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SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies
Open accessPublished version of a preprint
Abstract
The coronavirus disease 2019 (COVID-19) pandemic presents an urgent health crisis. Human neutralizing antibodies that target the host ACE2 receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein 1-5 show promise therapeutically and are being evaluated clinically 6-8. Here, to identify the structural correlates of SARS-CoV-2 neutralization, we solved eight new structures of distinct COVID-19 human neutralizing antibodies 5 in complex with the SARS-CoV-2 spike trimer or RBD. Structural comparisons allowed us to classify the antibodies into categories: (1) neutralizing antibodies encoded by the VH3-53 gene segment with short CDRH3 loops that block ACE2 and bind only to 'up' RBDs; (2) ACE2-blocking neutralizing antibodies that bind both up and 'down' RBDs and can contact adjacent RBDs; (3) neutralizing antibodies that bind outside the ACE2 site and recognize both up and down RBDs; and (4) previously described antibodies that do not block ACE2 and bind only to up RBDs 9. Class 2 contained four neutralizing antibodies with epitopes that bridged RBDs, including a VH3-53 antibody that used a long CDRH3 with a hydrophobic tip to bridge between adjacent down RBDs, thereby locking the spike into a closed conformation. Epitope and paratope mapping revealed few interactions with host-derived N-glycans and minor contributions of antibody somatic hypermutations to epitope contacts. Affinity measurements and mapping of naturally occurring and in vitro-selected spike mutants in 3D provided insight into the potential for SARS-CoV-2 to escape from antibodies elicited during infection or delivered therapeutically. These classifications and structural analyses provide rules for assigning current and future human RBD-targeting antibodies into classes, evaluating avidity effects and suggesting combinations for clinical use, and provide insight into immune responses against SARS-CoV-2.
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“A475V is resistant to class 1 antibodies (structurally defined as described29); E484K and Q493R are resistant to class 2 antibodies7,8,12,13,29,30,32,33; while R346S, N439K, and N440K are resistant to class 3 antibodies7,8,12,13,29,33.”
From mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants (2021) · cites this paper as [7]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In addition, antibodies that share the same combination of IGHV and IGLV genes in vaccinees comprised 39% of all the clonal sequences (Extended Data Fig. 4b) and 59% when combined with naturally infected individuals7,8 (Fig. 2f), and some of these antibodies were nearly identical (Extended Data Table 3 and 4).”
From mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants (2021) · cites this paper as [7]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The T478K mutation in the RBD is unique to the Delta variant and falls within the epitope region of potent neutralizing monoclonal antibodies categorized as 'Class1' 17”
From Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization (2021) · cites this paper as [17]
Experimental — accuracy not yet measuredIn the citing paper
“As expected, plasma neutralizing activity was directly correlated to anti-S and -RBD binding titers in ELISAs7,8 (Fig. 1c, d, and Extended Data Fig. 2a–d).”
From mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants (2021) · cites this paper as [7]
In the citing paper
“Moreover, the plasma neutralizing activity, and the relative numbers of RBD-specific memory B cells were equivalent to individuals who recovered from natural infection7,8.”
From mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants (2021) · cites this paper as [7]
In the citing paper
“Although circulating antibodies derived from plasma cells wane over time, long-lived immune memory can persist in expanded clones of memory B cells7,20.”
From mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants (2021) · cites this paper as [7]
In the citing paper
“As seen in natural infection, a majority of the antibodies tested (9/17) were at least ten-fold less effective against pseudotyped viruses carrying the E484K mutation7,12,29.”
From mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants (2021) · cites this paper as [7]
In the citing paper
“In anti-RBD ELISAs the mean half-maximal effective concentration (EC50) was higher than that observed in infected individuals after 6.2 months but not significantly different from antibodies obtained 1.3 months after infection (Extended Data Fig. 6a, and Table 5 and 7,8).”
From mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants (2021) · cites this paper as [7]
In the citing paper
“Class 1 and 2 antibodies are among the most potent and also the most abundant antibodies7,8,21,22,25,39.”
From mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants (2021) · cites this paper as [7]
In the citing paper
“Consistent with the plasma neutralization results, the geometric mean neutralization half-maximal inhibitory concentration of the Pfizer-BioNTech and Moderna vaccinee antibodies were not significantly different from each other or to antibody collections obtained from naturally infected individuals 1.3 or 6.2 months after infection (Fig. 3a and 7,8).”
From mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants (2021) · cites this paper as [7]
In the citing paper
“In contrast to the earlier time point, 13 of 15 neutralizing antibodies obtained after 12 months interfered only with C121, a class 2 antibody3,23 (Fig. 4c, Extended Data Fig. 9).”
From Naturally enhanced neutralizing breadth against SARS-CoV-2 one year after infection (2021) · cites this paper as [23]
In the citing paper
“Residue S477 is close to the receptor binding site (Fig ED2) and part of the epitope recognized by the S2E12 and C102 neutralizing antibodies 17,18 .”
From Spread of a SARS-CoV-2 variant through Europe in the summer of 2020 (2021) · cites this paper as [17]
In the citing paper
“a potent Ab that can recognize both “up” and “down” SARS-CoV-2 RBD conformations [41].”
From Deep geometric representations for modeling effects of mutations on protein-protein binding affinity (2021) · cites this paper as [41]
In the citing paper
“Importantly, our spike did not contain R346K, which has been observed at relatively low frequency (<10%) within the Omicron lineage, but which is known to mediate escape from class 3 neutralizing monoclonal antibodies such as AZD1061/cilgavimab (Barnes et al., 2020; Dong et al., 2021; Greaney et al., 2021b).”
From mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant (2022) · cites this paper as Barnes et al., 2020
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Citations
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Design of immunogens for eliciting antibody responses that may protect against SARS-CoV-2 variants
Wang, E. J. D., & Chakraborty, A. K. (2022) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1010563 · Cited by 7
Qiang, M., Ma, P., Li, Y., Liu, H., Harding, A. C., Min, C., Liu, L., Yuan, M., Ji, Q., Tao, P., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.11.06.370676 · Cited by 7
Isolation and comparative analysis of antibodies that broadly neutralize sarbecovirusesPreprint
Liu, L., Iketani, S., Guo, Y., Casner, R. G., Reddem, E. R., Nair, M. S., Yu, J., Chan, J. F., Wang, M., Cerutti, G., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.12.11.472236 · Cited by 7
Ju, B., Zheng, Q., Guo, H., Fan, Q., Li, T., Song, S., Sun, H., Shen, S., Zhou, X., Cheng, L., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.01.19.476892 · Cited by 7
Metadata
- Authors
- Barnes, C. O., Jette, C. A., Abernathy, M. E., Dam, K.-M. A., Esswein, S. R., Gristick, H. B., Malyutin, A. G., Sharaf, N. G., Huey-Tubman, K. E., Lee, Y. E., Robbiani, D. F., Nussenzweig, M. C., West, A. P., & Bjorkman, P. J.
- Affiliations
- California Institute of Technology (US)
- Institute for Research in Biomedicine (CH)
- Howard Hughes Medical Institute (US)
- ORCID
- Venue
- Nature
- Published
- 2020-10-12
- Volume
- 588
- Issue
- 7839
- Pages
- 682-687
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC8092461
- OpenAlex
- W3092403777
- Cited by
- 1,599
- References
- 70
- Citations by year
- 2026: 94 · 2025: 121 · 2024: 181 · 2023: 267 · 2022: 448 · 2021: 440 · 2020: 35
- FWCI
- 39.08
- Type
- journal article
- Language
- en
- Update notices
- correction (2024-04-02)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion, cc-by-nc-nd)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- U.S. Department of Energy (P41GM103393, DE-AC02-)
- Burroughs Wellcome Fund
- George Mason University
- California Institute of Technology
- Wellcome Trust
- National Institutes of Health (AI138938, P01 AI138938-S1, AI150464)
- Office of Science (P41GM103393, DE-AC02)
- Beckman Institute, California Institute of Technology
- National Institute of General Medical Sciences (AI150464, P41GM103393)
- National Institute of Allergy and Infectious Diseases (P50AI150464, F30AI147579, P01AI138938)
- Basic Energy Sciences (DE-AC02, P41GM103393)
- Biological and Environmental Research (P41 GM103393)
- SLAC National Accelerator Laboratory (P41GM103393)
- 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 › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
- Keywords
- SARS-CoV-2, COVID-19 pandemic, neutralizing antibodies, spike protein receptor-binding domain, antibody-antigen complex structure, ACE2 receptor, epitope mapping, N-glycans, somatic hypermutation, antibody escape, avidity, antibody combination therapy, spike trimer
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