Influenza virus vaccination regimens
Provided herein are immunization regimens for inducing an immune response (e.g., an antibody response) against influenza virus. In specific aspects, the immunization regimens involve the administration of a chimeric hemagglutinin (HA), a headless HA or another influenza virus stem domain based construct (e.g., the HA stem domain or a fragment thereof) to a subject. In certain aspects, the immunization regimens also involve the administration of an influenza virus neuraminidase immunogen.
1. A vaccine formulation comprising three vectors, an influenza virus neuraminidase polypeptide from an N1, an influenza virus neuraminidase polypeptide from an N2, and an influenza virus neuraminidase polypeptide from an influenza B virus, wherein each vector comprises a chimeric HA, wherein the first vector comprises a first chimeric HA comprising an HA stem domain polypeptide from an H1 influenza virus HA and a first HA globular head domain, the second vector comprises a second chimeric HA comprising an HA stem domain polypeptide from an H3 influenza virus HA and a second HA globular head domain, and the third vector comprises a third chimeric HA comprising an HA stem domain polypeptide from an influenza B virus HA and a third HA globular head domain, wherein the first, second and third HA globular head domains are each from a different subtype or strain of influenza virus hemagglutinin, and wherein the HA globular head domain of each chimeric HA is heterologous to the HA stem domain polypeptide of each chimeric HA.
2. The vaccine formulation of claim 1 , wherein one or more of the vectors is a viral vector.
3. The vaccine formulation of claim 2 , wherein each viral vector is an inactivated viral vector, or a live attenuated viral vector.
4. The vaccine formulation of claim 1 , which is a split virus vaccine.
5. The vaccine formulation of claim 1 , wherein one or more of the vectors is an influenza virus.
6. The vaccine of claim 4 , wherein each of the vectors is an influenza virus.
7. A vaccine formulation of comprising three vectors, an influenza virus neuraminidase polypeptide from an N1, an influenza virus neuraminidase polypeptide from an N2 and an influenza virus neuraminidase polypeptide from an influenza B virus, wherein each vector comprises a chimeric HA, wherein the first vector comprises a first chimeric HA comprising an HA stem domain polypeptide from an H1 influenza virus HA and a first HA globular head domain, the second vector comprises a second chimeric HA comprising an HA stem domain polypeptide from an H3 influenza virus HA and a second HA globular head domain, and the third vector comprises a third chimeric HA comprising an HA stem domain polypeptide from an influenza B virus HA and a third HA globular head domain, wherein the first, second and third HA globular head domains are each from a different subtype or strain of influenza virus hemagglutinin, wherein the HA globular head domain of each chimeric HA is heterologous to the HA stem domain polypeptide of each chimeric HA, and wherein one or more of the vectors is a Newcastle disease virus, an adeno-associated virus, vesicular stomatitis virus, a poxvirus, or an adenovirus.
8. The vaccine formulation of claim 1 , wherein each vector is an influenza virus.
9. A vaccine formulation of comprising three vectors, an influenza virus neuraminidase polypeptide from an N1, an influenza virus neuraminidase polypeptide from an N2, and an influenza virus neuraminidase polypeptide from an influenza B virus, wherein each vector comprises a chimeric HA, wherein the first vector comprises a first chimeric HA comprising an HA stem domain polypeptide from an H1 influenza virus HA and a first HA globular head domain, the second vector comprises a second chimeric HA comprising an HA stem domain polypeptide from an H3 influenza virus HA and a second HA globular head domain, and the third vector comprises a third chimeric HA comprising an HA stem domain polypeptide from an influenza B virus HA and a third HA globular head domain, wherein the first, second and third HA globular head domains are each from a different subtype or strain of influenza virus hemagglutinin, wherein the HA globular head domain of each chimeric HA is heterologous to the HA stem domain polypeptide of each chimeric HA, and wherein each vector is a Newcastle disease virus, an adeno-associated virus, vesicular stomatitis virus, a poxvirus, or an adenovirus.
