Patent application title: INFLUENZA VIRUS VACCINES AND USES THEREOF
Inventors:
IPC8 Class: AC07K14005FI
USPC Class:
1 1
Class name:
Publication date: 2019-04-11
Patent application number: 20190106461
Abstract:
Provided herein are flu hemagglutinin polypeptides, including chimeric
influenza virus hemagglutinin polypeptides, and flu hemagglutinin
polypeptides comprising modified glycosylation sites and non-naturally
glycosylation sites, compositions comprising the same, vaccines
comprising the same and methods of their use.Claims:
1.-11. (canceled)
12. A virus comprising a genome engineered to express nucleic acid encoding a chimeric influenza virus hemagglutinin (HA) polypeptide, said chimeric influenza virus HA polypeptide comprising an HA stem domain and an HA globular head domain, wherein the HA globular head domain is from a different influenza virus strain or subtype than the influenza virus strain or subtype of the HA stem domain, wherein (a) the HA stem domain comprises (i) an HA1 N-terminal stem segment, wherein the HA1 N-terminal stem segment consists of amino acid residues HA1.sub.N-term through A.sub.p-1, A.sub.p-2, A.sub.p-3, A.sub.p-4, A.sub.p-5, A.sub.p-6, A.sub.p-7, A.sub.p-8, A.sub.p-9, A.sub.p-10, A.sub.p, A.sub.p+1, A.sub.p+2, A.sub.p+3, A.sub.p+4, A.sub.p+5, A.sub.p+6, A.sub.p+7, A.sub.p+8, A.sub.p+9, or A.sub.p+10; (ii) an HA1 C-terminal stem segment, wherein the HA1 C-terminal stem segment consists of amino acid residues A.sub.q-1, A.sub.q-2, A.sub.q-3, A.sub.q-4, A.sub.q-5, A.sub.q-6, A.sub.p-7, A.sub.q-8, A.sub.p-9, A.sub.p-10, A.sub.q, A.sub.q+1, A.sub.q+2, A.sub.q+3, A.sub.q+4, A.sub.q+5, A.sub.q+6, A.sub.q+7, A.sub.p+8, A.sub.p+9, or A.sub.q+10 through HA1.sub.C-term; and (iii) an HA2 stem domain; and (b) the HA globular head domain comprises the amino acid residues between (i) A.sub.p-1, A.sub.p-2, A.sub.p-3, A.sub.p-4, A.sub.p-5, A.sub.p-6, A.sub.p-7, A.sub.p-8, A.sub.p-9, A.sub.p-10, A.sub.p, A.sub.p+1, A.sub.p+2, A.sub.p+3, A.sub.p+4, A.sub.p+5, A.sub.p+6, A.sub.p+7, A.sub.p+8, A.sub.p+9 or A.sub.p+10 and (ii) A.sub.q-1, A.sub.q-2, A.sub.q-3, A.sub.q-4, A.sub.q-5, A.sub.q-6, A.sub.q-7, A.sub.q-8, A.sub.q-9, A.sub.q-10, A.sub.q, A.sub.q+1, A.sub.q+2, A.sub.q+3, A.sub.q+4, A.sub.q+5, A.sub.q+6, A.sub.q+7, A.sub.q+8, A.sub.q+9, or A.sub.q+10; and wherein HA1.sub.N-term is the N-terminal amino acid of a mature HA0 protein lacking a signal peptide; wherein HA1.sub.C-term is the C-terminal amino acid of an HA1 domain; and wherein A.sub.p is the Cys that corresponds to amino acid position 52 of an HA1 domain using H3 numbering; wherein A.sub.q is the Cys that corresponds to amino acid position 277 of an HA1 domain using H3 numbering.
