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Identification of SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization
Open accessAbstract
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. However, viral escape mutants could compromise efficacy. To define immune-selected mutations in the S protein, we exposed a VSV-eGFP-SARS-CoV-2-S chimeric virus, in which the VSV glycoprotein is replaced with the S protein, to 19 neutralizing monoclonal antibodies (mAbs) against the receptor-binding domain (RBD) and generated 50 different escape mutants. Each mAb had a unique resistance profile, although many shared residues within an epitope of the RBD. Some variants (e.g., S477N) were resistant to neutralization by multiple mAbs, whereas others (e.g., E484K) escaped neutralization by convalescent sera. Additionally, sequential selection identified mutants that escape neutralization by antibody cocktails. Comparing these antibody-mediated mutations with sequence variation in circulating SARS-CoV-2 revealed substitutions that may attenuate neutralizing immune responses in some humans and thus warrant further investigation.
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In the citing paper
“F490S mutation helps the Lambda variant to escape convalescent sera and neutralizing antibodies from the CoronaVac vaccine and also reduced in vitro susceptibility to neutralization [54].”
From Waves and variants of SARS-CoV-2: understanding the causes and effect of the COVID-19 catastrophe (2022) · cites this paper as [54]
Experimental — accuracy not yet measuredIn the citing paper
“several were previously shown to modulate ACE2 binding and/or antibody evasion”
From The Omicron variant is highly resistant against antibody-mediated neutralization: Implications for control of the COVID-19 pandemic (2022) · cites this paper as Liu et al., 2021
In the citing paper
“Our results establishing the E484K substitution as a vulnerability for multiple neutralizing mAbs are consistent with deep mutational scanning or VSV-SARS-CoV-2-based neutralization escape screening campaigns31,33,34.”
From Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies (2021) · cites this paper as [34]
In the citing paper
“E484K has resulted in 3-fold to 10-fold reduced susceptibility to about 30% and >10-fold reduced susceptibility to about 10% of convalescent plasma samples”
From The biological and clinical significance of emerging SARS-CoV-2 variants (2021) · cites this paper as [160]
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Citations
Cites
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SARS-CoV-2 variants, spike mutations and immune escape
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Self-citationN-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2
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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
- Washington University in St. Louis (US)
- Harvard University (US)
- Mayo Clinic (US)
- Corresponding author
- Diamond, Michael S.
- Whelan, Sean P.J.
- ORCID
- Venue
- Cell Host & Microbe
- Publisher
- Elsevier BV
- Published
- 2021-03
- Volume
- 29
- Issue
- 3
- Pages
- 477-488.e4
- ISSN
- 1931-3128 (ISSN-L)
- PMC
- PMC7839837
- OpenAlex
- W3121995178
- Cited by
- 725
- References
- 38
- Citations by year
- 2026: 11 · 2025: 22 · 2024: 57 · 2023: 77 · 2022: 255 · 2021: 302
- FWCI
- 55.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 374 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Host & Microbe (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Washington University in St. Louis
- University of Washington
- Saint Louis University
- National Institutes of Health (75N93019C00062, R01 AI127828, R01 AI157155, R37 AI059371)
- AbbVie
- Defense Advanced Research Projects Agency (HR001117S0019)
- 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, antibody escape mutants, neutralizing monoclonal antibodies, receptor binding domain, E484K mutation
- MeSH terms
- Angiotensin-Converting Enzyme 2, COVID-19, SARS-CoV-2, COVID-19 Vaccines, Animals, Antibodies, Monoclonal, Antibodies, Viral, Chlorocebus aethiops, Female, Humans, Mice, Inbred BALB C, Models, Molecular, Mutation, Neutralization Tests, Protein Binding, Receptors, Virus, Vero Cells, Amino Acid Substitution, Mice, Antibodies, Neutralizing, Spike Glycoprotein, Coronavirus
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