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­­­The Antigenic Anatomy of SARS-CoV-2 Receptor Binding Domain

87 Pages Posted: 23 Dec 2020 Publication Status: Published

See all articles by Wanwisa Dejnirattisai

Wanwisa Dejnirattisai

University of Oxford - Wellcome Centre for Human Genetics

Daming Zhou

University of Oxford - Division of Structural Biology

Helen M. Ginn

University of Oxford - Division of Structural Biology

Helen ME Duyvesteyn

University of Oxford - Division of Structural Biology

Piyada Supasa

University of Oxford - Wellcome Centre for Human Genetics

James Brett Case

Washington University in St. Louis - Department of Medicine

Yuguang Zhao

University of Oxford - Division of Structural Biology

Thomas S. Walter

University of Oxford - Division of Structural Biology

Alexander J. Mentzer

University of Oxford - Wellcome Trust Centre for Human Genetics; University of Oxford - Li Ka Shing Centre for Health Information and Discovery

Chang Liu

University of Oxford - Wellcome Centre for Human Genetics

Beibei Wang

University of Oxford - Wellcome Centre for Human Genetics

Guido C. Paesen

University of Oxford - Division of Structural Biology

Jose Slon-Campos

University of Oxford - Wellcome Centre for Human Genetics

Cesar Lopez-Camacho

University of Oxford - Wellcome Centre for Human Genetics

Natasha M. Kafai

Washington University in St. Louis - Department of Medicine

Adam L. Bailey

Washington University in St. Louis - Department of Pathology and Immunology

Rita E. Chen

Washington University in St. Louis - Department of Medicine

Baoling Ying

Washington University in St. Louis - Department of Medicine

Craig P. Thompson

University of Oxford - Peter Medawar Building for Pathogen Research

Alex Fyfe

University of Oxford - Peter Medawar Building for Pathogen Research

Sunetra Gupta

University of Oxford - Department of Zoology

Tiong Tan

University of Oxford - MRC Human Immunology Unit

Javier Gilbert-Jaramillo

University of Oxford - Sir William Dunn School of Pathology

William James

University of Oxford - Sir William Dunn School of Pathology

Karen Buttigieg

Public Health England - National Infection Service

Naomi Coombes

Public Health England - National Infection Service

Miles W. Carroll

University of Oxford - Wellcome Centre for Human Genetics

Donal Skelly

University of Oxford - Nuffield Department of Clinical Neurosciences; Oxford University Hospitals NHS Foundation Trust

Christina Dold

University of Oxford - Oxford Vaccine Group

Yanchun Peng

University of Oxford - Chinese Academy of Medical Science Oxford Institute (COI)

Robert Levin

Worthing Hospital

Tao Dong

University of Oxford - Chinese Academy of Medical Science Oxford Institute (COI)

Andrew Pollard

University of Oxford - Oxford Vaccine Group

Julian Knight

University of Oxford - Wellcome Centre for Human Genetics

Paul Klenerman

University of Oxford - Peter Medawar Building for Pathogen Research

Nigel Temperton

University of Kent - Viral Pseudotype Unit

David R. Hall

Diamond Light Source - Harwell Science and Innovation Campus

Mark A. Williams

Diamond Light Source - Harwell Science and Innovation Campus

Neil G. Paterson

Diamond Light Source - Harwell Science and Innovation Campus

Felicity K.R. Bertram

Diamond Light Source - Harwell Science and Innovation Campus

C. Alistair Seibert

Diamond Light Source - Harwell Science and Innovation Campus

Daniel K. Clare

Diamond Light Source - Harwell Science and Innovation Campus

Andrew Howe

Diamond Light Source - Harwell Science and Innovation Campus

Julika Raedecke

Diamond Light Source - Harwell Science and Innovation Campus

Yun Song

Diamond Light Source - Harwell Science and Innovation Campus

Alain Townsend

University of Oxford - MRC Human Immunology Unit

Kuan-Ying A. Huang

Chang Gung University - Research Center for Emerging Viral Infections

Elizabeth E. Fry

University of Oxford - Division of Structural Biology

Juthathip Mongkolspaya

University of Oxford - Wellcome Centre for Human Genetics

Michael S. Diamond

Washington University in St. Louis - Department of Medicine

Jingshan Ren

University of Oxford - Division of Structural Biology

David I. Stuart

University of Oxford - Division of Structural Biology

Gavin R. Screaton

University of Oxford - Wellcome Centre for Human Genetics

More...

