Influenza virus vaccines and uses thereof

Patent metadata

Field	Value
Publication number	US-2016355553-A1
Application number	US-201615243738-A
Country	US
Kind code	A1
Filing date	Aug 22, 2016
Priority date	Nov 28, 2011
Publication date	Dec 8, 2016
Grant date	—

Abstract

The present disclosure provides influenza hemagglutinin stem domain polypeptides comprising (a) an influenza hemagglutinin HA1 domain that comprises an HA1 N-terminal stem segment, covalently linked by a linking sequence of 0-50 amino acid residues to an HA1 C-terminal stem segment, and (b) an influenza hemagglutinin HA2 domain, wherein on or more amino acids in the HA2 domain have been mutated. Also provided are nucleic acids encoding the polypeptides, compositions comprising the polypeptides and/or nucleic acid molecules, as well as methods of their use, in particular in the detection, prevention and/or treatment of influenza.

First claim

1 . An influenza hemagglutinin stem domain polypeptide comprising:
an influenza hemagglutinin HA1 domain comprising an HA1 N-terminal stem segment, covalently linked by a linking sequence of 0-50 amino acid residues to an HA1 C-terminal stem segment, and an influenza hemagglutinin HA2 domain, wherein the hemagglutinin stem domain polypeptide is resistant to protease cleavage at a junction between HA1 and HA2, wherein one or more amino acids in the peptide connecting the A helix and the helix CD of HA2 are mutated as compared to a wild-type influenza HA2 domain, and wherein the HA1 domain and HA2 domain are derived from an influenza A virus subtype selected from the group consisting of H1, H5, and H3.

2 . The influenza hemagglutinin stem domain polypeptide of claim 1 , wherein the influenza hemagglutinin stem domain polypeptide does not comprise a full-length HA1 domain.

3 . The influenza hemagglutinin stem domain polypeptide of claim 1 , wherein the influenza hemagglutinin stem domain polypeptide is glycosylated.

4 . The influenza hemagglutinin stem domain polypeptide of claim 1 , comprising:
an HA1 N-terminal segment comprising the amino acids 1-x of HA1 covalently linked by a linking sequence of 0-50 amino acid residues to an HA1 C-terminal stem segment comprising the amino acids y-end of HA1 and an influenza hemagglutinin HA2 domain.

5 . The influenza hemagglutinin stem domain polypeptide of claim 1 , comprising:
an influenza hemagglutinin HA1 and/or HA2 domain based upon influenza hemagglutinin from an influenza A virus comprising HA of the H1 subtype, and wherein x=any amino acid between 46 and 60 and y=any amino acid between 290 and 325.

6 . The influenza hemagglutinin stem domain polypeptide of claim 5 , comprising:
an influenza hemagglutinin HA1 and/or HA2 domain based upon influenza hemagglutinin from an influenza A virus comprising HA of the H1 subtype selected from the group consisting of A/Solomon Islands/6/2003, A/Brisbane/59/2007, A/New Caledonia/20/1999, A/California/07/2009, A/swine/Hubei/S1/2009, A/swine/Haseluenne/IDT2617/2003, A/NewYork/8/2006, A/SolomonIslands/3/2006, A/NewYork/146/2000, A/NewYork/653/1996, A/Beijing/262/1995, A/Texas/36/1991, A/Singapore/6/1986, A/Chile/1/1983, A/Baylor/11515/1982, A/Brazil/11/1978, A/USSR/90/1977, A/NewJersey/8/1976, A/Denver/1957, A/Albany/4835/1948, A/FortMonmouth/1/1947, A/Cameron/1946, A/Weiss/1943, A/Iowa/1943, A/Bellamy/1942, A/PuertoRico/8/1934, A/WSN/1933, and A/SouthCarolina/1/1918.

