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 Chen; Cyrus 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

doi:10.1038/s41586-021-04386-2

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 journal › Article › peer-review

397 Scopus citations

Abstract

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 language	English
Pages (from-to)	664-670
Number of pages	7
Journal	Nature
Volume	602
Issue number	7898
DOIs	https://doi.org/10.1038/s41586-021-04386-2
State	Published - Feb 24 2022

Access to Document

10.1038/s41586-021-04386-2

Cite this

Cameroni, E., Bowen, J. E., Rosen, L. E., Saliba, C., Zepeda, S. K., Culap, K., Pinto, D., VanBlargan, L. A., De Marco, A., di Iulio, J., Zatta, F., Kaiser, H., Noack, J., Farhat, N., Czudnochowski, N., Havenar-Daughton, C., Sprouse, K. R., Dillen, J. R., Powell, A. E., ... Corti, D. (2022). Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift. Nature, 602(7898), 664-670. https://doi.org/10.1038/s41586-021-04386-2

@article{a4a13ceb2ede4d7bb1c3970c03f79cf1,

title = "Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift",

abstract = "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.",

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

note = "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: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2022",

month = feb,

day = "24",

doi = "10.1038/s41586-021-04386-2",

language = "English",

volume = "602",

pages = "664--670",

journal = "Nature",

issn = "0028-0836",

number = "7898",

}

Cameroni, E, Bowen, JE, Rosen, LE, Saliba, C, Zepeda, SK, Culap, K, Pinto, D, VanBlargan, LA, De Marco, A, di Iulio, J, Zatta, F, Kaiser, H, Noack, J, Farhat, N, Czudnochowski, N, Havenar-Daughton, C, Sprouse, KR, Dillen, JR, Powell, AE, Chen, A, Maher, C, Yin, L, Sun, D, Soriaga, L, Bassi, J, Silacci-Fregni, C, Gustafsson, C, Franko, NM, Logue, J, Iqbal, NT, Mazzitelli, I, Geffner, J, Grifantini, R, Chu, H, Gori, A, Riva, A, Giannini, O, Ceschi, A, Ferrari, P, Cippà, PE, Franzetti-Pellanda, A, Garzoni, C, Halfmann, PJ, Kawaoka, Y, Hebner, C, Purcell, LA, Piccoli, L, Pizzuto, MS, Walls, AC, Diamond, MS, Telenti, A, Virgin, HW, Lanzavecchia, A, Snell, G, Veesler, D & Corti, D 2022, 'Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift', Nature, vol. 602, no. 7898, pp. 664-670. https://doi.org/10.1038/s41586-021-04386-2

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 -

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

Abstract

Access to Document

Other files and links

Fingerprint

Cite this