The antibody response to SARS-CoV-2 Beta underscores the antigenic distance to other variants

Chang Liu; Daming Zhou; Rungtiwa Nutalai; Helen M E Duyvesteyn; Aekkachai Tuekprakhon; Helen M Ginn; Wanwisa Dejnirattisai; Piyada Supasa; Alexander J Mentzer; Beibei Wang; James Brett Case; Yuguang Zhao; Donal T Skelly; Rita E Chen; Sile Ann Johnson; Thomas G Ritter; Chris Mason; Tariq Malik; Nigel Temperton; Neil G Paterson; Mark A Williams; David R Hall; Daniel K Clare; Andrew Howe; Philip J R Goulder; Elizabeth E Fry; Michael S Diamond; Juthathip Mongkolsapaya; Jingshan Ren; David I Stuart; Gavin R Screaton

doi:10.1016/j.chom.2021.11.013

The antibody response to SARS-CoV-2 Beta underscores the antigenic distance to other variants

Cell Host Microbe. 2022 Jan 12;30(1):53-68.e12. doi: 10.1016/j.chom.2021.11.013. Epub 2021 Nov 27.

Authors

Chang Liu¹, Daming Zhou², Rungtiwa Nutalai³, Helen M E Duyvesteyn⁴, Aekkachai Tuekprakhon³, Helen M Ginn⁵, Wanwisa Dejnirattisai³, Piyada Supasa³, Alexander J Mentzer⁶, Beibei Wang³, James Brett Case⁴, Yuguang Zhao⁴, Donal T Skelly⁷, Rita E Chen⁸, Sile Ann Johnson⁹, Thomas G Ritter¹⁰, Chris Mason¹⁰, Tariq Malik¹¹, Nigel Temperton¹², Neil G Paterson⁵, Mark A Williams⁵, David R Hall⁵, Daniel K Clare⁵, Andrew Howe⁵, Philip J R Goulder¹³, Elizabeth E Fry⁴, Michael S Diamond¹⁴, Juthathip Mongkolsapaya¹⁵, Jingshan Ren¹⁶, David I Stuart¹⁷, Gavin R Screaton¹⁸

Affiliations

¹ Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Chinese Academy of Medical Science Oxford Institute, University of Oxford, Oxford, UK.
² Chinese Academy of Medical Science Oxford Institute, University of Oxford, Oxford, UK; Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, The Wellcome Centre for Human Genetics, Oxford, UK.
³ Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
⁴ Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, The Wellcome Centre for Human Genetics, Oxford, UK.
⁵ Diamond Light Source Ltd, Harwell Science & Innovation Campus, Didcot, UK.
⁶ Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
⁷ Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
⁸ Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁹ Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
¹⁰ Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
¹¹ National Infection Service, Public Health England (PHE), Porton Down, Salisbury, UK.
¹² Viral Pseudotype Unit, Medway School of Pharmacy, University of Kent and Greenwich, Chatham Maritime, Kent ME4 4TB, UK.
¹³ Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Department of Paediatrics, University of Oxford, Oxford, UK.
¹⁴ Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, 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, MO 63110, USA.
¹⁵ Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Chinese Academy of Medical Science Oxford Institute, University of Oxford, Oxford, UK; Siriraj Center of Research Excellence in Dengue & Emerging Pathogens, Dean Office for Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Electronic address: jmongkol@well.ox.ac.uk.
¹⁶ Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, The Wellcome Centre for Human Genetics, Oxford, UK. Electronic address: ren@strubi.ox.ac.uk.
¹⁷ Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Chinese Academy of Medical Science Oxford Institute, University of Oxford, Oxford, UK; Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, The Wellcome Centre for Human Genetics, Oxford, UK; Diamond Light Source Ltd, Harwell Science & Innovation Campus, Didcot, UK; Instruct-ERIC, Oxford House, Parkway Court, John Smith Drive, Oxford, UK. Electronic address: dave@strubi.ox.ac.uk.
¹⁸ Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Chinese Academy of Medical Science Oxford Institute, University of Oxford, Oxford, UK. Electronic address: gavin.screaton@medsci.ox.ac.uk.

Abstract

Alpha-B.1.1.7, Beta-B.1.351, Gamma-P.1, and Delta-B.1.617.2 variants of SARS-CoV-2 express multiple mutations in the spike protein (S). These may alter the antigenic structure of S, causing escape from natural or vaccine-induced immunity. Beta is particularly difficult to neutralize using serum induced by early pandemic SARS-CoV-2 strains and is most antigenically separated from Delta. To understand this, we generated 674 mAbs from Beta-infected individuals and performed a detailed structure-function analysis of the 27 most potent mAbs: one binding the spike N-terminal domain (NTD), the rest the receptor-binding domain (RBD). Two of these RBD-binding mAbs recognize a neutralizing epitope conserved between SARS-CoV-1 and -2, while 18 target mutated residues in Beta: K417N, E484K, and N501Y. There is a major response to N501Y, including a public IgVH4-39 sequence, with E484K and K417N also targeted. Recognition of these key residues underscores why serum from Beta cases poorly neutralizes early pandemic and Delta viruses.

Keywords: Beta variant; COVID-19; SARS-CoV-2; antibody; immune responses; neutralization; receptor-binding domain; spike protein; structure; vaccine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Monoclonal / immunology
Antibodies, Neutralizing / immunology
Antibodies, Viral / immunology*
Antibody Formation / immunology*
COVID-19 / immunology*
Cells, Cultured
Chlorocebus aethiops
Female
HEK293 Cells
Humans
Male
Mice
Mice, Transgenic
Neutralization Tests / methods
Protein Binding / immunology
SARS-CoV-2 / immunology*
Spike Glycoprotein, Coronavirus / immunology
Vero Cells

The antibody response to SARS-CoV-2 Beta underscores the antigenic distance to other variants

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