wherein the inactivated split influenza virus comprises a chimeric HA described herein, and administering to the subject a CpG oligonucleotide adjuvant described herein. In another aspect, provided herein are methods of immunizing a subject against influenza virus disease, comprising administering to the subject an immunogenic composition comprising an inactivated split influenza virus, wherein the inactivated split influenza virus comprises a chimeric HA described herein, and administering to the subject a CpG oligonucleotide adjuvant described herein. In another aspect, provided herein are methods of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising administering to the subject an immunogenic composition comprising an inactivated split influenza virus, wherein the inactivated split influenza virus comprises a chimeric HA described herein, and administering to the subject a CpG oligonucleotide adjuvant described herein. In some embodiments, the CpGoligonucleotide adjuvant is administered to the subject first. In some embodiments, the immunogenic composition is administered to the subject first.

[0072] In some embodiments, provided herein is a method of preventing an influenza virus disease in a subject, comprising: (a) administering to the subject an immunogenic composition comprising an inactivated split influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated split influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0073] In some embodiments, provided herein is a method of immunizing a subject against influenza virus disease, comprising: (a) administering to the subject an immunogenic composition comprising an inactivated split influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated split influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) administering to the subject a CpG oligonucleotide adjuvant, wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0074] In some embodiments, provided herein is a method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: (a) administering to the subject an immunogenic composition comprising an inactivated split influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated split influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virusHA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0075] In some embodiments, the inactivated split influenza virus comprises neuraminidase of the group 2 influenza A virus of interest. In some embodiments, the group 2 influenza A virus of interest is of subtype H3. In some embodiments, the group 2 influenza A virus of interest is A / Hong Kong / 4801 / 2014, NYMC X-263 HA or A / Hong Kong / 4801 / 2014-like HA.

[0076] In some embodiments, the inactivated split influenza virus comprises one or more proteins encoded by one or more genes of influenza A virus A / Puerto Rico / 8 / 1934.

[0077] In some embodiments, the group 2 influenza A virus HA of interest is of subtype H3. In some embodiments, the group 2 influenza A virus HA of interest is A / Hong Kong / 4801 / 2014, NYMC X-263 HA or A / Hong Kong / 4801 / 2014-like HA.

[0078] In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is a group 1 influenza A virus HA. In some embodiments, the influenza A virus HA of a different strain, subtype, or group is subtype than the group 2 influenza A virus HA of interest is HA of subtype H2, H5, H6, H8, H9, Hl 1, H12, H13, H16, H17, or H18. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is HA of subtype H4, H7, H10, H14, or H15. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is the HA of an avian influenza virus which does not circulate in humans. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is A / wedge-tailed shearwater / Westem Australia / 2576 / 1979 HA or A / wedge-tailed shearwater / We stern Australia / 2576 / 1979-like HA. In some embodiments, the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is A / Duck / Czechoslovakia / 1956 HA or A / Duck / Czechoslovakia / 1956- like HA.

[0079] In some embodiments, the HA globular head domain is the HA globular head domain of A / wedge-tailed shearwater / Westem Australia / 2576 / 1979 HA or A / wedge-tailedshearwater / Westem Australia / 2576 / 1979-like HA and the HA stalk domain is the HA stalk domain of A / Hong Kong / 4801 / 2014, NYMC X-263 HA, or A / Hong Kong / 4801 / 2014-like HA. In some embodiments, the HA globular head domain is the HA globular head domain of A / Duck / Czechoslovakia / 1956 HA or A / Duck / Czechoslovakia / 1956-like HA and the HA stalk domain is the HA stalk domain of A / Hong Kong / 4801 / 2014, NYMC X-263 HA, or A / Hong Kong / 4801 / 2014-like HA.

[0080] In some embodiments, the oligonucleotide comprises the nucleotide sequence of 5’-TGACTGTGAACGTTCGAGATGA-3’ (SEQ ID NO:4). In some embodiments, the oligonucleotide is 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 nucleotides in length. In some embodiments, the oligonucleotide is a single stranded oligodeoxynucleotide. In some embodiments, the oligonucleotide comprises only phosphorothioate linkages, or a combination of one or more phosphodiester linkages and one or more phosphorothioate linkages. In some embodiments, the oligonucleotide is fully RNA or is an RNA / DNA chimera.

[0081] In some embodiments, the immunogenic composition, the CpG oligonucleotide adjuvant, or both are administered intramuscularly to the subject. In some embodiments, the immunogenic composition, the CpG oligonucleotide adjuvant, or both are administered intranasally to the subject.

[0082] In some embodiments, the immunogenic composition further comprises an aluminum salt. In some embodiments, the CpG oligonucleotide adjuvant further comprises an aluminum salt. In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate. In some embodiments, the aluminum salt comprises aluminum hydroxide or aluminum phosphate.

[0083] In some embodiments, the subject is human.

[0084] In some embodiments, the immunogenic composition and CpG oligonucleotide adjuvant are administered concurrently to the subject. In some embodiments, the immunogenic composition and CpG oligonucleotide adjuvant are administered to the subject within 30 minutes of each other. In some embodiments, the immunogenic composition and CpG oligonucleotide adjuvant are administered to the subject within 15 minutes of each other.

[0085] In another aspect, provided herein are kits comprising an immunogenic composition described herein. In some embodiments, provided herein is a kit comprising two or more containers, wherein each container comprises a different immunogenic compositiondescribed herein. In some embodiments, provided herein is a kit comprising at least two containers, wherein one container comprises an immunogenic composition comprising a chimeric HA described herein, and the second container comprises a CpG oligonucleotide adjuvant described herein. In some embodiments, provided herein is a kit comprising at least two containers, wherein one container comprises an immunogenic composition comprising an inactivated influenza virus, wherein the inactivated influenza virus comprises a chimeric HA described herein, and the second container comprises a CpG oligonucleotide adjuvant described herein. In some embodiments, provided herein is a kit comprising at least two containers, wherein one container comprises an immunogenic composition comprising an inactivated split influenza virus, wherein the inactivated split influenza virus comprises a chimeric HA described herein, and the second container comprises a CpG oligonucleotide adjuvant described herein.

[0086] In some embodiments, provided herein is a kit comprising a container containing an immunogenic composition comprising a chimeric hemagglutinin (HA) and a CpG oligonucleotide adjuvant, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain of the group 2 influenza A virus HA of interest, wherein the HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0087] In some embodiments, provided herein is a kit comprising a container containing an immunogenic composition comprising an inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the inactivated influenza virus comprises a first chimeric HA, and wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the CpG oligonucleotide adjuvant comprises anoligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0088] In some embodiments, provided herein is a kit comprising a container containing an immunogenic composition comprising an inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the inactivated split influenza virus comprises a first chimeric HA, and wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0089] In some embodiments, provided herein is a kit comprising: (a) a first container containing an immunogenic composition comprising a chimeric HA, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain of the group 2 influenza A virus HA of interest, wherein the HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a second container containing a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0090] In some embodiments, provided herein is a kit comprising: (a) a first container containing an immunogenic composition comprising a first inactivated influenza virus, wherein the first inactivated influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a second container containing a CpGoligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0091] In some embodiments, provided herein is a kit comprising: (a) a first container containing an immunogenic composition comprising a first inactivated split influenza virus, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a second container containing a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0092] In some embodiments, provided herein is a kit comprising: (a) a first container containing a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a second container containing a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

[0093] In some embodiments, provided herein is a kit comprising: (a) a first container containing a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and (b) a second container containing a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).3.1 Terminology

[0094] As used herein, the term “about” or “approximately” when used in conjunction with a number refers to any number within 1%, 5%, or 10% of the referenced number and includes the referenced number.

[0095] The term “and / or” as used in a phrase such as “A and / or B” herein is intended to include both A and B; A or B; A (alone); and B (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the followingembodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0096] The terms "chimeric influenza virus hemagglutinin," "chimeric influenza virus HA polypeptide," "chimeric hemagglutinin," "chimeric HA," "chimeric influenza hemagglutinin", “chimeric HA polypeptide”, and “cHA” are used herein interchangeably.

[0097] As used herein, the terms “comprising” and “including” can be used interchangeably. The terms “comprising” and “including” are to be interpreted as specifying the presence of the stated features or components as referred to, but does not preclude the presence or addition of one or more features, or components, or groups thereof. Additionally, the terms “comprising” and “including” are intended to include examples encompassed by the term “consisting of’. Consequently, the term “consisting of’ can be used in place of the terms “comprising” and “including” to provide for more specific embodiments.

[0098] The terms “CpG,” “CpG motif,” and “cytosine-phosphate-guanosine,” as used herein, refer to an unmethylated cytidine-phospho-guanosine dinucleotide, which when present in an oligonucleotide contributes to a measurable immune response in vitro, in vivo and / or ex vivo. Examples of measurable immune responses include, but are not limited to, antigen-specific antibody production, secretion of cytokines, activation or expansion of lymphocyte populations, such as NK cells, CD4+ T lymphocytes, CD8+ T lymphocytes, B lymphocytes, and the like. Preferably, the CpG oligonucleotide preferentially activates a Th 1 -type response.

[0099] As used herein, the term “elderly human” refers to a human that is 65 years old or older.

[0100] As used herein, the terms "HA" and "hemagglutinin" refer to any influenza virus hemagglutinin known to those of skill in the art or a derivative thereof. Typically, a precursor influenza A virus hemagglutinin comprises domains including a signal peptide, a stem domain (or stalk domain), a globular head domain, a transmembrane domain, and a cytoplasmic domain. In some embodiments, a hemagglutinin consists of a single polypeptide chain, such as HAO. In some embodiments, a hemagglutinin consists of more than one polypeptide chain in quaternary association, e.g., HA1 and HA2. Those of skill in the art will recognize that an immature HAO may be cleaved to release a signal peptide (generally approximately 15 to approximately 20 amino acids) to yield a mature hemagglutinin HAO (z.e., HAO without a signal peptide). In the context of an influenza A virus hemagglutinin, a mature hemagglutinin HAO is generally cleaved by proteolytic enzymes to yield an HA1 subunit (generally approximately 320 to approximately 327 amino acids, including theglobular head domain and a portion of the stem domain) and an HA2 subunit (generally approximately 220 to approximately 222 amino acids, including the remainder of the stem domain, a transmembrane domain and a cytoplasmic domain). The terms "hemagglutinin" and "HA", as used herein, encompass an influenza virus HA monomer as well as trimers of influenza virus HA. In addition, the terms "hemagglutinin" and "HA", as used herein, encompass influenza virus hemagglutinin that are modified by, e.g., glycosylation (e.g., N- linked glycosylation) and lipid modification (e.g., S-palmitoylation).

[0101] The terms “influenza virus globular head domain”, “influenza virus HA globular head domain”, “influenza HA globular head domain”, “globular head domain”, “head domain”, “HA head domain”, “HA globular head”, and “HA globular head domain” are used herein interchangeably.

[0102] The terms “influenza virus stem domain”, “influenza stem domain”, “influenza HA stem domain”, “stem domain”, “stalk domain”, ’’influenza virus HA stem domain”, “HA stalk”, “HA stalk domain”, and “HA stem domain” are used herein interchangeably.

[0103] As used herein, the term “HA1” refers to the HA1 of an influenza virus hemagglutinin. Typically, an HA1 includes the globular head domain and a portion of the stem domain of influenza virus hemagglutinin (see, e.g., Sriwilaijaroen and Suzuki, Proc Jpn Acad Ser B Phys Biol Sci. 2012 Jun 11; 88(6): 226-249, the contents of which is incorporated by reference in its entirety).

[0104] As used herein, the term “HA2" refers to the HA2 of an influenza virus hemagglutinin. Typically, an HA2 includes a portion of the stem domain, a transmembrane domain, and a cytoplasmic domain of influenza virus hemagglutinin (see, e.g., Sriwilaijaroen and Suzuki, Proc Jpn Acad Ser B Phys Biol Sci. 2012 Jun 11; 88(6): 226-249, the contents of which is incorporated by reference in its entirety).

[0105] As used herein, the term “HA2 stem domain” refers to the stem domain of the HA2 domain of an influenza virus hemagglutinin. An exemplary HA2 stem domain may be found in Table 5 (see SEQ ID NO: 14).

[0106] As used herein, the term "HA1 C-terminal stem segment" refers to a polypeptide segment that corresponds to the carboxy -terminal portion of the stem domain of HA1. In some embodiments, an HA1 C-terminal stem segment consists of amino acid residues corresponding approximately to amino acids Aq through Acterm of an HA1 of an influenza A virus hemagglutinin. Aq is the cysteine residue in the HA1 C-terminal stem segment that forms or is capable of forming a disulfide bond with a cysteine residue in an influenza A virus HA1 N-terminal stem segment. Acterm or otherwise referred to herein as HAlc-term isthe C-terminal amino acid of the HA1 domain as recognized by those of skill in the art. Residue Aq is identified in influenza A hemagglutinin polypeptides in FIGS. 11 A-l ID (z.e., Aq is Cys at amino acid position 277 of an HA1 according to H3 numbering; see also SEQ ID NOS: 70-74 in the sequence table below (Table 5)). In some embodiments, an HA1 C- terminal stem segment consists of amino acid residues corresponding approximately to amino acids 277-329 of HA1 according to H3 numbering. Note that, in this numbering system, 1 refers to the N-terminal amino acid of the mature HAO protein, from which the signal peptide has been removed. Those of skill in the art will readily be able to recognize the amino acid residues that correspond to the HA1 C-terminal stem segment of other influenza HA polypeptides, e.g., the amino acid residues that correspond to the HA1 C-terminal stem segment of HA1 from an Hl hemagglutinin (see, e.g., FIGS. 11 A-l ID; see also SEQ ID NOS: 70-74 in the sequence table below (Table 5)). Amino acid residues that correspond to the HA1 C-terminal stem segment may be identified by aligning the amino acid sequence of an influenza A virus HA for which the HA1 C-terminal stem segment has been identified with the amino acid sequence of the influenza A virus HA of interest. In some embodiments, the three-dimensional structure of HA may also be considered in determining the HA1 C- terminal stem segment of the influenza A virus of interest.

[0107] As used herein, the term "HA1 N-terminal stem segment" refers to a polypeptide segment that corresponds to the amino-terminal portion of the stem domain of an influenza virus hemagglutinin HA1. In some embodiments, an HA1 N-terminal stem segment consists of amino acid residues corresponding approximately to amino acids Ax-term through APof an HA1 of an influenza A virus hemagglutinin. Ax-term otherwise referred to herein as HAlx- term is the N-terminal amino acid of HA1 as recognized by those of skill in the art. APis the cysteine residue in the HA1 N-terminal stem segment that forms or is capable of forming a disulfide bond with a cysteine residue in an influenza A virus HA1 C-terminal stem segment. Residue APis identified in influenza A hemagglutinin polypeptides in FIGS. 11 A-l ID (i.e., APis Cys at amino acid position 52 of an HA1 according to H3 numbering; see also SEQ ID NOS: 70-74 in the sequence table below (Table 5)). In some embodiments, an HA1 N- terminal stem segment consists of amino acid residues corresponding approximately to amino acids 1-52 of HA1 according to H3 numbering. Note that, in this numbering system, 1 refers to the N-terminal amino acid of the mature HAO protein, from which the signal peptide has been removed. Those of skill in the art will readily be able to recognize the amino acid residues that correspond to the HA1 N-terminal stem segment of other influenza HA polypeptides, e.g., the amino acid residues that correspond to the HA1 N-terminal stemsegment of HA1 from an Hl hemagglutinin (see, e.g., FIGS. 11 A-l ID; see also SEQ ID NOS: 70-74 in the sequence table below (Table 5)). Amino acid residues that correspond to the HA1 N-terminal stem segment of HA1 may be identified by aligning the amino acid sequence of an influenza A virus HA for which the HA1 N-terminal stem segment has been identified with the amino acid sequence of the influenza A virus HA of interest. In some embodiments, the three-dimensional structure of HA may also be considered in determining the HA1 N-terminal stem segment of the influenza A virus of interest.

[0108] As used herein, the term "heterologous" in the context of a polypeptide, nucleic acid or virus refers to a polypeptide, nucleic acid or virus, respectively, that is not normally found in nature or not normally associated in nature with a polypeptide, nucleic acid or virus of interest. For example, an HA globular head domain that is heterologous to an HA stem domain refers to an HA globular head domain that would not be found in nature associated with the HA stem domain or would not normally be associated in nature with the HA stem domain.

[0109] As used herein, the term “human adult” refers to a human 18 years old and older.

[0110] As used herein, the term “human child” refers to a human 1 years old to 18 years old.

[0111] As used herein, the term “human infant” refers to a newborn human to 1 years old.

[0112] Immunologically distinct: In some embodiments, the HA globular head domain of a chimeric HA is immunologically distinct from the HA globular head domain normally associated with an HA stem domain if there is no cross-reactivity in an immunoassay described herein or known to one of skill in the art. In some embodiments, the HA globular head domain of a chimeric HA is immunologically distinct from the HA globular head domain normally associated with an HA stem domain if there is no cross-reactivity in a hemagglutinin inhibition assay known to one of skill in the art. In some embodiments, the HA globular head domain of a chimeric HA is immunologically distinct from the HA globular head domain normally associated with an HA stem domain if there is no crossreactivity in an immunoassay and a hemagglutinin assay described herein or known to one of skill in the art. In some embodiments, the HA globular head domain of a chimeric HA is immunologically distinct from the HA globular head domain normally associated with an HA stem domain if the HA globular head domain of the chimeric HA is considered of a different influenza A virus subtype than the HA globular head domain normally associated with the HA stem domain using CDC, FDA, or WHO criteria.

[0113] As used herein, the term “nucleic acid” and “nucleotide” is intended to include DNA molecules (e.g., cDNA or genomic DNA) and RNA molecules (e.g., mRNA) and analogs of the DNA or RNA generated using nucleotide analogs. In specific embodiments, the nucleic acid is a negative-sense single RNA. In some embodiments, the nucleic acid is cDNA.

[0114] As used herein, the term “or” is to be interpreted as an inclusive “or” meaning any one or any combination. Therefore, “A, B or C” means any of the following: “A; B; C; A and B; A and C; B and C; A, B and C”. An exception to this definition will occur only when a combination of elements, functions, steps or acts are in some way inherently mutually exclusive.

[0115] Percent identity: Techniques known to one of skill in the art can be used to determine the percent identity between two amino acid sequences or between two nucleotide sequences. Generally, to determine the percent identity of two amino acid sequences or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid or nucleic acid sequence for optimal alignment with a second amino acid or nucleic acid sequence). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (z.e., % identity = number of identical overlapping positions / total number of positions X 100%). In some embodiments, the two sequences are the same length. In some embodiments, the percent identity is determined over the entire length of an amino acid sequence or nucleotide sequence. The determination of percent identity between two sequences (e.g., amino acid sequences or nucleic acid sequences) can also be accomplished using a mathematical algorithm. A nonlimiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin and Altschul, 1990, Proc. Natl. Acad. Sci. U.S.A.87:22642268, modified as in Karlin and Altschul, 1993, Proc. Natl. Acad. Sci. U.S.A.90:58735877. Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul et al., 1990, J. Mol. Biol.215:403.

[0116] BLAST nucleotide searches can be performed with the NBLAST nucleotide program parameters set, e.g., for score=100, wordlength=12 to obtain nucleotide sequences homologous to nucleic acid molecules described herein. BLAST protein searches can beperformed with the XBLAST program parameters set, e.g., to score 50, wordlength=3 to obtain amino acid sequences homologous to a protein molecule described herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., 1997, Nucleic Acids Res.25:33893402. Alternatively, PSI BLAST can be used to perform an iterated search which detects distant relationships between molecules (Id). When utilizing BLAST, Gapped BLAST, and PSI Blast programs, the default parameters of the respective programs (e.g., of XBLAST and NBLAST) can be used (see, e.g., National Center for Biotechnology Information (NCBI) on the worldwide web, ncbi.nlm.nih.gov). In another non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, 1988, CABIOS 4: 1117. Such an algorithm is incorporated in the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM 120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used. The percent identity between two sequences can be determined using techniques similar to those described above, with or without allowing gaps. In calculating percent identity, typically only exact matches are counted. In some embodiments, two sequences are aligned using Clustal Omega.

