Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift

Elisabetta Cameroni, John E. Bowen, Laura E. Rosen, Christian Saliba, Samantha K. Zepeda, Katja Culap, Dora Pinto, Laura A. VanBlargan, Anna De Marco, Julia di Iulio, Fabrizia Zatta, Hannah Kaiser, Julia Noack, Nisar Farhat, Nadine Czudnochowski, Colin Havenar-Daughton, Kaitlin R. Sprouse, Josh R. Dillen, Abigail E. Powell, Alex ChenCyrus Maher, Li Yin, David Sun, Leah Soriaga, Jessica Bassi, Chiara Silacci-Fregni, Claes Gustafsson, Nicholas M. Franko, Jenni Logue, Najeeha Talat Iqbal, Ignacio Mazzitelli, Jorge Geffner, Renata Grifantini, Helen Chu, Andrea Gori, Agostino Riva, Olivier Giannini, Alessandro Ceschi, Paolo Ferrari, Pietro E. Cippà, Alessandra Franzetti-Pellanda, Christian Garzoni, Peter J. Halfmann, Yoshihiro Kawaoka, Christy Hebner, Lisa A. Purcell, Luca Piccoli, Matteo Samuele Pizzuto, Alexandra C. Walls, Michael S. Diamond, Amalio Telenti, Herbert W. Virgin, Antonio Lanzavecchia, Gyorgy Snell, David Veesler, Davide Corti

Research output: Contribution to journalArticlepeer-review

678 Scopus citations


The recently emerged SARS-CoV-2 Omicron variant encodes 37 amino acid substitutions in the spike protein, 15 of which are in the receptor-binding domain (RBD), thereby raising concerns about the effectiveness of available vaccines and antibody-based therapeutics. Here we show that the Omicron RBD binds to human ACE2 with enhanced affinity, relative to the Wuhan-Hu-1 RBD, and binds to mouse ACE2. Marked reductions in neutralizing activity were observed against Omicron compared to the ancestral pseudovirus in plasma from convalescent individuals and from individuals who had been vaccinated against SARS-CoV-2, but this loss was less pronounced after a third dose of vaccine. Most monoclonal antibodies that are directed against the receptor-binding motif lost in vitro neutralizing activity against Omicron, with only 3 out of 29 monoclonal antibodies retaining unaltered potency, including the ACE2-mimicking S2K146 antibody1. Furthermore, a fraction of broadly neutralizing sarbecovirus monoclonal antibodies neutralized Omicron through recognition of antigenic sites outside the receptor-binding motif, including sotrovimab2, S2X2593 and S2H974. The magnitude of Omicron-mediated immune evasion marks a major antigenic shift in SARS-CoV-2. Broadly neutralizing monoclonal antibodies that recognize RBD epitopes that are conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers.

Original languageEnglish
Pages (from-to)664-670
Number of pages7
Issue number7898
StatePublished - Feb 24 2022


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