PreprintCited by 27SARS-CoV-2 and COVID-19 Researchvaccines and immunoinformatics approachesAnimal Virus Infections Studies

Impact of the B.1.1.7 variant on neutralizing monoclonal antibodies recognizing diverse epitopes on SARS-CoV-2 Spike

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Graham, Carl, Seow, Jeffrey, Huettner, Isabella, Khan, Hataf, Kouphou, Neophytos, Acors, Sam, Winstone, Helena, Pickering, Suzanne +19 more·2021·bioRxiv (Cold Spring Harbor Laboratory)

Abstract

The interaction of the SARS-CoV-2 Spike receptor binding domain (RBD) with the ACE2 receptor on host cells is essential for viral entry. RBD is the dominant target for neutralizing antibodies and several neutralizing epitopes on RBD have been molecularly characterized. Analysis of circulating SARS-CoV-2 variants has revealed mutations arising in the RBD, the N-terminal domain (NTD) and S2 subunits of Spike. To fully understand how these mutations affect the antigenicity of Spike, we have isolated and characterized neutralizing antibodies targeting epitopes beyond the already identified RBD epitopes. Using recombinant Spike as a sorting bait, we isolated >100 Spike-reactive monoclonal antibodies from SARS-CoV-2 infected individuals. ~45% showed neutralizing activity of which ~20% were NTD-specific. None of the S2-specific antibodies showed neutralizing activity. Competition ELISA revealed that NTD-specific mAbs formed two distinct groups: the first group was highly potent against infectious virus, whereas the second was less potent and displayed glycan-dependant neutralization activity. Importantly, mutations present in B.1.1.7 Spike frequently conferred resistance to neutralization by the NTD-specific neutralizing antibodies. This work demonstrates that neutralizing antibodies targeting subdominant epitopes need to be considered when investigating antigenic drift in emerging variants.

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Authors
Graham, C., Seow, J., Huettner, I., Khan, H., Kouphou, N., Acors, S., Winstone, H., Pickering, S., Galao, R. P., Lista, M. J., Jimenez-Guardeno, J. M., Laing, A. G., Wu, Y., Joseph, M., Muir, L., Ng, W. M., Duyvesteyn, H. M. E., Zhao, Y., Bowden, T. A., Shankar-Hari, M., Rosa, A., Cherepanov, P., McCoy, L. E., Hayday, A. C., Neil, S. J. D., Malim, M. H., & Doores, K. J.
Affiliations
  • King's College London (GB)
  • University College London (GB)
  • Centre for Human Genetics (GB)
  • The Francis Crick Institute (GB)
Corresponding author
Doores, Katie J.
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2021-02-03
OpenAlex
W3127921995
Cited by
27
References
73
Citations by year
2023: 1 · 2022: 3 · 2021: 23
Type
posted content
Language
en
Open access
Locations
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • Wellcome Trust (203141/Z/16/Z, 208354/Z/17/Z, MR/S023747/1, 208354, 106223, Z/17/Z, 106223/Z/14/Z, FC001061, 203141, MR/R015643/1)
  • Francis Crick Institute (FC001061)
  • King's College Hospital NHS Foundation Trust
  • Cancer Research UK (FC001061, MR/N013700/1, MR/R015643/1, 203141/Z/16/Z)
  • National Institute for Health and Care Research (203141/Z/16/Z., 2016-16-011, MR/S007555/1, COVID-19, CS-2016-16-011)
  • Department of Health and Social Care (COVID-19)
  • King's College London (MR/N013700/1)
  • Rosetrees Trust
  • UK Coronavirus Immunology Consortium
  • Medical Research Council (MR/S023747/1, MR/R015643/1, FC001061, 203141/Z/16/Z, MR/N013700/1, MR/S007555/1, MR/R008698/1, MC_PC_15068, COVID-19)
  • National Institute of Allergy and Infectious Diseases (COVID-19, AI150472, U54AI150472)
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
  • Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
Keywords
SARS-CoV-2, B.1.1.7 variant, neutralizing monoclonal antibodies, spike protein, N-terminal domain, receptor binding domain, S2 subunit, neutralization resistance, antigenic drift, antibody epitopes, ACE2 receptor

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