Structural basis of SARS-CoV-2 Omicron immune evasion and receptor engagement

McCallum, Matthew; Czudnochowski, Nadine; Rosen, Laura E.; Zepeda, Samantha K.; Bowen, John E.; Walls, Alexandra C.; Hauser, Kevin; Joshi, Anshu; Stewart, Cameron; Dillen, Josh R.; Powell, Abigail E.; Croll, Tristan I.; Nix, Jay; Virgin, Herbert W.; Corti, Davide; Snell, Gyorgy; Veesler, David

doi:10.1126/science.abn8652

Structural basis of SARS-CoV-2 Omicron immune evasion and receptor engagement

Journal Article · Tue Jan 25 00:00:00 EST 2022 · Science

DOI:https://doi.org/10.1126/science.abn8652· OSTI ID:1891296

^[1]; ^[2]; ^[2]; ^[1]; ^[1]; ^[1]; Hauser, Kevin ^[2]; Joshi, Anshu ^[1]; ^[1]; ^[2]; ^[2]; ^[3]; ^[4]; ^[5]; ^[6]; ^[2]; ^[1]

Univ. of Washington, Seattle, WA (United States)
Vir Biotechnology, San Francisco, CA (United States)
Univ. of Cambridge (United Kingdom)
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Vir Biotechnology, San Francisco, CA (United States); Washington Univ., St. Louis, MO (United States). School of Medicine; Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
Humabs Biomed SA, Bellinzona, (Switzerland)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern evades antibody-mediated immunity that comes from vaccination or infection with earlier variants due to accumulation of numerous spike mutations. To understand the Omicron antigenic shift, we determined cryo–electron microscopy and x-ray crystal structures of the spike protein and the receptor-binding domain bound to the broadly neutralizing sarbecovirus monoclonal antibody (mAb) S309 (the parent mAb of sotrovimab) and to the human ACE2 receptor. We provide a blueprint for understanding the marked reduction of binding of other therapeutic mAbs that leads to dampened neutralizing activity. Remodeling of interactions between the Omicron receptor-binding domain and human ACE2 likely explains the enhanced affinity for the host receptor relative to the ancestral virus.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: Burroughs Wellcome Fund; Fast Grants; National Institute of General Medical Sciences; National Institutes of Health (NIH); USDOE Office of Science (SC); University of Washington Arnold and Mabel Beckman Cryo-EM Center

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1891296

Journal Information:: Science, Journal Name: Science Journal Issue: 6583 Vol. 375; ISSN 0036-8075

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: English

References (69)