Abstract

Antibodies are crucial to immune protection against SARS-CoV-2 with some in emergency use as therapeutics. Here we identified 377 human monoclonal antibodies (mAbs) recognizing the viral spike, and focused on 80 which bind the receptor binding domain (RBD). By mapping antigenic sites using a unique computational methodology and comparing with inhibitory activity, we show that binding sites are widely dispersed, but neutralizing epitopes highly focused. Nearly all highly potent neutralizing mAbs (IC50< 0.1mg/ml) block receptor interaction, although one binds a unique epitope in the N-terminal domain. Many mAbs use public V-genes and are close to germline, boding well for vaccine responses. 19 Fab-antigen structures, some as RBD complexed with two Fabs, reveal two novel modes of engagement for potently inhibitory mAbs. Several Fabs are glycosylated, enhancing neutralisation for three, for two of which the sugar contacts the antigen. The most potent mAbs protect, prophylactically or therapeutically, in animal models.

Ethical Approval: Patients were recruited into the Sepsis Immunomics project [Oxford REC
C, reference:19/SC/0296] ISARIC/WHO Clinical Characterisation Protocol
for Severe Emerging Infections [Oxford REC C, reference 13/SC/0149].

Animal studies were carried out in accordance with the recommendations
in the Guide for the Care and Use of Laboratory Animals of the
National Institutes of Health. The protocols were approved by the
Institutional Animal Care and Use Committee at the Washington
University School of Medicine (assurance number A3381–01).


Funding: The Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science (CIFMS), China (ID: 2018-I2M-2-002); Medical Research Council, UK. National Institute for Health Research Biomedical Research Centre Funding Scheme (to G.R.S.), the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science (CIFMS), China (grant number: 2018-I2M-2-002) to D.I.S. and G.R.S., and G.R.S. is supported as a Wellcome Trust Senior Investigator (grant 095541/A/11/Z). H.M.E.D. and J.Ren are supported by the Wellcome Trust (101122/Z/13/Z), Y.Z. by Cancer Research UK (C375/A17721) and D.I.S. by the UK Medical Research Council (MR/N00065X/1). D.I.S. and GRS are Jenner Investigators. N.M.K is supported by T32AI007172. The National Institute for Health Research Biomedical Research Centre Funding Scheme supports G.R.S. We are also grateful for a Fast Grant from Fast Grants, Mercatus Center to support the isolation of human monoclonal antibodies to SARS-2 and Schmidt Futures for support of this work. G.R.S. is also supported as a Wellcome Trust Senior Investigator (grant 095541/A/11/Z). This is a contribution from the UK Instruct-ERIC Centre. The Wellcome Centre for Human Genetics is supported by the Wellcome Trust (grant 090532/Z/09/Z). We acknowledge Diamond Light Source for time on Beamline I03 under Proposal lb27009 and for electron microscope time at the UK national electron bio-imaging centre (eBIC), Proposal BI26983. Computational aspects were supported by the Wellcome Trust Core Award Grant Number 203141/Z/16/Z and the NIHR Oxford BRC. This study was supported by grants from NIH (R01 AI157155) and the Defense Advanced Research Project Agency (HR001117S0019). J.B.C. is supported by a Helen Hay Whitney Foundation postdoctoral fellowship.

Competing Interest: M.S.D. is a consultant for Inbios, Vir Biotechnology, NGM
Biopharmaceuticals, Carnival Corporation and on the Scientific Advisory Boards of Moderna and Immunome. The M.S.D. laboratory has received unrelated funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. GRS sits
on the GSK Vaccines Scientific Advisory Board.

