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Structural basis for broad sarbecovirus neutralization by a human monoclonal antibody

Authors :
Tyler N. Starr
Michael P. Housley
Michael A. Schmid
Roberta Marzi
Martin Montiel-Ruiz
Katja Culap
Hanna Kaiser
Matteo Samuele Pizzuto
Nicole Sprugasci
Barbara Guarino
David Veesler
Fabio Benigni
Johan Neyts
Nadine Czudnochowski
Eneida Vetti
Exequiel Dellota
Martina Beltramello
Colin Havenar-Daughton
M. Alejandra Tortorici
Isabella Giacchetto-Sasselli
Florian A. Lempp
Caroline S. Foo
Dora Pinto
Anna De Marco
Gyorgy Snell
Julia di Iulio
Stefano Jaconi
Rana Abdelnabi
Z. Wang
Jiayi Zhou
Chiara Silacci Fregni
Amalio Telenti
Fabrizia Zatta
Jesse D. Bloom
Laura E. Rosen
Davide Corti
Herbert W. Virgin
Alexandra C. Walls
Christian Saliba
Samantha K Zepeda
Sean P. J. Whelan
Amin Addetia
John E. Bowen
Istvan Bartha
Elisabetta Cameroni
Zhuoming Liu
Source :
bioRxiv, article-version (status) pre, article-version (number) 1
Publication Year :
2021
Publisher :
Cold Spring Harbor Laboratory, 2021.

Abstract

The recent emergence of SARS-CoV-2 variants of concern (VOC) and the recurrent spillovers of coronaviruses in the human population highlight the need for broadly neutralizing antibodies that are not affected by the ongoing antigenic drift and that can prevent or treat future zoonotic infections. Here, we describe a human monoclonal antibody (mAb), designated S2×259, recognizing a highly conserved cryptic receptor-binding domain (RBD) epitope and cross-reacting with spikes from all sarbecovirus clades. S2×259 broadly neutralizes spike-mediated entry of SARS-CoV-2 including the B.1.1.7, B.1.351, P.1 and B.1.427/B.1.429 VOC, as well as a wide spectrum of human and zoonotic sarbecoviruses through inhibition of ACE2 binding to the RBD. Furthermore, deep-mutational scanning and in vitro escape selection experiments demonstrate that S2×259 possesses a remarkably high barrier to the emergence of resistance mutants. We show that prophylactic administration of S2×259 protects Syrian hamsters against challenges with the prototypic SARS-CoV-2 and the B.1.351 variant, suggesting this mAb is a promising candidate for the prevention and treatment of emergent VOC and zoonotic infections. Our data unveil a key antigenic site targeted by broadly-neutralizing antibodies and will guide the design of pan-sarbecovirus vaccines.

Details

Language :
English
Database :
OpenAIRE
Journal :
bioRxiv
Accession number :
edsair.doi.dedup.....5306585f6250e97d4520b08446d06de3