13. A virus comprising a chimeric influenza virus hemagglutinin (HA) polypeptide, wherein said chimeric influenza virus HA polypeptide comprises an HA stem domain and an HA globular head domain, wherein the HA globular head domain is from a different influenza virus strain or subtype than the influenza virus strain or subtype of the HA stem domain, wherein (a) the HA stem domain comprises (i) an HA1 N-terminal stem segment, wherein the HA1 N-terminal stem segment consists of amino acid residues HA1.sub.N-term through A.sub.p-1, A.sub.p-2, A.sub.p-3, A.sub.p-4, A.sub.p-5, A.sub.p-6, A.sub.p-7, A.sub.p-8, A.sub.p-9, A.sub.p-10, A.sub.p, A.sub.p+1, A.sub.p+2, A.sub.p+3, A.sub.p+4, A.sub.p+5, A.sub.p+6, A.sub.p+7, A.sub.p+8, A.sub.p+9, or A.sub.p+10; (ii) an HA1 C-terminal stem segment, wherein the HA1 C-terminal stem segment consists of amino acid residues A.sub.q-1, A.sub.q-2, A.sub.q-3, A.sub.q-4, A.sub.q-5, A.sub.q-6, A.sub.q-7, A.sub.q-8, A.sub.q-9, A.sub.q-10, A.sub.q, A.sub.q+1, A.sub.q+2, A.sub.q+3, A.sub.q+4, A.sub.q+5, A.sub.q+6, A.sub.q+7, A.sub.q+8, A.sub.q+9, or A.sub.q+10 through HA1.sub.C-term; and (iii) an HA2 stem domain and (b) the HA globular head domain comprises the amino acid residues between (i) A.sub.p-1, A.sub.p-2, A.sub.p-3, A.sub.p-4, A.sub.p-5, A.sub.p-6, A.sub.p-7, A.sub.p-8, A.sub.p-9, A.sub.p-10, A.sub.p, A.sub.p+1, A.sub.p+2, A.sub.p+3, A.sub.p+4, A.sub.p+5, A.sub.p+6, A.sub.p+7, A.sub.p+8, A.sub.p+9, or A.sub.p+10 and (ii) A.sub.q-1, A.sub.q-2, A.sub.q-3, A.sub.q-4, A.sub.q-5, A.sub.q-6, A.sub.q-7, A.sub.q-8, A.sub.q-9, A.sub.q-10, A.sub.q, A.sub.q+1, A.sub.q+2, A.sub.q+3, A.sub.q+4, A.sub.q+5, A.sub.q+6, A.sub.q+7, A.sub.q+8, A.sub.q+9, or A.sub.q+10; and wherein HA1.sub.N-term is the N-terminal amino acid of a mature HA0 protein lacking a signal peptide; wherein HA1.sub.C-term is the C-terminal amino acid of an HA1 domain; and wherein A.sub.p is the Cys that corresponds to amino acid position 52 of an HA1 domain using H3 numbering; wherein A.sub.q is the Cys that corresponds to amino acid position 277 of an HA1 domain using H3 numbering.
14. The virus of claim 12, wherein the virus is an influenza virus.
15. The virus of claim 13, wherein the virus is an influenza virus.
16. The virus of claim 14, which is inactivated or split.
17. The virus of claim 15, which is inactivated or split.
18. (canceled)
19. (canceled)
