Stabilized group 2 influenza hemagglutinin stem region trimers and uses thereof

Patent metadata

Field	Value
Publication number	US-2024050554-A1
Application number	US-202318491193-A
Country	US
Kind code	A1
Filing date	Oct 20, 2023
Priority date	Sep 2, 2016
Publication date	Feb 15, 2024
Grant date	—

Abstract

Vaccines that elicit broadly protective anti-influenza antibodies. The vaccines comprise nanoparticles that display HA trimers from Group 2 influenza virus on their surface. The nanoparticles are fusion proteins comprising a monomeric subunit (e.g., ferritin) joined to stabilized stem regions of Group 2 influenza virus HA proteins. The fusion proteins self-assemble to form the HA-displaying nanoparticles. Also provided are fusion proteins, and nucleic acid molecules encoding such proteins, and assays using nanoparticles of the invention to detect anti-influenza antibodies.

First claim

What is claimed:

1 . A protein construct comprising a Group 2 influenza hemagglutinin (HA) stabilized stem protein, wherein:
a head region of the HA stabilized stem protein is replaced with a linker sequence; a helix A in a stem region of the HA stabilized stem protein is extended in length by the addition of helix-forming amino acid residues, thereby improving the stability of the HA stabilized stem protein; and the HA stabilized stem protein comprises an amino acid sequence at least 80% identical to the HA stabilized stem of any one of SEQ ID NO: 47-159.

2 . The protein construct of claim 1 , wherein the linker sequence replacing the head region is less than 10 amino acids in length.

3 . The protein construct of claim 1 , wherein an inter-helix loop in the stem region of the HA stabilized stem protein is replaced with a linker sequence.

4 . The protein construct of claim 3 , wherein the linker sequence replacing the inter-helix loop comprises the amino acid sequence set forth as GGPD.

5 . The protein construct of claim 1 , wherein the helix A in the stem region of the HA stabilized stem protein is extended in length by the addition of five helix-forming amino acid residues.

6 . The protein construct of claim 5 , wherein the helix A in the stem region of the HA stabilized stem protein is extended relative to helix A of a wild-type HA protein by the addition of ALMAQ (SEQ ID NO: 36) or ELMEQ (SEQ ID NO: 37).

7 . The protein construct of claim 1 , wherein the HA stabilized stem protein comprises one or more mutations that form, or strengthen, an ionic interaction or a salt bridge within the HA stabilized stem protein.

8 . The protein construct of claim 1 , wherein the HA stabilized stem protein comprises one or more mutations that increases hydrophobic packing within the HA stabilized stem protein.

9 . The protein construct of claim 1 , wherein the HA stabilized stem protein comprises an amino acid sequence at least 90% identical to the HA stabilized stem region of any one of SEQ ID NO: 47-159.

10 . The protein construct of claim 1 , wherein the HA stabilized stem protein comprises an amino acid sequence at least 95% identical to the HA stabilized stem region of any one of SEQ ID NO: 47-159.

11 . The protein construct of claim 1 , wherein the HA stabilized stem protein comprises an amino acid sequence set forth as any one of SEQ ID NO: 47-159.

12 . A nucleic acid molecule encoding the protein construct of claim 1 .

13 . A vector comprising the nucleic acid of claim 12 .

14 . The vector of claim 13 , wherein the vector is a viral vector.

15 . A host cell comprising the vector of claim 13 .

16 . A nanoparticle vaccine comprising the protein construct of claim 1 .

17 . A pharmaceutical composition comprising the protein construct of claim 1 .

18 . A method of vaccination, comprising administering a prophylactically or therapeutically effective amount of the protein construct of claim 1 to a subject.

Assignees

• The Us Secretary Department Of Health And Human Servic

Inventors

• Boyington Jeffrey C
• Graham Barney S
• Mascola John R
• Yassine Hadi M
• Corbett Kizzmekia S
• Moin Syed M
• Wang Lingshu
• Kanekiyo Masaru

Classifications

• A61P31/16

  for influenza or rhinoviruses · CPC title

• A61K39/12

  Viral antigens · CPC title

• A61K39/145 Primary

  Orthomyxoviridae, e.g. influenza virus · CPC title

• G01N2469/20

  Detection of antibodies in sample from host which are directed against antigens from microorganisms · CPC title

• G01N2333/11

  Orthomyxoviridae, e.g. influenza virus · CPC title