[0117] As used interchangeably herein, the terms “polynucleotide” and “oligonucleotide” are oligomers of nucleic acids and include single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), single-stranded RNA (ssRNA) and double-stranded RNA (dsRNA), modified oligonucleotides and oligonucleosides or combinations thereof. The oligonucleotide can be linearly or circularly configured, or the oligonucleotide can contain both linear and circular segments. Oligonucleotides are polymers of nucleosides joined, generally, through phosphodiester linkages, although alternate linkages, such as phosphorothioate esters may also be used in oligonucleotides. A nucleoside consists of a purine (adenine (A) or guanine (G) or derivative thereof) or pyrimidine (thymine (T), cytosine (C) or uracil (U), or derivative thereof) base bonded to a sugar. The four nucleoside units (or bases) in DNA are called deoxyadenosine, deoxyguanosine, thymidine, and deoxy cytidine.

[0118] As used herein, the terms “purified” and “isolated” when used in the context of a polypeptide (including an antibody) that is obtained from a natural source, e.g., cells, refers to a polypeptide which is substantially free of contaminating materials from the natural source, e.g., minerals, chemicals from the environment, and / or cellular materials from the natural source, such as but not limited to cell debris, cell wall materials, membranes, organelles, thebulk of the nucleic acids, carbohydrates, proteins, and / or lipids present in cells. Thus, a polypeptide that is isolated includes preparations of a polypeptide having less than about 30%, 20%, 10%, 5%, 2%, or 1% (by dry weight) of cellular materials and / or contaminating materials. As used herein, the terms “purified” and “isolated” when used in the context of a polypeptide (including an antibody) that is chemically synthesized refers to a polypeptide which is substantially free of chemical precursors or other chemicals which are involved in the syntheses of the polypeptide. In a specific embodiment, a chimeric HA is chemically synthesized. In another specific embodiment, a chimeric HA is isolated.

[0119] As used herein, the terms "replication," "viral replication" and "virus replication" in the context of a virus refer to one or more, or all, of the stages of a viral life cycle which result in the propagation of virus. The steps of a viral life cycle include, but are not limited to, virus attachment to the host cell surface, penetration or entry of the host cell (e.g., through receptor mediated endocytosis or membrane fusion), uncoating (the process whereby the viral capsid is removed and degraded by viral enzymes or host enzymes thus releasing the viral genomic nucleic acid), genome replication, synthesis of viral messenger RNA (mRNA), viral protein synthesis, and assembly of viral ribonucleoprotein complexes for genome replication, assembly of virus particles, post-translational modification of the viral proteins, and release from the host cell by lysis or budding and acquisition of a phospholipid envelope which contains embedded viral glycoproteins. In some embodiments, the terms "replication," "viral replication" and "virus replication" refer to the replication of the viral genome. In some embodiments, the terms "replication," "viral replication" and "virus replication" refer to the synthesis of viral proteins.

[0120] As used herein, terms “subject” or “patient” are used interchangeably to refer to an animal (e.g., birds, reptiles, and mammals). In some embodiments, a subject is a bird. In some embodiments, a subject is a mammal including a non-primate (e.g., a camel, donkey, zebra, cow, pig, horse, goat, sheep, cat, dog, rat, and mouse) and a primate (e.g. , a monkey, chimpanzee, and a human). In some embodiments, a subject is a non-human animal. In some embodiments, a subject is a farm animal or pet. In specific embodiments, a subject is a human. In some embodiments, a subject is a human adult. In some embodiments, a subject is an elderly human. In some embodiments, a subject is a human child. In some embodiments, a subject is a human infant.

[0121] As used herein, the term “seasonal influenza virus strain” refers to a strain of influenza virus to which a subject population is exposed to on a seasonal basis. In specific embodiments, the term seasonal influenza virus strain refers to a strain of influenza A virus.In some embodiments, the term seasonal influenza virus strain refers to a strain of influenza A virus that belongs to the H3 subtype, z.e., one of the two subtypes that presently persist in the human subject population.

[0122] The terms “tertiary structure” and “quaternary structure” have the meanings understood by those of skill in the art. Tertiary structure refers to the three-dimensional structure of a single polypeptide chain. Quaternary structure refers to the three dimensional structure of a polypeptide having multiple polypeptide chains.

[0123] As used herein, in some embodiments, the phrase “wild-type” in the context of a viral polypeptide refers to a viral polypeptide that is found in nature and is associated with a naturally occurring virus.

[0124] In some embodiments, the phrase “wild-type” in the context of a virus refers to a virus that is prevalent, circulating naturally and producing typical outbreaks of disease. In some embodiments, the term “wild-type” in the context of a virus refers to a parental virus.4. DESCRIPTION OF THE FIGURES

[0125] FIG. 1 depicts a timeline of global evolutionary frequencies of H3N2 viruses (02- Dec-2010 to 03-Jun-2022). The graph was adapted from nextstrain / flu / seasonal / h3n2 / ha / 12y (accessed on November 10, 2022) (78).

[0126] FIGS. 2A-2C depict Group 2 cHA vaccination strategy and experimental design. FIG. 2A depicts a schematic of sequential vaccination with group 2 cHA constructs to induce antibodies that target the immunosubdominant HA stalk domain, as contemplated to be present in humans with pre-existing immunity to H3N2. FIG. 2B depicts a cladogram of HAs from the influenza viruses used in this study for challenge and of recombinant HA proteins used for serology analysis. HAs from challenge viruses were marked with an asterisk. The tree was constructed using amino acid sequences aligned in Clustal Omega (79) and visualized with the FigTree software (tree.bio.ed.ac.uk / software / figtree / ). Bris07 (H1N1): A / Brisbane / 59 / 2007 (H1N1), Cal09 (H1N1): A / California / 07 / 2009 (H1N1), Singl5 (H1N1): A / Singapore / GP 1908 / 2015 (H1N1), canine (H3N2): A / canine / Illinois / 41915 / 2015 (H3N2), HK14 (H3N2): A / Hong Kong / 4801 / 2014 (H3N2), HK68 (H3N2): A / Hong Kong / 1 / 1968 (H3N2), Switzl3 (H3N2): A / Switzerland / 9715293 / 2013 (H3N2), X-79 (H3N2): A / Philippines / 2 / 1982 (H3N2, X-79), Wisc05 (H3N2): A / Wisconsin / 67 / 2005 (H3N2), duck (H4N6): A / duck / Czechoslovakia / 1956 (H4N6), swine (H4N6): A / swine / Missouri / AO 1727926 / 2915 (H4N6), H7N9: A / Shanghai / 1 / 2013 (H7N9), H10N7: A / mallard / Interior Alaska / 9BM3355R0 / 2009 (H10N7), H10N8: A / Jiangxi-Donghu / 346 / 2013(H10N8), H15N5: A / shearwater / West Australia / 2576 / 1979 (H15N9), B / Coll7: B / Colorado / 06 / 2017. FIG. 2C depicts experimental design; different groups of BALB / c mice (n = 10) were primed intranasally (i.n.) with either a sublethal infection of the B-cH5 / l virus (105PFU / mouse) or PBS. After four weeks, mice were vaccinated with CH15 / 3HKI4N2HKI4 split vaccine (1 pg HA / mouse), bovine serum albumin (BSA), or whole inactivated A / Philippines / 2 / 1982 (H3N2, X-79) virus or A / Hunan / 02285 / 2017 (H7N1) virus (WIV, positive control) via the intramuscular (i.m.) route. Five mice per group were used for WIV control groups. Alternatively, mice were also vaccinated with CH15 / 3HKI4N2HKI4 LAIV (105PFU / mouse) i.n., or with allantoic fluid (AF), or PBS delivered i.n. After four additional weeks, mice were vaccinated in the same manner but with CH4 / 3HKI4N2HKI4 split vaccine or LAIV. Groups co-administered with the CpG 1018® adjuvant (Adj) received a dose of 30 pg CpG 1018® adjuvant / mouse. Six weeks after the second boost, mice were bled and challenged with 5*LD50 of the heterologous A / Philippines / 2 / 1982 (H3N2, X-79) virus. This vaccination experiment was performed in two sets of independent mice (n = 5 mice / set) for serum analysis. Only one set of mice was challenged.

[0127] FIGS. 3A-3J show that sequential vaccination with group 2 cHA constructs protects mice from lethal challenge and elicits cross-reactive and functional antibodies six weeks after the second vaccination. FIG. 3 A depicts weight loss and survival plots of mice (n = 5) challenged with 5*LD50 of the A / Philippines / 2 / 1982 (H3N2, X-79) virus. Average weight values and the standard deviation (SD) are shown (y-axis of the weight loss plot). Statistical comparison of Split and Split / CpG weight loss curves is also indicated (right side of the weight loss plot). Lines in the survival graphs are nudged to allow for distinction between the lines which would otherwise overlap. FIG. 3B depicts geometric mean titers (GMT) of total serum IgG responses of the two sets of mice (n = 10) against a variety of influenza A and B virus HA proteins and against the matched vaccine NA protein analyzed by ELISA. For group 2 HAs, at least one HA protein representative was tested by subtype. Serum from mice vaccinated with the WIV A / Hunan / 02285 / 2017 (H7N1) virus (n = 5) following the same regimen of vaccination as previously shown was also included as serology control. Comparisons between groups of mice were performed by considering all IgG responses to all tested influenza virus antigens in the split / CpG group and comparing these to the total IgG responses of the other groups. FIG. 3C depicts results from a competition ELISA of individual serum samples from the two sets of vaccinated mice (n = 10) with the trimer interface monoclonal antibody (mAb) FluA-20 against the H3 HK14 protein. FIGS. 3D-3E show GMT titers of individual serum IgGl and IgG2a responsesagainst the vaccine matched A / Hong Kong / 4801 / 2014 H3 (H3 HK14) protein from one set of mice (n = 5). FIG. 3F depicts the ratio of individual IgG2a to IgGl responses against the H3 HK14 protein. As shown in FIG. 3G, serum from the two sets of vaccinated mice (n = 10) were analyzed for antibody dependent cell mediated cytotoxicity (ADCC) activity against the A / Hong Kong / 4801 / 2014 (H3N2) virus using a reporter assay. The fold induction of the reporter signal from individual mouse serum over those from blanks were analyzed. FIG. 3H depicts results from a neuraminidase inhibition (NAI) assay of sera from the two sets of mice (n = 10) against an H6N2 reassortant virus expressing the N2 of the A / Hong Kong / 4801 / 2014 (H3N2) virus. Serum dilutions inhibiting 50% of the NA activity (IC50) were plotted. FIGS. 3I-3J show neutralizing activity of mouse sera against A / Philippines / 2 / 1982 (H3N2, X-79) and A / Hong Kong / 4801 / 2014 (H3N2) viruses. Mouse sera from each one of the sets of vaccinated mice (n = 5) were pooled within each group from each set and analyzed in technical duplicate. The A / Philippines / 2 / 1982 H3 head mAb 1F12 was used as a positive control (30 pg / mL). The GMT readout values per mouse group are represented in each graph with a black line. The limit of detection (LoD) was defined as 1 for ELISA and for the ADCC assay, as 476 (GMT of PBS group) for competition ELISA, as 2 for the NAI assay, and as 10 for the microneutralization assays. Half the value of the LoD was assigned for negative samples. Statistical analyses were performed using one-way ANOVA corrected for Dunnett’s multiple comparison test. Only statistically significant p-values (<0.05) are shown.

[0128] FIGS. 4A-4G show that split vaccination reduces viral load in lungs and protects mice in serum passive transfer and dose-de-escalation experiments. FIG. 4A depicts viral load in the lungs of mice vaccinated following the same vaccination regimen as shown in the previous experiment. Lungs of a subset of BALB / c mice from each group (n = 6) were collected on day 3 and 6 post challenge with the A / Philippines / 2 / 1982 (H3N2, X-79) virus. Whole lungs were homogenized in 1 mL of PBS. Viral titers were measured on MDCK cells by the plaque assay method and plotted as PFU / mL. The limit of detection was defined as 50 PFU / mL. A titer of 25 PFU / mL was assigned to negative samples. The GMT of viral titers are also shown. FIG. 4B show analysis results for sera from sequentially vaccinated DBA / 2J mice that were pooled and transferred into naive DBA / 2J mice (n = 5). Two to three hours after the transfer, mice were challenged with the heterologous A / Switzerland / 9715293 / 2013 (H3N2) virus and monitored for weight loss and survival. Average weight values and SD are shown (y-axis of the weight loss plot). Statistical comparison of Split and Split / CpG weight loss curves is also indicated (right side of the weight loss plot). Lines in the survival graphs are nudged to allow for distinction between the lines which would otherwise overlap, i.p. =intraperitoneal. FIGS. 4C and 4D depict GMT of total serum IgG responses from the dose- de-escalation experiment of CpG 1018® adjuvant and combination with alum against the H3 HK14 protein and a stabilized headless H3 protein (mini H3) from the A / Wisconsin / 67 / 2005 (H3N2) virus, respectively. FIGS. 4E-4F depict serum IgGl and IgG2a responses from the dose-de-escalation experiment of CpG 1018® adjuvant and combination with alum against the H3 HK14 protein. FIG. 4G shows the ratio of IgG2a to IgGl responses against the H3 HK14 protein. The GMT of readout values per mouse group are represented in each graph with a black line. The limit of detection for ELISA (LoD) was defined as 1. Half the value of the LoD was assigned for negative samples. In all cases, mice vaccinated with split vaccines and BSA were initially primed with the B-cH5 / l virus. Statistical analyses were performed using one-way ANOVA corrected with the non-parametric Dunn’s test for viral titers, and one-way ANOVA corrected for Dunnett’s multiple comparison test for the rest of assays. Only statistically significant p-values (<0.05) are shown.

[0129] FIGS. 5A-5C depict results of systemic and local CD4+ effector memory (EM) T-cell responses induced by split vaccines. FIG. 5 A depicts vaccination strategy and experimental design. FIG. 5B depicts representative flow cytometry plots showing the percentage of IFNy- and TNFa-producing CD4+ EM T lymphocytes in mouse spleens and lungs 6 days after challenge with A / Philippines / 2 / 1982 (H3N2, X-79) virus (n = 3 mice / group). T-cells were stimulated with overlapping peptide libraries covering the H3 protein sequence from A / Perth / 16 / 2009 (H3N2) virus, the N2 protein from A / Perth / 16 / 2009 (H3N2) virus, and the NP protein from A / Puerto Rico / 8 / 1934 (H1N1) virus. Different groups of BALB / c mice were sequentially vaccinated with PBS, BSA + 10 pg / mouse of CpG 1018® adjuvant, or 1 pg / mouse of split vaccine + 10 pg / mouse of CpG 1018® adjuvant following vaccination regimen as shown in previous experiments. FIG. 5C depicts the percentage of different cytokine producing cell populations within the total CD4+ EM T-cell subset (n = 3) after background subtraction. Average and SD values are shown. In all cases, mice vaccinated with split vaccines and BSA were initially primed with the B-cH5 / l virus. Statistical analyses were performed using one-way ANOVA corrected for Dunn’s multiple comparison test. Only statistically significant p-values (<0.05) are shown.

[0130] FIGS. 6A-6I show that sequential vaccination with group 2 cHA split vaccines protects mice from challenge with a broad spectrum of influenza A viruses. FIG. 6A depicts experimental design. Different groups of mice (n = 5) were sequentially vaccinated with 1 pg / mouse of split vaccine adjuvanted with 10 pg / mouse of CpG 1018® adjuvant as shown in previous experiments and challenged with the heterologous A / Switzerland / 9715293 / 2013(H3N2) and A / canine / Illinois / 41915 / 2015 (H3N2) viruses (FIGS. 6B and 6C, respectively), the heterologous group 2 A / swine / Missouri / AO 1727926 / 2015 (H4N6) (FIG. 6D), A / Shanghai / 1 / 2013 (H7N9) (FIG. 6E), A / Jiangxi-Donghu / 346 / 2013 (H10N8) (FIG. 6F), A / mallard / Gurjev / 263 / 1982 (H14N1) (FIG. 6G), A / wedge-tailed shearwater / Western Australia / 2576 / 1979 (H15N5) viruses (FIG. 6H), and the group 1 A / Singapore / GP1908 / 2015 (H1N1) virus (FIG. 61). Body weight and survival were monitored over the course of 14 days after challenge. Vaccination and challenge experiments with H3N2, H4N6, and H14N1 viruses were conducted in DBA / 2J mice, whereas H7N9, H10N8, H15N5, and H1N1 challenge experiments were performed in BALB / c mice. The average weight values and SD are shown (y-axes of the weight loss plots). In all cases, mice vaccinated with split vaccines and BSA were initially primed with the B-cH5 / l virus. Comparison of Split / CpG and BSA / CpG weight loss curves are shown (right sides of the weight loss plots). Statistical analyses were performed using one-way ANOVA corrected with the non-parametric Dunn’s test for viral titers, and one-way ANOVA corrected for Dunnett’s multiple comparison test for the rest of assays. Lines in the survival graphs are nudged to allow for distinction between the lines which would otherwise overlap.

[0131] FIG. 7 show that infection with B-cH5 / l virus induces IgG titers against the influenza B NA. GMT of total serum IgG responses against B / Colorado / 06 / 2017 NA from one set of BALB / c mice (n = 5) primed with B-cH5 / l virus or PBS analyzed by ELISA are shown. Black lines represent the GMT.

[0132] FIG. 8 depicts results of serum from one set of vaccinated BALB / c mice (n = 5) that was analyzed for antibody dependent cell mediated cytotoxicity (ADCC) activity against the A / Philippines / 2 / 1982 (H3N2, X-79) virus using a reporter assay. The fold induction of the reporter signal from individual mouse serum over those from blanks were analyzed. The H3 stalk mAb 9H10 was used as a positive control (30 pg / mL). Black lines represent the GMT.

[0133] FIGS. 9A-9C depict results of dose-de-escalation experiments of split vaccine and CpG 1018® adjuvant. FIG. 9A shows dose-de-escalation of split vaccine. Different groups of BALB / c mice (n = 5) were sequentially vaccinated with different doses of split vaccine (3, 1, 0.3, 0.1 pg / mouse) adjuvanted with 30 pg / mouse of CpG 1018® adjuvant following the same vaccination regimen as in previous experiments, and were challenged with the A / Philippines / 2 / 1982 (H3N2, X-79) virus. Weight loss and survival were monitored (left and right side, respectively). Average weight values and SD are shown. FIG. 9B shows dose-de-escalation of CpG 1018® adjuvant and combination of CpG 1018® adjuvant andaluminum hydroxide gel 2% (alum). Different groups of BALB / c mice (n = 5) were sequentially vaccinated with 1 pg / mouse of split vaccine and different doses of CpG 1018® adjuvant (30, 10, 3 pg / mouse) with and without the combination with alum (50, 15, 5 pg / mouse) at a ratio 1 :5 following the same vaccination regimen as in previous experiments. Mice were challenged with the A / Philippines / 2 / 1982 (H3N2, X-79) virus. The same group of mice vaccinated with 1 pg / mouse of split vaccine and 30 pg / mouse (the first set on the left, FIG. 4C) was included for comparison. Average weight values and SD are shown. FIG. 9C depicts the gating strategy utilized for the identification of cytokine-producing T-cells. Splenocytes from immunized mice were stimulated 6h with 1 pL / well of peptide pool library containing 15-mer peptides with 11 amino acid overlap (5 pg / mL) covering the whole sequences of HA of the A / Perth / 16 / 2009 (H3N2) influenza virus strain in the presence of 5 pg / mL Brefeldin A (Biolegend), 2 pM Monensin (Biolegend), and 25 pg / mL of costimulatory anti-CD28 antibodies (Biolegend). Live CD3+ cells were isolated after the exclusion of doublets, debris (based on the FSC-A / SSC-A and FSCA / FSC-H light scattering), and dead cells (Zombie Aqua+). T-lymphocytes were further subdivided into CD8+ and CD4+ T cell populations. CD4+ and CD8+ effector memory (EM) cells were identified as CD44+CD62L-. TNFa+, IL-2+, and IFNy+ events were selected, and Boolean gating was applied to obtain the subpopulations producing all possible combinations of analyzed cytokines.

