A structure-function analysis shows SARS-CoV-2 BA.2.86 balances antibody escape and ACE2 affinity

Chang Liu; Daming Zhou; Aiste Dijokaite-Guraliuc; Piyada Supasa; Helen M E Duyvesteyn; Helen M Ginn; Muneeswaran Selvaraj; Alexander J Mentzer; Raksha Das; Thushan I de Silva; Thomas G Ritter; Megan Plowright; Thomas A H Newman; Lizzie Stafford; Barbara Kronsteiner; Nigel Temperton; Yuan Lui; Martin Fellermeyer; Philip Goulder; Paul Klenerman; Susanna J Dunachie; Michael I Barton; Mikhail A Kutuzov; Omer Dushek; OPTIC Consortium; Elizabeth E Fry; Juthathip Mongkolsapaya; Jingshan Ren; David I Stuart; Gavin R Screaton

doi:10.1016/j.xcrm.2024.101553

A structure-function analysis shows SARS-CoV-2 BA.2.86 balances antibody escape and ACE2 affinity

Cell Rep Med. 2024 May 21;5(5):101553. doi: 10.1016/j.xcrm.2024.101553. Epub 2024 May 8.

Authors

Chang Liu¹, Daming Zhou², Aiste Dijokaite-Guraliuc³, Piyada Supasa⁴, Helen M E Duyvesteyn⁵, Helen M Ginn⁶, Muneeswaran Selvaraj⁴, Alexander J Mentzer⁷, Raksha Das⁴, Thushan I de Silva⁸, Thomas G Ritter⁹, Megan Plowright¹⁰, Thomas A H Newman¹⁰, Lizzie Stafford⁹, Barbara Kronsteiner¹¹, Nigel Temperton¹², Yuan Lui¹³, Martin Fellermeyer¹³, Philip Goulder¹⁴, Paul Klenerman¹⁵, Susanna J Dunachie¹⁶, Michael I Barton¹⁷, Mikhail A Kutuzov¹⁷, Omer Dushek¹⁷; OPTIC Consortium; Elizabeth E Fry¹⁸, Juthathip Mongkolsapaya¹⁹, Jingshan Ren²⁰, David I Stuart²¹, Gavin R Screaton²²

Affiliations

¹ Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK; Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
² Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK; Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, Centre for Human Genetics, Oxford, UK.
³ Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
⁴ Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK.
⁵ Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, Centre for Human Genetics, Oxford, UK.
⁶ Centre for Free Electron Laser Science, Hamburg, Germany.
⁷ Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
⁸ Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK; Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
⁹ NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
¹⁰ Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
¹¹ NDM Centre for Global Health Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK.
¹² Viral Pseudotype Unit, Medway School of Pharmacy, University of Kent and University of Greenwich Chatham Maritime, Kent ME4 4TB, UK.
¹³ Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
¹⁴ Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK; Department of Paediatrics, University of Oxford, Oxford, UK.
¹⁵ NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK; Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
¹⁶ NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; NDM Centre for Global Health Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK; Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand.
¹⁷ Diamond Light Source Ltd, Harwell Science & Innovation Campus, Didcot, UK.
¹⁸ Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, Centre for Human Genetics, Oxford, UK. Electronic address: liz@strubi.ox.ac.uk.
¹⁹ Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK; Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand. Electronic address: juthathip.mongkolsapaya@well.ox.ac.uk.
²⁰ Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, Centre for Human Genetics, Oxford, UK. Electronic address: ren@strubi.ox.ac.uk.
²¹ Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK; Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, Centre for Human Genetics, Oxford, UK; Sir William Dunn School of Pathology, Oxford, UK. Electronic address: dave@strubi.ox.ac.uk.
²² Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK; Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK. Electronic address: gavin.screaton@medsci.ox.ac.uk.

Abstract

BA.2.86, a recently described sublineage of SARS-CoV-2 Omicron, contains many mutations in the spike gene. It appears to have originated from BA.2 and is distinct from the XBB variants responsible for many infections in 2023. The global spread and plethora of mutations in BA.2.86 has caused concern that it may possess greater immune-evasive potential, leading to a new wave of infection. Here, we examine the ability of BA.2.86 to evade the antibody response to infection using a panel of vaccinated or naturally infected sera and find that it shows marginally less immune evasion than XBB.1.5. We locate BA.2.86 in the antigenic landscape of recent variants and look at its ability to escape panels of potent monoclonal antibodies generated against contemporary SARS-CoV-2 infections. We demonstrate, and provide a structural explanation for, increased affinity of BA.2.86 to ACE2, which may increase transmissibility.

Keywords: ACE2 binding; BA.2.65; SARS-CoV-2; antigenic escape; coronavirus; receptor binding; virus evolution; virus structure.

MeSH terms

Angiotensin-Converting Enzyme 2* / chemistry
Angiotensin-Converting Enzyme 2* / metabolism
Antibodies, Monoclonal / immunology
Antibodies, Neutralizing / immunology
Antibodies, Viral* / immunology
Antibody Affinity
COVID-19* / immunology
COVID-19* / virology
Humans
Immune Evasion*
Mutation / genetics
SARS-CoV-2* / genetics
SARS-CoV-2* / immunology
SARS-CoV-2* / metabolism
Spike Glycoprotein, Coronavirus* / chemistry
Spike Glycoprotein, Coronavirus* / genetics
Spike Glycoprotein, Coronavirus* / immunology
Spike Glycoprotein, Coronavirus* / metabolism
Structure-Activity Relationship

Substances

Angiotensin-Converting Enzyme 2
Antibodies, Viral
Spike Glycoprotein, Coronavirus
ACE2 protein, human
spike protein, SARS-CoV-2
Antibodies, Monoclonal
Antibodies, Neutralizing

Supplementary concepts

SARS-CoV-2 variants