Keywords: SARS-CoV-2, antibody, germline, V-gene, receptor-binding-domain, spike, neutralisation, protection, glycosylation, valency

Suggested Citation

Dejnirattisai, Wanwisa and Zhou, Daming and Ginn, Helen M. and Duyvesteyn, Helen ME and Supasa, Piyada and Case, James Brett and Zhao, Yuguang and Walter, Thomas S. and Mentzer, Alexander J. and Liu, Chang and Wang, Beibei and Paesen, Guido C. and Slon-Campos, Jose and Lopez-Camacho, Cesar and Kafai, Natasha M. and Bailey, Adam L. and Chen, Rita E. and Ying, Baoling and Thompson, Craig P. and Fyfe, Alex and Gupta, Sunetra and Tan, Tiong and Gilbert-Jaramillo, Javier and James, William and Buttigieg, Karen and Coombes, Naomi and Carroll, Miles W. and Skelly, Donal and Dold, Christina and Peng, Yanchun and Levin, Robert and Dong, Tao and Pollard, Andrew and Knight, Julian and Klenerman, Paul and Temperton, Nigel and Hall, David R. and Williams, Mark A. and Paterson, Neil G. and Bertram, Felicity K.R. and Seibert, C. Alistair and Clare, Daniel K. and Howe, Andrew and Raedecke, Julika and Song, Yun and Townsend, Alain and Huang, Kuan-Ying A. and Fry, Elizabeth E. and Mongkolspaya, Juthathip and Diamond, Michael S. and Ren, Jingshan and Stuart, David I. and Screaton, Gavin R., ­­­The Antigenic Anatomy of SARS-CoV-2 Receptor Binding Domain. Available at SSRN: https://ssrn.com/abstract=3754542 or http://dx.doi.org/10.2139/ssrn.3754542
This version of the paper has not been formally peer reviewed.

Wanwisa Dejnirattisai

University of Oxford - Wellcome Centre for Human Genetics ( email )

Oxford, OX3 7BN
United Kingdom

Daming Zhou

University of Oxford - Division of Structural Biology

United Kingdom

Helen M. Ginn

University of Oxford - Division of Structural Biology ( email )

United Kingdom

Helen ME Duyvesteyn

University of Oxford - Division of Structural Biology ( email )

United Kingdom

Piyada Supasa

University of Oxford - Wellcome Centre for Human Genetics ( email )

Oxford, OX3 7BN
United Kingdom

James Brett Case

Washington University in St. Louis - Department of Medicine ( email )

St. Louis, MO 63110
United States

Yuguang Zhao

University of Oxford - Division of Structural Biology ( email )

United Kingdom

Thomas S. Walter

University of Oxford - Division of Structural Biology ( email )

United Kingdom

Alexander J. Mentzer

University of Oxford - Wellcome Trust Centre for Human Genetics

Old Road Campus
Roosevelt Drive
Oxford, OX3 7FZ
United Kingdom

University of Oxford - Li Ka Shing Centre for Health Information and Discovery ( email )

Oxford, OX3 7FZ
United Kingdom

Chang Liu

University of Oxford - Wellcome Centre for Human Genetics

Oxford, OX3 7BN
United Kingdom

Beibei Wang

University of Oxford - Wellcome Centre for Human Genetics

Oxford, OX3 7BN
United Kingdom

Guido C. Paesen

University of Oxford - Division of Structural Biology ( email )

United Kingdom

Jose Slon-Campos

University of Oxford - Wellcome Centre for Human Genetics ( email )

Oxford, OX3 7BN
United Kingdom

Cesar Lopez-Camacho

University of Oxford - Wellcome Centre for Human Genetics ( email )

Oxford, OX3 7BN
United Kingdom

Natasha M. Kafai

Washington University in St. Louis - Department of Medicine ( email )

St. Louis, MO 63110
United States

Adam L. Bailey

Washington University in St. Louis - Department of Pathology and Immunology ( email )

One Brookings Drive
Campus Box 1208
Saint Louis, MO 63130-4899
United States

Rita E. Chen

Washington University in St. Louis - Department of Medicine ( email )

St. Louis, MO 63110
United States

Baoling Ying

Washington University in St. Louis - Department of Medicine ( email )

St. Louis, MO 63110
United States

Craig P. Thompson

University of Oxford - Peter Medawar Building for Pathogen Research ( email )