UCSF Chimera?A visualization system for exploratory research and analysis Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C. Journal of Computational Chemistry, Vol. 25, Issue 13 https://doi.org/10.1002/jcc.20084	journal	January 2004
UCSF ChimeraX: Meeting modern challenges in visualization and analysis: UCSF ChimeraX Visualization System Goddard, Thomas D.; Huang, Conrad C.; Meng, Elaine C. Protein Science, Vol. 27, Issue 1 https://doi.org/10.1002/pro.3235	journal	September 2017
Structural insights into coronavirus entry Tortorici, M. Alejandra; Veesler, David Advances in Virus Research https://doi.org/10.1016/bs.aivir.2019.08.002	book	January 2019
Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein Walls, Alexandra C.; Park, Young-Jun; Tortorici, M. Alejandra Cell, Vol. 181, Issue 2 https://doi.org/10.1016/j.cell.2020.02.058	journal	April 2020
Structures of Human Antibodies Bound to SARS-CoV-2 Spike Reveal Common Epitopes and Recurrent Features of Antibodies Barnes, Christopher O.; West, Anthony P.; Huey-Tubman, Kathryn E. Cell, Vol. 182, Issue 4 https://doi.org/10.1016/j.cell.2020.06.025	journal	August 2020
Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding Starr, Tyler N.; Greaney, Allison J.; Hilton, Sarah K. Cell, Vol. 182, Issue 5 https://doi.org/10.1016/j.cell.2020.08.012	journal	September 2020
Mapping Neutralizing and Immunodominant Sites on the SARS-CoV-2 Spike Receptor-Binding Domain by Structure-Guided High-Resolution Serology Piccoli, Luca; Park, Young-Jun; Tortorici, M. Alejandra Cell, Vol. 183, Issue 4 https://doi.org/10.1016/j.cell.2020.09.037	journal	November 2020
A Mouse-Adapted SARS-CoV-2 Induces Acute Lung Injury and Mortality in Standard Laboratory Mice Leist, Sarah R.; Dinnon, Kenneth H.; Schäfer, Alexandra Cell, Vol. 183, Issue 4 https://doi.org/10.1016/j.cell.2020.09.050	journal	November 2020
Elicitation of Potent Neutralizing Antibody Responses by Designed Protein Nanoparticle Vaccines for SARS-CoV-2 Walls, Alexandra C.; Fiala, Brooke; Schäfer, Alexandra Cell, Vol. 183, Issue 5 https://doi.org/10.1016/j.cell.2020.10.043	journal	November 2020
Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity Thomson, Emma C.; Rosen, Laura E.; Shepherd, James G. Cell, Vol. 184, Issue 5 https://doi.org/10.1016/j.cell.2021.01.037	journal	March 2021
N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2 McCallum, Matthew; De Marco, Anna; Lempp, Florian A. Cell, Vol. 184, Issue 9 https://doi.org/10.1016/j.cell.2021.03.028	journal	April 2021
Tackling COVID-19 with neutralizing monoclonal antibodies Corti, Davide; Purcell, Lisa A.; Snell, Gyorgy Cell, Vol. 184, Issue 12 https://doi.org/10.1016/j.cell.2021.05.005	journal	June 2021
Elicitation of broadly protective sarbecovirus immunity by receptor-binding domain nanoparticle vaccines Walls, Alexandra C.; Miranda, Marcos C.; Schäfer, Alexandra Cell, Vol. 184, Issue 21 https://doi.org/10.1016/j.cell.2021.09.015	journal	October 2021
Broad cross-reactivity across sarbecoviruses exhibited by a subset of COVID-19 donor-derived neutralizing antibodies Jette, Claudia A.; Cohen, Alexander A.; Gnanapragasam, Priyanthi N. P. Cell Reports, Vol. 36, Issue 13 https://doi.org/10.1016/j.celrep.2021.109760	journal	September 2021
Emerging SARS-CoV-2 variants expand species tropism to murines Shuai, Huiping; Chan, Jasper Fuk-Woo; Yuen, Terrence Tsz-Tai EBioMedicine, Vol. 73 https://doi.org/10.1016/j.ebiom.2021.103643	journal	November 2021
Optimal Determination of Particle Orientation, Absolute Hand, and Contrast Loss in Single-particle Electron Cryomicroscopy Rosenthal, Peter B.; Henderson, Richard Journal of Molecular Biology, Vol. 333, Issue 4 https://doi.org/10.1016/j.jmb.2003.07.013	journal	October 2003
Automated molecular microscopy: The new Leginon system Suloway, Christian; Pulokas, James; Fellmann, Denis Journal of Structural Biology, Vol. 151, Issue 1 https://doi.org/10.1016/j.jsb.2005.03.010	journal	July 2005
