Broad betacoronavirus neutralization by a stem helix-specific human antibody.

Dora Pinto,Roberta Marzi,Alessandro Ceschi,Katja Culap,Antonio Lanzavecchia,Jun Siong Low,Rana Abdelnabi,Julia Noack,Paolo Ferrari,Gyorgy Snell,Nicole Sprugasci,Florian A Lempp,Laura E Rosen,Colin Havenar-Daughton,Julia Di Iulio,M Alejandra Tortorici,Federica Sallusto,Christian Garzoni,Michael P Housley,Samuele Ceruti,Barbara Guarino,Saiful Islam,Martina Beltramello,Amalio Telenti,Davide Corti,Chiara Silacci-Fregni,Fabio Benigni,Elisabetta Cameroni,David Veesler,Nadine Czudnochowski,Eneida Vetti,Alexandra C Walls,Johan Neyts,Agostino Riva,Antonino Cassotta,Siro Bianchi,Luca Piccoli,Stefano Jaconi,Lotte Coelmont,Jessica Bassi,Josipa Jerak,Olivier Giannini,Herbert W Virgin,Hannah Kaiser,John E Bowen,David K Hong ,M.m Sauer ,Caroline S Foo ,Megan J Smithey ,Pietro E Cippà ,Matteo Samuele Pizzuto ,István Bartha

doi:10.1126/science.abj3321

Abstract

The spillovers of betacoronaviruses in humans and the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants highlight the need for broad coronavirus countermeasures. We describe five monoclonal antibodies (mAbs) cross-reacting with the stem helix of multiple betacoronavirus spike glycoproteins isolated from COVID-19 convalescent individuals. Using structural and functional studies, we show that the mAb with the greatest breadth (S2P6) neutralizes pseudotyped viruses from three different subgenera through the inhibition of membrane fusion, and we delineate the molecular basis for its cross-reactivity. S2P6 reduces viral burden in hamsters challenged with SARS-CoV-2 through viral neutralization and Fc-mediated effector functions. Stem helix antibodies are rare, oftentimes of narrow specificity, and can acquire neutralization breadth through somatic mutations. These data provide a framework for structure-guided design of pan-betacoronavirus vaccines eliciting broad protection.

Highlights

The coronavirus spike (S) glycoprotein promotes viral entry into host cells through an S1 subunit which engages host receptors and an S2 subunit mediating membrane fusion (1)
S1A), which correspond to a higher level of mutations than that observed for receptor-binding domain (RBD)- and N-terminal domain (NTD)-specific monoclonal antibodies (mAbs) isolated early after SARS-CoV-2 infection or vaccination (5, 19–21)
The recent identification of 4 cross-reactive mAbs targeting the stem helix in the S2 subunit highlighted the importance of this epitope, which is conserved among β-coronavirus but not α-coronavirus S glycoproteins (14–16, 47), none of these mAbs inhibit members of all three β-coronavirus subgenera

Summary

Introduction

The coronavirus spike (S) glycoprotein promotes viral entry into host cells through an S1 subunit which engages host receptors and an S2 subunit mediating membrane fusion (1). Isolation of a broadly neutralizing β-coronavirus mAb from a convalescent SARS-CoV-2-exposed individual S1B) and they all neutralize SARS-CoV-2 S VSV pseudotypes (fig.S1C). We observed S2P6 binding to post-fusion SARS-CoV-2 S To validate the inferred mechanism of S2P6-mediated broad coronavirus neutralization, we first showed that S2P6 binding did not block engagement of SARS-CoV-2 S by ACE2 using ELISA, as expected based on the distance of its epitope from the RBD (Fig. 3A).

Results

Conclusion