Stabilized group 2 influenza hemagglutinin stem region trimers and uses thereof

Patent metadata

Field	Value
Publication number	US-11338033-B2
Application number	US-201716329592-A
Country	US
Kind code	B2
Filing date	Sep 1, 2017
Priority date	Sep 2, 2016
Publication date	May 24, 2022
Grant date	May 24, 2022

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 nanoparticle comprising a fusion protein that comprises a monomeric subunit protein joined to a Group 2 influenza virus 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 fusion protein; and
wherein the fusion protein comprises an amino acid sequence at least 80% identical to SEQ ID NO: 49.

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

3. The nanoparticle of claim 1 , wherein the stem region of the HA protein comprises one or more mutations that forms, or strengthens, an ionic interaction or a salt bridge within the HA protein.

4. The nanoparticle 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 nanoparticle of claim 1 , wherein the monomeric subunit protein is a ferritin monomeric subunit protein or a lumazine synthase monomeric subunit protein.

6. The nanoparticle of claim 1 , wherein the fusion protein comprises an amino acid sequence set forth as SEQ ID NO: 49.

7. The nanoparticle 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.

8. A fusion protein comprising a monomeric subunit protein joined to a Group 2 influenza virus 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 the 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 fusion protein; and
wherein the fusion protein comprises an amino acid sequence at least 80% identical to SEQ ID NO:49.

9. The fusion protein of claim 8 , wherein an inter-helix loop in the stem region of the HA protein is replaced with a linker sequence.

10. The fusion protein of claim 8 , wherein the stem region of the HA protein comprises one or more mutations that forms, or strengthens, an ionic interaction or a salt bridge within the HA protein.

11. The fusion protein of claim 8 , wherein the stem region of the HA protein comprises one or more mutations that increases hydrophobic packing within the HA protein.

12. The fusion protein of claim 8 , wherein the monomeric subunit protein is a ferritin monomeric subunit protein or a lumazine synthase monomeric subunit protein.

13. A nucleic acid molecule encoding the fusion protein of claim 8 .

14. The fusion protein of claim 8 , wherein the fusion protein comprises an amino acid sequence set forth as SEQ ID NO: 49.

15. A method of vaccinating an individual against influenza virus, comprising administering a prophylactically or therapeutically effective amount of the nanoparticle of claim 1 to the individual.

Assignees

• The Usa As Represented By The Secretary Dept Of Health And Human Services
• 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

• 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

• C12N2760/16134

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

• C07K2319/03

  containing a transmembrane segment · CPC title

• C12N2760/16122

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