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Comprehensive mapping of mutations in the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human plasma antibodies
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Abstract
The evolution of SARS-CoV-2 could impair recognition of the virus by human antibody-mediated immunity. To facilitate prospective surveillance for such evolution, we map how convalescent plasma antibodies are impacted by all mutations to the spike's receptor-binding domain (RBD), the main target of plasma neutralizing activity. Binding by polyclonal plasma antibodies is affected by mutations in three main epitopes in the RBD, but longitudinal samples reveal that the impact of these mutations on antibody binding varies substantially both among individuals and within the same individual over time. Despite this inter- and intra-person heterogeneity, the mutations that most reduce antibody binding usually occur at just a few sites in the RBD's receptor-binding motif. The most important site is E484, where neutralization by some plasma is reduced >10-fold by several mutations, including one in the emerging 20H/501Y.V2 and 20J/501Y.V3 SARS-CoV-2 lineages. Going forward, these plasma escape maps can inform surveillance of SARS-CoV-2 evolution.
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In the citing paper
“This variant has substitutions in the spike protein at T95I, G142D, E154K, D614G, P681R, Q1071H, and L452R, E484Q in its RBD region, which may provide this variant reduced resistance to neutralization by post-vaccination sera [47].”
From Waves and variants of SARS-CoV-2: understanding the causes and effect of the COVID-19 catastrophe (2022) · cites this paper as [47]
Experimental — accuracy not yet measuredIn the citing paper
“The loss of plasma neutralizing activity against B.1.351could be largely attributed to the E484K substitution (Fig. 3b), which has been shown to attenuate the neutralizing activity of convalescent sera 30 .”
From Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7 (2021) · cites this paper as [30]
In the citing paper
“Several of the RBD mutations directly affect angiotensin-converting enzyme 2 (ACE2) receptor-binding affinity, which may affect infectivity, viral load, or transmissibility.11, 12, 13, 14”
From Impact of SARS-CoV-2 variants on the total CD4+ and CD8+ T cell reactivity in infected or vaccinated individuals (2021) · cites this paper as [11]
In the citing paper
“Continued viral evolution led to the emergence and selection of SARS-CoV-2 variants with enhanced infectivity/transmissibility2,3 4,5 and ability to circumvent drug6 and immune control7,8.”
From Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies (2021) · cites this paper as [8]
In the citing paper
“The E484K mutation, which can mediate antibody escape of B.1.351and P.1 variants, has been recently detected in the B.1.1.7 lineage in the United Kingdom, and thus represents a major potential threat for previously immune populations.”
From Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies (2021) · cites this paper as [24]
In the citing paper
“Mutations in the B.1.351and P.1 strains, including E484K and K417N/T, are of high concern, since they partly compromise neutralization generated by previous infection or vaccination [23][24][25] or may increase inherent viral fitness.”
From Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies (2021) · cites this paper as [24]
In the citing paper
“Mutations at F486 are associated with a reduction in neutralizing activity by class 1 (and some class 2) neutralizing antibodies and by polyclonal sera9–11.”
From Emergence of SARS-CoV-2 Omicron lineages BA.4 and BA.5 in South Africa (2022) · cites this paper as [10]
In the citing paper
“mutations at this position have been associated with a reduction in neutralization by monoclonal antibodies (particularly class 2 antibodies) and polyclonal sera9–11.”
From Emergence of SARS-CoV-2 Omicron lineages BA.4 and BA.5 in South Africa (2022) · cites this paper as [10]
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Assessment of the Prevalence and Incidence of COVID-19 in Saudi Arabia
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Chothe, S. K., Jakka, P., Boorla, V. S., Ramasamy, S., Gontu, A., Nissly, R. H., Brown, J. D., Turner, G. G., Sewall, B. J., Reeder, D. M., et al. (2023) · Viruses · doi:10.3390/v15051103 · Cited by 4
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Ratswohl, C., García, C. V., Ahmad, A., Gonschior, H., Lebedin, M. Y., Silvis, C. E., Spatt, L., Gerhard, C., Lehmann, M., Sander, L. E., et al. (2023) · European Journal of Immunology · doi:10.1002/eji.202350408 · Cited by 3
“The data were used as selection assays in the original experiments as reported previously [20, 21].”
BackgroundMethodLong-range linkage effects in adapting sexual populations
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Chakraborty, S., & Saha, C. (2023) · Molecular Informatics · doi:10.1002/minf.202300055 · Cited by 3
In silico prediction of immune-escaping hot spots for future COVID-19 vaccine design
Huang, S., Chen, Y.-T., Lin, X.-Y., Ly, Y.-Y., Lien, S.-T., Chen, P.-H., Wang, C.-T., Wu, S., Chen, C.-C., & Lin, C. (2023) · Scientific Reports · doi:10.1038/s41598-023-40741-1 · Cited by 4
“S494R was reported as the potential escape risk mutation 41 , and G485R also caused decreases in neutralization titer 33 .”
BackgroundDsouza, N., & Selvaa Kumar, C. (2023) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2023.2252084 · Cited by 3
“Similarly, the mutations in the RBD domain of the SARS CoV-2 spike protein reduced the ability to bind to human polyclonal antibodies (Greaney et al., 2021).”