10. The vaccine formulation of claim 1 , wherein the HA stem domain polypeptides of the H1 and H3 influenza viruses each comprise an HA1 N-terminal stem segment, an HA1 C-terminal stem segment, an HA2 stem domain; wherein the HA1 N-terminal stem segment consists of amino acid residues HA N-term through A p of an influenza virus hemagglutinin HA1 domain, and wherein the HA1 C-terminal stem segment consists of amino acid residues A q through HA C-term of an influenza virus hemagglutinin HA1 domain, wherein HA N-term is the N-terminal amino acid of a mature HA0 protein lacking a signal peptide, wherein HA C-term is the C-terminal amino acid of the HA1 domain, wherein A p is Cys that corresponds to amino acid position 52 of an influenza virus hemagglutinin HA1 domain according to H3 numbering, and wherein A q is Cys that corresponds to amino acid position 277 of an influenza virus hemagglutinin HA1 domain of an H3 hemagglutinin according to H3 numbering.
11. The vaccine formulation of claim 10 , wherein the first and second influenza virus HA globular head domains consist of the amino acid residues intervening Ap and Aq.
12. The vaccine formulation of claim 1 , wherein the first chimeric HA further comprises the H1 influenza virus HA transmembrane and cytoplasmic domains, the second chimeric HA further comprises the H3 influenza virus HA transmembrane and cytoplasmic domains, and the third chimeric HA further comprises the influenza B virus transmembrane and cytoplasmic domains.
13. The vaccine formulation of claim 1 , wherein the H1 influenza virus is A/California/4/2009 and the H3 influenza virus is A/Perth/16/09.
14. The vaccine formulation of claim 1 , wherein the first and second globular head domains are selected from an H4, H5, H7, H8, H11, H12, H14 and H15 subtype.
15. A method for immunizing against influenza virus in a human subject, comprising administering the vaccine formulation of claim 1 .
16. The vaccine formulation of claim 12 , wherein each vector is an influenza virus.
17. The vaccine formulation of claim 11 , wherein the first chimeric HA further comprises the H1 influenza virus HA transmembrane and cytoplasmic domains, the second chimeric HA further comprises the H3 influenza virus HA transmembrane and cytoplasmic domains, and the third chimeric HA further comprises the influenza B virus transmembrane and cytoplasmic domains.
18. The vaccine formulation of claim 17 , wherein each vector is an influenza virus.
19. The vaccine formulation of claim 18 , wherein the influenza virus is inactivated.
20. The vaccine formulation of claim 18 , wherein the influenza virus is live attenuated.
21. The vaccine formulation of claim 7 , wherein the HA stem domain polypeptides of the H1 and H3 influenza viruses each comprise an HA1 N-terminal stem segment, an HA1 C-terminal stem segment, an HA2 stem domain; wherein the HA1 N-terminal stem segment consists of amino acid residues HA N-term through A p of an influenza virus hemagglutinin HA1 domain, and wherein the HA1 C-terminal stem segment consists of amino acid residues A q through HA C-term of an influenza virus hemagglutinin HA1 domain, wherein HA N-term is the N-terminal amino acid of a mature HA0 protein lacking a signal peptide, wherein HA C-term is the C-terminal amino acid of the HA1 domain, wherein A p is Cys that corresponds to amino acid position 52 of an influenza virus hemagglutinin HA1 domain according to H3 numbering, and wherein A q is Cys that corresponds to amino acid position 277 of an influenza virus hemagglutinin HA1 domain of an H3 hemagglutinin according to H3 numbering.
22. The vaccine formulation of claim 21 , wherein the first and second influenza virus HA globular head domains consist of the amino acid residues intervening A p and A q .
23. The vaccine formulation of claim 9 , wherein the HA stem domain polypeptides of the H1 and H3 influenza viruses each comprise an HA1 N-terminal stem segment, an HA1 C-terminal stem segment, an HA2 stem domain; wherein the HA1 N-terminal stem segment consists of amino acid residues HA N-term through A p of an influenza virus hemagglutinin HA1 domain, and wherein the HA1 C-terminal stem segment consists of amino acid residues A q through HA C-term of an influenza virus hemagglutinin HA1 domain, wherein HA N-term is the N-terminal amino acid of a mature HA0 protein lacking a signal peptide, wherein HA C-term is the C-terminal amino acid of the HA1 domain, wherein A p is Cys that corresponds to amino acid position 52 of an influenza virus hemagglutinin HA1 domain according to H3 numbering, and wherein A q is Cys that corresponds to amino acid position 277 of an influenza virus hemagglutinin HA1 domain of an H3 hemagglutinin according to H3 numbering.
24. The vaccine formulation of claim 23 , wherein the first and second influenza virus HA globular head domains consist of the amino acid residues intervening A p and A q.