A multifunctional human monoclonal neutralizing antibody that targets a unique conserved epitope on influenza HA

Sandhya Bangaru,Randy A Albrecht,Shanshan Lang,Robin Bombardi,Xueyong Zhu,Stephen J Kent,Thomas G Voss,Iuliia M Gilchuk,Travis Nieusma,Pavlo Gilchuk,Hillary A Vanderven,Ryan P Irving,James E Crowe,Ian A Wilson,Juergen A Richt,Pranathi Matta,Andrew B Ward,Heng Zhang

doi:10.1038/s41467-018-04704-9

Abstract

The high rate of antigenic drift in seasonal influenza viruses necessitates frequent changes in vaccine composition. Recent seasonal H3 vaccines do not protect against swine-origin H3N2 variant (H3N2v) strains that recently have caused severe human infections. Here, we report a human VH1-69 gene-encoded monoclonal antibody (mAb) designated H3v-47 that exhibits potent cross-reactive neutralization activity against human and swine H3N2 viruses that circulated since 1989. The crystal structure and electron microscopy reconstruction of H3v-47 Fab with the H3N2v hemagglutinin (HA) identify a unique epitope spanning the vestigial esterase and receptor-binding subdomains that is distinct from that of any known neutralizing antibody for influenza A H3 viruses. MAb H3v-47 functions largely by blocking viral egress from infected cells. Interestingly, H3v-47 also engages Fcγ receptor and mediates antibody dependent cellular cytotoxicity (ADCC). This newly identified conserved epitope can be used in design of novel immunogens for development of broadly protective H3 vaccines.

Highlights

The high rate of antigenic drift in seasonal influenza viruses necessitates frequent changes in vaccine composition
H3v-47 functions primarily by inhibiting viral egress and effectively engages Fc receptor to elicit antibody dependent cellular cytotoxicity (ADCC) activity. These findings identify a novel conserved epitope on H3 HA that can aid in development of a broad H3N2 vaccine and provide insights into unique antiviral approaches exploited by a vestigial esterase domain-binding antibody
We previously reported the isolation of H3v-reactive human monoclonal antibodies from donors vaccinated with an experimental H3N2 variant (H3N2v) vaccine containing the A/Minnesota/11/ 2010 strain[39,40]

Summary

Introduction

The high rate of antigenic drift in seasonal influenza viruses necessitates frequent changes in vaccine composition. H3v-47 engages Fcγ receptor and mediates antibody dependent cellular cytotoxicity (ADCC) This newly identified conserved epitope can be used in design of novel immunogens for development of broadly protective H3 vaccines. A broad influenza B antibody CR8071 that binds the vestigial esterase domain on HA head was shown to function primarily by inhibiting viral egress, similar to the function exhibited by NA inhibitors[23,27]. Neutralizing antibodies to influenza virus, often encoded by the human VH1-69 germline gene segment[27,34,35], generally target the structurally conserved HA stem domain[27,34,35,36,37,38]

Methods

Results

Conclusion