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

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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., Theel, Elitza S., Liebeskind, Mariel J., Alford, Brynn, Buchser, William J., Ellebedy, Ali H., Fremont, Daved H., Diamond, Michael S., Whelan, Sean P. J.·2020·SSRN Electronic Journal

DOI 10.1101/2020.11.06.372037PMC PMC7805447

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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.
ORCID: Liu, Zhuoming
VanBlargan, Laura A.
Bloyet, Louis-Marie
Rothlauf, Paul W.
Chen, Rita E.
Stumpf, Spencer
Zhao, Haiyan
Errico, John M.
Theel, Elitza S.
Liebeskind, Mariel J.
Buchser, William J.
Ellebedy, Ali H.
Fremont, Daved H.
Diamond, Michael S.
Whelan, Sean P. J.
Venue: SSRN Electronic Journal
Publisher: openRxiv
Published: 2020-11-08
ISSN: 1556-5068 (ISSN-L)
DOI: 10.1101/2020.11.06.372037
PMC: PMC7805447
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: green
doi.org
Licence: www.biorxiv.org/about/FAQ#license (vor)
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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Landscape analysis of escape variants identifies SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization

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