[0134] FIGS. 10A-10B FIG. 10A depicts representative flow cytometry plots showing the percentage of IL-2- and TNFa-producing CD8+ effector memory (EM) T- lymphocytes in BALB / c mouse spleens and lungs 6 days after challenge with A / Philippines / 2 / 1982 (H3N2, X-79) virus (n = 3 mice / group). T-cells were stimulated with overlapping peptide libraries covering the H3 protein sequence from A / Perth / 16 / 2009 (H3N2) virus, the N2 protein from A / Perth / 16 / 2009 (H3N2) virus, and the NP protein from A / Puerto Rico / 8 / 1934 (H1N1) virus. Different groups of BALB / c mice were sequentially vaccinated with PBS, BSA + 10 pg / mouse of CpG 1018® adjuvant, or 1 pg HA / mouse of split vaccine + 10 pg / mouse of CpG 1018® adjuvant. FIG. 10B depicts the percentage of different cytokineproducing cell populations within the total CD8+ EM T-cell subset (n = 3) after background subtraction. Average and SD values are shown. Statistical analyses were performed using one-way ANOVA corrected for Dunn’s multiple comparison test. Only statistically significant p-values (<0.05) are shown.

[0135] FIGS. 11A-11D show an alignment of influenza A virus HAs (SEQ ID NOS:53- 69). The start of the mature HA sequence is indicated, the Ap is indicated, the Aq isindicated, and the start of the HA2 domain is indicated. Ap designates cysteine at amino acid position 52 of mature influenza A virus HA according to H3 numbering. Aq designates cysteine at amino acid position 277 of mature influenza A virus HA according to H3 numbering.5. DETAILED DESCRIPTION

[0136] In one aspect, provided herein are immunogenic compositions comprising a chimeric hemagglutinin and a CpG oligonucleotide adjuvant described herein In a specific embodiment, provided herein are immunogenic compositions comprising an inactivated influenza A virus or inactivated split influenza A virus and a CpG oligonucleotide adjuvant described herein, wherein the inactivated influenza A virus or inactivated split influenza A virus comprises a chimeric hemagglutinin described herein. In another aspect, provided herein are methods of immunizing a subject against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) using an immunogenic composition described herein. In another aspect, provided herein are methods of preventing influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g, group 2 influenza A virus) in a subject using an immunogenic composition described herein.5.1 Immunogenic Compositions

[0137] In one aspect, provided herein are immunogenic compositions comprising a chimeric hemagglutinin (HA) and a CpG oligonucleotide adjuvant described herein. In some embodiments, provided herein are immunogenic compositions comprising a chimeric HA and a CpG oligonucleotide adjuvant described herein in an admixture with a pharmaceutically acceptable carrier. In some embodiments, provided herein are immunogenic compositions comprising an inactivated influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the inactivated influenza virus comprises a chimeric HA described herein. In some embodiments, provided herein are immunogenic compositions comprising an inactivated influenza virus and a CpG oligonucleotide adjuvant described herein in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated influenza virus comprises a chimeric HA described herein. In some embodiments, provided herein are immunogenic compositions comprising an inactivated influenza virus and a CpG oligonucleotide adjuvant described herein in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated influenza A virus comprises a chimeric HA described herein.In some embodiments, provided herein are immunogenic compositions comprising an inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the inactivated split influenza virus comprises a chimeric HA described herein. In some embodiments, provided herein are immunogenic compositions comprising an inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated split influenza virus comprises a chimeric HA described herein. In some embodiments, provided herein are immunogenic compositions comprising an inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated split influenza A virus comprises a chimeric HA described herein. In specific embodiments, the chimeric HA is one described in this Section or Section 5.3 or 6, infra. In specific embodiments, the CpG oligonucleotide adjuvant is one described in this Section or Section 5.2 or 6, infra. In some embodiments, the immunogenic composition does not comprise an aluminum salt (e.g., aluminum hydroxide, amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, or a combination thereof). In some embodiments, the immunogenic composition comprises an aluminum salt (e.g., aluminum hydroxide, amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, or a combination thereof).

[0138] In some embodiments, provided herein is an immunogenic composition comprising: (a) a chimeric HA comprising an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain, and wherein the HA globular head domain of the chimeric HA is immunologically distinct from the globular head domain of the group 2 influenza A virus HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, provided herein is an immunogenic composition comprising: (a) a chimeric HA comprising an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain, and wherein the HA globular head domain of the chimeric HA is immunologically distinct fromthe globular head domain of the group 2 influenza A virus HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3), in an admixture with a pharmaceutically acceptable carrier. In specific embodiments, the chimeric HA is one described in this Section or Section 5.3 or 6, infra. In specific embodiments, the CpG oligonucleotide adjuvant is one described in this Section or Section 5.2 or 6, infra. In some embodiments, the immunogenic composition described herein does not comprise an aluminum salt (e.g., aluminum hydroxide, amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, or a combination thereof). In some embodiments, the immunogenic composition described herein comprises an aluminum salt (e.g., aluminum hydroxide, amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, or a combination thereof).

[0139] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain, and wherein the HA globular head domain of the chimeric HA is immunologically distinct from the globular head domain of the group 2 influenza A virus HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain, and wherein the HA globular head domain of the chimeric HA is immunologically distinct from the globular head domain of the group 2 influenza A virus HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising achimeric HA, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain, and wherein the HA globular head domain of the chimeric HA is immunologically distinct from the globular head domain of the group 2 influenza A virus HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3), in an admixture with a pharmaceutically acceptable carrier. In specific embodiments, the chimeric HA is one described in this Section or Section 5.3 or 6, infra. In specific embodiments, the CpG oligonucleotide adjuvant is one described in this Section or Section 5.2 or 6, infra. In some embodiments, the immunogenic composition described herein does not comprise an aluminum salt (e.g., aluminum hydroxide, amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, or a combination thereof). In some embodiments, the immunogenic composition described herein comprises an aluminum salt e.g., aluminum hydroxide, amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, or a combination thereof).

[0140] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus of adifferent strain, subtype, or group than the group 2 influenza A virus HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3), in an admixture with a pharmaceutically acceptable carrier. In specific embodiments, the chimeric HA is one described in this Section or Section 5.3 or 6, infra. In specific embodiments, the CpG oligonucleotide adjuvant is one described in this Section or Section 5.2 or 6, infra. In some embodiments, the immunogenic composition described herein does not comprise an aluminum salt (e.g., aluminum hydroxide, amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, or a combination thereof). In some embodiments, the immunogenic composition described herein comprises an aluminum salt (e.g., aluminum hydroxide, amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, or a combination thereof).

[0141] In some embodiments, provided herein are immunogenic compositions comprising an inactivated split influenza virus and a CpG oligonucleotide adjuvant described herein, wherein the inactivated split influenza virus comprises a chimeric hemagglutinin described herein. In some embodiments, provided herein are immunogenic compositions comprising an inactivated split influenza A virus and a CpG oligonucleotide adjuvant described herein in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated split influenza virus comprises a chimeric hemagglutinin described herein. In specific embodiments, the chimeric HA is one described in this Section or Section 5.3 or 6, infra. In specific embodiments, the CpG oligonucleotide adjuvant is one described in this Section or Section 5.2 or 6, infra. In some embodiments, the immunogenic composition does not comprise an aluminum salt (e.g., aluminum hydroxide, amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, or a combination thereof). In some embodiments, the immunogenic composition comprises an aluminum salt (e.g., aluminum hydroxide, amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, or a combination thereof).

[0142] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, wherein the HAglobular head domain of the chimeric HA is heterologous to the HA stalk domain, and wherein the HA globular head domain of the chimeric HA is immunologically distinct from the globular head domain of the group 2 influenza A virus HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain, and wherein the HA globular head domain of the chimeric HA is immunologically distinct from the globular head domain of the group 2 influenza A virus HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3), in an admixture with a pharmaceutically acceptable carrier. In specific embodiments, the chimeric HA is one described in this Section or Section 5.3 or 6, infra. In specific embodiments, the CpG oligonucleotide adjuvant is one described in this Section or Section 5.2 or 6, infra. In some embodiments, the immunogenic composition described herein does not comprise an aluminum salt (e.g., aluminum hydroxide, amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, or a combination thereof). In some embodiments, the immunogenic composition described herein comprises an aluminum salt (e.g., aluminum hydroxide, amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, or a combination thereof).

[0143] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising thenucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus of a different strain, subtype, or group than the group 2 influenza A virus HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3), in an admixture with a pharmaceutically acceptable carrier. In specific embodiments, the chimeric HA is one described in this Section or Section 5.3 or 6, infra. In specific embodiments, the CpG oligonucleotide adjuvant is one described in this Section or Section 5.2 or 6, infra. In some embodiments, the immunogenic composition described herein does not comprise an aluminum salt (e.g., aluminum hydroxide, amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, or a combination thereof). In some embodiments, the immunogenic composition described herein comprises an aluminum salt (e.g., aluminum hydroxide, amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, or potassium aluminum sulfate, or a combination thereof).

[0144] In some embodiments, provided herein is an immunogenic composition comprising: (a) a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / wedged-tailed / shearwater / Western Australia / 2576 / 9134 (H15N9) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, provided herein is an immunogenic composition comprising: (a) a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / wedged- tailed / shearwater / Western Australia / 2576 / 9134 (H15N9) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3), in an admixture with a pharmaceutically acceptable carrier.

[0145] In some embodiments, provided herein is an immunogenic composition comprising: (a) a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / duck / Czechoslovakia / 1956 (H4N6) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, provided herein is an immunogenic composition comprising: (a) a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / duck / Czechoslovakia / 1956 (H4N6) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3), in an admixture with a pharmaceutically acceptable carrier.

[0146] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / wedged- tailed / shearwater / Western Australia / 2576 / 9134 (H15N9) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / wedged-tailed / shearwater / Western Australia / 2576 / 9134 (H15N9) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3), in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated influenza virus comprises the NA of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263. In some embodiments, the inactivated influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the inactivated influenza virus comprises the non- structural proteins and matrix protein of influenza virus A / Puerto Rico / 8 / 1934 (H1N1).

[0147] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / wedged- tailed / shearwater / Western Australia / 2576 / 9134 (H15N9) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / wedged-tailed / shearwater / Western Australia / 2576 / 9134 (H15N9) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3), in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated split influenza virus comprises the NA of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263. In some embodiments, the inactivated split influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the inactivated split influenza virus comprises the non- structural proteins and matrix protein of influenza virus A / Puerto Rico / 8 / 1934 (H1N1).

[0148] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / duck / Czechoslovakia / 1956 (H4N6) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / duck / Czechoslovakia / 1956 (H4N6) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3), in anadmixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated influenza virus comprises the NA of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263. In some embodiments, the inactivated influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes (e.g., non- structural and / or matrix encoding genes) of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the inactivated influenza virus comprises the non-structural proteins and matrix protein of influenza virus A / Puerto Rico / 8 / 1934 (H1N1).

[0149] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A A / duck / Czechoslovakia / 1956 (H4N6) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / duck / Czechoslovakia / 1956 (H4N6) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3), in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated split influenza virus comprises the NA of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263. In some embodiments, the inactivated split influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes e.g., non- structural and / or matrix encoding genes) of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the inactivated split influenza virus comprises the non-structural proteins and matrix protein of influenza virus A / Puerto Rico / 8 / 1934 (H1N1).

[0150] In some embodiments, provided herein is an immunogenic composition comprising: (a) a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / wedged-tailed / shearwater / Western Australia / 2576 / 9134 (H15N9) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant. In some embodiments, provided herein is an immunogenic composition comprising: (a) a chimeric HA, wherein the chimeric HAcomprises the HA globular head domain of influenza virus A / wedged- tailed / shearwater / Western Australia / 2576 / 9134 (H15N9) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant, in an admixture with a pharmaceutically acceptable carrier.

[0151] In some embodiments, provided herein is an immunogenic composition comprising: (a) a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / duck / Czechoslovakia / 1956 (H4N6) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant. In some embodiments, provided herein is an immunogenic composition comprising: (a) a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / duck / Czechoslovakia / 1956 (H4N6) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant, in an admixture with a pharmaceutically acceptable carrier.

[0152] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / wedged- tailed / shearwater / Western Australia / 2576 / 9134 (H15N9) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / wedged- tailed / shearwater / Western Australia / 2576 / 9134 (H15N9) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant, in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated influenza virus comprises the NA of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263. In some embodiments, the inactivated influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, theinactivated influenza virus comprises the non- structural proteins and matrix protein of influenza virus A / Puerto Rico / 8 / 1934 (H1N1).

[0153] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / wedged- tailed / shearwater / Western Australia / 2576 / 9134 (H15N9) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / wedged- tailed / shearwater / Western Australia / 2576 / 9134 (H15N9) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant, in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated split influenza virus comprises the NA of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263. In some embodiments, the inactivated split influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the inactivated split influenza virus comprises the non- structural proteins and matrix protein of influenza virus A / Puerto Rico / 8 / 1934 (H1N1).

[0154] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / duck / Czechoslovakia / 1956 (H4N6) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / duck / Czechoslovakia / 1956 (H4N6) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant, in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated influenza virus comprises the NA of influenza virusA / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263. In some embodiments, the inactivated influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes (e.g., non-structural and / or matrix encoding genes) of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the inactivated influenza virus comprises the non-structural proteins and matrix protein of influenza virus A / Puerto Rico / 8 / 1934 (H1N1).In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A A / duck / Czechoslovakia / 1956 (H4N6) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / duck / Czechoslovakia / 1956 (H4N6) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant, in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated split influenza virus comprises the NA of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263. In some embodiments, the inactivated split influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes (e.g., non-structural and / or matrix encoding genes) of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the inactivated split influenza virus comprises the non-structural proteins and matrix protein of influenza virus A / Puerto Rico / 8 / 1934 (H1N1).

[0155] In some embodiments, provided herein is an immunogenic composition comprising: (a) a chimeric HA comprising the amino acid sequence of SEQ ID NO: 5 or 6; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant. In some embodiments, provided herein is an immunogenic composition comprising: (a) a chimeric HA comprising the amino acid sequence of SEQ ID NO: 7 or 8; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant.

[0156] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein thechimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant. In some embodiments, the inactivated influenza virus comprises the NA of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263. In some embodiments, the inactivated influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the inactivated influenza virus comprises the non-structural proteins and matrix protein of influenza virus A / Puerto Rico / 8 / 1934 (H1N1).

[0157] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8; and (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant. In some embodiments, the inactivated influenza virus comprises the NA of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263. In some embodiments, the inactivated split influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the inactivated split influenza virus comprises the non-structural proteins and matrix protein of influenza virus A / Puerto Rico / 8 / 1934 (H1N1).

[0158] In some embodiments, provided herein is an immunogenic composition comprising a live attenuated influenza A virus, wherein the live attenuated influenza A virus comprises a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / wedged-tailed / shearwater / Western Australia / 2576 / 9134 (H15N9) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA). In some embodiments, provided herein is an immunogenic composition comprising a live attenuated influenza A virus, wherein the live attenuated influenza A virus comprises a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenzavirus A / wedged-tailed / shearwater / Western Australia / 2576 / 9134 (H15N9) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA, in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the live attenuated influenza A virus comprises the NA of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263. In some embodiments, the live attenuated influenza A virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the live attenuated influenza A virus comprises the non- structural proteins and matrix protein of influenza virus A / Puerto Rico / 8 / 1934 (H1N1).

[0159] In some embodiments, provided herein is an immunogenic composition comprising a live attenuated influenza A virus, wherein the live attenuated influenza A virus comprises a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / duck / Czechoslovakia / 1956 (H4N6) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA. In some embodiments, provided herein is an immunogenic composition comprising a live attenuated influenza A virus, wherein the live attenuated influenza A virus comprises a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / duck / Czechoslovakia / 1956 (H4N6) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA, in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the live attenuated influenza A virus comprises the NA of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263. In some embodiments, the live attenuated influenza A virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes (e.g. , non-structural and / or matrix encoding genes) of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the live attenuated influenza A virus comprises the non-structural proteins and matrix protein of influenza virus A / Puerto Rico / 8 / 1934 (H1N1).

[0160] In some embodiments, provided herein is an immunogenic composition comprising a chimeric HA described herein. In some embodiments, the chimeric HA comprises the HA globular head domain of influenza virus A / wedged- tailed / shearwater / Western Australia / 2576 / 9134 (H15N9) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA). In some embodiments, the chimeric HA comprises the HA globular head domain of influenza virus A / duck / Czechoslovakia / 1956 (H4N6) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA. In some embodiments, providedherein is an immunogenic composition comprising an inactivated influenza virus described herein (e.g., on Section 6). In some embodiments, provided herein is an immunogenic composition comprising an inactivated split influenza virus described herein (e.g., on Section 6). In some embodiments, provided herein is an immunogenic composition comprising the live attenuated influenza virus described in Section 6. In some embodiments, provided herein is an immunogenic composition described in Section 6.

[0161] In another aspect, provided herein are immunogenic compositions comprising a chimeric HA described herein, a CpG oligonucleotide adjuvant described herein, and an aluminum salt. In some embodiments, provided herein are immunogenic compositions comprising a chimeric HA described herein, a CpG oligonucleotide adjuvant described herein, and an aluminum salt in an admixture with a pharmaceutically acceptable carrier. In some embodiments, provided herein are immunogenic compositions comprising an inactivated influenza virus, a CpG oligonucleotide adjuvant described herein, and an aluminum salt, wherein the inactivated influenza virus comprises a chimeric HA described herein. In some embodiments, provided herein are immunogenic compositions comprising an inactivated influenza virus, a CpG oligonucleotide adjuvant described herein, and an aluminum salt in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated influenza virus comprises a chimeric HA described herein. In some embodiments, provided herein are immunogenic compositions comprising an inactivated split influenza virus, a CpG oligonucleotide adjuvant described herein, and an aluminum salt, wherein the inactivated split influenza virus comprises a chimeric HA described herein. In some embodiments, provided herein are immunogenic compositions comprising an inactivated split influenza virus, a CpG oligonucleotide adjuvant described herein, and an aluminum salt in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated split influenza virus comprises a chimeric HA described herein. In specific embodiments, the chimeric HA is one described in this Section or Section 5.3 or 6, infra. In some embodiments, the CpG oligonucleotide adjuvant is one described in this Section or Section 5.2 or 6, infra. In some embodiment, the aluminum salt is one described in this Section or Section 6, infra.

[0162] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, wherein the HAglobular head domain of the chimeric HA is heterologous to the HA stalk domain, and wherein the HA globular head domain of the chimeric HA is immunologically distinct from the globular head domain of the group 2 influenza A virus HA; (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3); and (c) an aluminum salt, in an admixture with a pharmaceutically acceptable carrier. In specific embodiments, the chimeric HA is one described in this Section or Section 5.3 or 6, infra. In some embodiments, the CpG oligonucleotide adjuvant is one described in this Section or Section 5.2 or 6, infra. In some embodiment, the aluminum salt is one described in this Section or Section 6, infra.

[0163] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus of a different strain, subtype, or group than the group 2 influenza A virus HA; (b) a CpG oligonucleotide adjuvant, wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3); and (c) an aluminum adjuvant, in an admixture with a pharmaceutically acceptable carrier. In specific embodiments, the chimeric HA is one described in this Section or Section 5.3 or 6, infra. In some embodiments, the CpG oligonucleotide adjuvant is one described in this Section or Section 5.2 or 6, infra. In some embodiments, the aluminum adjuvant is an aluminum salt. In some embodiment, the aluminum salt is one described in this Section or Section 6, infra.

