A conserved immunogenic and vulnerable site on the coronavirus spike protein delineated by cross-reactive monoclonal antibodies

Chunyan Wang,Ivy Widjaja,Frank J M Van Kuppeveld,Rien Van Haperen,Frank Grosveld,Berend-Jan Bosch,Bart L Haagmans,Dubravka Drabek,Olalekan Daramola,Raul Fernandez-Delgado,Javier Gutiérrez-Álvarez,Brenda Van Dieren,Nisreen M A Okba,Luis Enjuanes,Isabel Sola,Daniel L Hurdiss,Irina Albulescu,Wentao Li

doi:10.1038/s41467-021-21968-w

Abstract

The coronavirus spike glycoprotein, located on the virion surface, is the key mediator of cell entry and the focus for development of protective antibodies and vaccines. Structural studies show exposed sites on the spike trimer that might be targeted by antibodies with cross-species specificity. Here we isolated two human monoclonal antibodies from immunized humanized mice that display a remarkable cross-reactivity against distinct spike proteins of betacoronaviruses including SARS-CoV, SARS-CoV-2, MERS-CoV and the endemic human coronavirus HCoV-OC43. Both cross-reactive antibodies target the stem helix in the spike S2 fusion subunit which, in the prefusion conformation of trimeric spike, forms a surface exposed membrane-proximal helical bundle. Both antibodies block MERS-CoV infection in cells and provide protection to mice from lethal MERS-CoV challenge in prophylactic and/or therapeutic models. Our work highlights an immunogenic and vulnerable site on the betacoronavirus spike protein enabling elicitation of antibodies with unusual binding breadth.

Highlights

The coronavirus spike glycoprotein, located on the virion surface, is the key mediator of cell entry and the focus for development of protective antibodies and vaccines
Five out of seven coronaviruses that are currently known to cause disease in humans belong to the Betacoronavirus genus, including SARS-CoV and SARS-CoV-2, Middle East respiratory syndrome (MERS)-CoV, and the endemic human coronaviruses (HCoVs) HCoV-OC43 and HCoV-HKU1
We selected 203 hybridomas based on reactivity against at least one of the three spike antigens and screened their supernatants for cross-reactivity against five distinct betacoronavirus spike proteins by ELISA (Supplementary Fig. 1b)

Summary

Introduction

The coronavirus spike glycoprotein, located on the virion surface, is the key mediator of cell entry and the focus for development of protective antibodies and vaccines. We isolated two human monoclonal antibodies from immunized humanized mice that display a remarkable cross-reactivity against distinct spike proteins of betacoronaviruses including SARS-CoV, SARS-CoV-2, MERS-CoV and the endemic human coronavirus HCoV-OC43. Both cross-reactive antibodies target the stem helix in the spike S2 fusion subunit which, in the prefusion conformation of trimeric spike, forms a surface exposed membrane-proximal helical bundle. Ten years later in 2012, the Middle East respiratory syndrome (MERS) coronavirus (subgenus Merbecovirus, genus Betacoronavirus) surfaced in Saudi Arabia This virus is recurrently introduced in the human population from a dromedary camel reservoir with limited human-to-human spread and has led to ~2500 cases with ~35% of reported patients succumbing to the infection[4]. We report first evidence of a class of S2-targeting antibodies with broad reactivity towards several human betacoronaviruses from distinct subgenera, and characterized their antiviral activity, epitope and in vivo protective efficacy

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