Monitoring and tracking the spread of SARS-CoV-2 in Asturias, Spain
González‐Alba, J. M., Rojo‐Alba, S., Pérez-Martínez, Z., Boga, J. A., Álvarez‐Argüelles, M. E., Gómez, J., Herrero, P., Costales, I., Alba, L. M., Martín, G., et al. (2023) · Access Microbiology · doi:10.1099/acmi.0.000573.v4 · Cited by 3
Systems biology of B cells in COVID-19
Woodruff, M. C., Faliti, C. E., & Sanz, I. (2024) · Seminars in Immunology · doi:10.1016/j.smim.2024.101875 · Cited by 3
The human microbiota is a beneficial reservoir for SARS-CoV-2 mutations
Cao, B., Wang, X.-X., Yin, W., Gao, Z., & Xia, B.-Q. (2024) · mBio · doi:10.1128/mbio.03187-23 · Cited by 3
A speed limit on serial strain replacement from original antigenic sin
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Impact of Missense Mutations on Spike Protein Stability and Binding Affinity in the Omicron Variant
Mahase, V., Sobitan, A., Yao, Q., Shi, X. M., Qin, H. H., Kidane, D., Tang, Q., & Teng, S. (2024) · Viruses · doi:10.3390/v16071150 · Cited by 4
“This knowledge can guide the development of the next generation of neutralizing antibodies capable of counteracting the immune-evading mechanisms of future SARS-CoV-2 variants.”
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SAS: A Platform of Spike Antigenicity for SARS-CoV-2
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“At level C of the 10 mAbs, J. Greaney’s work (Greaney et al., 2021b) displayed 36 mutational sites with 29 overlapping with SAS epitope positions.”
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“to the emergence of new variants of this virus it is very difficult to assess how long the available vaccine will remain durable and effective.(4,5) Coronavirus (CoVs) is an enveloped, single-stranded, positive sense RNA virus of ~30 kb length .”
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Natural heteroclitic-like peptides are generated by SARS-CoV-2 mutations
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Use of compressed sensing to expedite high-throughput diagnostic testing for COVID-19 and beyond
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“This has resulted in monoclonal antibody therapeutics and infection-derived antibodies becoming ineffective as the pandemic has continued, due to the highly specific nature of antibody binding [16,19-22].”
BackgroundA New SARS-CoV-2 Variant Poorly Detected by RT-PCR on Nasopharyngeal Samples, with High LethalityPreprint
Fillâtre, P., Dufour, M.-J., Behillil, S., Vatan, R., Reusse, P., Gabellec, A., Velmans, N., Montagne, C., Coudret, S. G. D., Droumaguet, E., et al. (2021) · SSRN Electronic Journal · doi:10.2139/ssrn.3844810 · Cited by 4
Ultrafast topological data analysis reveals pandemic-scale dynamics of convergent evolutionPreprint
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The Impact of Vaccination Frequency on COVID-19 Public Health Outcomes: A Model-Based Analysis
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“This may be associated with the fact that neutralization depends more on epitope specificity than on the total binding strength measured by the assay [36,37].”
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“In addition to these measures, some studies have explored the possibility that previous infections or vaccinations may provide partial cross-protection between influenza and COVID-19, which could influence disease dynamics by affecting susceptibility [17, 20].”
Metadata
- Authors
- Greaney, A. J., Loes, A. N., Crawford, K. H. D., Starr, T. N., Malone, K. D., Chu, H. Y., & Bloom, J. D.
- Affiliations
- University of Washington (US)
- Howard Hughes Medical Institute (US)
- Fred Hutch Cancer Center (US)
- Corresponding author
- Bloom, Jesse D.
- ORCID
- Venue
- Cell Host & Microbe
- Publisher
- Elsevier BV
- Published
- 2021-03
- Volume
- 29
- Issue
- 3
- Pages
- 463-476.e6
- ISSN
- 1931-3128 (ISSN-L)
- PMC
- PMC7869748
- OpenAlex
- W3127852352
- Cited by
- 1,178
- References
- 88
- Citations by year
- 2026: 43 · 2025: 64 · 2024: 79 · 2023: 158 · 2022: 361 · 2021: 459
- FWCI
- 83.70
- 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)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Gates Foundation (INV-004949)
- Howard Hughes Medical Institute
- NIAID (T32AI083203, R01AI141707, F30AI149928, R01AI127893)
- Damon Runyon Cancer Research Foundation (DRG-2381-19)
- Office of Research Infrastructure Programs, National Institutes of Health (S10OD028685)
- National Institutes of Health
- Vanderbilt University
- 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
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 detection and testing
- Keywords
- SARS-CoV-2, spike protein receptor-binding domain, antibody escape mutations, neutralizing antibodies, E484K mutation, antibody epitopes, convalescent plasma, humoral immunity
- MeSH terms
- Protein Domains, COVID-19, SARS-CoV-2, Adult, Aged, Antibodies, Monoclonal, Antibodies, Viral, Binding Sites, Cell Line, Female, Humans, Male, Middle Aged, Mutation, Prospective Studies, Protein Binding, Receptors, Virus, Young Adult, Antibodies, Neutralizing, Spike Glycoprotein, Coronavirus
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