[0164] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain, and wherein the HA globular head domain of the chimeric HA is immunologically distinct from the globular head domain of the group 2 influenza A virus HA; (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ IDN0:3); and (c) an aluminum salt, in an admixture with a pharmaceutically acceptable carrier. In specific embodiments, the chimeric HA is one described in this Section or Section 5.3 or 6, infra. In some embodiments, the CpG oligonucleotide adjuvant is one described in this Section or Section 5.2 or 6, infra. In some embodiment, the aluminum salt is one described in this Section or Section 6, infra.

[0165] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus of a different strain, subtype, or group than the group 2 influenza A virus HA; (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3); and (c) an aluminum adjuvant, in an admixture with a pharmaceutically acceptable carrier. In specific embodiments, the chimeric HA is one described in this Section or Section 5.3 or 6, infra. In some embodiments, the CpG oligonucleotide adjuvant is one described in this Section or Section 5.2 or 6, infra. In some embodiments, the aluminum adjuvant is an aluminum salt. In some embodiment, the aluminum salt is one described in this Section or Section 6, infra.

[0166] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / wedged- tailed / shearwater / Western Australia / 2576 / 9134 (H15N9) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3); and (c) an aluminum salt. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / wedged- tailed / shearwater / Western Australia / 2576 / 9134 (H15N9) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3); and (c)an aluminum salt, in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated influenza virus comprises the NA of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263. In some embodiments, the inactivated influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the inactivated influenza virus comprises the non- structural proteins and matrix protein of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, potassium aluminum sulfate, and a combination thereof.

[0167] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / wedged- tailed / shearwater / Western Australia / 2576 / 9134 (H15N9) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3); and (c) an aluminum salt. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / wedged- tailed / shearwater / Western Australia / 2576 / 9134 (H15N9) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3); and (c) an aluminum salt, in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated split influenza virus comprises the NA of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263. In some embodiments, the inactivated split influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the inactivated split influenza virus comprises the non- structural proteins and matrix protein of influenza virus A / Puerto Rico / 8 / 1934 (H1N1).

[0168] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virusA / duck / Czechoslovakia / 1956 (H4N6) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3); and (c) an aluminum salt. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / duck / Czechoslovakia / 1956 (H4N6) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3); and (c) an aluminum salt, in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated influenza virus comprises the NA of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263. In some embodiments, the inactivated influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the inactivated influenza virus comprises the non- structural proteins and matrix protein of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, potassium aluminum sulfate, and a combination thereof.

[0169] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A A / duck / Czechoslovakia / 1956 (H4N6) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3); and (c) an aluminum salt. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / duck / Czechoslovakia / 1956 (H4N6) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3); and (c) an aluminum salt, in an admixture with apharmaceutically acceptable carrier. In some embodiments, the inactivated split influenza virus comprises the NA of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263. In some embodiments, the inactivated split influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the inactivated split influenza virus comprises the non- structural proteins and matrix protein of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, potassium aluminum sulfate, and a combination thereof

[0170] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / wedged- tailed / shearwater / Western Australia / 2576 / 9134 (H15N9) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant; and (c) an aluminum salt. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / wedged-tailed / shearwater / Western Australia / 2576 / 9134 (H15N9) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant; and (c) an aluminum salt, in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated influenza virus comprises the NA of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263. In some embodiments, the inactivated influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the inactivated influenza virus comprises the non-structural proteins and matrix protein of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, potassium aluminum sulfate, and a combination thereof.

[0171] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein thechimeric HA comprises the HA globular head domain of influenza virus A / wedged- tailed / shearwater / Western Australia / 2576 / 9134 (H15N9) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant; and (c) an aluminum salt. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / wedged-tailed / shearwater / Western Australia / 2576 / 9134 (H15N9) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant; and (c) an aluminum salt, in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated split influenza virus comprises the NA of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263. In some embodiments, the inactivated split influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the inactivated split influenza virus comprises the non-structural proteins and matrix protein of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, potassium aluminum sulfate, and a combination thereof.

[0172] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / duck / Czechoslovakia / 1956 (H4N6) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant; and (c) an aluminum salt. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / duck / Czechoslovakia / 1956 (H4N6) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant; and (c) an aluminum salt, in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated influenza virus comprises the NA of influenza virus A / HongKong / 4801 / 2014 (H3N2) NYMC X-263. In some embodiments, the inactivated influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the inactivated influenza virus comprises the non- structural proteins and matrix protein of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, potassium aluminum sulfate, and a combination thereof.

[0173] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A A / duck / Czechoslovakia / 1956 (H4N6) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant; and (c) an aluminum salt. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the HA globular head domain of influenza virus A / duck / Czechoslovakia / 1956 (H4N6) HA and the HA stalk domain of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263 HA; (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO:4, or CpG 1018® adjuvant; and (c) an aluminum salt, in an admixture with a pharmaceutically acceptable carrier. In some embodiments, the inactivated split influenza virus comprises the NA of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263. In some embodiments, the inactivated split influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the inactivated split influenza virus comprises the non- structural proteins and matrix protein of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, potassium aluminum sulfate, and a combination thereof

[0174] In some embodiments, provided herein is an immunogenic composition comprising: (a) a chimeric HA comprising the amino acid sequence of SEQ ID NO: 5 or 6; (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant; and (c) an aluminum salt. In some embodiments, provided herein is animmunogenic composition comprising: (a) a chimeric HA comprising the amino acid sequence of SEQ ID NO: 7 or 8; (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant; and (c) an aluminum salt. In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, potassium aluminum sulfate, and a combination thereof.

[0175] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6; (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant; and (c) an aluminum salt. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8; (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant; and (c) an aluminum salt. In some embodiments, the inactivated influenza virus comprises the NA of influenza virus A / Hong Kong / 4801 / 2014 (H3N2) NYMC X-263. In some embodiments, the inactivated influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the inactivated influenza virus comprises the non- structural proteins and matrix protein of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, potassium aluminum sulfate, and a combination thereof.

[0176] In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6; (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant; and (c) an aluminum salt. In some embodiments, provided herein is an immunogenic composition comprising: (a) an inactivated split influenza virus comprising a chimeric HA, wherein the chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8; (b) a CpG oligonucleotide adjuvant comprising the nucleotide sequence of SEQ ID NO: 4, or CpG 1018® adjuvant; and (c) an aluminum salt. In some embodiments, the inactivated influenza virus comprises the NA of influenza virus A / Hong Kong / 4801 / 2014 (H3N2)NYMC X-263. In some embodiments, the inactivated split influenza virus comprises one or more, or all proteins other than HA and NA encoded by one or more, or all genes of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the inactivated split influenza virus comprises the non-structural proteins and matrix protein of influenza virus A / Puerto Rico / 8 / 1934 (H1N1). In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, potassium aluminum sulfate, and a combination thereof.

[0177] In some embodiments, an immunogenic composition described herein comprises from about 3.75 pg to about 150 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 3.75 pg to about 75 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 3.75 pg to about 50 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 3.75 pg to about 25 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 3.75 pg to about 15 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 3.75 pg to about 10 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 10 pg to about 150 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 10 pg to about 75 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 50 pg to about 150 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 50 pg to about 100 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 50 pg to about 150 pg of HA (e.g, a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 75 pg to about 150 pg of HA (e.g, a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 25 pg to about 100 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 25 pg to about 75 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 10 pg to about 50 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 10 pg toabout 25 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 0.1 pg to about 5 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 10 pg to about 15 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 10 pg to about 60 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 5 pg to about 50 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 5 pg to about 45 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 5 pg to about 40 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 10 pg to about 40 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 10 pg to about 35 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 15 pg to about 35 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 15 pg to about 30 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises about 3.75 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises about 5 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises about 10 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises about 15 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises about 20 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 25 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 30 pg of HA (e.g., a chimeric HA). In some embodiments, an immunogenic composition described herein comprises from about 60 pg of HA (e.g., a chimeric HA).

[0178] In some embodiments, the chimeric HA comprises the HA globular head domain and HA stem domain of a chimeric HA set forth in Table 1.

[0179] In some embodiments, the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of the H3 subtype. In some embodiments, the chimeric HA comprises the amino acid sequence of the HA stalk domainof group 2 influenza A virus A / Hong Kong / 4801 / 2014, NYMC X-263 HA or A / Hong Kong / 4801 / 2014-like HA.

[0180] In some embodiments, the chimeric HA comprises the amino acid sequence of the HA globular head domain of a group 1 influenza A virus HA. In some embodiments, the chimeric HA comprises the amino acid sequence of the HA globular head domain of an H2, H5, H6, H8, H9, Hl l, H12, H13, H16, H17, or H18 subtype. In some embodiments, the chimeric HA comprises the amino acid sequence of the HA globular head domain of an H4, H7, H10, H14, or H15 subtype. In some embodiments, the chimeric HA comprises the amino acid sequence of the HA globular head domain of an avian influenza virus HA (e.g., avian influenza A virus HA) which does not circulate in humans. In some embodiments, the chimeric HA comprises the amino acid sequence of the HA globular head domain of influenza A virus A / wedge-tailed shearwater / Westem Australia / 2576 / 1979 HA or A / wedge- tailed shearwater / Westem Australia / 2576 / 1979-like HA. In some embodiments, the chimeric HA comprises the amino acid sequence of the HA globular head domain of influenza A vims A / Duck / Czechoslovakia / 1956 HA or A / Duck / Czechoslovakia / 1956-like HA.

[0181] In some embodiments, the chimeric HA comprises the amino acid sequence of the HA globular head domain of an H4 and the amino acid sequence of the HA stem domain of an H3. In some embodiments, the chimeric HA comprises the amino acid sequence of the HA globular head domain of an Hl 5 and the amino acid sequence of the HA stem domain of an H3. In some embodiments, the chimeric HA comprises the amino acid sequence of the HA globular head domain of influenza A virus A / Duck / Czechoslovakia / 1956 HA or A / Duck / Czechoslovakia / 1956-like HA and the amino acid sequence of the HA stem domain of influenza A virus A / Hong Kong / 4801 / 2014 H3N2, NYMC X-263 HA or A / Hong Kong / 4801 / 2014-like HA. In some embodiments, the chimeric HA comprises the amino acid sequence of the HA globular head domain of influenza A virus A / wedge-tailed shearwater / Western Australia / 2576 / 1979 HA or A / wedge-tailed shearwater / We stern Australia / 2576 / 1979-like HA and the amino acid sequence of HA stem domain of influenza A virus A / Hong Kong / 4801 / 2014 H3N2, NYMC X-263 HA or A / Hong Kong / 4801 / 2014-like HA.

[0182] In some embodiments, the chimeric HA comprises an amino acid sequence that is at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 5. In some embodiments, the chimeric HA comprises an amino acid sequence that is at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:6. In some embodiments, the chimeric HA comprises an amino acidsequence that is at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:7. In some embodiments, the chimeric HA comprises an amino acid sequence that is at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 8.

[0183] In specific embodiments, the chimeric HA comprises the amino acid sequence of SEQ ID NO:5. In specific embodiments, the chimeric HA comprises the amino acid sequence of SEQ ID NO:6. In specific embodiments, the chimeric HA comprises the amino acid sequence of SEQ ID NO:7. In specific embodiments, the chimeric HA comprises the amino acid sequence of SEQ ID NO: 8.

[0184] In some embodiments, the inactivated influenza virus comprises neuraminidase from the same group 2 influenza A virus from which the HA stem domain of the chimeric domain is derived. In some embodiments, the inactivated influenza virus comprises proteins encoded by genes of influenza A virus A / Puerto Rico / 8 / 1934. In some embodiments, the inactivated influenza A virus comprises non- structural proteins and matrix protein encoded by genes of influenza A virus A / Puerto Rico / 8 / 1934. In some embodiments, the inactivated influenza virus comprises: (a) neuraminidase from the same group 2 influenza A virus from which the HA stem domain of the chimeric domain is derived; and (b) proteins encoded by genes of influenza A virus A / Puerto Rico / 8 / 1934. In some embodiments, the inactivated influenza virus comprises: (a) neuraminidase from the same group 2 influenza A virus from which the HA stem domain of the chimeric domain is derived; and (b) non- structural proteins and matrix protein encoded by genes of influenza A virus A / Puerto Rico / 8 / 1934.

[0185] In some embodiments, the inactivated split influenza virus comprises neuraminidase from the same group 2 influenza A virus from which the HA stem domain of the chimeric domain is derived. In some embodiments, the inactivated split influenza virus comprises proteins encoded by genes of influenza A virus A / Puerto Rico / 8 / 1934. In some embodiments, the inactivated split influenza virus comprises non- structural proteins and matrix protein encoded by genes of influenza A virus A / Puerto Rico / 8 / 1934. In some embodiments, the inactivated split influenza virus comprises: (a) neuraminidase from the same group 2 influenza A virus from which the HA stem domain of the chimeric domain is derived; and (b) proteins encoded by genes of influenza A virus A / Puerto Rico / 8 / 1934. In some embodiments, the inactivated split influenza virus comprises: (a) neuraminidase from the same group 2 influenza A virus from which the HA stem domain of the chimeric domain is derived; and (b) non-structural proteins and matrix protein encoded by genes of influenza A virus A / Puerto Rico / 8 / 1934.

[0186] In some embodiments, an immunogenic composition described herein comprises from about 1 pg to about 50 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises from about 5 pg to about 50 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises from about 5 pg to about 40 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises from about 5 pg to about 30 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises from about 5 pg to about 25 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises from about 5 pg to about 20 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises from about 5 pg to about 10 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises about 1 pg, about 2 pg, about 3 pg, about 4 pg, or about 5 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises about 6 pg, about 7 pg, about 8 pg, about 9 pg, or about 10 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises about 11 pg, about 12 pg, about 13 pg, about 14 pg, or about 15 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises about 20 pg, about 25 pg, about 30 pg, about 40 pg, or about 50 pg of a CpG oligonucleotide adjuvant.

[0187] In some embodiments, an immunogenic composition described herein comprises from about 50 pg to about 400 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises from about 75 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises from about 100 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises from about 150 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises from about 200 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises from about 250 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises from about 300 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises from about 350 pg of a CpG oligonucleotide adjuvant. In some embodiments, an immunogenic composition described herein comprises from about 400 pg of a CpG oligonucleotide adjuvant.

[0188] In some embodiments, an immunogenic composition described herein comprises from about 375 pg to about 6000 pg of a CpG oligonucleotide of a CpG oligonucleotide adjuvant described herein (e.g., in Section 5.2 or Example 1), preferably from about 500 pg to about 5000 pg of the CpG oligonucleotide, preferably from about 750 pg to about 3000 pg of the CpG oligonucleotide. In some embodiments, an immunogenic composition described herein comprises greater than about 250 pg, about 500 pg, about 750 pg, about 1000 pg, or about 1250 pg of the CpG oligonucleotide of a CpG oligonucleotide adjuvant described herein (e.g., in Section 5.2 or Example 1), and less than about 6000 pg, about 5000 pg, about 4000 pg, about 3000 pg, or about 2000 pg of the CpG oligonucleotide. In some embodiments, an immunogenic composition described herein comprises about 375 pg, about 750 pg, about 1500 pg, about 3000 pg or about 6000 pg of the CpG oligonucleotide of a CpG oligonucleotide adjuvant described herein (e.g., in Section 5.2 or Example 1). In some embodiments, an immunogenic composition comprises about 750 pg of the CpG oligonucleotide adjuvant described herein (e.g., in Section 5.2 or Example 1). In some embodiments, an immunogenic composition described herein comprises about 1500 pg of the CpG oligonucleotide of a CpG oligonucleotide adjuvant described herein (e.g., in Section 5.2 or Example 1). In some embodiments, an immunogenic composition described herein comprises about 3000 pg of the CpG oligonucleotide of a CpG oligonucleotide adjuvant described herein (e.g., in Section 5.2 or Example 1). In some embodiments, an immunogenic composition described herein comprises about 6000 pg of the CpG oligonucleotide of a CpG oligonucleotide adjuvant described herein (e.g, in Section 5.2 or Example 1).

[0189] In some embodiments, the oligonucleotide of the CpG oligonucleotide adjuvant comprises the nucleotide sequence of 5’-TGACTGTGAACGTTCGAGATGA-3’ (SEQ ID NO:4). In some embodiments, the oligonucleotide of the CpG oligonucleotide adjuvant is 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 nucleotides in length. In some embodiments, the oligonucleotide of the CpG oligonucleotide adjuvant is a single stranded oligodeoxynucleotide. In some embodiments, the oligonucleotide of the CpG oligonucleotide adjuvant comprises only phosphorothioate linkages, or a combination of one or more phosphodiester linkages and one or more phosphorothioate linkages. In some embodiments, the oligonucleotide of the CpG oligonucleotide adjuvant is fully RNA or is an RNA / DNA chimera.

[0190] In some embodiments, an immunogenic composition described herein comprises from about 5 pg to about 50 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises from about 5 pg to about 25 pg of an aluminum salt.In some embodiments, an immunogenic composition described herein comprises from about 5 pg to about 15 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises from about 15 pg to about 25 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises from about 15 pg to about 50 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 5 pg, about 15 pg, about 25 pg, or about 50 pg of an aluminum salt.

[0191] In some embodiments, an immunogenic composition described herein comprises from about 50 pg to about 800 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises from about 100 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 150 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 200 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 250 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 300 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 350 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 400 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 450 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 500 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 550 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 600 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 650 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 700 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 750 pg of an aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 800 pg of an aluminum salt.

[0192] In some embodiments, an immunogenic composition described herein comprises from about 0.25 to about 1.25 mg of A13+. In some embodiments, an immunogenic composition comprises from about 0.50 to about 1.00 mg of an A13+. In some embodiments, the immunogenic composition comprises about 0.375 mg, about 0.75 mg, or about 1.00 mgof A13+. In some embodiments, the immunogenic composition comprises about 0.375 mg of A13+.

[0193] In some embodiments, an immunogenic composition described herein comprises about 0.05% to about 3%, or about 1% to about 3% of aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 1%, about 1.5%, about 2%, about 2.5%, or about 3% of aluminum salt. In some embodiments, an immunogenic composition described herein comprises about 1% or about 2% of an aluminum salt.

[0194] In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, potassium aluminum sulfate, and a combination thereof. In some embodiments, the aluminum salt comprises one or both of aluminum hydroxide and aluminum phosphate. In some embodiments, the aluminum salt comprises aluminum hydroxide. In some embodiments, the aluminum salt comprises aluminum phosphate. In some embodiments, the immunogenic composition described herein does not comprise an aluminum salt.

[0195] In specific embodiments, an aluminum salt functions as an adjuvant.

[0196] In some embodiments, an immunogenic composition described herein further comprises a group 1 chimeric HA, such as, e.g., described in Nachbagauer et al., 2016, npj Vaccines 131 1, 1-10, and / or Nachbagauer et al., 2021, Nature Medicine 27, 106-114. In some embodiments, an immunogenic composition described herein further comprises a group 1 chimeric HA, wherein the group 1 chimeric HA comprises an HA globular head domain of an influenza virus H8 and the HA stem domain of an influenza virus Hl. In some embodiments, an immunogenic composition described herein further comprises a group 1 chimeric HA, wherein the group 1 chimeric HA comprises an HA globular head domain of an influenza virus H8 and the HA stem domain of an influenza A virus A / California / 04 / 09 HA. In some embodiments, an immunogenic composition described herein further comprises a group 1 chimeric HA, wherein the group 1 chimeric HA comprises an HA globular head domain of an influenza A virus A / mallard / Sweden / 24 / 02 HA and the HA stem domain of an influenza A virus A / California / 04 / 09 HA. In some embodiments, an immunogenic composition described herein further comprises a group 1 chimeric HA, wherein the group 1 chimeric HA comprises an HA globular head domain of an influenza virus H5 and the HA stem domain of an influenza A virus A / California / 04 / 09 HA. In some embodiments, an immunogenic composition described herein further comprises a group 1 chimeric HA, wherein the group 1 chimeric HA comprises an HA globular head domain of an influenza Avirus A / Vietnam / 1203 / 04 HA and the HA stem domain of an influenza A virus A / California / 04 / 09 HA. In some embodiments, the immunogenic composition described herein further comprises mosaic HA influenza B, such as, e.g., described in Liu et al., 2021, Front Immunol 12, 746447. In some embodiments, the mosaic HA influenza B comprises influenza B virus B / Yamagata / 16 / 1988 (Yam) HA in which the major antigenic sites are replaced by corresponding sequences from H5, H8 or H13.

