Stabilized group 2 influenza hemagglutinin stem region trimers and uses thereof

Patent metadata

Field	Value
Publication number	US-2022339278-A1
Application number	US-202217742201-A
Country	US
Kind code	A1
Filing date	May 11, 2022
Priority date	Sep 2, 2016
Publication date	Oct 27, 2022
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 nucleic acid molecule, encoding:
a recombinant Group 2 influenza hemagglutinin (HA) protein, wherein at least 95% of the amino acid sequence of a head region of the HA protein is replaced with a linker sequence; wherein a helix A in a stem region of the HA protein is extended in length by the addition of helix-forming amino acid residues, thereby improving the stability of the recombinant Group 2 influenza HA protein; and wherein the HA protein comprises an amino acid sequence at least 80% identical to SEQ ID NO: 113.

2 . The nucleic acid molecule of claim 1 , wherein an inter-helix loop in the stem region of the HA protein is replaced with a linker sequence.

3 . The nucleic acid molecule of claim 1 , wherein the stem region of the HA protein comprises one or more mutations that form, or strengthen, an ionic interaction or a salt bridge within the HA protein.

4 . The nucleic acid molecule of claim 1 , wherein the stem region of the HA protein comprises one or more mutations that increases hydrophobic packing within the HA protein.

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

6 . The nucleic acid molecule of claim 5 , wherein the helix A in the stem region of the HA 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 nucleic acid molecule of claim 1 , wherein the HA protein comprises an amino acid sequence at least 90% identical to SEQ ID NO: 113.

8 . The nucleic acid molecule of claim 1 , wherein the HA protein comprises an amino acid sequence at least 95% identical to SEQ ID NO: 113.

9 . The nucleic acid molecule of claim 1 , wherein the HA protein comprises an amino acid sequence set forth as SEQ ID NO: 113.

10 . A method of vaccinating an individual against influenza virus, comprising administering a prophylactically or therapeutically effective amount of the nucleic acid molecule of claim 9 to the individual.

11 . The nucleic acid molecule of claim 1 , wherein the nucleic acid is RNA.

12 . The nucleic acid molecule of claim 1 , wherein the nucleic acid is DNA.

13 . A vector comprising the nucleic acid of claim 1 .

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 pharmaceutical composition comprising the nucleic acid molecule of claim 1 .

17 . A method of vaccination, comprising administering a prophylactically or therapeutically effective amount of the nucleic acid molecule of claim 1 to a subject.

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

• C07K14/195

  from bacteria · CPC title

• A61P31/16

  for influenza or rhinoviruses · CPC title

• C12N2760/16122

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

• C12N2760/16134

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

• A61K2039/55555

  Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers · CPC title