7 . The influenza hemagglutinin stem domain polypeptide of claim 1 , comprising:
an influenza hemagglutinin HA1. and/or HA2 domain based upon influenza hemagglutinin from an influenza A virus comprising HA of the H3 subtype, wherein x=any amino acid between 56 and 69, and wherein and y=any amino acid between 292 and 325.

8 . The influenza hemagglutinin stem domain polypeptide of claim 1 , wherein the C-terminal amino acid residue of the HA1 C-terminal stem segment is any amino acid other than arginine (R),or lysine (K).

9 . The influenza hemagglutinin stem domain polypeptide of claim 1 , comprising:
at least one or further mutations in the HA1 domain and/or the HA2 domain.

10 . The influenza hemagglutinin stem domain polypeptide of claim 1 , wherein the influenza hemagglutinin stem domain polypeptide comprises at least one disulfide bridge.

11 . The influenza hemagglutinin stem domain polypeptide of claim 1 , wherein the influenza hemagglutinin stem domain polypeptide does not comprise the signal sequence.

12 . The influenza hemagglutinin stem domain polypeptide of claim 11 , comprising:
an HA1 N-terminal segment comprising amino acids p-x of HA1, covalently linked by a linking sequence of 0-50 amino acid residues to an HA1 C-terminal stem segment comprising the amino acids y-end of HA1, and an influenza hemagglutinin HA2 domain, wherein p=the first amino acid of the mature HA.

13 . The influenza hemagglutinin stem domain polypeptide of claim 1 , wherein the influenza hemagglutinin stem domain polypeptide does not comprise the intracellular sequence and transmembrane sequence of HA.

14 . The influenza hemagglutinin stem domain polypeptide of claim 13 , wherein the influenza hemagglutinin stem domain polypeptide does not comprise the C-terminal part of the influenza H1 HA2 domain spanning from amino acid residue 520, 521, 522, 523, 524, 525, 526, 527, 528, 529 or 530 to the C-terminal amino acid of H1 HA2.

15 . The influenza hemagglutinin stem domain polypeptide of claim 1 , wherein the influenza hemagglutinin stem domain polypeptide selectively binds to antibody CR6261 and/or antibody CR9114, but does not bind to antibody CR8057.

16 . The influenza hemagglutinin stem domain polypeptide of claim 1 , wherein the influenza hemagglutinin stem domain polypeptide selectively binds to antibody CR8020, antibody CR843 and/or antibody CR9114, but does not bind to antibody CR8057.

17 . An influenza hemagglutinin stem domain polypeptide produced by a method comprising:
providing an influenza HA0 peptide; removing the cleavage site between HA1. and HA2 of the influenza HA0 peptide; removing the peptide of the globular head domain from the HA0 sequence; introducing one or more mutations in the peptide connecting the C-terminal residue of helix A to the N-terminal residue of helix CD; and introducing one or more disulfide bridges in the HA stem domain polypeptide.

18 . A nucleic acid molecule encoding the influenza hemagglutinin stem domain polypeptide of claim 1 .

19 . An immunogenic composition comprising:
the influenza hemagglutinin stem domain polypeptide of claim 1 .

20 . A medicament comprising:
the influenza hemagglutinin stem domain polypeptide of claim 1 .

21 . The influenza hemagglutinin stem domain polypeptide of claim 8 , wherein the C-terminal amino acid residue of the HA1. C-terminal stem segment is glutamine (Q).

Assignees

• Janssen Vaccines & Prevention Bv

Inventors

• Meijberg Jan Willem
• Impagliazzo Antonietta
• Vogels Ronald
• Friesen Robert H E
• Alard Philippe
• Loverix Stefan
• Radosevic Katarina

Classifications

• A61P31/14

  for RNA viruses · CPC title

• A61P31/16

  for influenza or rhinoviruses · CPC title

• C07K16/108

  Orthomyxoviridae (F), e.g. influenza virus · CPC title

• C12N2760/16151

  Methods of production or purification of viral material · CPC title

• C07K2319/73

  containing coiled-coiled motif (leucine zippers) · CPC title