[0197] In some embodiments, an immunogenic composition described herein further comprises mosaic HA influenza B, such as, e.g., described in Liu et al., 2021, Front Immunol 12, 746447; Sun et al., J. Virol. 93(12):e00333-19; Sun et al., 2019, J. Virol. 93(2):e01673- 18; and Ermler et al., 2017, J. Virol. 91(12):e00286-17. In some embodiments, the mosaic HA influenza B comprises influenza B virus B / Yamagata / 16 / 1988 (Yam) HA in which the major antigenic sites are replaced by corresponding sequences from H5, H8 or Hl 3.

[0198] In some embodiments, an immunogenic composition described herein has a volume of about 0.5 mL to about 2 mL. In some embodiments, an immunogenic composition described herein has a volume of about 0.5 mL, about 1 mL, about 1.5 mL, or about 2 mL.

[0199] As used herein, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans. The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the pharmaceutical composition is administered. In specific embodiments, the pharmaceutically acceptable carrier is a diluent, excipient, or vehicle. For example, the pharmaceutically acceptable carrier is a diluent (e.g., saline). Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Examples of suitable pharmaceutical carriers are described in “Remington’s Pharmaceutical Sciences” by E.W. Martin. The formulation should suit the mode of administration.

[0200] In specific embodiments, an immunogenic compositions described herein are formulated to be suitable for the intended route of administration to a subject. For example, an immunogenic composition may be formulated to be suitable for parenteral, oral, intradermal, intranasal, transdermal, or intraperitoneal administration. In a specific embodiment, an immunogenic composition may be formulated for intravenous, oral, intraperitoneal, intranasal, intratracheal, subcutaneous, intramuscular, topical, intradermal,transdermal, or pulmonary administration. In a specific embodiment, an immunogenic composition may be formulated for intramuscular administration. In another specific embodiment, an immunogenic composition may be formulated for subcutaneous administration. In another specific embodiment, an immunogenic composition may be formulated for intranasal administration.

[0201] In specific embodiments, provided herein is an immunogenic composition described in Section 6, infra.

[0202] An immunogenic composition described herein may be used to induce an immune response to one, two, or multiple (e.g., 3, 4, 5, 6, or more) influenza viruses (e.g., influenza A viruses) in a subject (e.g., human subject). In specific embodiments, an immunogenic composition described herein may be used to induce a cross-reactive immune response to two or more (e.g., 3, 4, 5, 6, or more) influenza A viruses (e.g., group 2 influenza A viruses) in a subject (e.g., human subject). An immunogenic composition described herein may be used to induce an immune response that provides protection (e.g., full or partial protection) against one, two, or multiple (e.g., 3, 4, 5, 6, or more) influenza viruses (e.g., influenza A virus, such as, e.g., group 2 influenza A viruses) in a subject (e.g., human subject). An immunogenic composition described herein may be used to induce an immune response that provides protection (e.g., full or partial protection) against one, two, or multiple (e.g., 3, 4, 5, 6, or more) influenza virus subtypes (e.g., influenza A virus, such as, e.g., group 2 influenza A virus subtypes) in a subject (e.g., human subject). In some embodiments, the immune response induced provides protection (e.g., full or partial protection) against a homologous influenza A virus. In some embodiments, the immune response induced provides protection (e.g., full or partial protection) against a heterotypic influenza A virus. An immunogenic composition described herein may be used to immunize a subject (e.g., human subject) against influenza virus (e.g., influenza A virus). In some embodiments, an immunogenic composition described herein may be used to immunize a subject (e.g., human subject) against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus). An immunogenic composition described herein may also be used to prevent an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject (e.g., human subject). In a specific embodiment, an immunogenic composition described herein may be used in a method described herein. In some embodiments, two or more immunogenic compositions described herein may be used in a method described herein (e.g., to prevent an influenza virus disease and / or immunize a subject against an influenza virus disease). In some embodiments,two or more immunogenic compositions described herein may be used in a sequential immunization method described herein

[0203] In some embodiments, provided herein is the use of an immunogenic composition described herein in the manufacture of a medicament for inducing an immune response to one, two, or multiple (e.g., 3, 4, 5, 6, or more) influenza viruses (e.g., influenza A viruses) in a subject (e.g., human subject). In some embodiments, provided herein is the use of an immunogenic composition described herein in the manufacture of a medicament for inducing a cross-reactive immune response to two or more (e.g., 3, 4, 5, 6, or more) influenza A viruses (e.g., group 2 influenza A viruses) in a subject (e.g., human subject). In some embodiments, the immune response induced provides protection (e.g., full or partial protection) against a heterotypic influenza A virus. An immunogenic composition described herein may be used in the preparation of a medicament for immunizing a subject (e.g., human subject) against influenza virus (e.g., influenza A virus). In some embodiments, provided herein is the use of an immunogenic composition described herein in the manufacture of a medicament for immunizing a subject (e.g., human subject) against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus). In some embodiments, provided herein is the use of an immunogenic composition described herein in the manufacture of a medicament for preventing an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject (e.g., human subject).

[0204] In some embodiments, provided herein is the use of a first immunogenic composition described herein in the manufacture of a medicament for use in combination with a second immunogenic composition described herein to immunize a subject (e.g., human subject) against influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus). In some embodiments, provided herein is the use of an immunogenic composition described herein in the manufacture of a medicament for use in combination with a second immunogenic composition described herein to prevent an influenza virus disease (e.g., influenza virus disease caused by influenza A virus, such as, e.g., group 2 influenza A virus) in a subject (e.g., human subject).

[0205] In specific embodiments, an immunogenic composition described herein is a vaccine.

[0206] The immunogenic compositions described herein can be included in a container, pack, or dispenser together with instructions for administration.

[0207] In a specific embodiment, provided herein is a composition (e.g., a pharmaceutical composition) comprising an antibody(ies) that binds to influenza virus HA (e.g., a group 2 influenza A virus HA), which was generated using an immunogenic composition described herein. The composition may further comprise a pharmaceutically acceptable carrier. The antibody may be polyclonal or monoclonal. In some embodiments, the antibody is human or humanized. The antibody(ies) may be used to passively immunize a subject (e.g., a human subject).5.2 CpG Oligonucleotide Adjuvants

[0208] Toll-like receptors are expressed in and on dendritic cells and other innate immune cells and are among the most important receptors for stimulating a response to the presence of invading pathogens. Humans have multiple types of TLRs that are similar in structure but recognize different parts of viruses or bacteria. By activating specific TLRs, it is possible to stimulate and control specific types of innate immune responses that can be harnessed to enhance adaptive responses.

[0209] TLR9 (CD289) recognizes unmethylated cytidine-phospho-guanosine (CpG) motifs found in microbial DNA, which can be mimicked using synthetic CpG-containing oligodeoxynucleotides (CpG-ODNs). CpG-ODNs are known to enhance antibody production and to stimulate T helper 1 (Thl) cell responses (Coffman et al., Immunity, 33:492-503, 2010). Based on structure and biological function, CpG-ODNs have been divided into three general classes: CpG-A, CpG-B, and CpG-C (Campbell, Methods Mol Biol, 1494: 15-27, 2017). The degree of B cell activation varies between the classes with CpG-A ODNs being weak, CpG-C ODNs being good, and CpG-B ODNs being strong B cell activators.

[0210] In specific embodiments, the compositions described herein comprise, or are administered in combination with, a CpG oligonucleotide adjuvant. The CpG oligonucleotide adjuvants of the present disclosure are TLR9 agonists. In specific embodiments, CpG oligonucleotide adjuvants of the present disclosure are good B cell activators (CpG-C ODN) or more preferably strong (CpG-B ODN) B cell activators.

[0211] Optimal oligonucleotide TLR9 agonists often contain a palindromic sequence following the general formula of: 5’-purine-purine-CG-pyrimidine-pyrimidine-3’, or 5’- purine-purine-CG-pyrimidine-pyrimidine-CG-3’ (U.S. Patent No. 6,589,940). TLR9 agonism is also observed with certain non-palindromic CpG-enriched phosphorothioate oligonucleotides, but may be affected by changes in the nucleotide sequence. Additionally, TLR9 agonism is abolished by methylation of the cytosine within the CpG dinucleotide.Accordingly in some embodiments, a CpG oligonucleotide adjuvant comprises an oligonucleotide of from 8 to 35 nucleotides in length comprising the sequence 5’- AACGTTCG-3’ (SEQ ID NO: 1). In some embodiments, the oligonucleotide is greater than 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotides in length, and the oligonucleotide is less than 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, or 24 nucleotides in length. In some embodiments, a CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the sequence 5’-AACGTTCGAG-3’ (SEQ ID NO:2). In some embodiments, the oligonucleotide is greater than 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotides in length, and the oligonucleotide is less than 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, or 24 nucleotides in length. In some embodiments, a CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the sequence 5’-GAACGTTCG-3’ (SEQ ID NO:3). In some embodiments, the oligonucleotide is greater than 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotides in length, and the oligonucleotide is less than 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, or 24 nucleotides in length.

[0212] Researchers at Dynavax Technologies Corporation (Emeryville, CA) have identified a 22-mer phosphorothioate linked oligodeoxynucleotide, CpG 1018® adjuvant, which contains specific sequences that can substantially enhance the immune response to coadministered antigens across species (Campbell JD. Development of the CpG Adjuvant 1018: A Case Study. Methods Mol Biol. 2017;1494: 15-27. doi: 10.1007 / 978-l-4939-6445-l_2. PMID: 27718183). CpG 1018® adjuvant has a nucleotide sequence of 5’- TGACTGTGAACGTTCGAGATGA-3’ (SEQ ID NO:4) and was chosen after screening a broad panel of oligonucleotides for immunostimulatory activity in vitro and in vivo. CpG 1018® adjuvant is a CpG-B ODN that is active in mice, rabbits, dogs, baboons, cynomolgus monkeys, and humans. CpG 1018® adjuvant is also referred to by the term ODN 1018. In specific embodiments, a CpG oligonucleotide adjuvant (e.g., as described herein Section 5.2 or Example 1) comprises an oligonucleotide comprising the sequence of SEQ ID NO:4. In some embodiments, a CpG oligonucleotide adjuvant comprises an oligonucleotide of from 22 to 35 nucleotides in length comprising the sequence of SEQ ID NO:4. In some embodiments, the oligonucleotide is greater than 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31 nucleotides in length, and the oligonucleotide is less than 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, or 24 nucleotides in length.

[0213] Although the exemplary CpG oligonucleotide adjuvant, CpG 1018® adjuvant, is a CpG-ODN, the present disclosure is not restricted to fully DNA molecules. That is, in someembodiments, the oligonucleotide of the CpG oligonucleotide adjuvant is a DNA / RNA chimeric molecule in which the CpG(s) and the palindromic sequence are deoxyribonucleic acids and one or more nucleic acids outside of these regions are ribonucleic acids. In some embodiments, the oligonucleotide of the CpG oligonucleotide adjuvant is linear. In other embodiments, the oligonucleotide of the CpG oligonucleotide adjuvant is circular or includes hairpin loop(s). The oligonucleotide of the CpG oligonucleotide adjuvant may be single stranded. Alternatively, the oligonucleotide of the CpG oligonucleotide adjuvant may be double stranded.

[0214] In some embodiments, the CpG oligonucleotide of the CpG oligonucleotide adjuvant may contain modifications. Modifications include but are not limited to, modifications of the 3 ’OH or 5 ’OH group, modifications of the nucleotide base, modifications of the sugar component, and modifications of the phosphate group. Modified bases may be included in the palindromic sequence of the CpG oligonucleotide as long as the modified base(s) maintains the same specificity for its natural complement through Watson- Crick base pairing (e.g., the palindromic portion is still self-complementary). In some embodiments, the CpG oligonucleotide comprises a non-canonical base. In some embodiments, the CpG oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside is selected from the group consisting of 2’-deoxy-7- deazaguanosine, 2’-deoxy-6-thioguanosine, arabinoguanosine, 2’-deoxy-2’substituted- arabinoguanosine, and 2’-O-substituted-arabinoguanosine.

[0215] The CpG oligonucleotide of the CpG oligonucleotide adjuvant may contain a modification of the phosphate group. For example, in addition to phosphodiester linkages, phosphate modifications include, but are not limited to, phosphorothioate (e.g., phosphoromonothioate), phosphorodithioate, methyl phosphonate, phosphoramidate (bridging or non-bridging), and phosphotriester, and may be used in any combination. Other non-phosphate oligomer linkages may also be used. In some embodiments, the oligonucleotides comprise only phosphorothioate backbones. In some embodiments, the oligonucleotides comprise only phosphorodithioate backbones. In some embodiments, the oligonucleotides comprise only phosphodiester backbones. In some embodiments, the oligonucleotide comprises a combination of phosphate linkages in the phosphate backbone such as a combination of phosphodiester and phosphorothioate linkages. In some embodiments, the oligonucleotide comprises a combination of phosphate linkages in the phosphate backbone such as a combination of phosphodiester, phosphorothioate, and phosphorodithioate linkages. Oligonucleotides with thioated phosphate (e.g.,phosphorothioate) backbones can be more immunogenic than those with phosphodiester backbones and appear to be more resistant to degradation after injection into the host [18, 19], The CpG oligonucleotide of an CpG oligonucleotide adjuvant of the present disclosure include at least one, two or three intemucleotide phosphorothioate ester linkages. In some embodiments, when a plurality of CpG oligonucleotide molecules are present in a pharmaceutical composition comprising at least one excipient, both stereoisomers of the phosphorothioate ester linkage are present in the plurality of CpG oligonucleotide molecules. In some embodiments, all of the internucleotide linkages of the CpG oligonucleotide are phosphorothioate linkages, or said another way, the CpG oligonucleotide has a phosphorothioate backbone.

[0216] In some embodiments, the CpG oligonucleotide of the CpG oligonucleotide adjuvant is produced synthetically, or is an isolated natural product or fragment thereof. In some embodiments, a CpG oligonucleotide is synthesized using H-phosphonate, phosphotriester, phosphodiester, phosphite-triester, and / or phosphoramidite chemistry. In some embodiments, a the CpG oligonucleotide of the CpG oligonucleotide adjuvant is synthesized using a solid support, optionally controlled pore glass. In some embodiments, a CpG oligonucleotide is thioated using environmental sulfur (S8), Beaucage reagent, a thioazoline derivative (i.e., DtsNH, EDITH, MEDITH, ADTT, DDTT), or sulfurizing reagent II (Glen Research). In some embodiments, the CpG oligonucleotide of the CpG oligonucleotide adjuvant is purified using column chromatography (e.g., HPLC).

[0217] The CpG oligonucleotides are in their pharmaceutically acceptable salt form unless otherwise indicated. In specific embodiments, a CpG oligonucleotide adjuvant described herein comprises a pharmaceutically acceptable salt form. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, zinc salts, salts with organic bases (for example, organic amines) such as N-Me-D-glucamine, N-[l-(2,3- dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride, choline, tromethamine, dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. In some embodiment, the CpG oligonucleotides are in the ammonium, sodium, lithium, or potassium salt form. In one preferred embodiment, the CpG oligonucleotides are in the sodium salt form. In a specific embodiment, a CpG oligonucleotide adjuvant described herein comprises an aluminum salt. In some embodiments, the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate. Thealuminum salt may be aluminum hydroxide or aluminum phosphate. In a specific embodiment, the aluminum salt comprises aluminum hydroxide and aluminum phosphate. In a specific embodiment, the aluminum salt comprises aluminum phosphate. In a specific embodiment, the aluminum salt is aluminum hydroxide. In some embodiments, the CpG oligonucleotide adjuvant described herein does not comprise an aluminum salt.

[0218] In a specific embodiment, a CpG oligonucleotide adjuvant comprises CpG 1018® adjuvant. In a specific embodiment, a CpG oligonucleotide adjuvant is one described in Section 6, infra.

[0219] In some embodiments, a CpG oligonucleotide adjuvant described herein (e.g., in Example 1) enhances or boosts an immune response to influenza virus and does not produce an allergy or other adverse reaction. For example, the CpG oligonucleotide adjuvant can enhance an immune response by several mechanisms including, e.g., lymphocyte recruitment, stimulation of B and / or T cells, and stimulation of macrophages.5.3 Chimeric HA

[0220] In one aspect, provided herein are chimeric hemagglutinins (cHAs) comprising an influenza virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA globular head domain is heterologous to the influenza virus HA stem domain. In some embodiments, the influenza virus HA globular head domain is heterologous to the influenza virus HA stem domain if the influenza virus hemagglutinin globular head is less than 80%, less than 75%, less than 70%, less than 65%, or less than 60% identical to the HA globular head domain that would normally be associated with the influenza virus HA stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain is heterologous to the influenza virus HA stem domain if the influenza virus hemagglutinin globular head is less than 55%, less than 50%, less than 45%, less than 40%, or less than 35% identical to the HA globular head domain that would normally be associated with the influenza virus hemagglutinin stem domain of the chimeric HA. In some embodiments, the influenza virus hemagglutinin globular head domain is heterologous to the influenza virus hemagglutinin stem domain if the influenza virus HA globular head is less than 55%, less than 30%, less than 25%, or less than 20% identical to the HA globular head domain that would normally be associated with the influenza virus HA stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain is heterologous to the influenza virus hemagglutinin stem domain if the influenza virus HA globular head is about 70% to about 80%, about 60% to about 80%, about 50% to about 75%,or about 45% to about 70% identical to the HA globular head domain that would normally be associated with the influenza virus HA stem domain of the chimeric HA. In some embodiments, the influenza virus hemagglutinin globular head domain is heterologous to the influenza virus hemagglutinin stem domain if the influenza virus HA globular head that is about 20% to about 50%, about 25 to about 50%, about 20% to about 30%, or about 30% to about 70% identical to the HA globular head domain that would normally be associated with the influenza virus HA stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain is one described in Section 5.3.1 or 6. In some embodiments, the influenza virus HA stem domain is one described in Section 5.3.2 or 6. In specific embodiments, the influenza virus HA stem domain comprise the HA stem domain of an influenza virus H3. In specific embodiments, the influenza virus HA stem domain comprise the HA stem domain of influenza A virus HA is A / Hong Kong / 4801 / 2014, NYMC X-263 HA or A / Hong Kong / 4801 / 2014-like HA.

[0221] In some embodiments, a chimeric HA comprises an influenza virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA globular head domain is heterologous to the influenza virus HA stem domain, and wherein the influenza virus HA globular head domain of the chimeric HA is immunologically distinct from the globular head domain of the HA that would normally be associated with the influenza virus HA stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain is one described in Section 5.3.1 or 6. In some embodiments, the influenza virus HA stem domain is one described in Section 5.3.2 or 6. In specific embodiments, the influenza virus HA stem domain comprise the HA stem domain of an influenza virus H3. In specific embodiments, the influenza virus HA stem domain comprise the HA stem domain of influenza A virus HA is A / Hong Kong / 4801 / 2014, NYMC X-263 HA or A / Hong Kong / 4801 / 2014-like HA.