20. An immunogenic composition comprising the virus of claim 12.
21. An immunogenic composition comprising the virus of claim 13.
22. An immunogenic composition comprising the virus of claim 14.
23. An immunogenic composition comprising the virus of claim 15.
24.-85. (canceled)
86. The virus of claim 12, wherein the HA1 N-terminal stem segment consists of amino acid residues HA1.sub.N-term through A.sub.p-1, A.sub.p-2, A.sub.p-3, A.sub.p-4, A.sub.p-5, A.sub.p-6, A.sub.p-7, A.sub.p-8, A.sub.p-9, A.sub.p-10, A.sub.p, A.sub.p+1, A.sub.p+2, A.sub.p+3, A.sub.p+4, A.sub.p+5, A.sub.p+6, A.sub.p+7, A.sub.p+8, A.sub.p+9, or A.sub.p+10, wherein the HA1 C-terminal stem segment consists of amino acid residues A.sub.q-1, A.sub.q-2, A.sub.q-3, A.sub.q-4, A.sub.q, A.sub.q+1, A.sub.q+2, or A.sub.q+3 through HA1.sub.C-term, and wherein the HA globular head domain comprises the amino acid residues between (i) A.sub.p-1, A.sub.p-2, A.sub.p-3, A.sub.p-4, A.sub.p-5, A.sub.p-6, A.sub.p-7, A.sub.p-8, A.sub.p-9, A.sub.p-10, A.sub.p, A.sub.p+1, A.sub.p+2, A.sub.p+3, A.sub.p+4, A.sub.p+5, A.sub.p+6, A.sub.p+7, A.sub.p+8, A.sub.p+9, or A.sub.p+10 and (ii) A.sub.q-1, A.sub.q-2, A.sub.q-3, A.sub.q-4, A.sub.q, A.sub.q+1, A.sub.q+2, or A.sub.q+3 of an HA1 domain.
87. The virus of claim 13, wherein the HA1 N-terminal stem segment consists of amino acid residues HA1.sub.N-term through A.sub.p-1, A.sub.p-2, A.sub.p-3, A.sub.p-4, A.sub.p-5, A.sub.p-6, A.sub.p-7, A.sub.p-8, A.sub.p-9, A.sub.p-10, A.sub.p, A.sub.p+1, A.sub.p+2, A.sub.p+3, A.sub.p+4, A.sub.p+5, A.sub.p+6, A.sub.p+7, A.sub.p+8, A.sub.p+9, or A.sub.p+10, wherein the HA1 C-terminal stem segment consists of amino acid residues A.sub.q-1, A.sub.q-2, A.sub.q-3, A.sub.q-4, A.sub.q, A.sub.q+1, A.sub.q+2, or A.sub.q+3 through HA1.sub.C-term, and wherein the HA globular head domain comprises the amino acid residues between (i) A.sub.p-1, A.sub.p-2, A.sub.p-3, A.sub.p-4, A.sub.p-5, A.sub.p-6, A.sub.p-7, A.sub.p-8, A.sub.p-9, A.sub.p-10, A.sub.p, A.sub.p+1, A.sub.p+2, A.sub.p+3, A.sub.p+4, A.sub.p+5, A.sub.p+6, A.sub.p+7, A.sub.p+8, A.sub.p+9, or A.sub.p+10 and (ii) A.sub.q-1, A.sub.q-2, A.sub.q-3, A.sub.q-4, A.sub.q, A.sub.q+1, A.sub.q+2, or A.sub.q+3 of an HA1 domain.
88. The virus of claim 12, wherein the HA1 N-terminal stem segment consists of amino acid residues HA1.sub.N-term through A.sub.p, wherein the HA1 C-terminal stem segment consists of amino acid residues A.sub.q, and wherein the HA globular head domain comprises the amino acid residues between A.sub.p and A.sub.q.
89. The virus of claim 13, wherein the HA1 N-terminal stem segment consists of amino acid residues HA1.sub.N-term through A.sub.p, wherein the HA1 C-terminal stem segment consists of amino acid residues A.sub.q, and wherein the HA globular head domain comprises the amino acid residues between A.sub.p and A.sub.q.
90. The virus of claim 88, wherein the HA globular head domain is from a different influenza virus subtype than the influenza virus subtype of the HA stem domain.
91. The virus of claim 89, wherein the HA globular head domain is from a different influenza virus subtype than the influenza virus subtype of the HA stem domain.
