US2019106461A1PendingUtilityA1

Influenza virus vaccines and uses thereof

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Assignee: ICAHN SCHOOL MED MOUNT SINAIPriority: Sep 20, 2011Filed: Sep 24, 2018Published: Apr 11, 2019
Est. expirySep 20, 2031(~5.1 yrs left)· nominal 20-yr term from priority
Inventors:Adolfo Garcia-SastrePeter PaleseFlorian KrammerNatalie PicaDirk EgginkRafael A. Medina-SilvaRong Hai
C12N 2760/16171A61K 2039/521A61K 2039/5258C07K 14/005C12N 2760/16123A61K 39/12A61K 39/145C12N 2710/14143C07K 2319/00A61P 37/04C12N 2760/16122A61P 43/00C12N 2760/16162A61K 2039/53C12N 2760/16134A61P 31/16C12N 7/00
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Claims

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

exact text as granted — not AI-modified
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 N-term  through A p−1 , A p−2 , A p−3 , A p−4 , A p−5 , A p−6 , A p−7 , A p−8 , A p−9 , A p−10 , A p , A p+1 , A p+2 , A p+3 , A p+4 , A p+5 , A p+6 , A p+7 , A p+8 , A p+9 , or A p+10 ; (ii) an HA1 C-terminal stem segment, wherein the HA1 C-terminal stem segment consists of amino acid residues A q−1 , A q−2 , A q−3 , A q−4 , A q−5 , A q−6 , A p−7 , A q−8 , A p−9 , A p−10 , A q , A q+1 , A q+2 , A q+3 , A q+4 , A q+5 , A q+6 , A q+7 , A p+8 , A p+9 , or A q+10  through HA1 C-term ; and (iii) an HA2 stem domain; and
 (b) the HA globular head domain comprises the amino acid residues between (i) A p−1 , A p−2 , A p−3 , A p−4 , A p−5 , A p−6 , A p−7 , A p−8 , A p−9 , A p−10 , A p , A p+1 , A p+2 , A p+3 , A p+4 , A p+5 , A p+6 , A p+7 , A p+8 , A p+9  or A p+10  and (ii) A q−1 , A q−2 , A q−3 , A q−4 , A q−5 , A q−6 , A q−7 , A q−8 , A q−9 , A q−10 , A q , A q+1 , A q+2 , A q+3 , A q+4 , A q+5 , A q+6 , A q+7 , A q+8 , A q+9 , or A q+10 ; and   
       wherein HA1 N-term  is the N-terminal amino acid of a mature HA0 protein lacking a signal peptide; wherein HA1 C-term  is the C-terminal amino acid of an HA1 domain; and wherein A p  is the Cys that corresponds to amino acid position 52 of an HA1 domain using H3 numbering; wherein A 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 N-term  through A p−1 , A p−2 , A p−3 , A p−4 , A p−5 , A p−6 , A p−7 , A p−8 , A p−9 , A p−10 , A p , A p+1 , A p+2 , A p+3 , A p+4 , A p+5 , A p+6 , A p+7 , A p+8 , A p+9 , or A p+10 ; (ii) an HA1 C-terminal stem segment, wherein the HA1 C-terminal stem segment consists of amino acid residues A q−1 , A q−2 , A q−3 , A q−4 , A q−5 , A q−6 , A q−7 , A q−8 , A q−9 , A q−10 , A q , A q+1 , A q+2 , A q+3 , A q+4 , A q+5 , A q+6 , A q+7 , A q+8 , A q+9 , or A q+10  through HA1 C-term ; and (iii) an HA2 stem domain and   (b) the HA globular head domain comprises the amino acid residues between (i) A p−1 , A p−2 , A p−3 , A p−4 , A p−5 , A p−6 , A p−7 , A p−8 , A p−9 , A p−10 , A p , A p+1 , A p+2 , A p+3 , A p+4 , A p+5 , A p+6 , A p+7 , A p+8 , A p+9 , or A p+10  and (ii) A q−1 , A q−2 , A q−3 , A q−4 , A q−5 , A q−6 , A q−7 , A q−8 , A q−9 , A q−10 , A q , A q+1 , A q+2 , A q+3 , A q+4 , A q+5 , A q+6 , A q+7 , A q+8 , A q+9 , or A q+10 ; and   
       wherein HA1 N-term  is the N-terminal amino acid of a mature HA0 protein lacking a signal peptide; wherein HA1 C-term  is the C-terminal amino acid of an HA1 domain; and wherein A p  is the Cys that corresponds to amino acid position 52 of an HA1 domain using H3 numbering; wherein A 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 N-term  through A p−1 , A p−2 , A p−3 , A p−4 , A p−5 , A p−6 , A p−7 , A p−8 , A p−9 , A p−10 , A p , A p+1 , A p+2 , A p+3 , A p+4 , A p+5 , A p+6 , A p+7 , A p+8 , A p+9 , or A p+10 , wherein the HA1 C-terminal stem segment consists of amino acid residues A q−1 , A q−2 , A q−3 , A q−4 , A q , A q+1 , A q+2 , or A q+3  through HA1 C-term , and wherein the HA globular head domain comprises the amino acid residues between (i) A p−1 , A p−2 , A p−3 , A p−4 , A p−5 , A p−6 , A p−7 , A p−8 , A p−9 , A p−10 , A p , A p+1 , A p+2 , A p+3 , A p+4 , A p+5 , A p+6 , A p+7 , A p+8 , A p+9 , or A p+10  and (ii) A q−1 , A q−2 , A q−3 , A q−4 , A q , A q+1 , A q+2 , or A 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 N-term  through A p−1 , A p−2 , A p−3 , A p−4 , A p−5 , A p−6 , A p−7 , A p−8 , A p−9 , A p−10 , A p , A p+1 , A p+2 , A p+3 , A p+4 , A p+5 , A p+6 , A p+7 , A p+8 , A p+9 , or A p+10 , wherein the HA1 C-terminal stem segment consists of amino acid residues A q−1 , A q−2 , A q−3 , A q−4 , A q , A q+1 , A q+2 , or A q+3  through HA1 C-term , and wherein the HA globular head domain comprises the amino acid residues between (i) A p−1 , A p−2 , A p−3 , A p−4 , A p−5 , A p−6 , A p−7 , A p−8 , A p−9 , A p−10 , A p , A p+1 , A p+2 , A p+3 , A p+4 , A p+5 , A p+6 , A p+7 , A p+8 , A p+9 , or A p+10  and (ii) A q−1 , A q−2 , A q−3 , A q−4 , A q , A q+1 , A q+2 , or A 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 N-term  through A p , wherein the HA1 C-terminal stem segment consists of amino acid residues A q , and wherein the HA globular head domain comprises the amino acid residues between A p  and A q . 
     
     
         89 . The virus of  claim 13 , wherein the HA1 N-terminal stem segment consists of amino acid residues HA1 N-term  through A p , wherein the HA1 C-terminal stem segment consists of amino acid residues A q , and wherein the HA globular head domain comprises the amino acid residues between A p  and A 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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