Stabilized group 2 influenza hemagglutinin stem region trimers and uses thereof

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.

Description

Background technique [0001] The protective immune response induced by vaccination against influenza virus is mainly directed against the viral HA protein, a glycoprotein on the viral surface responsible for the interaction of the virus with host cell receptors. The HA protein on the viral surface is a trimer of HA protein monomers that is enzymatically cleaved to produce amino-terminal HA1 and carboxy-terminal HA2 polypeptides. The globular head consists of only the major part of the HA1 polypeptide, while the stem, which anchors the HA protein into the viral lipid envelope, consists of HA2 and part of HA1. The globular head of the HA protein contains two domains: the receptor-binding domain (RBD), a domain of ~148 amino acid residues that contains the sialic acid binding site, and the residual esterase domain, which is located right at the A smaller region of ~75 amino acid residues below the RBD. The globular head contains several antigenic sites containing immunodominant ...

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Problems solved by technology

On the contrary, due to the nature of their assembly, enveloped VLPs contain small and limited host cell components, which may pose potential safety, immunogenicity challenges after repeated use of the platform [Wu, C.Y. et al., PLoS One 5, e9784 (2010)]

Also, VLPs induce the same immunity as existing vaccines, and are therefore unlikely to significantly improve the potency and breadth of vaccine-induced protective immunity

In addition to VLPs, recombinant HA proteins have also been evaluated in humans [Treanor, J.J. et al., Vaccine 19, 1732-1737 (2001); Treanor, J.J. JAMA 297, 1577-1582 (2007)], but their induction of protection was modest. and antibody titer capabilities are limited

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