PreprintCited by 143SARS-CoV-2 and COVID-19 Researchvaccines and immunoinformatics approachesAnimal Virus Infections Studies

Landscape analysis of escape variants identifies SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization

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Liu, Zhuoming, VanBlargan, Laura A., Bloyet, Louis-Marie, Rothlauf, Paul W., Chen, Rita E., Stumpf, Spencer, Zhao, Haiyan, Errico, John M. +8 more·2020·SSRN Electronic Journal

Abstract

Although neutralizing antibodies against the SARS-CoV-2 spike (S) protein are a goal of COVID-19 vaccines and have received emergency use authorization as therapeutics, viral escape mutants could compromise their efficacy. To define the immune-selected mutational landscape in S protein, we used a VSV-eGFP-SARS-CoV-2-S chimeric virus and 19 neutralizing monoclonal antibodies (mAbs) against the receptor-binding domain (RBD) to generate 50 different escape mutants. The variants were mapped onto the RBD structure and evaluated for cross-resistance to mAbs and convalescent human sera. Each mAb had a unique resistance profile, although many shared residues within an epitope. Some variants ( e.g ., S477N) were resistant to neutralization by multiple mAbs, whereas others ( e.g ., E484K) escaped neutralization by convalescent sera, suggesting some humans induce a narrow repertoire of neutralizing antibodies. Comparing the antibody-mediated mutational landscape in S with sequence variation in circulating SARS-CoV-2, we define substitutions that may attenuate neutralizing immune responses in some humans.

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Authors
Liu, Z., VanBlargan, L. A., Bloyet, L.-M., Rothlauf, P. W., Chen, R. E., Stumpf, S., Zhao, H., Errico, J. M., Theel, E. S., Liebeskind, M. J., Alford, B., Buchser, W. J., Ellebedy, A. H., Fremont, D. H., Diamond, M. S., & Whelan, S. P. J.
Affiliations
  • Harvard University (US)
  • Mayo Clinic (US)
Corresponding author
  • Diamond, Michael S.
  • Whelan, Sean P. J.
Venue
SSRN Electronic Journal
Publisher
openRxiv
Published
2020-11-08
ISSN
1556-5068 (ISSN-L)
OpenAlex
W3097675158
Cited by
135
References
40
Citations by year
2025: 1 · 2024: 3 · 2023: 6 · 2022: 14 · 2021: 111
Type
posted content
Language
en
Open access
Locations
  • SSRN Electronic Journal (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • National Institutes of Health (HR001117S0019, 75N93019C00062, AI059371)
  • McDonnell Center for Systems Neuroscience
  • National Institute of Allergy and Infectious Diseases (R01AI157155, R01AI127828, R37AI059371)
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, spike protein, receptor binding domain, escape variants, neutralizing antibodies, monoclonal antibodies, E484K, convalescent sera, epitope mapping, immune evasion

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