Cross-Neutralization of a SARS-CoV-2 Antibody to a Functionally Conserved Site Is Mediated by Avidity

Liu, Hejun; Wu, Nicholas C.; Yuan, Meng; Bangaru, Sandhya; Torres, Jonathan L.; Caniels, Tom G.; van Schooten, Jelle; Zhu, Xueyong; Lee, Chang-Chun D.; Brouwer, Philip J. M.; van Gils, Marit J.; Sanders, Rogier W.; Ward, Andrew B.; Wilson, Ian A.

doi:10.1016/j.immuni.2020.10.023

Cross-Neutralization of a SARS-CoV-2 Antibody to a Functionally Conserved Site Is Mediated by Avidity

Journal Article · Wed Nov 25 00:00:00 EST 2020 · Immunity

DOI:https://doi.org/10.1016/j.immuni.2020.10.023· OSTI ID:1816211

Liu, Hejun ^[1]; Wu, Nicholas C. ^[2]; Yuan, Meng ^[2]; Bangaru, Sandhya ^[2]; Torres, Jonathan L. ^[2]; Caniels, Tom G. ^[3]; van Schooten, Jelle ^[3]; Zhu, Xueyong ^[2]; Lee, Chang-Chun D. ^[2]; Brouwer, Philip J. M. ^[3]; van Gils, Marit J. ^[3]; Sanders, Rogier W. ^[4]; Ward, Andrew B. ^[5]; Wilson, Ian A. ^[6]

The Scripps Research Inst., La Jolla, CA (United States). Dept. of Integrative Structural and Computational Biology; OSTI
The Scripps Research Inst., La Jolla, CA (United States). Dept. of Integrative Structural and Computational Biology
Univ. of Amsterdam (Netherlands). Amsterdam UMC. Dept. of Medical Microbiology
Univ. of Amsterdam (Netherlands). Amsterdam UMC. Dept. of Medical Microbiology; Cornell Univ., Ithaca, NY (United States). Weill Medical College. Dept. of Microbiology and Immunology
The Scripps Research Inst., La Jolla, CA (United States). Dept. of Integrative Structural and Computational Biology; The Scripps Research Inst., La Jolla, CA (United States). IAVI Neutralizing Antibody Center; The Scripps Research Inst., La Jolla, CA (United States). Consortium for HIV/AIDS Vaccine Development (CHAVD)
The Scripps Research Inst., La Jolla, CA (United States). Dept. of Integrative Structural and Computational Biology. IAVI Neutralizing Antibody Center. Consortium for HIV/AIDS Vaccine Development (CHAVD). The Skaggs Institute for Chemical Biology

Most antibodies isolated from individuals with coronavirus disease 2019 (COVID-19) are specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, COVA1-16 is a relatively rare antibody that also cross-neutralizes SARS-CoV. Here, we determined a crystal structure of the COVA1-16 antibody fragment (Fab) with the SARS-CoV-2 receptor-binding domain (RBD) and negative-stain electron microscopy reconstructions with the spike glycoprotein trimer to elucidate the structural basis of its cross-reactivity. COVA1-16 binds a highly conserved epitope on the SARS-CoV-2 RBD, mainly through a long complementarity-determining region (CDR) H3, and competes with the angiotensin-converting enzyme 2 (ACE2) receptor because of steric hindrance rather than epitope overlap. COVA1-16 binds to a flexible up conformation of the RBD on the spike and relies on antibody avidity for neutralization. These findings, along with the structural and functional rationale for epitope conservation, provide insights for development of more universal SARS-like coronavirus vaccines and therapies.

