TY - JOUR
T1 - Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift
AU - Cameroni, Elisabetta
AU - Bowen, John E.
AU - Rosen, Laura E.
AU - Saliba, Christian
AU - Zepeda, Samantha K.
AU - Culap, Katja
AU - Pinto, Dora
AU - VanBlargan, Laura A.
AU - De Marco, Anna
AU - di Iulio, Julia
AU - Zatta, Fabrizia
AU - Kaiser, Hannah
AU - Noack, Julia
AU - Farhat, Nisar
AU - Czudnochowski, Nadine
AU - Havenar-Daughton, Colin
AU - Sprouse, Kaitlin R.
AU - Dillen, Josh R.
AU - Powell, Abigail E.
AU - Chen, Alex
AU - Maher, Cyrus
AU - Yin, Li
AU - Sun, David
AU - Soriaga, Leah
AU - Bassi, Jessica
AU - Silacci-Fregni, Chiara
AU - Gustafsson, Claes
AU - Franko, Nicholas M.
AU - Logue, Jenni
AU - Iqbal, Najeeha Talat
AU - Mazzitelli, Ignacio
AU - Geffner, Jorge
AU - Grifantini, Renata
AU - Chu, Helen
AU - Gori, Andrea
AU - Riva, Agostino
AU - Giannini, Olivier
AU - Ceschi, Alessandro
AU - Ferrari, Paolo
AU - Cippà, Pietro E.
AU - Franzetti-Pellanda, Alessandra
AU - Garzoni, Christian
AU - Halfmann, Peter J.
AU - Kawaoka, Yoshihiro
AU - Hebner, Christy
AU - Purcell, Lisa A.
AU - Piccoli, Luca
AU - Pizzuto, Matteo Samuele
AU - Walls, Alexandra C.
AU - Diamond, Michael S.
AU - Telenti, Amalio
AU - Virgin, Herbert W.
AU - Lanzavecchia, Antonio
AU - Snell, Gyorgy
AU - Veesler, David
AU - Corti, Davide
N1 - Funding Information:
Competing interests E.C., K.C., C.S., D.P., F.Z., A.D.M., A.L., L.P., M.S.P., D.C., H.K., J.N., N.F., J.d.I., L.E.R., N.C., C.H.-D., K.R.S., J.R.D., A.E.P., A.C., C.M., L.Y., D.S., L.S., L.A.P., C.H., A.T., H.W.V. and G.S. are employees of Vir Biotechnology and may hold shares in Vir Biotechnology. L.A.P. is a former employee and shareholder in Regeneron Pharmaceuticals. Regeneron provided no funding for this work. H.W.V. is a founder and holds shares in PierianDx and Casma Therapeutics. Neither company provided resources. The D.V. laboratory has received a sponsored research agreement from Vir Biotechnology. H.C. reported consulting with Ellume, Pfizer, the Bill and Melinda Gates Foundation, Glaxo Smith Kline and Merck. She has received research funding from Emergent Ventures, Gates Ventures, Sanofi Pasteur and the Bill and Melinda Gates Foundation, and support and reagents from Ellume and Cepheid outside of the submitted work. M.S.D. is a consultant for Inbios, Vir Biotechnology, Senda Biosciences and Carnival Corporation, and is on the Scientific Advisory Boards of Moderna and Immunome. The M.S.D. laboratory has received funding support in sponsored research agreements from Moderna, Vir Biotechnology and Emergent BioSolutions. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Funding Information:
Acknowledgements We thank H. Tani for providing the reagents necessary for preparing VSV pseudotyped viruses. This study was supported by the National Institute of Allergy and Infectious Diseases (DP1AI158186 and HHSN272201700059C to D.V.), a Pew Biomedical Scholars Award (D.V.), an Investigators in the Pathogenesis of Infectious Disease Awards from the Burroughs Wellcome Fund (D.V.), Fast Grants (D.V.) and the National Institute of General Medical Sciences (5T32GM008268-32 to S.K.Z.). D.V. is an Investigator of the Howard Hughes Medical Institute. O.G. is funded by the Swiss Kidney Foundation. This work was supported, in part, by the National Institutes of Allergy and Infectious Diseases Center for Research on Influenza Pathogenesis (HHSN272201400008C), the Center for Research on Influenza Pathogenesis and Transmission (CRIPT) (75N93021C00014) and the Japan Program for Infectious Diseases Research and Infrastructure (JP21wm0125002) from the Japan Agency for Medical Research and Development (AMED). This work was supported in part through National Institutes of Health USA grant U01 AI151698 for the United World Antivirus Research Network (UWARN).
Funding Information:
We thank H. Tani for providing the reagents necessary for preparing VSV pseudotyped viruses. This study was supported by the National Institute of Allergy and Infectious Diseases (DP1AI158186 and HHSN272201700059C to D.V.), a Pew Biomedical Scholars Award (D.V.), an Investigators in the Pathogenesis of Infectious Disease Awards from the Burroughs Wellcome Fund (D.V.), Fast Grants (D.V.) and the National Institute of General Medical Sciences (5T32GM008268-32 to S.K.Z.). D.V. is an Investigator of the Howard Hughes Medical Institute. O.G. is funded by the Swiss Kidney Foundation. This work was supported, in part, by the National Institutes of Allergy and Infectious Diseases Center for Research on Influenza Pathogenesis (HHSN272201400008C), the Center for Research on Influenza Pathogenesis and Transmission (CRIPT) (75N93021C00014) and the Japan Program for Infectious Diseases Research and Infrastructure (JP21wm0125002) from the Japan Agency for Medical Research and Development (AMED).?This work was supported in part through National Institutes of Health USA grant U01 AI151698 for the United World Antivirus Research Network (UWARN).
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/2/24
Y1 - 2022/2/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85122706315&partnerID=8YFLogxK
U2 - 10.1038/s41586-021-04386-2
DO - 10.1038/s41586-021-04386-2
M3 - Article
C2 - 35016195
AN - SCOPUS:85122706315
VL - 602
SP - 664
EP - 670
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7898
ER -