RESEARCH BRIEFINGS 23 December 2021 Elisabetta Cameroni 0 , John E. Bowen 1 , Laura E. Rosen 2 , Christian Saliba 3 , Samantha K. Zepeda 4 , Katja Culap 5 , Dora Pinto 6 , Laura A. VanBlargan 7 , Anna De Marco 8 , Julia di Iulio 9 , Fabrizia Zatta 10 , Hannah Kaiser 11 , Julia Noack 12 , Nisar Farhat 13 , Nadine Czudnochowski 14 , Colin Havenar-Daughton 15 , Kaitlin R. Sprouse 16 , Josh R. Dillen 17 , Abigail E. Powell 18 , Alex Chen 19 , Cyrus Maher 20 , Li Yin 21 , David Sun 22 , Leah Soriaga 23 , Jessica Bassi 24 , Chiara Silacci-Fregni 25 , Claes Gustafsson 26 , Nicholas M. Franko 27 , Jenni Logue 28 , Najeeha Talat Iqbal 29 , Ignacio Mazzitelli 30 , Jorge Geffner 31 , Renata Grifantini 32 , Helen Chu 33 , Andrea Gori 34 , Agostino Riva 35 , Olivier Giannini 36 , Alessandro Ceschi 37 , Paolo Ferrari 38 , Pietro E. Cippà 39 , Alessandra Franzetti-Pellanda 40 , Christian Garzoni 41 , Peter J. Halfmann 42 , Yoshihiro Kawaoka 43 , Christy Hebner 44 , Lisa A. Purcell 45 , Luca Piccoli 46 , Matteo Samuele Pizzuto 47 , Alexandra C. Walls 48 , Michael S. Diamond 49 , Amalio Telenti 50 , Herbert W. Virgin 51 , Antonio Lanzavecchia 52 , Gyorgy Snell 53 , David Veesler 54 & Davide Corti 55
This manuscript has been peer reviewed and accepted for publication in Nature and is provided in this format here as a response to the exceptional public-health crisis. This accepted manuscript will continue through the processes of copy editing and formatting to publication of a finalized version of record on nature.com. Please note there may be errors present in this version, which may affect the content, and all legal disclaimers apply. The recently emerged SARS-CoV-2 Omicron variant encodes 37 amino acid substitutions in the spike (S) protein, 15 of which are in the receptor-binding domain (RBD), thereby raising concerns about the effectiveness of available vaccines and antibody 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 of plasma neutralizing activity were observed against Omicron compared to the ancestral pseudovirus for convalescent and vaccinated individuals, but this loss was less pronounced after a third vaccine dose. Most receptor-binding motif (RBM)-directed monoclonal antibodies (mAbs) lost in vitro neutralizing activity against Omicron, with only 3 out of 29 mAbs retaining unaltered potency, including the ACE2-mimicking S2K146 mAb1. Furthermore, a fraction of broadly neutralizing sarbecovirus mAbs neutralized Omicron through recognition of antigenic sites outside the RBM, including sotrovimab2, S2X2593 and S2H974. The magnitude of Omicron-mediated immune evasion marks a major SARS-CoV-2 antigenic shift. Broadly neutralizing mAbs recognizing RBD epitopes conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers. doi: https://doi.org/10.1038/d41586-021-03825-4 Supplementary Information Supplementary information figs 1-3, table 1 Reporting Summary
https://www.nature.com/articles/d41586-021-03825-4
