Tweet
Received: 29 March 2021
Accepted: 9 July 2021
Published online: 19 July 2021
M. Alejandra Tortorici1,2,9, Nadine Czudnochowski3,9, Tyler N. Starr4,9, Roberta Marzi5,9, Alexandra C. Walls1, Fabrizia Zatta5, John E. Bowen1, Stefano Jaconi5, Julia Di Iulio3,
Zhaoqian Wang1, Anna De Marco5, Samantha K. Zepeda1, Dora Pinto5, Zhuoming Liu6,
Martina Beltramello5, Istvan Bartha5, Michael P. Housley3, Florian A. Lempp3, Laura E. Rosen3, Exequiel Dellota Jr3, Hannah Kaiser3, Martin Montiel-Ruiz3, Jiayi Zhou3, Amin Addetia4, Barbara Guarino3, Katja Culap5, Nicole Sprugasci5, Christian Saliba5, Eneida Vetti5, Isabella Giacchetto-Sasselli5, Chiara Silacci Fregni5, Rana Abdelnabi7, Shi-Yan Caroline Foo7, Colin Havenar-Daughton3, Michael A. Schmid5, Fabio Benigni5, Elisabetta Cameroni5, Johan Neyts7, Amalio Telenti3, Herbert W. Virgin3, Sean P. J. Whelan6, Gyorgy Snell3, Jesse D. Bloom4,8, Davide Corti5✉, David Veesler1✉ & Matteo Samuele Pizzuto5✉
The recent emergence of SARS-CoV-2 variants of concern (VOC)1–10 and the recurrent spillovers of coronaviruses11,12 in the human population highlight the need for broadly neutralizing antibodies that are not a ected by the ongoing antigenic drift and that can prevent or treat future zoonotic infections. Here, we describe a human monoclonal antibody (mAb), designated S2X259, recognizing a highly conserved cryptic receptor-binding domain (RBD) epitope and cross-reacting with spikes from all sarbecovirus clades. S2X259 broadly neutralizes spike-mediated entry of SARS-CoV-2 including the B.1.1.7, B.1.351, P.1, B.1.427/B.1.429 VOC, as well as a wide spectrum of human and potentially zoonotic sarbecoviruses through inhibition of ACE2 binding to the RBD. Furthermore, deep-mutational scanning and in vitro escape selection experiments demonstrate that S2X259 possesses an escape pro le limited to the single substitution G504D. We show that prophylactic and therapeutic administration of S2X259 protects Syrian hamsters against challenge with the prototypic SARS-CoV-2 and the B.1.351 VOC, suggesting this mAb is a promising candidate for the prevention and treatment of emergent variants and zoonotic infections. Our data unveil a key antigenic site targeted by broadly-neutralizing antibodies and will guide the design of pan-sarbecovirus vaccines.
...