View Accepted Manuscript (DOE)

Research Organization:: The Scripps Research Inst., La Jolla, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1816211

Journal Information:: Immunity, Journal Name: Immunity Journal Issue: 6 Vol. 53; ISSN 1074-7613

Publisher:: Cell PressCopyright Statement

Country of Publication:: United States

Language:: English

References (67)

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
Shape Complementarity at Protein/Protein Interfaces Lawrence, Michael C.; Colman, Peter M. Journal of Molecular Biology, Vol. 234, Issue 4 https://doi.org/10.1006/jmbi.1993.1648	journal	December 1993
[20] Processing of X-ray diffraction data collected in oscillation mode Otwinowski, Zbyszek; Minor, Wladek Macromolecular Crystallography Part A, 307-326 https://doi.org/10.1016/S0076-6879(97)76066-X	book	January 1997
Antibodies to a Conserved Influenza Head Interface Epitope Protect by an IgG Subtype-Dependent Mechanism Watanabe, Akiko; McCarthy, Kevin R.; Kuraoka, Masayuki Cell, Vol. 177, Issue 5 https://doi.org/10.1016/j.cell.2019.03.048	journal	May 2019
A Site of Vulnerability on the Influenza Virus Hemagglutinin Head Domain Trimer Interface Bangaru, Sandhya; Lang, Shanshan; Schotsaert, Michael Cell, Vol. 177, Issue 5 https://doi.org/10.1016/j.cell.2019.04.011	journal	May 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
Structural Basis for Potent Neutralization of Betacoronaviruses by Single-Domain Camelid Antibodies Wrapp, Daniel; De Vlieger, Dorien; Corbett, Kizzmekia S. Cell, Vol. 181, Issue 5 https://doi.org/10.1016/j.cell.2020.04.031	journal	May 2020
Potent Neutralizing Antibodies against SARS-CoV-2 Identified by High-Throughput Single-Cell Sequencing of Convalescent Patients’ B Cells Cao, Yunlong; Su, Bin; Guo, Xianghua Cell, Vol. 182, Issue 1 https://doi.org/10.1016/j.cell.2020.05.025	journal	July 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
Molecular Architecture of the SARS-CoV-2 Virus Yao, Hangping; Song, Yutong; Chen, Yong Cell, Vol. 183, Issue 3 https://doi.org/10.1016/j.cell.2020.09.018	journal	October 2020
Cross-reactive Antibody Response between SARS-CoV-2 and SARS-CoV Infections Lv, Huibin; Wu, Nicholas C.; Tsang, Owen Tak-Yin Cell Reports, Vol. 31, Issue 9 https://doi.org/10.1016/j.celrep.2020.107725	journal	June 2020
An Alternative Binding Mode of IGHV3-53 Antibodies to the SARS-CoV-2 Receptor Binding Domain Wu, Nicholas C.; Yuan, Meng; Liu, Hejun Cell Reports, Vol. 33, Issue 3 https://doi.org/10.1016/j.celrep.2020.108274	journal	October 2020
Influenza Antigen Engineering Focuses Immune Responses to a Subdominant but Broadly Protective Viral Epitope Bajic, Goran; Maron, Max J.; Adachi, Yu Cell Host & Microbe, Vol. 25, Issue 6 https://doi.org/10.1016/j.chom.2019.04.003	journal	June 2019
Neutralization of SARS-CoV-2 by Destruction of the Prefusion Spike Huo, Jiandong; Zhao, Yuguang; Ren, Jingshan Cell Host & Microbe, Vol. 28, Issue 3 https://doi.org/10.1016/j.chom.2020.06.010	journal	September 2020
Innovations in structure-based antigen design and immune monitoring for next generation vaccines Ward, Andrew B.; Wilson, Ian A. Current Opinion in Immunology, Vol. 65 https://doi.org/10.1016/j.coi.2020.03.013	journal	August 2020
Analysis of a SARS-CoV-2-Infected Individual Reveals Development of Potent Neutralizing Antibodies with Limited Somatic Mutation Seydoux, Emilie; Homad, Leah J.; MacCamy, Anna J. Immunity, Vol. 53, Issue 1 https://doi.org/10.1016/j.immuni.2020.06.001	journal	July 2020
Inference of Macromolecular Assemblies from Crystalline State Krissinel, Evgeny; Henrick, Kim Journal of Molecular Biology, Vol. 372, Issue 3 https://doi.org/10.1016/j.jmb.2007.05.022	journal	September 2007
Cryo-EM Structure of Full-length HIV-1 Env Bound With the Fab of Antibody PG16 Pan, Junhua; Peng, Hanqin; Chen, Bing Journal of Molecular Biology, Vol. 432, Issue 4 https://doi.org/10.1016/j.jmb.2019.11.028	journal	February 2020
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
Appion: An integrated, database-driven pipeline to facilitate EM image processing Lander, Gabriel C.; Stagg, Scott M.; Voss, Neil R. Journal of Structural Biology, Vol. 166, Issue 1 https://doi.org/10.1016/j.jsb.2009.01.002	journal	April 2009
