Broad sarbecovirus neutralization by a human monoclonal antibody

M. Alejandra Tortorici, Nadine Czudnochowski, Tyler N. Starr, Roberta Marzi, Alexandra C. Walls, Fabrizia Zatta, John E. Bowen, Stefano Jaconi, Julia Di Iulio, Zhaoqian Wang, Anna De Marco, Samantha K. Zepeda, Dora Pinto, Zhuoming Liu, Martina Beltramello, Istvan Bartha, Michael P. Housley, Florian A. Lempp, Laura E. Rosen, Exequiel DellotaHannah Kaiser, Martin Montiel-Ruiz, Jiayi Zhou, Amin Addetia, Barbara Guarino, Katja Culap, Nicole Sprugasci, Christian Saliba, Eneida Vetti, Isabella Giacchetto-Sasselli, Chiara Silacci Fregni, Rana Abdelnabi, Shi Yan Caroline Foo, Colin Havenar-Daughton, Michael A. Schmid, Fabio Benigni, Elisabetta Cameroni, Johan Neyts, Amalio Telenti, Herbert W. Virgin, Sean P.J. Whelan, Gyorgy Snell, Jesse D. Bloom, Davide Corti, David Veesler, Matteo Samuele Pizzuto

Research output: Contribution to journalArticlepeer-review

145 Scopus citations


The recent emergence of SARS-CoV-2 variants of concern1–10 and the recurrent spillovers of coronaviruses11,12 into 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 designated S2X259, which recognizes a highly conserved cryptic epitope of the receptor-binding domain and cross-reacts with spikes from all clades of sarbecovirus. S2X259 broadly neutralizes spike-mediated cell entry of SARS-CoV-2, including variants of concern (B.1.1.7, B.1.351, P.1, and B.1.427/B.1.429), as well as a wide spectrum of human and potentially zoonotic sarbecoviruses through inhibition of angiotensin-converting enzyme 2 (ACE2) binding to the receptor-binding domain. Furthermore, deep-mutational scanning and in vitro escape selection experiments demonstrate that S2X259 possesses an escape profile that is limited to a single substitution, G504D. We show that prophylactic and therapeutic administration of S2X259 protects Syrian hamsters (Mesocricetus auratus) against challenge with the prototypic SARS-CoV-2 and the B.1.351 variant of concern, which suggests that this monoclonal antibody is a promising candidate for the prevention and treatment of emergent variants and zoonotic infections. Our data reveal a key antigenic site that is targeted by broadly neutralizing antibodies and will guide the design of vaccines that are effective against all sarbecoviruses.

Original languageEnglish
Pages (from-to)103-108
Number of pages6
Issue number7874
StatePublished - Sep 2 2021


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