Stabilized group 2 influenza hemagglutinin stem region trimers and uses thereof

Patent metadata

Field	Value
Publication number	US-12527857-B2
Application number	US-202318491193-A
Country	US
Kind code	B2
Filing date	Oct 20, 2023
Priority date	Sep 2, 2016
Publication date	Jan 20, 2026
Grant date	Jan 20, 2026

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 SEQ ID NO: 49.

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 interhelix loop comprises the amino acid sequence set forth as GGPD (SEQ ID NO: 39).

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 SEQ ID NO: 49.

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 SEQ ID NO: 49.

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 nanoparticle vaccine comprising the protein construct of claim 1 .

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

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

15 . The protein construct of claim 1 , wherein the HA stabilized stem protein comprises an amino acid sequence at least 80% identical to the HA stabilized stem of SEQ ID NO: 49.

16 . The protein construct of claim 1 , wherein the HA stabilized stem protein comprises an amino acid sequence at least 99% identical to the HA stabilized stem of SEQ ID NO: 49.

Assignees

• Us Health

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

• C12N2760/16134

  Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein · CPC title

• C07K2319/00

  Fusion polypeptide · CPC title

• C12N2760/16122

  New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes · CPC title