Influenza virus vaccines and uses thereof

A multimeric influenza hemagglutinin stem domain polypeptide, wherein the multimeric influenza hemagglutinin stem domain polypeptide comprises at least a first and a second influenza hemagglutinin stem domain monomer, said first and second monomer each comprising:

• (a) an influenza hemagglutinin HA1 domain that comprises an HA1 amino (N)-terminal stem segment, wherein said HA1 N-terminal segment comprises the amino acids 1-52 of HA1, preferably the amino acids 18-52 of HA1, covalently linked by a linking sequence of less than 10 residues to an HA1 carboxy (C)-terminal stem segment, comprising the amino acids from position 321 to the C-terminal amino acid of HA1, wherein said HA1 C-terminal segment is linked to (b) an influenza hemagglutinin HA2 domain, and
• (c) wherein the polypeptide comprises no protease cleavage site at the junction between the HA1 and HA2 domains;
• and
• (d) wherein the first monomer is linked to said second monomer by a disulfide bridge between the amino acid on position 411 of the first monomer and the amino acid on position 419 of the second monomer, and wherein in each influenza hemagglutinin stem domain monomer the region comprising the amino acid residues 402-418 comprises the amino acid sequence X1NTQX2TAX3GKEX4N(H/K)X5E(K/R) (SEQ ID NO:
• 8),
• wherein X1 is M, X2 is Y, X3 is I, X4 is Y and X5 is S;
• and
• wherein in each influenza hemagglutinin stem domain monomer the amino acid sequence CMKQIEDKIEEIESK (SEQ ID NO:
• 193) has been introduced at positions 419-433;
• and
• wherein the amino acid residue on position 337 is K;
• the amino acid residue on position 340 is K, the amino acid residue on position 352 is F and the amino acid residue on position 353 is T;
• wherein the HA1 and HA2 domains are derived from an influenza A virus subtype derived from phylogenetic group 1, preferably from an influenza A virus subtype comprising HA of the H1 subtype, and wherein the numbering of the amino acid positions is in relation to SEQ ID NO:
• 1.