1. Structural basis for broad sarbecovirus neutralization by a human monoclonal antibody
- Author
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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, and Zhuoming Liu
- Subjects
medicine.drug_class ,Population ,Cross Reactions ,Monoclonal antibody ,Antibodies, Viral ,Viral Zoonoses ,Epitope ,Antigenic drift ,Neutralization ,Article ,Antigen ,Neutralization Tests ,medicine ,Animals ,Humans ,education ,Immune Evasion ,education.field_of_study ,biology ,Zoonotic Infection ,Mesocricetus ,SARS-CoV-2 ,Antibodies, Monoclonal ,COVID-19 ,Virology ,Disease Models, Animal ,Mutation ,biology.protein ,Female ,Antibody ,Broadly Neutralizing Antibodies - 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.
- Published
- 2021