[0222] In some embodiments, provided herein are chimeric hemagglutinins (cHAs) comprising a group 2 influenza A virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA globular head domain is heterologous to the group 2 influenza A virus HA stem domain. In some embodiments, the influenza virus HA globular head domain is heterologous to the group 2 influenza A virus HA stem domain if the influenza virus HA globular head is less than 80%, less than 75%, less than 70%, less than 65%, or less than 60% identical to the HA globular head domain that would normally be associated with the group 2 influenza A virus HA stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain is heterologous to the group 2influenza A virus HA stem domain the influenza virus HA globular head is less than 55%, less than 50%, less than 45%, less than 40%, or less than 35% identical to the HA globular head domain that would normally be associated with the group 2 influenza A virus hemagglutinin stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain is heterologous to the group 2 influenza A virus HA stem domain the influenza virus HA globular head is less than 55%, less than 30%, less than 25%, or less than 20% identical to the HA globular head domain that would normally be associated with the group 2 influenza A virus hemagglutinin stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain is heterologous to the group 2 influenza A virus HA stem domain the influenza virus hemagglutinin globular head is about 70% to about 80%, about 60% to about 80%, about 50% to about 75%, or about 45% to about 70% identical to the HA globular head domain that would normally be associated with the group 2 influenza A virus hemagglutinin stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain is heterologous to the group 2 influenza A virus HA stem domain the influenza virus HA globular head that is about 20% to about 50%, about 25% to about 50%, about 20% to about 30%, or about 30% to about 70% identical to the HA globular head domain that would normally be associated with the group 2 influenza A virus HA stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain is one described in Section 5.3.1 or 6. In some embodiments, the influenza virus HA stem domain is one described in Section 5.3.2 or 6. In specific embodiments, the influenza virus HA stem domain comprise the HA stem domain of an influenza virus H3. In specific embodiments, the influenza virus HA stem domain comprise the HA stem domain of influenza A virus HA is A / Hong Kong / 4801 / 2014, NYMC X-263 HA or A / Hong Kong / 4801 / 2014-like HA.

[0223] In some embodiments, a chimeric HA comprises a group 2 influenza A virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA globular head domain is heterologous to the group 2 influenza A virus HA stem domain, and wherein the influenza virus HA globular head domain of the chimeric HA is immunologically distinct from the globular head domain of the HA that would normally be associated with the group 2 influenza A virus HA stem domain of the chimeric HA. In some embodiments, an influenza virus HA globular head domain of a chimeric HA that is immunologically distinct from the globular head domain of the HA that would normally be associated with the group 2 influenza A virus HA stem domain of the chimeric HA is another group 2 influenza A virus HA subtype (e.g., an H4, H7, Hl 0, Hl 4, or Hl 5 subtype). In someembodiments, an influenza virus HA globular head domain of a chimeric HA that is immunologically distinct from the globular head domain of the HA that would normally be associated with the group 2 influenza A virus HA stem domain of the chimeric HA is a group 1 influenza A virus HA subtype. Group 2 influenza A viruses include H3, H4, H7, H10, H14, and H15 subtypes. Group 1 influenza A viruses include Hl, H2, H5, H6, H8, H9, Hl 1, H12, H13, H16, H17, and H18 subtypes.

[0224] In some embodiments, a chimeric HA comprises an influenza virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA globular head domain of the chimeric HA is from a different strain, subtype, or group of influenza virus than the influenza virus HA stem domain. In some embodiments, a chimeric HA comprises an influenza virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA globular head domain of the chimeric HA is from a different strain of influenza virus than the influenza virus HA stem domain. In some embodiments, a chimeric HA comprises an influenza virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA globular head domain of the chimeric HA is from a different subtype of influenza virus than the influenza virus HA stem domain. In some embodiments, a chimeric HA comprises an influenza virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA globular head domain of the chimeric HA is from a different group of influenza virus than the influenza virus HA stem domain. In some embodiments, a chimeric HA comprises an influenza virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA stem domain of the chimeric HA comprises the HA stem domain of a seasonal influenza virus HA and the influenza virus globular head domain of the chimeric HA comprises the HA globular head domain of an influenza virus subtype that does not circulate in humans. In some embodiments, a chimeric HA comprises an influenza virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA stem domain of the chimeric HA comprises the HA stem domain of a seasonal influenza virus HA and the influenza virus globular head domain of the chimeric HA comprises the HA globular head domain of an avian influenza virus subtype that does not circulate in humans. In some embodiments, a chimeric HA comprises an influenza virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA stem domain of the chimeric HA comprises the HA stem domain of a seasonal influenza virus HA and the influenza virus globular head domain of the chimeric HA comprises the HA globular head domain of an exotic influenza virus that does not circulate in humans. In some embodiments,a chimeric HA comprises an influenza virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA stem domain of the chimeric HA comprises the HA stem domain of a seasonal influenza virus HA and the influenza virus globular head domain of the chimeric HA comprises the HA globular head domain of an avian influenza virus that does not circulate in humans. In some embodiments, the influenza virus HA globular head domain is one described in Section 5.3.1 or 6. In some embodiments, the influenza virus HA stem domain is one described in Section 5.3.2 or 6. In specific embodiments, the influenza virus HA stem domain comprises the HA stem domain of an influenza A virus H3. In specific embodiments, the influenza virus HA stem domain comprises the HA stem domain of an influenza A virus A / Hong Kong / 4801 / 2014, NYMC X- 263 HA or A / Hong Kong / 4801 / 2014-like HA.

[0225] In some embodiments, the influenza virus HA globular head domain of a chimeric HA is less than 80%, less than 75%, less than 70%, less than 65%, or less than 60% identical to the HA globular head domain that would normally be associated with the HA stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA refers to an influenza virus hemagglutinin globular head that is less than 55%, less than 50%, less than 45%, less than 40%, or less than 35% identical to the to the HA globular head domain that would normally be associated with the HA stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is less than 55%, less than 30%, less than 25%, or less than 20% identical to the HA globular head domain that would normally be associated with the HA stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is about 70% to about 80%, about 60% to about 80%, about 50% to about 75%, or about 45% to about 70% identical to the HA globular head domain that would normally be associated with the HA stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is about 20% to about 50%, about 25 to about 50%, about 20% to about 30%, or about 30% to about 70% identical to the HA globular head domain that would normally be associated with the HA stem domain of the chimeric HA. In specific embodiments, the influenza virus HA stem domain comprises the HA stem domain of an influenza A virus H3. In specific embodiments, the influenza virus HA stem domain comprises the HA stem domain of an influenza A virus A / Hong Kong / 4801 / 2014, NYMC X-263 HA or A / Hong Kong / 4801 / 2014-like HA.

[0226] In some embodiments, a chimeric HA comprises a group 2 influenza A virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virusHA globular head domain of the chimeric HA is from a different strain, subtype, or group of influenza virus than the group 2 influenza A virus HA stem domain. In some embodiments, a chimeric HA comprises a group 2 influenza A virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA globular head domain of the chimeric HA is from a different strain of influenza virus than the group 2 influenza A virus HA stem domain. In some embodiments, a chimeric HA comprises a group 2 influenza A virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA globular head domain of the chimeric HA is from a different subtype of influenza virus than the group 2 influenza A virus HA stem domain. In some embodiments, a chimeric HA comprises a group 2 influenza A virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA globular head domain of the chimeric HA is from a different group of influenza virus than the group 2 influenza A virus HA stem domain. In some embodiments, a chimeric HA comprises a group 2 influenza A virus HA stem domain and an influenza virus HA globular head domain, wherein the group 2 influenza A virus HA stem domain of the chimeric HA comprises the HA stem domain of a seasonal influenza virus HA and the influenza virus globular head domain of the chimeric HA comprises the HA globular head domain of an influenza virus subtype (e.g., an avian influenza A virus subtype) that does not circulate in humans. In some embodiments, a chimeric HA comprises a group 2 influenza A virus HA stem domain and an influenza virus HA globular head domain, wherein the group 2 influenza A virus HA stem domain of the chimeric HA comprises the HA stem domain of a seasonal influenza virus HA and the influenza virus globular head domain of the chimeric HA comprises the HA globular head domain of an exotic influenza virus (e.g., an avian influenza A virus) that does not circulate in humans.

[0227] In some embodiments, the influenza virus HA globular head domain of a chimeric HA is the HA globular head domain of a group 1 influenza A virus HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is the HA globular head domain of an Hl, H2, H5, H6, H8, H9, Hl 1, H12, H13, H16, H17, or H18 subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is the HA globular head domain of an H2, H5, H6, H8, H9, Hl 1, H12, H13, H16, H17, or H18 subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is the HA globular head domain of an H5, H8, H9, Hl 1, H12, or H13 subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is the HAglobular head domain of an H4, H7, H10, H14, or H15 subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is the HA globular head domain of an avian influenza A virus. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is the HA globular head domain of A / wedge-tailed shearwater / We stern Australia / 2576 / 1979 HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is the HA globular head domain of A / wedge-tailed shearwater / Western Australia / 2576 / 1979-like HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is the HA globular head domain of A / Duck / Czechoslovakia / 1956 HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is the HA globular head domain of A / Duck / Czechoslovakia / 1956-like HA.

[0228] In some embodiments, the influenza virus HA globular head domain of a chimeric HA is less than 80%, less than 75%, less than 70%, less than 65%, or less than 60% identical to the HA globular head domain that would normally be associated with the group 2 influenza A virus HA stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA refers to an influenza virus HA globular head that is less than 55%, less than 50%, less than 45%, less than 40%, or less than 35% identical to the to the HA globular head domain that would normally be associated with the group 2 influenza A virus HA stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is less than 55%, less than 30%, less than 25%, or less than 20% identical to the HA globular head domain that would normally be associated with the group 2 influenza A virus HA stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is about 70% to about 80%, about 60% to about 80%, about 50% to about 75%, or about 45% to about 70% identical to the HA globular head domain that would normally be associated with the group 2 influenza A virus HA stem domain of the chimeric HA. In some embodiments, the influenza virus HA globular head domain of a chimeric HA is about 20% to about 50%, about 25 to about 50%, about 20% to about 30%, or about 30% to about 70% identical to the HA globular head domain that would normally be associated with the group 2 influenza A virus HA stem domain of the chimeric HA.

[0229] In some embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A / Hong Kong / 4801 / 14 (H3) HA; and (ii) an influenza virus HA globular head domain of the HA globular head domain of an Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl l, H12, H13, H14,H15, H16, Hl 7, or H18 subtype of an influenza A virus HA, wherein the influenza virus HA globular head domain is heterologous to the influenza virus HA stem domain. In some embodiments, the influenza virus HA globular head domain is an Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl l, H12, H13, H14, H15, H16, H17, or H18 subtype of an avian influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is an H4, H7, H10, H14, or H15 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is an H5 subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of influenza A virus A / Vietnam / 1203 / 04 (H5) HA. In some embodiments, the influenza virus HA globular head domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:46. In some embodiments, the influenza virus HA globular head domain comprises the amino acid sequence of SEQ ID NO:46. In some embodiments, the influenza virus HA globular head domain is an H8 subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of A / mallard / Sweden / 24 / 2002 H8N4. In some embodiments, the influenza virus HA globular head domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:47. In some embodiments, the influenza virus HA globular head domain comprises the amino acid sequence of SEQ ID NO:47. In some embodiments, the influenza virus HA globular head domain of an H4 subtype (e.g., A / duck / Czech / 56) of influenza A virus HA, an H10 subtype (e.g., A / mallard / Interior or Alaska / IOBMO 1929 / 10) of influenza A virus HA, an H14 subtype (e.g., A / mallard / Gurjev / 263 / 82) of influenza A virus HA, or an Hl 5 subtype (e.g., A / wedge tailed shearwater / Western Australia / 2576 / 79) of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of an H7 subtype (e.g., A / mallard / Alberta / 24 / 01 or A / Anhui / 1 / 13) of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of influenza A virus A / Alberta / 24 / 01 (H7) HA. In some embodiments, the influenza virus HA globular head domain is not the HA globular head domain of an Hl subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H2 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H3 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H5 subtype of an influenza A virus HA.

[0230] In some embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A / Hong Kong / 4801 / 14 (H3) HA; and (ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A / mallard / Sweden / 24 / 2002 H8N4 HA. In some embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A / Hong Kong / 4801 / 14 (H3) HA; and (ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A / Vietnam / 1203 / 2004 H5N1 HA.

[0231] In some embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A / Hong Kong / 4801 / 14 (H3) HA; and (ii) an influenza virus HA globular head domain comprising the amino acid sequence of SEQ ID NO:46. In some embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A / Hong Kong / 4801 / 14 (H3) HA; and (ii) an influenza virus HA globular head domain comprising the amino acid sequence of SEQ ID NO:47.

[0232] In specific embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A / Hong Kong / 4801 / 14 (H3) HA; and (ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A / Shearwater / West Australia / 2576 / 1979 HA. In specific embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A / Hong Kong / 4801 / 14 (H3) HA; and (ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A / duck / Czechoslovakia / 1956 HA.

[0233] In specific embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A / Hong Kong / 4801 / 14 (H3)-like HA; and (ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A / Shearwater / West Australia / 2576 / 1979 HA. In specific embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A / Hong Kong / 4801 / 14-like (H3) HA; and (ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A / duck / Czechoslovakia / 1956 HA.

[0234] In specific embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A / Hong Kong / 4801 / 14 (H3)-like HA; and (ii) an influenza virus HA globular head domain of the HAglobular head domain of influenza A virus A / Shearwater / West Australia / 2576 / 1979-like HA. In specific embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A / Hong Kong / 4801 / 14-like (H3) HA; and (ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A / duck / Czechoslovakia / 1956-like HA.

[0235] In some embodiments, provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A / Perth / 16 / 2009 (H3) HA; and (ii) an influenza virus HA globular head domain of the HA globular head domain of an Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl l, H12, H13, H14, H15, H16, H17, or H18 subtype of an influenza A virus HA, wherein the influenza virus HA globular head domain is heterologous to the influenza virus HA stem domain. In some embodiments, the influenza virus HA globular head domain is an Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl l, H12, H13, H14, Hl 5, Hl 6, Hl 7, or Hl 8 subtype of an avian influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is an H4, H7, H10, H14, or H15 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is an H5 subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of influenza A virus A / Vietnam / 1203 / 04 (H5) HA. In some embodiments, the influenza virus HA globular head domain of an H4 subtype (e.g., A / duck / Czech / 56) of influenza A virus HA, an H10 subtype (e.g., A / mallard / Interior or Alaska / IOBMO 1929 / 10) of influenza A virus HA, an H14 subtype (e.g., A / mallard / Gurjev / 263 / 82) of influenza A virus HA, or an Hl 5 subtype (e.g., A / wedge tailed shearwater / Western Australia / 2576 / 79) of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of an H7 subtype (e.g., A / mallard / Alberta / 24 / 01 or A / Anhui / 1 / 13) of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of influenza A virus A / Alberta / 24 / 01 (H7) HA. In some embodiments, the influenza virus HA globular head domain is not the HA globular head domain of an Hl subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H2 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H3 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H5 subtype of an influenza A virus HA.

[0236] In some embodiments, provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A / Brisbane / 10 / 2007-like (H3) HA; and(ii) an influenza virus HA globular head domain of the HA globular head domain of an Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl l, H12, H13, H14, H15, H16, H17, or H18 subtype of an influenza A virus HA, wherein the influenza virus HA globular head domain is heterologous to the influenza virus HA stem domain. In some embodiments, the influenza virus HA globular head domain is an Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl l, H12, H13, H14, H15, H16, H17, or H18 subtype of an avian influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is an H4, H7, H10, H14, or H15 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is an H5 subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of influenza A virus A / Vietnam / 1203 / 04 (H5) HA. In some embodiments, the influenza virus HA globular head domain of an H4 subtype (e.g., A / duck / Czech / 56) of influenza A virus HA, an H10 subtype (e.g., A / mallard / Interior or Alaska / IOBMO 1929 / 10) of influenza A virus HA, an H14 subtype (e.g., A / mallard / Gurjev / 263 / 82) of influenza A virus HA, or an Hl 5 subtype (e.g., A / wedge tailed shearwater / Western Australia / 2576 / 79) of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of an H7 subtype (e.g., A / mallard / Alberta / 24 / 01 or A / Anhui / 1 / 13) of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of influenza A virus A / Alberta / 24 / 01 (H7) HA. In some embodiments, the influenza virus HA globular head domain is not the HA globular head domain of an Hl subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H2 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H3 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H5 subtype of an influenza A virus HA.

[0237] In some embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A / Hong Kong / 1 / 1968 (H3) HA; and (ii) an influenza virus HA globular head domain of the HA globular head domain of an Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl l, H12, H13, H14, H15, H16, Hl 7, or H18 subtype of an influenza A virus HA, wherein the influenza virus HA globular head domain is heterologous to the influenza virus HA stem domain. In some embodiments, the influenza virus HA globular head domain is an Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl l, H12, H13, H14, H15, H16, H17, or H18 subtype of an avian influenza A virus HA. In some embodiments, the influenza virus HA globular head domainis an H4, H7, H10, H14, or H15 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is an H5 subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of influenza A virus A / Vietnam / 1203 / 04 (H5) HA. In some embodiments, the influenza virus HA globular head domain of an H4 subtype (e.g., A / duck / Czech / 56) of influenza A virus HA, an H10 subtype (e.g., A / mallard / Interior or Alaska / IOBMO 1929 / 10) of influenza A virus HA, an H14 subtype (e.g, A / mallard / Gurjev / 263 / 82) of influenza A virus HA, or an Hl 5 subtype (e.g, A / wedge tailed shearwater / Westem Australia / 2576 / 79) of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of an H7 subtype (e.g., A / mallard / Alberta / 24 / 01 or A / Anhui / 1 / 13) of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of influenza A virus A / Alberta / 24 / 01 (H7) HA. In some embodiments, the influenza virus HA globular head domain is not the HA globular head domain of an Hl subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H2 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H3 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H5 subtype of an influenza A virus HA.

[0238] In some embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A / Victoria / 361 / 2011(H3) HA; and (ii) an influenza virus HA globular head domain of the HA globular head domain of an Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl 1, H12, H13, Hl 4, H15, Hl 6, Hl 7, or H18 subtype of an influenza A virus HA, wherein the influenza virus HA globular head domain is heterologous to the influenza virus HA stem domain. In some embodiments, the influenza virus HA globular head domain is an Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl l, H12, H13, H14, H15, H16, H17, or H18 subtype of an avian influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is an H4, H7, H10, H14, or H15 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is an H5 subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of influenza A virus A / Vietnam / 1203 / 04 (H5) HA. In some embodiments, the influenza virus HA globular head domain of an H4 subtype (e.g., A / duck / Czech / 56) of influenza A virus HA, an H10 subtype (e.g., A / mallard / Interior or Alaska / IOBMO 1929 / 10) of influenza A virus HA, an H14 subtype (e.g., A / mallard / Gurjev / 263 / 82) of influenza A virusHA, or an Hl 5 subtype (e.g., A / wedge tailed shearwater / Westem Australia / 2576 / 79) of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of an H7 subtype (e.g., A / mallard / Alberta / 24 / 01 or A / Anhui / 1 / 13) of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is the HA globular head domain of influenza A virus A / Alberta / 24 / 01 (H7) HA. In some embodiments, the influenza virus HA globular head domain is not the HA globular head domain of an Hl subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H2 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H3 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H5 subtype of an influenza A virus HA.

[0239] In another specific embodiment, provided herein is a chimeric influenza virus HA polypeptide comprising or consisting of (i) an influenza virus HA stem domain polypeptide from influenza A virus A / harbor / Massachusetts / 1 / 2011 (H3); and (ii) an influenza virus HA globular head domain from an influenza A virus of subtype Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl l, H12, H13, H14, H15, H16, H17, or H18, wherein said influenza virus HA globular head domain is heterologous to said influenza virus HA stem domain polypeptide. In a specific embodiment, the influenza virus HA globular head domain is from an avian influenza A virus of subtype Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl l, H12, H13, H14, H15, H16, H17, or H18. In a specific embodiment, the influenza virus HA globular head domain is from an influenza A virus of subtype H4, H7, H 10, Hl 4, or Hl 5. In another specific embodiment, the influenza virus HA globular head domain is from an influenza A virus of subtype H4 (e.g. A / duck / Czech / 56), subtype H5 (e.g., A / VietNam / 1203 / 04), subtype H7 (e.g., A / mallard / Alberta / 24 / 01 or A / Anhui / 1 / 13), subtype H10 (e.g., A / mallard / Interior or Alaska / IOBMO 1929 / 10), subtype H14 (e.g., A / mallard / Gurjev / 263 / 82), or subtype H15 (e.g., A / wedge tailed shearwater / Western Australia / 2576 / 79). In some embodiments, the influenza virus HA globular head domain is not the HA globular head domain of an Hl subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H2 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H3 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H5 subtype of an influenza A virus HA.