RELION: Implementation of a Bayesian approach to cryo-EM structure determination Scheres, Sjors H. W. Journal of Structural Biology, Vol. 180, Issue 3, p. 519-530 https://doi.org/10.1016/j.jsb.2012.09.006	journal	December 2012
Automatically Fixing Errors in Glycoprotein Structures with Rosetta Frenz, Brandon; Rämisch, Sebastian; Borst, Andrew J. Structure, Vol. 27, Issue 1 https://doi.org/10.1016/j.str.2018.09.006	journal	January 2019
High-resolution noise substitution to measure overfitting and validate resolution in 3D structure determination by single particle electron cryomicroscopy Chen, Shaoxia; McMullan, Greg; Faruqi, Abdul R. Ultramicroscopy, Vol. 135 https://doi.org/10.1016/j.ultramic.2013.06.004	journal	December 2013
Cryo-electron microscopy structure of a coronavirus spike glycoprotein trimer Walls, Alexandra C.; Tortorici, M. Alejandra; Bosch, Berend-Jan Nature, Vol. 531, Issue 7592 https://doi.org/10.1038/nature16988	journal	February 2016
EMRinger: side chain–directed model and map validation for 3D cryo-electron microscopy Barad, Benjamin A.; Echols, Nathaniel; Wang, Ray Yu-Ruei Nature Methods, Vol. 12, Issue 10 https://doi.org/10.1038/nmeth.3541	journal	August 2015
cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination Punjani, Ali; Rubinstein, John L.; Fleet, David J. Nature Methods, Vol. 14, Issue 3 https://doi.org/10.1038/nmeth.4169	journal	February 2017
Privateer: software for the conformational validation of carbohydrate structures Agirre, Jon; Iglesias-Fernández, Javier; Rovira, Carme Nature Structural & Molecular Biology, Vol. 22, Issue 11 https://doi.org/10.1038/nsmb.3115	journal	November 2015
Infection of wild-type mice by SARS-CoV-2 B.1.351 variant indicates a possible novel cross-species transmission route Pan, Ting; Chen, Ran; He, Xin Signal Transduction and Targeted Therapy, Vol. 6, Issue 1 https://doi.org/10.1038/s41392-021-00848-1	journal	December 2021
Genetic and structural basis for SARS-CoV-2 variant neutralization by a two-antibody cocktail Dong, Jinhui; Zost, Seth J.; Greaney, Allison J. Nature Microbiology, Vol. 6, Issue 10 https://doi.org/10.1038/s41564-021-00972-2	journal	September 2021
Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor Lan, Jun; Ge, Jiwan; Yu, Jinfang Nature, Vol. 581, Issue 7807 https://doi.org/10.1038/s41586-020-2180-5	journal	March 2020
Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody Pinto, Dora; Park, Young-Jun; Beltramello, Martina Nature, Vol. 583, Issue 7815 https://doi.org/10.1038/s41586-020-2349-y	journal	May 2020
Potently neutralizing and protective human antibodies against SARS-CoV-2 Zost, Seth J.; Gilchuk, Pavlo; Case, James Brett Nature, Vol. 584, Issue 7821 https://doi.org/10.1038/s41586-020-2548-6	journal	July 2020
SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies Barnes, Christopher O.; Jette, Claudia A.; Abernathy, Morgan E. Nature, Vol. 588, Issue 7839 https://doi.org/10.1038/s41586-020-2852-1	journal	October 2020
Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7 Wang, Pengfei; Nair, Manoj S.; Liu, Lihong Nature, Vol. 593, Issue 7857 https://doi.org/10.1038/s41586-021-03398-2	journal	March 2021
Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies Collier, Dami A.; De Marco, Anna; Ferreira, Isabella A. T. M. Nature, Vol. 593, Issue 7857 https://doi.org/10.1038/s41586-021-03412-7	journal	March 2021
Adjuvanting a subunit COVID-19 vaccine to induce protective immunity Arunachalam, Prabhu S.; Walls, Alexandra C.; Golden, Nadia Nature, Vol. 594, Issue 7862 https://doi.org/10.1038/s41586-021-03530-2	journal	April 2021
SARS-CoV-2 RBD antibodies that maximize breadth and resistance to escape Starr, Tyler N.; Czudnochowski, Nadine; Liu, Zhuoming Nature https://doi.org/10.1038/s41586-021-03807-6	journal	July 2021
Broad sarbecovirus neutralization by a human monoclonal antibody Tortorici, M. Alejandra; Czudnochowski, Nadine; Starr, Tyler N. Nature, Vol. 597, Issue 7874 https://doi.org/10.1038/s41586-021-03817-4	journal	July 2021
Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies Cao, Yunlong; Wang, Jing; Jian, Fanchong Nature, Vol. 602, Issue 7898 https://doi.org/10.1038/s41586-021-04385-3	journal	December 2021
Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift Cameroni, Elisabetta; Bowen, John E.; Rosen, Laura E. Nature, Vol. 602, Issue 7898 https://doi.org/10.1038/s41586-021-04386-2	journal	December 2021
Striking antibody evasion manifested by the Omicron variant of SARS-CoV-2 Liu, Lihong; Iketani, Sho; Guo, Yicheng Nature, Vol. 602, Issue 7898 https://doi.org/10.1038/s41586-021-04388-0	journal	December 2021
Considerable escape of SARS-CoV-2 Omicron to antibody neutralization Planas, Delphine; Saunders, Nell; Maes, Piet Nature, Vol. 602, Issue 7898 https://doi.org/10.1038/s41586-021-04389-z	journal	December 2021
Rapid epidemic expansion of the SARS-CoV-2 Omicron variant in southern Africa Viana, Raquel; Moyo, Sikhulile; Amoako, Daniel G. Nature, Vol. 603, Issue 7902 https://doi.org/10.1038/s41586-022-04411-y	journal	January 2022
Real-time cryo-electron microscopy data preprocessing with Warp Tegunov, Dimitry; Cramer, Patrick Nature Methods, Vol. 16, Issue 11 https://doi.org/10.1038/s41592-019-0580-y	journal	October 2019
Non-uniform refinement: adaptive regularization improves single-particle cryo-EM reconstruction Punjani, Ali; Zhang, Haowei; Fleet, David J. Nature Methods, Vol. 17, Issue 12 https://doi.org/10.1038/s41592-020-00990-8	journal	November 2020
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
MolProbity : all-atom structure validation for macromolecular crystallography Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1 https://doi.org/10.1107/S0907444909042073	journal	December 2009
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
REFMAC 5 for the refinement of macromolecular crystal structures Murshudov, Garib N.; Skubák, Pavol; Lebedev, Andrey A. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444911001314	journal	March 2011
A Bayesian approach to beam-induced motion correction in cryo-EM single-particle analysis Zivanov, Jasenko; Nakane, Takanori; Scheres, Sjors H. W. IUCrJ, Vol. 6, Issue 1 https://doi.org/10.1107/S205225251801463X	journal	January 2019
ISOLDE : a physically realistic environment for model building into low-resolution electron-density maps Croll, Tristan Ian Acta Crystallographica Section D Structural Biology, Vol. 74, Issue 6 https://doi.org/10.1107/S2059798318002425	journal	April 2018
Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix Liebschner, Dorothee; Afonine, Pavel V.; Baker, Matthew L. Acta Crystallographica Section D Structural Biology, Vol. 75, Issue 10 https://doi.org/10.1107/S2059798319011471	journal	October 2019
Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation Wrapp, Daniel; Wang, Nianshuang; Corbett, Kizzmekia S. Science, Vol. 367, Issue 6483 https://doi.org/10.1126/science.abb2507	journal	February 2020
Broad neutralization of SARS-related viruses by human monoclonal antibodies Wec, Anna Z.; Wrapp, Daniel; Herbert, Andrew S. Science, Vol. 369, Issue 6504 https://doi.org/10.1126/science.abc7424	journal	June 2020
Structure-based design of prefusion-stabilized SARS-CoV-2 spikes Hsieh, Ching-Lin; Goldsmith, Jory A.; Schaub, Jeffrey M. Science, Vol. 369, Issue 6510 https://doi.org/10.1126/science.abd0826	journal	July 2020
Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail Hansen, Johanna; Baum, Alina; Pascal, Kristen E. Science https://doi.org/10.1126/science.abd0827	journal	June 2020
Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein Toelzer, Christine; Gupta, Kapil; Yadav, Sathish K. N. Science, Vol. 370, Issue 6517 https://doi.org/10.1126/science.abd3255	journal	September 2020
Broad and potent activity against SARS-like viruses by an engineered human monoclonal antibody Rappazzo, C. Garrett; Tse, Longping V.; Kaku, Chengzi I. Science, Vol. 371, Issue 6531 https://doi.org/10.1126/science.abf4830	journal	February 2021