DoG Picker and TiltPicker: Software tools to facilitate particle selection in single particle electron microscopy Voss, N. R.; Yoshioka, C. K.; Radermacher, M. Journal of Structural Biology, Vol. 166, Issue 2 https://doi.org/10.1016/j.jsb.2009.01.004	journal	May 2009
Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9 McLellan, Jason S.; Pancera, Marie; Carrico, Chris Nature, Vol. 480, Issue 7377 https://doi.org/10.1038/nature10696	journal	November 2011
Cross-neutralization of influenza A viruses mediated by a single antibody loop Ekiert, Damian C.; Kashyap, Arun K.; Steel, John Nature, Vol. 489, Issue 7417 https://doi.org/10.1038/nature11414	journal	September 2012
Computational design of trimeric influenza-neutralizing proteins targeting the hemagglutinin receptor binding site Strauch, Eva-Maria; Bernard, Steffen M.; La, David Nature Biotechnology, Vol. 35, Issue 7 https://doi.org/10.1038/nbt.3907	journal	June 2017
A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence Menachery, Vineet D.; Yount, Boyd L.; Debbink, Kari Nature Medicine, Vol. 21, Issue 12 https://doi.org/10.1038/nm.3985	journal	November 2015
Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses Letko, Michael; Marzi, Andrea; Munster, Vincent Nature Microbiology, Vol. 5, Issue 4 https://doi.org/10.1038/s41564-020-0688-y	journal	February 2020
A pneumonia outbreak associated with a new coronavirus of probable bat origin Zhou, Peng; Yang, Xing-Lou; Wang, Xian-Guang Nature, Vol. 579, Issue 7798 https://doi.org/10.1038/s41586-020-2012-7	journal	February 2020
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
Human neutralizing antibodies elicited by SARS-CoV-2 infection Ju, Bin; Zhang, Qi; Ge, Jiwan Nature, Vol. 584, Issue 7819 https://doi.org/10.1038/s41586-020-2380-z	journal	May 2020
A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2 Shi, Rui; Shan, Chao; Duan, Xiaomin Nature, Vol. 584, Issue 7819 https://doi.org/10.1038/s41586-020-2381-y	journal	May 2020
Convergent antibody responses to SARS-CoV-2 in convalescent individuals Robbiani, Davide F.; Gaebler, Christian; Muecksch, Frauke Nature, Vol. 584, Issue 7821 https://doi.org/10.1038/s41586-020-2456-9	journal	June 2020
Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike Liu, Lihong; Wang, Pengfei; Nair, Manoj S. Nature, Vol. 584, Issue 7821 https://doi.org/10.1038/s41586-020-2571-7	journal	July 2020
Structures and distributions of SARS-CoV-2 spike proteins on intact virions Ke, Zunlong; Oton, Joaquin; Qu, Kun Nature, Vol. 588, Issue 7838 https://doi.org/10.1038/s41586-020-2665-2	journal	August 2020
Rapid isolation and profiling of a diverse panel of human monoclonal antibodies targeting the SARS-CoV-2 spike protein Zost, Seth J.; Gilchuk, Pavlo; Chen, Rita E. Nature Medicine, Vol. 26, Issue 9 https://doi.org/10.1038/s41591-020-0998-x	journal	July 2020
Structural insights into the design of novel anti-influenza therapies Wu, Nicholas C.; Wilson, Ian A. Nature Structural & Molecular Biology, Vol. 25, Issue 2 https://doi.org/10.1038/s41594-018-0025-9	journal	February 2018
Structural basis for the neutralization of SARS-CoV-2 by an antibody from a convalescent patient Zhou, Daming; Duyvesteyn, Helen M. E.; Chen, Cheng-Pin Nature Structural & Molecular Biology, Vol. 27, Issue 10 https://doi.org/10.1038/s41594-020-0480-y	journal	July 2020
Heterosubtypic antibody recognition of the influenza virus hemagglutinin receptor binding site enhanced by avidity Lee, P. S.; Yoshida, R.; Ekiert, D. C. Proceedings of the National Academy of Sciences, Vol. 109, Issue 42 https://doi.org/10.1073/pnas.1212371109	journal	October 2012
Cell entry mechanisms of SARS-CoV-2 Shang, Jian; Wan, Yushun; Luo, Chuming Proceedings of the National Academy of Sciences, Vol. 117, Issue 21 https://doi.org/10.1073/pnas.2003138117	journal	May 2020
Altered Dimer Interface Decreases Stability in an Amyloidogenic Protein Baden, Elizabeth M.; Owen, Barbara A. L.; Peterson, Francis C. Journal of Biological Chemistry, Vol. 283, Issue 23 https://doi.org/10.1074/jbc.M705347200	journal	April 2008
Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody Tian, Xiaolong; Li, Cheng; Huang, Ailing Emerging Microbes & Infections, Vol. 9, Issue 1 https://doi.org/10.1080/22221751.2020.1729069	journal	January 2020