[0240] In another specific embodiment, provided herein is a chimeric influenza virus HA polypeptide comprising or consisting of (i) an influenza virus HA stem domain polypeptidefrom influenza A virus A / Indiana / 10 / 2011 (H3); and (ii) an influenza virus HA globular head domain from an influenza A virus of subtype Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl 1, H12, H13, H14, H15, H16, H17, or H18, wherein said influenza virus HA globular head domain is heterologous to said influenza virus HA stem domain polypeptide. In a specific embodiment, the influenza virus HA globular head domain is from an avian influenza A virus of subtype Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl l, H12, H13, H14, H15, H16, H17, or Hl 8. In a specific embodiment, the influenza virus HA globular head domain is from an influenza A virus of subtype H4, H7, H10, H14, or H15. In another specific embodiment, the influenza virus HA globular head domain is from an influenza A virus of subtype H4 (e.g. A / duck / Czech / 56), subtype H5 (e.g., A / Viet Nam / 1203 / 04), subtype H7 (e.g., A / mallard / Alberta / 24 / 01 or A / Anhui / 1 / 13), subtype H10 (e.g., A / mallard / Interior or Alaska / IOBMO 1929 / 10), subtype H14 (e.g., A / mallard / Gurjev / 263 / 82), or subtype H15 (e.g., A / wedge tailed shearwater / Western Australia / 2576 / 79). In some embodiments, the influenza virus HA globular head domain is not the HA globular head domain of an Hl subtype of influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H2 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H3 subtype of an influenza A virus HA. In some embodiments, the influenza virus HA globular head domain is not an H5 subtype of an influenza A virus HA.

[0241] Table 1. Exemplary cH4 / 3, cH5 / 3, cH7 / 3, cH10 / 3, cH14 / 3, cH15 / 3 chimeric influenza HA.

[0242] In some embodiments, a chimeric HA provided herein comprises: (i) the HA stem domain of a HA of an influenza A virus of the H3 subtype; and (ii) the HA globular head domain of a HA of an influenza A virus of the H5 subtype (sometimes referred to herein as a “cH5 / 3” chimeric HA). In a specific embodiment, the cH5 / 3 chimeric HA is a cH5 / 3 chimeric HA described in Table 1, above.

[0243] In some embodiments, a chimeric HA provided herein comprises :(i) the HA stem domain of a HA of an influenza A virus of the H3 subtype; and (ii) the HA globular head domain of a HA of an influenza A virus of the H7 subtype (sometimes referred to herein as a “cH7 / 3” chimeric HA). In a specific embodiment, the cH7 / 3 chimeric HA is a cH7 / 3 chimeric HA described in Table 1, above.

[0244] In some embodiments, a chimeric HA provided herein comprises: (i) the stem domain of a HA of an influenza A virus of the H3 subtype; and (ii) the HA globular head domain of a HA of an influenza A virus of the H4 subtype (sometimes referred to herein as a “cH4 / 3” chimeric HA). In a specific embodiment, the cH4 / 3 chimeric HA is a cH4 / 3 chimeric influenza HA described in Table 1, above.

[0245] In some embodiments, a chimeric HA provided herein comprises: (i) the HA stem domain of a HA of an influenza A virus of the H3 subtype; and (ii) the HA globular head domain of a HA of an influenza A virus of the H10 subtype (sometimes referred to herein as a “cH10 / 3” chimeric HA). In a specific embodiment, the cH10 / 3 chimeric HA is a cH10 / 3 chimeric HA described in Table 1, above.

[0246] In some embodiments, a chimeric HA polypeptide provided herein comprises: (i) the HA stem domain of a HA of an influenza A virus of the H3 subtype; and (ii) the HA globular head domain of a HA of an influenza A virus of the H14 subtype (sometimes referred to herein as a “cH14 / 3” chimeric HA). In a specific embodiment, the cH14 / 3 chimeric HA is a cH14 / 3 chimeric HA described in Table 1, above.

[0247] In some embodiments, a chimeric HA provided herein comprises: (i) the HA stem domain of a HA of an influenza A virus of the H3 subtype; and (ii) the HA globular head domain of a HA of an influenza A virus of the Hl 5 subtype (sometimes referred to herein as a “cH15 / 3” chimeric HA). In a specific embodiment, the cH15 / 3 chimeric HA is a cH15 / 3 chimeric HA described in Table 1, above.

[0248] In a specific embodiment, a chimeric HA is a chimeric HA described in in Table 1, above. In a specific embodiment, a chimeric HA is a chimeric HA described in Section 5.3, below.

[0249] A full-length influenza HA typically comprises an HA1 domain an HA2 domain. The HA stem domain is formed by two segments of the HA1 domain and most of the HA2 domain (e.g., the portion of the HA2 domain that does not include the transmembrane and cytoplasmic domains). The two segments of the HA1 domain are separated, in primary sequence, by the globular head domain see, e.g., the amino acid residues between the residues designated APand Aqin FIGS. 11 A-l ID for influenza A viruses). In some embodiments, the chimeric HA described herein maintain such a structure. That is, in some embodiments, the chimeric HA described herein comprise a stable stem structure composed of an HA1 domain and an HA2 domain, and a globular head domain separating the two segments of the HA1 domain (in primary sequence), wherein said globular head domain is heterologous to the stem domain formed by the other segments of the HA1 domain and the HA2 domain.

[0250] In some embodiments, a chimeric HA provided herein comprises an influenza virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA head domain is heterologous to the influenza virus HA stem domain, and wherein the chimeric HA has a primary structure of, in the following order: an HA1 N- terminal stem segment, an influenza virus HA globular head domain, an HA1 C-terminal stem segment, and an HA2. In some embodiments, a chimeric HA provided herein comprises an influenza virus HA stem domain and an influenza virus HA globular head domain, wherein the influenza virus HA globular head domain is heterologous to the influenza virus HA stem domain polypeptide, and wherein the chimeric HA has a primarystructure of, in the following order: an HA1 N-terminal stem segment, an influenza virus HA globular head domain, an HA1 C-terminal stem segment, and a portion of the HA2 domain (e.g., the HA2 domain lacking the transmembrane and cytoplasmic domains). The primary sequence of a chimeric HA provided herein might be formed by a single polypeptide, or it might be formed by multiple polypeptides. Typically, a single polypeptide is expressed by any technique deemed suitable by one of skill in the art.

[0251] In some embodiments, a chimeric HA provided herein is monomeric. In certain embodiments, a chimeric HA provided herein is multimeric. In specific embodiments, a chimeric HA provided herein is trimeric. In some embodiments, a chimeric HA provided herein is in a pre-fusion conformation. In some embodiments, a chimeric HA provided herein is in a post-fusion conformation. In some embodiments, chimeric HAs provided herein are in a mix of pre-fusion and post-fusion conformations.

[0252] In some embodiments, a chimeric HA provided herein comprises a signal peptide. Typically, the signal peptide is cleaved during or after polypeptide expression and translation to yield a mature chimeric HA. In specific embodiments, provided herein are mature chimeric HAs that lack a signal peptide. In some embodiments where a chimeric HA provided herein comprises a signal peptide, the signal peptide might be based on any influenza virus signal peptide known to those of skill in the art. The signal peptide of an influenza virus HA may be determined using software, such as, e.g., signalP 5.0. In some embodiments, the signal peptides are based on influenza A virus HA signal peptides. In some embodiments, the signal peptides are based on the signal peptide of an influenza A HA selected from the group consisting of Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl 1, H12, H13, H14, H15, H16, H17, and H18. In some embodiments, the signal peptide comprises the amino acid sequence of the signal peptide of the HA of an influenza virus in Table 1. In some embodiments, the signal peptide comprises the amino acid sequence of the signal peptide of the HA of influenza virus A / Hong Kong / 4801 / 14. In some embodiments, the signal peptide comprises the amino acid sequence of the signal peptide of the HA of influenza virus A / Shearwater / West Australia / 2576 / 1979 or influenza virusA / duck / Czechoslovakia / 1956. In some embodiments, the signal peptide might be any signal peptide deemed useful to one of skill in the art. In some embodiments, the signal peptide is selected from any one of SEQ ID NOS: 16 to 31 (see Table 2). In some embodiments, the signal peptide is selected from any one of SEQ ID NOS:48 to 52.

[0253] Table 2. Exemplary signal peptide sequences.

[0254] In some embodiments, a chimeric HA provided herein comprises a transmembrane domain. In specific embodiments, the transmembrane domain is from the same group 2 influenza A virus HA as the HA stem domain. In specific embodiments, the transmembrane domain is from the same group 2 influenza A virus HA as the HA2 stem domain. In some embodiments, the transmembrane domain comprises the amino acid sequence of the transmembrane domain of the HA of an influenza virus in Table 1. In some embodiments, the transmembrane domain comprises the amino acid sequence of the HA of influenza virus A / Hong Kong / 4801 / 14. In some embodiments, the transmembrane domain of a chimeric HA comprises one described in Table 3 (e.g., any one of SEQ ID NO:32 to 37).

[0255] Table 3. Exemplary influenza A virus HA transmembrane domain sequences.

[0256] In some embodiments, a chimeric HA provided herein comprises a cytoplasmic domain. In specific embodiments, the cytoplasmic domain is from the same group 2 influenza A virus HA as the HA stem domain. In specific embodiments, the cytoplasmic domain is from the same group 2 influenza A virus HA as the HA2 stem domain. In some embodiments, the cytoplasmic domain comprises the amino acid sequence of the cytoplasmic domain of the HA of an influenza virus in Table 1. In some embodiments, the cytoplasmic domain comprises the amino acid sequence of the cytoplasmic domain of the HA of influenza virus A / Hong Kong / 4801 / 14. In some embodiments, the cytoplasmic domain of a chimeric HA comprises one described in Table 4 (e.g., any one of SEQ ID NO:38 to 43).

[0257] Table 4. Exemplary influenza virus HA cytoplasmic domain sequences.

[0258] In some embodiments, a chimeric HA provided herein comprises an influenza virus HA cytoplasmic domain and an influenza virus HA transmembrane domain. In specific embodiments, the cytoplasmic domain and transmembrane domain are from the same group 2 influenza A virus HA as the HA stem domain. In specific embodiments, the cytoplasmic domain and transmembrane domain are from the same group 2 influenza A virus HA as theHA2 stem domain. In some embodiments, the cytoplasmic domain and transmembrane domain comprise the amino acid sequence of the cytoplasmic domain and transmembrane domain of the HA of an influenza virus in Table 1. In some embodiments, the cytoplasmic domain and transmembrane domain comprise the amino acid sequence of the cytoplasmic domain and transmembrane domain of the HA of influenza virus A / Hong Kong / 4801 / 14.

[0259] In some embodiments, a chimeric HA provided herein comprises an HA globular head domain, an HA stem domain, an HA transmembrane domain, and an HA cytoplasmic domain. In some embodiments, a chimeric HA provided herein comprises an HA globular head domain, an HA stem domain, an HA transmembrane domain, and an HA cytoplasmic domain, wherein the HA stem domain comprises an HA1 N-terminal stem segment and an HA1 C-terminal stem segment. In some embodiments, a chimeric HA provided herein comprises an HA globular head domain, an HA stem domain, an HA transmembrane domain, and an HA cytoplasmic domain, wherein the HA stem domain comprises an HA1 N-terminal stem segment, an HA1 C-terminal stem segment, and HA2 stem domain, wherein the HA1 N-terminal stem segment comprises the amino acid sequence of SEQ ID NO: 11, wherein the HA1 C-terminal stem segment comprises the amino acid sequence of SEQ ID NO: 12, and wherein the HA2 stem domain comprise the amino acid sequence of SEQ ID NO: 14.

[0260] In specific embodiments, a chimeric HA provided herein comprises an HA globular head domain, an HA stem domain, an HA transmembrane domain, and an HA cytoplasmic domain, wherein the HA stem domain comprises an HA1 N-terminal stem segment, an HA1 C-terminal stem segment, and HA2 stem domain, wherein the HA1 N- terminal stem segment comprises the amino acid sequence of SEQ ID NO: 11, and wherein the HA1 C-terminal stem segment and HA2 stem domain comprise the amino acid sequence of SEQ ID NO: 13.

[0261] In specific embodiments, a chimeric HA provided herein comprises an HA globular head domain, an HA stem domain, an HA transmembrane domain, and an HA cytoplasmic domain, wherein the HA stem domain comprises an HA1 N-terminal stem segment, an HA1 C-terminal stem segment, wherein the HA1 N-terminal stem segment comprises the amino acid sequence of SEQ ID NO: 11, and wherein the HA1 C-terminal stem segment, HA transmembrane domain, and HA cytoplasmic domain comprises the amino acid sequence of SEQ ID NO: 15.

[0262] In specific embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A / Hong Kong / 4801 / 14 (H3) HA; (ii) an influenza virus HA globular head domain of the HA globularhead domain of influenza A virus A / Shearwater / West Australia / 2576 / 1979 HA; (iii) the transmembrane domain of influenza A virus A / Hong Kong / 4801 / 14 (H3) HA; and (iv) the cytoplasmic domain of influenza A virus A / Hong Kong / 4801 / 14 (H3) HA. In specific embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A / Hong Kong / 4801 / 14 (H3) HA; (ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A / duck / Czechoslovakia / 1956 HA; (iii) the transmembrane domain of influenza A virus A / Hong Kong / 4801 / 14 (H3) HA; and (iv) the cytoplasmic domain of influenza A virus A / Hong Kong / 4801 / 14 (H3) HA.

[0263] In specific embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A / Hong Kong / 4801 / 14 (H3)-like HA; (ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A / Shearwater / West Australia / 2576 / 1979 HA; (iii) the transmembrane domain of influenza A virus A / Hong Kong / 4801 / 14-like (H3) HA; and (iv) the cytoplasmic domain of influenza A virus A / Hong Kong / 4801 / 14-like (H3) HA. In specific embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A / Hong Kong / 4801 / 14-like (H3) HA;(ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A / duck / Czechoslovakia / 1956 HA; (iii) the transmembrane domain of influenza A virus A / Hong Kong / 4801 / 14-like (H3) HA; and (iv) the cytoplasmic domain of influenza A virus A / Hong Kong / 4801 / 14-like (H3) HA.

[0264] In specific embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A / Hong Kong / 4801 / 14 (H3)-like HA; (ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A / Shearwater / West Australia / 2576 / 1979-like HA;(iii) the transmembrane domain of influenza A virus A / Hong Kong / 4801 / 14-like (H3) HA; and (iv) the cytoplasmic domain of influenza A virus A / Hong Kong / 4801 / 14-like (H3) HA. In specific embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A / Hong Kong / 4801 / 14-like (H3) HA; (ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A / duck / Czechoslovakia / 1956-like HA; (iii) the transmembrane domain of influenza A virus A / Hong Kong / 4801 / 14-like (H3) HA; and (iv) the cytoplasmic domain of influenza A virus A / Hong Kong / 4801 / 14-like (H3) HA.

[0265] In some embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A / Hong Kong / 4801 / 14 (H3) HA; (ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A / mallard / Sweden / 24 / 2002 H8N4 HA; (iii) the transmembrane domain of an influenza A virus A / Hong Kong / 4801 / 14 (H3) HA; and (iv) the cytoplasmic domain of an influenza A virus A / Hong Kong / 4801 / 14 (H3) HA. In some embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A / Hong Kong / 4801 / 14 (H3) HA; (ii) an influenza virus HA globular head domain of the HA globular head domain of influenza A virus A / Vietnam / 1203 / 2004 H5N1 HA; (iii) the transmembrane domain of an influenza A virus A / Hong Kong / 4801 / 14 (H3) HA; and (iv) the cytoplasmic domain of an influenza A virus A / Hong Kong / 4801 / 14 (H3) HA.

[0266] In some embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A / Hong Kong / 4801 / 14 (H3) HA; (ii) an influenza virus HA globular head domain comprising the amino acid sequence of SEQ ID NO:46; (iii) the transmembrane domain of an influenza A virus A / Hong Kong / 4801 / 14 (H3) HA; and (iv) the cytoplasmic domain of an influenza A virus A / Hong Kong / 4801 / 14 (H3) HA. In some embodiments, provided herein is provided herein is a chimeric HA comprising: (i) an influenza virus HA stem domain of influenza A virus A / Hong Kong / 4801 / 14 (H3) HA; (ii) an influenza virus HA globular head domain comprising the amino acid sequence of SEQ ID NO:47; (iii) the transmembrane domain of an influenza A virus A / Hong Kong / 4801 / 14 (H3) HA; and (iv) the cytoplasmic domain of an influenza A virus A / Hong Kong / 4801 / 14 (H3) HA.

[0267] In some embodiments, a chimeric HA comprises an amino acid sequence that is at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:5. In some embodiments, a chimeric HA comprises an amino acid sequence that is at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:6. In some embodiments, a chimeric HA comprises an amino acid sequence that is at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:7. In some embodiments, a chimeric HA comprises an amino acid sequence that is at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 8.

[0268] In a specific embodiment, a chimeric HA comprises the amino acid sequence of SEQ ID NO:5. In a specific embodiment, a chimeric HA comprises the amino acid sequenceI l lof SEQ ID NO:6. In a specific embodiment, a chimeric HA comprises the amino acid sequence of SEQ ID NO:7. In a specific embodiment, a chimeric HA comprises the amino acid sequence of SEQ ID NO: 8.

[0269] In specific embodiments, the chimeric HAs provided herein are capable of forming a three dimensional structure that is similar to the three dimensional structure of a native influenza HA. Structural similarity might be evaluated based on any technique deemed suitable by those of skill in the art. For instance, reaction, e.g.. under non-denaturing conditions, of a chimeric HA with a neutralizing antibody or antiserum that recognizes a native influenza HA might indicate structural similarity. Useful neutralizing antibodies or antisera are described in, e.g., Sui, et al., 2009, Nat. Struct. Mol. Biol. 16(3):265-273, Ekiert et al., February 26, 2009, Science [DOI: 10.1126 / science.1171491], and Kashyap etal., 2008, Proc. Natl. Acad. Sci. USA 105(16):5986-5991, the contents of which are hereby incorporated by reference in their entireties. In some embodiments, the antibody or antiserum is an antibody or antiserum that reacts with a non-contiguous epitope (i.e., not contiguous in primary sequence) that is formed by the tertiary or quaternary structure of a HA.

[0270] In specific embodiments, a chimeric HA described herein retains one, two, or more, or all of the functions of a wild-type influenza virus HA. Non-limiting examples of functions of a wild-type influenza virus HA include fusogenic activity, receptor binding activity, budding, and particle formation. In a specific embodiment, a chimeric HA described herein has fusogenic activity. Assays known to one skilled in the art can be utilized the assess the fusogenic activity of a chimeric HA described herein, such as, for example, immunofluorescence assays and pseudotyped virus-like-particle assays.

[0271] It will be understood by those of skill in the art that the chimeric HA provided herein can be prepared according to any technique known by and deemed suitable to those of skill in the art, including the techniques described herein.5.3.1 HA Globular Head Domain

[0272] In some embodiments, an influenza virus HA globular head domain comprises a known (e.g., wild-type) HA globular head domain. In some embodiments, an influenza virus HA globular head domain comprises a derivative, e.g., an engineered derivative, of a known (e.g., wild-type) HA globular head domain. For example, the HA globular head domain may contain one or more mutations (e.g., one or more amino acid substitutions) relative to the HA globular head domain of a known (e.g., wild-type) influenza virus HA. In someembodiments, an influenza virus HA globular head domain provided herein comprises an amino acid sequence having at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 98%, or 99% identity to the amino acid sequence of an influenza virus HA globular head domain known to those of skill in the art. In some embodiments, an influenza virus HA globular head domain provided herein comprises an amino acid sequence having at least 85%, at least 90%, or least 95% identity to the amino acid sequence of an influenza virus HA globular head domain known to those of skill in the art. In some embodiments, an influenza virus HA globular head domain provided herein comprises an amino acid sequence having at least 96%, at least 97%, at least 98%, or least 99% identity to the amino acid sequence of an influenza virus HA globular head domain known to those of skill in the art. In some embodiment, the influenza virus HA globular head domain known to those of skill in the art is one described herein.