Mosaic nanoparticles elicit cross-reactive immune responses to zoonotic coronaviruses in mice Cohen, Alexander A.; Gnanapragasam, Priyanthi N. P.; Lee, Yu E. Science, Vol. 371, Issue 6530 https://doi.org/10.1126/science.abf6840	journal	February 2021
Prospective mapping of viral mutations that escape antibodies used to treat COVID-19 Starr, Tyler N.; Greaney, Allison J.; Addetia, Amin Science, Vol. 371, Issue 6531 https://doi.org/10.1126/science.abf9302	journal	January 2021
Structural and functional ramifications of antigenic drift in recent SARS-CoV-2 variants Yuan, Meng; Huang, Deli; Lee, Chang-Chun D. Science, Vol. 373, Issue 6556 https://doi.org/10.1126/science.abh1139	journal	August 2021
Chimeric spike mRNA vaccines protect against Sarbecovirus challenge in mice Martinez, David R.; Schäfer, Alexandra; Leist, Sarah R. Science, Vol. 373, Issue 6558 https://doi.org/10.1126/science.abi4506	journal	August 2021
SARS-CoV-2 immune evasion by the B.1.427/B.1.429 variant of concern McCallum, Matthew; Bassi, Jessica; De Marco, Anna Science https://doi.org/10.1126/science.abi7994	journal	July 2021
Molecular basis of immune evasion by the Delta and Kappa SARS-CoV-2 variants McCallum, Matthew; Walls, Alexandra C.; Sprouse, Kaitlin R. Science, Vol. 374, Issue 6575 https://doi.org/10.1126/science.abl8506	journal	December 2021
Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry Park, Young-Jun; De Marco, Anna; Starr, Tyler N. Science, Vol. 375, Issue 6579 https://doi.org/10.1126/science.abm8143	journal	January 2022
Antibodies elicited by mRNA-1273 vaccination bind more broadly to the receptor binding domain than do those from SARS-CoV-2 infection Greaney, Allison J.; Loes, Andrea N.; Gentles, Lauren E. Science Translational Medicine, Vol. 13, Issue 600 https://doi.org/10.1126/scitranslmed.abi9915	journal	June 2021
A broadly cross-reactive antibody neutralizes and protects against sarbecovirus challenge in mice Martinez, David R.; Schäfer, Alexandra; Gobeil, Sophie Science Translational Medicine, Vol. 14, Issue 629 https://doi.org/10.1126/scitranslmed.abj7125	journal	January 2022
Convalescent-Phase Sera and Vaccine-Elicited Antibodies Largely Maintain Neutralizing Titer against Global SARS-CoV-2 Variant Spikes Tada, Takuya; Dcosta, Belinda M.; Samanovic, Marie I. mBio, Vol. 12, Issue 3 https://doi.org/10.1128/mBio.00696-21	journal	June 2021
Cryo-electron microscopy structures of the N501Y SARS-CoV-2 spike protein in complex with ACE2 and 2 potent neutralizing antibodies Zhu, Xing; Mannar, Dhiraj; Srivastava, Shanti S. PLOS Biology, Vol. 19, Issue 4 https://doi.org/10.1371/journal.pbio.3001237	journal	April 2021
Automated structure refinement of macromolecular assemblies from cryo-EM maps using Rosetta Wang, Ray Yu-Ruei; Song, Yifan; Barad, Benjamin A. eLife, Vol. 5 https://doi.org/10.7554/eLife.17219	journal	September 2016
New tools for automated high-resolution cryo-EM structure determination in RELION-3 Zivanov, Jasenko; Nakane, Takanori; Forsberg, Björn O. eLife, Vol. 7 https://doi.org/10.7554/eLife.42166	journal	November 2018
Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants Weisblum, Yiska; Schmidt, Fabian; Zhang, Fengwen eLife, Vol. 9 https://doi.org/10.7554/eLife.61312	journal	October 2020

Cited By (1)

SARS-CoV-2 spike N-terminal domain modulates TMPRSS2-dependent viral entry and fusogenicity. Meng, Bo; Datir, Rawlings; Choi, Jinwook Elsevier BV https://doi.org/10.17863/cam.87042	journalarticle	January 2022

Similar Records

Distinct Conformations of SARS-CoV-2 Omicron Spike Protein and Its Interaction with ACE2 and Antibody

Journal Article · Mon Feb 13 19:00:00 EST 2023 · International Journal of Molecular Sciences (Online) · OSTI ID:2471224

SARS-CoV-2 spike protein variant binding affinity to an angiotensin-converting enzyme 2 fusion glycoproteins

Journal Article · Mon Dec 05 19:00:00 EST 2022 · PLoS ONE · OSTI ID:2425791

Related Subjects

60 APPLIED LIFE SCIENCES

Structural basis of SARS-CoV-2 Omicron immune evasion and receptor engagement

Citation Formats

References (69)

Cited By (1)

Similar Records

Related Subjects