Measuring SARS-CoV-2 neutralizing antibody activity using pseudotyped and chimeric viruses Schmidt, Fabian; Weisblum, Yiska; Muecksch, Frauke Journal of Experimental Medicine, Vol. 217, Issue 11 https://doi.org/10.1084/jem.20201181	journal	July 2020
MUSCLE: multiple sequence alignment with high accuracy and high throughput Edgar, R. C. Nucleic Acids Research, Vol. 32, Issue 5, p. 1792-1797 https://doi.org/10.1093/nar/gkh340	journal	March 2004
ConSurf 2016: an improved methodology to estimate and visualize evolutionary conservation in macromolecules Ashkenazy, Haim; Abadi, Shiran; Martz, Eric Nucleic Acids Research, Vol. 44, Issue W1 https://doi.org/10.1093/nar/gkw408	journal	May 2016
WebLogo: A Sequence Logo Generator Crooks, Gavin E.; Hon, Gary; Chandonia, John-Marc Genome Research, Vol. 14, Issue 6, p. 1188-1190 https://doi.org/10.1101/gr.849004	journal	May 2004
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
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
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
A Highly Conserved Neutralizing Epitope on Group 2 Influenza A Viruses Ekiert, D. C.; Friesen, R. H. E.; Bhabha, G. Science, Vol. 333, Issue 6044 https://doi.org/10.1126/science.1204839	journal	July 2011
A Neutralizing Antibody Selected from Plasma Cells That Binds to Group 1 and Group 2 Influenza A Hemagglutinins Corti, D.; Voss, J.; Gamblin, S. J. Science, Vol. 333, Issue 6044 https://doi.org/10.1126/science.1205669	journal	July 2011
Potent peptidic fusion inhibitors of influenza virus Kadam, Rameshwar U.; Juraszek, Jarek; Brandenburg, Boerries Science, Vol. 358, Issue 6362 https://doi.org/10.1126/science.aan0516	journal	September 2017
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
Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2 Yan, Renhong; Zhang, Yuanyuan; Li, Yaning Science, Vol. 367, Issue 6485 https://doi.org/10.1126/science.abb2762	journal	March 2020
Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period Kissler, Stephen M.; Tedijanto, Christine; Goldstein, Edward Science, Vol. 368, Issue 6493 https://doi.org/10.1126/science.abb5793	journal	April 2020
A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV Yuan, Meng; Wu, Nicholas C.; Zhu, Xueyong Science, Vol. 368, Issue 6491 https://doi.org/10.1126/science.abb7269	journal	April 2020
Site-specific glycan analysis of the SARS-CoV-2 spike Watanabe, Yasunori; Allen, Joel D.; Wrapp, Daniel Science, Vol. 369, Issue 6501 https://doi.org/10.1126/science.abb9983	journal	May 2020
A noncompeting pair of human neutralizing antibodies block COVID-19 virus binding to its receptor ACE2 Wu, Yan; Wang, Feiran; Shen, Chenguang Science, Vol. 368, Issue 6496 https://doi.org/10.1126/science.abc2241	journal	May 2020
Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability Brouwer, Philip J. M.; Caniels, Tom G.; van der Straten, Karlijn Science, Vol. 369, Issue 6504 https://doi.org/10.1126/science.abc5902	journal	June 2020
A neutralizing human antibody binds to the N-terminal domain of the Spike protein of SARS-CoV-2 Chi, Xiangyang; Yan, Renhong; Zhang, Jun Science, Vol. 369, Issue 6504 https://doi.org/10.1126/science.abc6952	journal	June 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
Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model Rogers, Thomas F.; Zhao, Fangzhu; Huang, Deli Science, Vol. 369, Issue 6506 https://doi.org/10.1126/science.abc7520	journal	June 2020
Structural basis of a shared antibody response to SARS-CoV-2 Yuan, Meng; Liu, Hejun; Wu, Nicholas C. Science, Vol. 369, Issue 6507 https://doi.org/10.1126/science.abd2321	journal	July 2020
Human Monoclonal Antibody Combination against SARS Coronavirus: Synergy and Coverage of Escape Mutants ter Meulen, Jan; van den Brink, Edward N.; Poon, Leo L. M. PLoS Medicine, Vol. 3, Issue 7 https://doi.org/10.1371/journal.pmed.0030237	journal	July 2006
Crystal Structure of an Anti-Ang2 CrossFab Demonstrates Complete Structural and Functional Integrity of the Variable Domain Fenn, Sebastian; Schiller, Christian B.; Griese, Julia J. PLoS ONE, Vol. 8, Issue 4 https://doi.org/10.1371/journal.pone.0061953	journal	April 2013
Few and Far Between: How HIV May Be Evading Antibody Avidity Klein, Joshua S.; Bjorkman, Pamela J. PLoS Pathogens, Vol. 6, Issue 5 https://doi.org/10.1371/journal.ppat.1000908	journal	May 2010
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

