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 Iulio, Zhaoqian Wang, Anna Marco, Samantha K. Zepeda, Dora Pinto, Zhuoming Liu, Martina Beltramello, Istvan Bartha, Michael P. Housley, Florian A. Lempp, Laura E. Rosen, Exequiel Dellota, Hannah 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 () and Matteo Samuele Pizzuto ()
Additional contact information
M. Alejandra Tortorici: University of Washington
Nadine Czudnochowski: Vir Biotechnology
Tyler N. Starr: Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Research Center
Roberta Marzi: Humabs Biomed SA, a subsidiary of Vir Biotechnology
Alexandra C. Walls: University of Washington
Fabrizia Zatta: Humabs Biomed SA, a subsidiary of Vir Biotechnology
John E. Bowen: University of Washington
Stefano Jaconi: Humabs Biomed SA, a subsidiary of Vir Biotechnology
Julia Iulio: Vir Biotechnology
Zhaoqian Wang: University of Washington
Anna Marco: Humabs Biomed SA, a subsidiary of Vir Biotechnology
Samantha K. Zepeda: University of Washington
Dora Pinto: Humabs Biomed SA, a subsidiary of Vir Biotechnology
Zhuoming Liu: Washington University School of Medicine
Martina Beltramello: Humabs Biomed SA, a subsidiary of Vir Biotechnology
Istvan Bartha: Humabs Biomed SA, a subsidiary of Vir Biotechnology
Michael P. Housley: Vir Biotechnology
Florian A. Lempp: Vir Biotechnology
Laura E. Rosen: Vir Biotechnology
Exequiel Dellota: Vir Biotechnology
Hannah Kaiser: Vir Biotechnology
Martin Montiel-Ruiz: Vir Biotechnology
Jiayi Zhou: Vir Biotechnology
Amin Addetia: Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Research Center
Barbara Guarino: Vir Biotechnology
Katja Culap: Humabs Biomed SA, a subsidiary of Vir Biotechnology
Nicole Sprugasci: Humabs Biomed SA, a subsidiary of Vir Biotechnology
Christian Saliba: Humabs Biomed SA, a subsidiary of Vir Biotechnology
Eneida Vetti: Humabs Biomed SA, a subsidiary of Vir Biotechnology
Isabella Giacchetto-Sasselli: Humabs Biomed SA, a subsidiary of Vir Biotechnology
Chiara Silacci Fregni: Humabs Biomed SA, a subsidiary of Vir Biotechnology
Rana Abdelnabi: KU Leuven
Shi-Yan Caroline Foo: KU Leuven
Colin Havenar-Daughton: Vir Biotechnology
Michael A. Schmid: Humabs Biomed SA, a subsidiary of Vir Biotechnology
Fabio Benigni: Humabs Biomed SA, a subsidiary of Vir Biotechnology
Elisabetta Cameroni: Humabs Biomed SA, a subsidiary of Vir Biotechnology
Johan Neyts: KU Leuven
Amalio Telenti: Vir Biotechnology
Herbert W. Virgin: Vir Biotechnology
Sean P. J. Whelan: Washington University School of Medicine
Gyorgy Snell: Vir Biotechnology
Jesse D. Bloom: Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Research Center
Davide Corti: Humabs Biomed SA, a subsidiary of Vir Biotechnology
David Veesler: University of Washington
Matteo Samuele Pizzuto: Humabs Biomed SA, a subsidiary of Vir Biotechnology

Nature, 2021, vol. 597, issue 7874, 103-108

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41586-021-03817-4

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