[0273] Those of skill in the art will recognize that an influenza A virus HA globular head domain typically comprises the amino acid residues intervening the cysteine (Cys) that corresponds to amino acid position 52 of an in...

Claims

We Claim:

1. An immunogenic composition, comprising: a) a chimeric hemagglutinin (HA) comprising an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

2. An immunogenic composition, comprising: a) an inactivated influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

3. The immunogenic composition according to claim 2, wherein the inactivated influenza virus comprises neuraminidase of the group 2 influenza A virus.

4. The immunogenic composition according to claim 2 or 3, wherein the inactivated influenza virus comprises one or more proteins encoded by one or more genes of influenza A virus A / Puerto Rico / 8 / 1934.

5. An immunogenic composition, comprising:a) an inactivated split influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

6. The immunogenic composition according to claim 5, wherein the inactivated split influenza virus comprises neuraminidase of the group 2 influenza A virus.

7. The immunogenic composition according to claim 5 or 6, wherein the inactivated split influenza virus comprises one or more proteins encoded by one or more genes of influenza A virus A / Puerto Rico / 8 / 1934.

8. The immunogenic composition according to any one of claims 1 to 7, wherein the group 2 influenza A virus HA of interest is of subtype H3.

9. The immunogenic composition according to any one of claims 1 to 7, wherein the group 2 influenza A virus HA of interest is A / Hong Kong / 4801 / 2014, NYMC X-263 HA or A / Hong Kong / 4801 / 2014-like HA.

10. The immunogenic composition according to any one of claims 1 to 9, wherein the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is a group 1 influenza A virus HA.

11. The immunogenic composition according to any one of claims 1 to 9, wherein the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is of subtype H2, H5, H6, H8, H9, Hl l, H12, H13, H16, H17, or H18.

12. The immunogenic composition according to claim 1 or 9, wherein the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is of subtype H4, H7, H10, H14, or Hl 5.

13. The immunogenic composition according to claim 8 or 9, wherein the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is A / wedge-tailed shearwater / Westem Australia / 2576 / 1979 HA or A / wedge-tailed shearwater / Western Australia / 2576 / 1979-like HA.

14. The immunogenic composition according to claim 8 or 9, wherein the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is A / Duck / Czechoslovakia / 1956 HA or A / Duck / Czechoslovakia / 1956-like HA.

15. The immunogenic composition of claim 1, wherein the chimeric HA comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:5, 6, 7, or 8, or the amino acid sequence of SEQ ID NO:5, 6, 7, or 8.

16. An immunogenic composition, comprising: a) an inactivated influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:5, 6, 7, or 8, or the amino acid sequence of SEQ ID NO:5, 6, 7, or 8; and b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

17. An immunogenic composition, comprising: a) an inactivated split influenza virus comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:5, 6, 7, or 8, or the amino acid sequence of SEQ ID NO:5, 6, 7, or 8; and b) a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

18. The immunogenic composition according to any one of claims 1 to 17, wherein the oligonucleotide comprises the nucleotide sequence of 5’- TGACTGTGAACGTTCGAGATGA-3’ (SEQ ID NO:4).

19. The immunogenic composition according to any one of claims 1 to 18, wherein the oligonucleotide is 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 nucleotides in length.

20. The immunogenic composition according to any one of claims 1 to 19, wherein the oligonucleotide is a single stranded oligodeoxynucleotide.

21. The immunogenic composition according to any one of claims 1 to 20, wherein the oligonucleotide comprises only phosphorothioate linkages, or a combination of one or more phosphodiester linkages and one or more phosphorothioate linkages.

22. The immunogenic composition according to any one of claims 1 to 21, wherein the oligonucleotide is fully RNA or is an RNA / DNA chimera.

23. The immunogenic composition according to any one of claims 1 to 22, wherein the composition further comprises an aluminum salt.

24. The immunogenic composition according to claim 23, wherein the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate.

25. The immunogenic composition according to claim 23, wherein the aluminum salt comprises aluminum hydroxide or aluminum phosphate.

26. A method of preventing influenza virus disease in a subject, comprising administering to the subject the immunogenic composition of any one of claims 1 to 25.

27. A method of immunizing a subject against influenza virus disease, comprising administering to the subject the immunogenic composition of any one of claims 1 to 25.

28. A method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising administering to the subject the immunogenic composition of any one of claims 1 to 25.

29. The method according to any one of claims 26 to 28, wherein the immunogenic composition is administered intramuscularly to the subject.

30. A method of preventing influenza virus disease in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

31. A method of immunizing a subject against influenza virus disease, comprising:a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

32. A method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of theHA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

33. The method according to any one of claims 30 to 32, wherein the first inactivated influenza virus and the second inactivated influenza virus each comprise neuraminidase of the group 2 influenza A virus.

34. The method according to any one of claims 30 to 33, wherein the first inactivated influenza virus and the second inactivated influenza virus each comprise one or more proteins encoded by one or more genes of influenza A virus A / Puerto Rico / 8 / 1934.

35. The method according to any one of claims 30 to 34, wherein the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the third inactivated influenza virus comprises a thirdchimeric HA, wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain.

36. A method of preventing influenza virus disease in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, andwherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID N0:3).

37. A method of immunizing a subject against influenza virus disease, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

38. A method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising:a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

39. The method according to any one of claims 36 to 38, wherein the first inactivated split influenza virus and the second inactivated split influenza virus each comprise neuraminidase of the group 2 influenza A virus.

40. The method according to any one of claims 36 to 39, the first inactivated split influenza virus and the second inactivated split influenza virus each comprise one or more proteins encoded by one or more genes of influenza A virus A / Puerto Rico / 8 / 1934.

41. The method according to any one of claims 36 to 40, wherein the method further comprises administering to the subject a third immunogenic composition a certain time after the administration of the second immunogenic composition to the subject, wherein the third immunogenic composition comprises a third inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the third inactivated split influenza virus comprises a third chimeric HA, and wherein the third chimeric HA comprises a third influenza virus HA globular head domain and a third influenza virus HA stalk domain, wherein the third HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the third HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the first HA globular head domain and the second HA globular head domain.

42. A method of preventing influenza virus disease in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first chimeric hemagglutinin (HA) and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, andwherein the first globular head comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID N0:3).

43. A method of immunizing a subject against influenza virus disease, comprising: a) administering to the subject a first immunogenic composition comprising a first chimeric hemagglutinin (HA) and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

44. A method of inducing a cross-reactive immune response to at least two group2 influenza A viruses in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first chimeric hemagglutinin (HA) and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the first globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

45. The method according to any one of claims 30 to 44, wherein the group 2 influenza A virus HA of interest is of subtype H3.

46. The method according to any one of claims 30 to 45, wherein the group 2 influenza A virus HA of interest is A / Hong Kong / 4801 / 2014, NYMC X-263 HA, or A / Hong Kong / 4801 / 2014-like HA.

47. The method according to any one of claims 30 to 46, wherein the first HA globular head domain or the second HA globular head domain is the HA globular head domain of a group 1 influenza A virus HA.

48. The method according to any one of claims 30 to 46, wherein the first HA globular head domain and the second HA globular head domain are the HA globular head domain of group 1 influenza A virus HAs.

49. The method according to any one of claims 30 to 46, wherein the first HA globular head domain or the second HA globular head domain is the HA globular head domain of an HA of subtype H2, H5, H6, H8, H9, Hl 1, H12, H13, H16, H17, or H18.

50. The method according to any one of claims 30 to 46, wherein the first HA globular head domain and the second HA globular head domain are the HA globular head domain of an HA of subtype H2, H5, H6, H8, H9, Hl 1, H12, H13, H16, H17, or H18.

51. The method according to claim 45 or 46, wherein the first HA globular head domain and the second HA globular head domain are the HA globular head domain of subtype H4, H7, H10, H14, or H15.

52. The method according to claim 45 or 46, wherein the first HA globular head domain is the HA globular head domain of A / wedge-tailed shearwater / Westem Australia / 2576 / 1979 HA or A / wedge-tailed shearwater / Western Australia / 2576 / 1979-like HA.

53. The method according to claim 45 or 46, wherein the second HA globular head domain is the HA globular head domain of A / Duck / Czechoslovakia / 1956 HA or A / Duck / Czechoslovakia / 1956-like HA.

54. A method of preventing influenza virus disease in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant, whereinthe second inactivated influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein(i) the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8; or(ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

55. A method of immunizing a subject against influenza virus disease, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition, wherein the second immunogenic composition comprises a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein(i) the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8; or(ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, andwherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID N0:3).

56. A method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition, wherein the second immunogenic composition comprises a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein(i) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8; or(ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

57. A method of preventing influenza virus disease in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic compositioncomprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein(i) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8; or(ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

58. A method of immunizing a subject against influenza virus disease, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein(i) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8; or(ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, andwherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID N0:3).

59. A method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein(i) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8; or(ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

60. A method of preventing influenza virus disease in a subject, comprising: a) administering to the subject a first immunogenic composition comprising a first chimeric HA and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic compositioncomprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein(i) the second chimeric HA comprises the amino acid sequence of SEQ IDNO: 5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8; or(ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

61. A method of immunizing a subject against influenza virus disease, comprising: a) administering to the subject a first immunogenic composition comprising a first chimeric HA and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein(i) the second chimeric HA comprises the amino acid sequence of SEQ IDNO: 5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 7 or 8; or(ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

62. A method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising:a) administering to the subject a first immunogenic composition comprising a first chimeric HA and a CpG oligonucleotide adjuvant, wherein the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8; and b) a certain period of time after administration of the first immunogenic composition to the subject, administering to the subject a second immunogenic composition comprising a second chimeric HA and a CpG oligonucleotide adjuvant, wherein the second chimeric HA comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, or 8, wherein(i) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:5 or 6, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8; or(ii) the second chimeric HA comprises the amino acid sequence of SEQ ID NO:7 or 8, if the first chimeric HA comprises the amino acid sequence of SEQ ID NO: 5 or 6, and wherein each CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

63. The method according to any one of claims 30 to 62, wherein the second immunogenic composition is administered to the subject about 21 to about 6 months after the administration of the first immunogenic composition to the subject.

64. The method according to any one of claims 30 to 63, wherein the oligonucleotide comprises the nucleotide sequence of 5’-TGACTGTGAACGTTCGAGATGA-3’(SEQ ID NO:4).

65. The method according to any one according to claims 30 to 64, wherein the oligonucleotide is 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 nucleotides in length.

66. The method according to any one of claims 30 to 65, wherein the oligonucleotide is a single stranded oligodeoxynucleotide.

67. The method according to any one of claims 30 to 66, wherein the oligonucleotide comprises only phosphorothioate linkages, or a combination of one or more phosphodiester linkages and one or more phosphorothioate linkages.

68. The method according to any one of claims 30 to 67, wherein the oligonucleotide is fully RNA or is an RNA / DNA chimera.

69. The method according to any one of claims 30 to 68, wherein the composition further comprises an aluminum salt.

70. The method according to claim 69, wherein the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate.

71. The method according to claim 69, wherein the aluminum salt comprises aluminum hydroxide or aluminum phosphate.

72. The method according to any one of claims 30 to 71, wherein the first immunogenic composition or second immunogenic is administered to the subject intramuscularly or intranasally.

73. The method according to any one of claims 30 to 71, wherein the first immunogenic composition and second immunogenic are administered to the subject intramuscularly or intranasally.

74. The method according to any one of claims 26 to 73, wherein the subject is human.

75. A method of preventing an influenza virus disease in a subject, comprising: a) administering to the subject an immunogenic composition comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA is from an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

76. A method of immunizing a subject against influenza virus disease, comprising: a) administering to the subject an immunogenic composition comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA is from an influenza A virus HA of a different strain, subtype, or group than the globular head domain of the group 2 influenza A virus HA of interest; and b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

77. A method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: a) administering to the subject an immunogenic composition comprising a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA is from an influenza A virus HA of a different strain, subtype, or group than the globular head domain of the group 2 influenza A virus HA of interest; and b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

78. A method of preventing an influenza virus disease in a subject, comprising:a) administering to the subject an immunogenic composition comprising an inactivated influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

79. A method of immunizing a subject against influenza virus disease, comprising: a) administering to the subject an immunogenic composition comprising an inactivated influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

80. A method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: a) administering to the subject an immunogenic composition comprising an inactivated influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated influenza virus comprises a chimeric hemagglutinin (HA), whereinthe chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

81. The method according to any one of claims 78 to 80, wherein the inactivated influenza virus comprises neuraminidase of the group 2 influenza A virus.

82. The method according to any one of claims 78 to 81, wherein the inactivated influenza virus comprises one or more proteins encoded by one or more genes of influenza A virus A / Puerto Rico / 8 / 1934.

83. A method of preventing an influenza virus disease in a subject, comprising: a) administering to the subject an immunogenic composition comprising an inactivated split influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated split influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

84. A method of immunizing a subject against influenza virus disease, comprising:a) administering to the subject an immunogenic composition comprising an inactivated split influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated split influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) administering to the subject a CpG oligonucleotide adjuvant, wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

85. A method of inducing a cross-reactive immune response to at least two group 2 influenza A viruses in a subject, comprising: a) administering to the subject an immunogenic composition comprising an inactivated split influenza virus in an admixture with a pharmaceutically acceptable carrier, wherein the inactivated split influenza virus comprises a chimeric hemagglutinin (HA), wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the HA globular head domain of the chimeric HA comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) administering to the subject a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

86. The method according to any one of claims 83 to 85, wherein the inactivated split influenza virus comprises neuraminidase of the group 2 influenza A virus.

87. The method according to any one of claims 83 to 86, wherein the inactivated split influenza virus comprises one or more proteins encoded by one or more genes of influenza A virus A / Puerto Rico / 8 / 1934.

88. The method according to any one of claims 75 to 87, wherein the group 2 influenza A virus HA of interest is of subtype H3.

89. The method according to any one of claims 75 to 87, wherein the group 2 influenza A virus HA of interest is A / Hong Kong / 4801 / 2014, NYMC X-263 HA or A / Hong Kong / 4801 / 2014-like HA.

90. The method according to any one of claims 75 to 89, wherein the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is a group 1 influenza A virus HA.

91. The method according to any one of claims 75 to 89, wherein the influenza A virus HA of a different strain, subtype, or group is subtype than the group 2 influenza A virus HA of interest is HA of subtype H2, H5, H6, H8, H9, Hl l, H12, H13, H16, H17, or H18.

92. The method according to claim 75 or 89, wherein the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is HA of subtype H4, H7, H10, H14, or H15.

93. The method according to claim 88 or 89, wherein the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is A / wedge-tailed shearwater / We stern Australia / 2576 / 1979 HA or A / wedge-tailed shearwater / Western Australia / 2576 / 1979-like HA.

94. The method according to claim 88 or 89, wherein the influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest is A / Duck / Czechoslovakia / 1956 HA or A / Duck / Czechoslovakia / 1956-like HA.

95. The method according to any one of claims 75 to 94, wherein the oligonucleotide comprises the nucleotide sequence of 5’-TGACTGTGAACGTTCGAGATGA-3’ (SEQ ID NO:4).

96. The method according to any one of claims 75 to 95, wherein the oligonucleotide is 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 nucleotides in length.

97. The method according to any one of claims 75 to 96, wherein the oligonucleotide is a single stranded oligodeoxynucleotide.

98. The method according to any one of claims 75 to 97, wherein the oligonucleotide comprises only phosphorothioate linkages, or a combination of one or more phosphodiester linkages and one or more phosphorothioate linkages.

99. The method according to any one of claims 75 to 98, wherein the oligonucleotide is fully RNA or is an RNA / DNA chimera.

100. The method according to any one of method 75 to 99, wherein the immunogenic composition, the CpG oligonucleotide adjuvant, or both are administered intramuscularly to the subject.

101. The method according to any one of claims 75 to 100, wherein the composition further comprises an aluminum salt.

102. The method according to claim 101, wherein the aluminum salt comprises one or more selected from the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate.

103. The method according to claim 101, wherein the aluminum salt comprises aluminum hydroxide or aluminum phosphate.

104. The method according to any one of claims 75 to 103, wherein the subject is human.

105. The method according to any one of claims 75 and 104, wherein the immunogenic composition and CpG oligonucleotide adjuvant are administered concurrently to the subject.

106. The method according to any one of claims 75 and 104, wherein the immunogenic composition and CpG oligonucleotide adjuvant are administered to the subject within 30 minutes of each other.

107. The method according to any one of claims 75 and 104, wherein the immunogenic composition and CpG oligonucleotide adjuvant are administered to the subject within 15 minutes of each other.

108. A kit comprising a container containing an immunogenic composition comprising a chimeric hemagglutinin (HA) and a CpG oligonucleotide adjuvant, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain of the group 2 influenza A virus HA of interest, wherein the HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

109. A kit comprising a container containing an immunogenic composition comprising an inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the inactivated influenza virus comprises a first chimeric HA, and wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

110. A kit comprising a container containing an immunogenic composition comprising an inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the inactivated split influenza virus comprises a first chimeric HA, and wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, and wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

111. A kit comprising: a) a first container containing an immunogenic composition comprising a chimeric HA, wherein the chimeric HA comprises an influenza virus HA globular head domain and an influenza virus HA stalk domain, wherein the HA stalk domain of the chimeric HA comprises an amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, wherein the HA globular head domain of the chimeric HA is heterologous to the HA stalk domain of the group 2 influenza A virus HA of interest, wherein the HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a second container containing a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

112. A kit compri sing : a) a first container containing an immunogenic composition comprising a first inactivated influenza virus, wherein the first inactivated influenza virus comprises a first chimeric HA, wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a second container containing a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

113. A kit compri sing :a) a first container containing an immunogenic composition comprising a first inactivated split influenza virus, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a second container containing a CpG oligonucleotide adjuvant comprising an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

114. A kit compri sing : a) a first container containing a first immunogenic composition comprising a first inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a second container containing a second immunogenic composition comprising a second inactivated influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and wherein the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virusHA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

115. A kit compri sing : a) a first container containing a first immunogenic composition comprising a first inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the first inactivated split influenza virus comprises a first chimeric HA, and wherein the first chimeric HA comprises a first influenza virus HA globular head domain and a first influenza virus HA stalk domain, wherein the first HA stalk domain comprises the amino acid sequence of the HA stalk domain of a group 2 influenza A virus HA of interest, and wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest; and b) a second container containing a second immunogenic composition comprising a second inactivated split influenza virus and a CpG oligonucleotide adjuvant, wherein the second inactivated split influenza virus comprises a second chimeric HA, and wherein the second chimeric HA comprises a second influenza virus HA globular head domain and a second influenza virus HA stalk domain, wherein the second HA stalk domain comprises the amino acid sequence of the HA stalk domain of the group 2 influenza A virus HA of interest, and the second HA globular head domain comprises the amino acid sequence of an HA globular head of an influenza A virus HA of a different strain, subtype, or group than the group 2 influenza A virus HA of interest, wherein the first HA globular head domain comprises the amino acid sequence of an HA globular head domain of an influenza A virus HA of a different strain, subtype, or group than the influenza A virus HA of the second HA globular head domain, and wherein the CpG oligonucleotide adjuvant comprises an oligonucleotide of from 10 to 35 nucleotides in length comprising the nucleotide sequence of 5’-GAACGTTCG-3’ (SEQ ID NO:3).

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