The antigenic anatomy of SARS-CoV-2 receptor binding domain

10.1016/j.cell.2021.02.032

Cell

18th February 2021

Contributing to research themes:

Antibodies are crucial to immune protection against SARS-CoV-2, with some in emergency use as therapeutics. Here, we identify 377 human monoclonal antibodies (mAbs) recognizing the virus spike and focus mainly on 80 that bind the receptor binding domain (RBD). We devise a competition data-driven method to map RBD binding sites. We find that although antibody binding sites are widely dispersed, neutralizing antibody binding is focused, with nearly all highly inhibitory mAbs (IC50 < 0.1 μg/mL) blocking receptor interaction, except for one that binds a unique epitope in the N-terminal domain. Many of these neutralizing mAbs use public V-genes and are close to germline. We dissect the structural basis of recognition for this large panel of antibodies through X-ray crystallography and cryoelectron microscopy of 19 Fab-antigen structures. We find novel binding modes for some potently inhibitory antibodies and demonstrate that strongly neutralizing mAbs protect, prophylactically or therapeutically, in animal models.

Author list:

Affiliations:

Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford OX3 7BN, UK
Department of Medicine, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, USA
Oxford University Hospitals NHS Foundation Trust, Oxford, UK
Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford, Oxford OX3 7FZ, UK
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, USA
Peter Medawar Building for Pathogen Research, Oxford OX1 3SY, UK
Department of Zoology, University of Oxford, Oxford OX1 3SZ, UK
MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK
Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
National Infection Service, Public Health England (PHE), Porton Down, Salisbury SP4 0JG, UK
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK
Department of Paediatrics, Oxford Vaccine Group, University of Oxford, Oxford OX3 7LE, UK
NIHR Oxford Biomedical Research Centre, Oxford OX3 9DU, UK
Worthing Hospital, Worthing BN11 2DH, UK
Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK
Viral Pseudotype Unit, Medway School of Pharmacy, University of Kent, Chatham ME4 4TB, UK
Diamond Light Source Ltd, Harwell Science & Innovation Campus, Didcot OX11 0DE, UK
Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan, Taiwan
Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan
Siriraj Center of Research Excellence in Dengue & Emerging Pathogens, Dean Office for Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Thailand
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, USA
The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, St. Louis, MO 63110 USA
Instruct-ERIC, Oxford House, Parkway Court, John Smith Drive, Oxford OX4 2JY, UK

Authors:

Wanwisa Dejnirattisai,^1,25 Daming Zhou,^2,25 Helen M. Ginn,^18,25 Helen M.E. Duyvesteyn,^2,25 Piyada Supasa,¹
James Brett Case,³ Yuguang Zhao,² Thomas S. Walter,² Alexander J. Mentzer,^1,4 Chang Liu,^1,5 Beibei Wang,¹
Guido C. Paesen,²Jose Slon-Campos,¹ César López-Camacho,¹ Natasha M. Kafai,^3,6 Adam L. Bailey,6 Rita E. Chen,^3,6 Baoling Ying,³ Craig Thompson,^7,8 Jai Bolton,⁸ Alex Fyfe,^7,8 Sunetra Gupta,^7,8Tiong Kit Tan,⁹ Javier Gilbert-Jaramillo,¹⁰ William James,¹⁰ Michael Knight,¹⁰ Miles W. Carroll,^1,11 Donal Skelly,^4,12 Christina Dold,^13,14 Yanchun Peng,⁹ Robert Levin,¹⁵ Tao Dong,^5,9,16 Andrew J. Pollard,^4,13,14 Julian C. Knight,^1,4 Paul Klenerman,^4,7,14,16 Nigel Temperton,¹⁷ David R. Hall,¹⁸ Mark A. Williams,¹⁸ Neil G. Paterson,¹⁸ Felicity K.R. Bertram,¹⁸ C. Alistair Siebert,¹⁸ Daniel K. Clare,¹⁸ Andrew Howe,¹⁸ Julika Radecke,¹⁸ Yun Song,¹⁸ Alain R. Townsend,^5,9 Kuan-Ying A. Huang,^19,20 Elizabeth E. Fry,² Juthathip Mongkolsapaya,^1,5,21,* Michael S. Diamond,^3,6,22,23,* Jingshan Ren,²,* David I. Stuart,^2,5,18,24,26,* and
Gavin R. Screaton^1,4,*