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Landscape analysis of escape variants identifies SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization
Open accessAbstract
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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“Mutations found in emergent S variants decrease sensitivity to neutralization by mAbs, convalescent plasma, and sera from vaccinated individuals (27, 37, 58, 61–70).”
From mRNA vaccination boosts cross-variant neutralizing antibodies elicited by SARS-CoV-2 infection (2021) · cites this paper as [61]
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“…escape mutants with reduced neutralization sensitivity (Andreano et al., 2020; Weisblum et al., 2020) , or characterizing the antigenic effects of specific mutations such as those observed in circulating viral isolates (Kemp et al., 2020b; Li et al., 2020; Liu et al., 2020b; Thomson et al., 2020) .”
BackgroundInfluential
Metadata
- 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
- Venue
- SSRN Electronic Journal
- Publisher
- openRxiv
- Published
- 2020-11-08
- ISSN
- 1556-5068 (ISSN-L)
- 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
- 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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