Cited By (3)

Additional file 2 of Comprehensive mapping of binding hot spots of SARS-CoV-2 RBD-specific neutralizing antibodies for tracking immune escape variants Yi, Chunyan; Sun, Xiaoyu; Lin, Yixiao figshare https://doi.org/10.6084/m9.figshare.16815702	dataset	January 2021
Additional file 3 of Comprehensive mapping of binding hot spots of SARS-CoV-2 RBD-specific neutralizing antibodies for tracking immune escape variants Yi, Chunyan; Sun, Xiaoyu; Lin, Yixiao figshare https://doi.org/10.6084/m9.figshare.16815705	dataset	January 2021
Additional file 4 of Comprehensive mapping of binding hot spots of SARS-CoV-2 RBD-specific neutralizing antibodies for tracking immune escape variants Yi, Chunyan; Sun, Xiaoyu; Lin, Yixiao figshare https://doi.org/10.6084/m9.figshare.16815708	dataset	January 2021

Similar Records

Structures of Human Antibodies Bound to SARS-CoV-2 Spike Reveal Common Epitopes and Recurrent Features of Antibodies

Journal Article · Tue Jun 23 20:00:00 EDT 2020 · Cell · OSTI ID:1816377

Structural basis of a shared antibody response to SARS-CoV-2

Journal Article · Sun Jul 12 20:00:00 EDT 2020 · Science · OSTI ID:1816389

Related Subjects

59 BASIC BIOLOGICAL SCIENCES

Cross-Neutralization of a SARS-CoV-2 Antibody to a Functionally Conserved Site Is Mediated by Avidity

Citation Formats

References (67)

Cited By (3)

Similar Records

Related Subjects