92. The virus of claim 91, wherein the HA stem domain is the HA stem domain of an influenza virus of subtype H1.
93. The virus of claim 91, wherein the HA stem domain is the HA stem domain of an influenza virus of subtype H3.
94. The virus of claim 92, wherein the H1 subtype is A/California/04/09.
95. The virus of claim 93, wherein the H3 subtype is A/Perth/16/2009.
96. The virus of claim 94, wherein the HA globular head domain is the HA globular head domain of an influenza virus of subtype H5.
97. The virus of claim 91, wherein the HA globular head domain is the HA globular head domain of an influenza virus of subtype H2, H4, H5, H6, H7, H8, H9, H11, H12, H13, H14, H15 or H16.
98. The virus of claim 94, wherein the HA globular head domain is the HA globular head domain of an influenza virus of subtype H8, H11, or H12.
99. The virus of claim 95, wherein the HA globular head domain is the HA globular head domain of an influenza virus of subtype H4, H7, H10, H14, or H15.
98. The virus of claim 95, wherein the HA globular head domain is the HA globular head domain of A/VietNam/1203/04 (H5).
99. The virus of claim 93, wherein the HA globular head domain is the HA globular head domain of A/Alberta/24/01 (H7).
100. The virus of claim 98, wherein the virus is an influenza A virus.
101. The virus of claim 90, wherein the virus is an influenza A virus.
102. The virus of claim 91, wherein the virus is an influenza A virus.
103. A split virus vaccine comprising the virus of claim 102.
104. The split virus vaccine of claim 103 further comprising an adjuvant.
105. The split virus vaccine of claim 104, wherein the adjuvant is an aluminum salt, 3 De-O-acylated monophosphoryl lipid A (MPL), MF59, AS03, AS04, polysorbate 80, an imidazopyridine compound, an imidazoquinoxaline compound, a saponin, Freund's adjuvant, an oil in water emulsion, or CpG.
106. The virus of claim 91, wherein the chimeric influenza virus HA polypeptide comprises the luminal, transmembrane and cytoplasmic domains of the HA of the same subtype as the HA stem domain.
107. The immunogenic composition of claim 22, wherein the immunogenic composition further comprises an adjuvant.
108. The immunogenic composition of claim 107, wherein the adjuvant is an aluminum salt, 3 De-O-acylated monophosphoryl lipid A (MPL), MF59, AS03, AS04, polysorbate 80, an imidazopyridine compound, an imidazoquinoxaline compound, a saponin, Freund's adjuvant, an oil in water emulsion, or CpG.
109. The immunogenic composition of claim 23, wherein the immunogenic composition further comprises an adjuvant.
110. The immunogenic composition of claim 109, wherein the adjuvant is an aluminum salt, 3 De-O-acylated monophosphoryl lipid A (MPL), MF59, AS03, AS04, polysorbate 80, an imidazopyridine compound, an imidazoquinoxaline compound, a saponin, Freund's adjuvant, an oil in water emulsion, or CpG.
111. An immunogenic composition comprising the virus of claim 101.
112. The immunogenic composition of claim 111, wherein the immunogenic composition further comprises an adjuvant.
113. The immunogenic composition of claim 112, wherein the adjuvant is an aluminum salt, 3 De-O-acylated monophosphoryl lipid A (MPL), MF59, AS03, AS04, polysorbate 80, an imidazopyridine compound, an imidazoquinoxaline compound, a saponin, Freund's adjuvant, an oil in water emulsion, or CpG.
114. An immunogenic composition comprising the virus of claim 102.
115. The immunogenic composition of claim 114, wherein the virus is inactivated.
116. The immunogenic composition of claim 115, wherein the immunogenic composition further comprises an adjuvant.
117. The immunogenic composition of claim 116, wherein the adjuvant is an aluminum salt, 3 De-O-acylated monophosphoryl lipid A (MPL), MF59, AS03, AS04, polysorbate 80, an imidazopyridine compound, an imidazoquinoxaline compound, a saponin, Freund's adjuvant, an oil in water emulsion, or CpG.
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