Structural basis for 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 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, Gyorgy Snell, Herbert W. Virgin, Sean P.J. Whelan, Jesse D. Bloom, Davide Corti, David Veesler, Matteo Samuele Pizzuto
2021 · doi:10.1101/2021.04.07.438818
preprint OA: gold publisher-OA-unknown
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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.

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