Human antibody 3E1 targets the HA stem region of H1N1 and H5N6 influenza A viruses.

Wenshuai Wang,Yanbing Li,Hong Zhang,Tianlong Zhang,Jianping Ding,Xiaoyu Sun,Fang Wang,Zhiyang Ling,Hualan Chen,Bing Sun,Jinpeng Su

doi:10.1038/ncomms13577

Abstract

As influenza A viruses remain a major threat to human health worldwide, the discovery of broadly neutralizing monoclonal antibodies that recognize conserved epitopes would facilitate the development of antibody-based therapeutic strategies. Here we report that a VH4-4-encoded human mAb named 3E1 could neutralize H1 and H5 subtype viruses in vitro and protect mice against the H1N1 and H5N6 viruses by inhibiting the low pH-induced conformational rearrangement of haemagglutinin (HA), hence blocking membrane fusion. The crystal structures of 3E1 Fab in complex with HA of two H1N1 strains reveal that 3E1, with both heavy and light chains, binds to a conserved epitope of the HA stem region, comprising parts of the fusion peptide, the F subdomain and the outermost β-strand preceding helix A. Altogether, these data suggest the potential of 3E1 as a therapeutic drug against H1 and H5 subtype viruses.

Highlights

As influenza A viruses remain a major threat to human health worldwide, the discovery of broadly neutralizing monoclonal antibodies that recognize conserved epitopes would facilitate the development of antibody-based therapeutic strategies
We demonstrate that 3E1 exhibited broad neutralizing activity against HA 3E1-CA09 (H1) and H5 subtype viruses in vitro and protected mice against H1N1 and H5N6 viruses in vivo by inhibiting the low pH-induced HA conformational rearrangement, blocking membrane fusion
We previously identified a fully human mAb named 3E1 from the pandemic H1N1 HA-specific memory B cells isolated from the peripheral blood mononuclear cells of a volunteer vaccinated with the A(H1N1)09pdm vaccine; this mAb was shown to have a broad neutralizing activity against several subtypes of Influenza A virus (IAV) and to target the conserved stem region of HA

Summary

Introduction

As influenza A viruses remain a major threat to human health worldwide, the discovery of broadly neutralizing monoclonal antibodies that recognize conserved epitopes would facilitate the development of antibody-based therapeutic strategies. The crystal structures of 3E1 Fab in complex with HA of two H1N1 strains reveal that 3E1, with both heavy and light chains, binds to a conserved epitope of the HA stem region, comprising parts of the fusion peptide, the F subdomain and the outermost b-strand preceding helix A. These data suggest the potential of 3E1 as a therapeutic drug against H1 and H5 subtype viruses. Our structural and biological data suggest the potential of 3E1 as a therapeutic drug against H1 and H5 subtype viruses

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Conclusion