Journal Article

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

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

2022

Overview

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 antibody 1 . Furthermore, a fraction of broadly neutralizing sarbecovirus monoclonal antibodies neutralized Omicron through recognition of antigenic sites outside the receptor-binding motif, including sotrovimab 2 , S2X259 3 and S2H97 4 . 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. Pseudovirus assays and surface plasmon resonance show that the Omicron receptor-binding domain binds to human ACE2 with increased affinity relative to the ancestral virus, and that most neutralizing antibodies are considerably less potent against Omicron.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/109 / 13/56 / 631/250/255/2514 / 631/326/596/4130 / 82/47 / 82/58 / 9/10 / ACE2 / Amino acids / Angiotensin-converting enzyme 2 / Angiotensin-Converting Enzyme 2 - metabolism / Animals / Antibodies, Monoclonal - immunology / Antibodies, Monoclonal - therapeutic use / Antibodies, Monoclonal, Humanized - immunology / Antibodies, Neutralizing - immunology / Antibodies, Viral - blood / Antibodies, Viral - immunology / Antigenic Drift and Shift - genetics / Antigenic Drift and Shift - immunology / Antigens / Binding / Broadly Neutralizing Antibodies - immunology / Cell Line / Convalescence / Coronaviruses / COVID-19 / COVID-19 vaccines / COVID-19 Vaccines - immunology / Disease transmission / Epitopes / Epitopes, B-Lymphocyte - immunology / Haplotypes / Humanities and Social Sciences / Humans / Immune Evasion / Infections / Mice / Mimicry / Monoclonal antibodies / multidisciplinary / Mutation / Neutralization Tests / Neutralizing / Pandemics / Plasma / Proteins / Receptors / SARS-CoV-2 - chemistry / SARS-CoV-2 - classification / SARS-CoV-2 - genetics / SARS-CoV-2 - immunology / Science / Science (multidisciplinary) / Severe acute respiratory syndrome coronavirus 2 / Spike Glycoprotein, Coronavirus - chemistry / Spike Glycoprotein, Coronavirus - genetics / Spike Glycoprotein, Coronavirus - immunology / Spike Glycoprotein, Coronavirus - metabolism / Spike protein / Vaccines / Vesiculovirus - genetics / Viruses