South Parks Road
OX2 3SY
United Kingdom

Alex Fyfe

University of Oxford - Peter Medawar Building for Pathogen Research

South Parks Road
OX2 3SY
United Kingdom

Sunetra Gupta

University of Oxford - Department of Zoology ( email )

New Radcliffe House
Radcliffe Observatory Quarter
Oxford, OX13 5QL
United Kingdom

Tiong Tan

University of Oxford - MRC Human Immunology Unit

Oxford, Oxfordshire, England
United Kingdom

Javier Gilbert-Jaramillo

University of Oxford - Sir William Dunn School of Pathology ( email )

South Parks Road
Oxford, OX1 3RE
United Kingdom

William James

University of Oxford - Sir William Dunn School of Pathology

South Parks Road
Oxford, OX1 3RE
United Kingdom

Karen Buttigieg

Public Health England - National Infection Service ( email )

United Kingdom

Naomi Coombes

Public Health England - National Infection Service

United Kingdom

Miles W. Carroll

University of Oxford - Wellcome Centre for Human Genetics ( email )

Oxford, OX3 7BN
United Kingdom

Donal Skelly

University of Oxford - Nuffield Department of Clinical Neurosciences ( email )

Oxford
United Kingdom

Oxford University Hospitals NHS Foundation Trust ( email )

Headley Way
Headington
Oxford, OX3 9DU
United Kingdom

Christina Dold

University of Oxford - Oxford Vaccine Group ( email )

Oxford
United Kingdom

Yanchun Peng

University of Oxford - Chinese Academy of Medical Science Oxford Institute (COI)

United Kingdom

Robert Levin

Worthing Hospital

Tao Dong

University of Oxford - Chinese Academy of Medical Science Oxford Institute (COI) ( email )

United Kingdom

Andrew Pollard

University of Oxford - Oxford Vaccine Group ( email )

United Kingdom

Julian Knight

University of Oxford - Wellcome Centre for Human Genetics ( email )

Oxford, OX3 7BN
United Kingdom

Paul Klenerman

University of Oxford - Peter Medawar Building for Pathogen Research ( email )

South Parks Road
OX2 3SY
United Kingdom

Nigel Temperton

University of Kent - Viral Pseudotype Unit ( email )

CT2 7NP
United Kingdom

David R. Hall

Diamond Light Source - Harwell Science and Innovation Campus ( email )

United Kingdom

Mark A. Williams

Diamond Light Source - Harwell Science and Innovation Campus ( email )

United Kingdom

Neil G. Paterson

Diamond Light Source - Harwell Science and Innovation Campus ( email )

United Kingdom

Felicity K.R. Bertram

Diamond Light Source - Harwell Science and Innovation Campus ( email )

United Kingdom

C. Alistair Seibert

Diamond Light Source - Harwell Science and Innovation Campus ( email )

United Kingdom

Daniel K. Clare

Diamond Light Source - Harwell Science and Innovation Campus ( email )

United Kingdom

Andrew Howe

Diamond Light Source - Harwell Science and Innovation Campus

United Kingdom

Julika Raedecke

Diamond Light Source - Harwell Science and Innovation Campus ( email )

United Kingdom

Yun Song

Diamond Light Source - Harwell Science and Innovation Campus

United Kingdom

Alain Townsend

University of Oxford - MRC Human Immunology Unit ( email )

Oxford, Oxfordshire, England
United Kingdom

Kuan-Ying A. Huang

Chang Gung University - Research Center for Emerging Viral Infections ( email )

Tauyuan
Taiwan

Elizabeth E. Fry

University of Oxford - Division of Structural Biology ( email )

United Kingdom

Juthathip Mongkolspaya

University of Oxford - Wellcome Centre for Human Genetics ( email )

Oxford, OX3 7BN
United Kingdom

Michael S. Diamond

Washington University in St. Louis - Department of Medicine ( email )

St. Louis, MO 63110
United States

Jingshan Ren

University of Oxford - Division of Structural Biology

United Kingdom

David I. Stuart (Contact Author)

University of Oxford - Division of Structural Biology ( email )

United Kingdom

Gavin R. Screaton

University of Oxford - Wellcome Centre for Human Genetics ( email )

Oxford, OX3 7BN
United Kingdom

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