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PreprintCited by 365SARS-CoV-2 and COVID-19 Researchvaccines and immunoinformatics approachesAnimal Virus Infections Studies

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Structural and functional ramifications of antigenic drift in recent SARS-CoV-2 variants

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Yuan, Meng, Huang, Deli, Lee, Chang-Chun D., Wu, Nicholas C., Jackson, Abigail M., Zhu, Xueyong, Liu, Hejun, Peng, Linghang, van Gils, Marit J., Sanders, Rogier W., Burton, Dennis R., Reincke, S. Momsen, Prüss, Harald, Kreye, Jakob, Nemazee, David, Ward, Andrew B., Wilson, Ian A.·2021·Science
DOI 10.1101/2021.02.16.430500PMC PMC7899451
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Abstract

The protective efficacy of neutralizing antibodies (nAbs) elicited during natural infection with SARS-CoV-2 and by vaccination based on its spike protein has been compromised with emergence of the recent SARS-CoV-2 variants. Residues E484 and K417 in the receptor-binding site (RBS) are both mutated in lineages first described in South Africa (B.1.351) and Brazil (B.1.1.28.1). The nAbs isolated from SARS-CoV-2 patients are preferentially encoded by certain heavy-chain germline genes and the two most frequently elicited antibody families (IGHV3-53/3-66 and IGHV1-2) can each bind the RBS in two different binding modes. However, their binding and neutralization are abrogated by either the E484K or K417N mutation, whereas nAbs to the cross-reactive CR3022 and S309 sites are largely unaffected. This structural and functional analysis illustrates why mutations at E484 and K417 adversely affect major classes of nAbs to SARS-CoV-2 with consequences for next-generation COVID-19 vaccines.

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Figures

Figure 1. Emergent SARS-CoV-2 variants escape two major classes of neutralizing antibodies. (A) Emergent mutations (spheres) in the RBS of B.1.351 and B.1.1.28.1 lineages are mapped onto a structure of SARS-CoV-2 RBD (white) in complex with ACE2 (green) (PDB ID: 6M0J) (61). (B) Distribution of IGHV gene usage. The IGHV gene usage in 1,593 SARS-CoV-2 RBD-targeting antibodies (12–43) compared to healthy individuals (baseline) (48) is shown as bars. IGHV gene frequencies in healthy individuals that were not reported in (48) are shown with asterisks (*). Fold-enrichment of germlines used in SARS-CoV-2 antibodies over baseline is shown as black lines. A fold enrichment of one (red dashed line) represents no difference over baseline. The frequently used IGHV3–53 and IGHV3–66 genes are highlighted in blue, and IGHV1–2 in orange. Numbers of RBD-targeting antibodies encoded by each IGHV gene is shown as black lines. (C) Effect of single mutations on the neutralization activity of each neutralizing antibody. IC50 increases that are less than 10-fold are represented by “−”, between 10- and 100-fold as “+”, and greater than 100-fold as “++”. Results in red with “✕” indicate no neutralization activity was detected at 10 μg/ml of IgG. N.C.: not categorized in the original studies. N.S.: No structure available. (D) Neutralization of pseudotyped SARS-CoV-2 virus and variants carrying K417N or E484K mutations. A panel of 18 neutralizing antibodies were tested, including four mode-1 IGHV3–53 antibodies (blue), two mode-2 IGHV3–53 antibodies (purple), and two IGHV1–2 antibodies (orange).
Figure 1. Emergent SARS-CoV-2 variants escape two major classes of neutralizing antibodies. (A) Emergent mutations (spheres) in the RBS of B.1.351 and B.1.1.28.1 lineages are mapped onto a structure of SARS-CoV-2 RBD (white) in complex with ACE2 (green) (PDB ID: 6M0J) (61). (B) Distribution of IGHV gene usage. The IGHV gene usage in 1,593 SARS-CoV-2 RBD-targeting antibodies (12–43) compared to healthy individuals (baseline) (48) is shown as bars. IGHV gene frequencies in healthy individuals that were not reported in (48) are shown with asterisks (*). Fold-enrichment of germlines used in SARS-CoV-2 antibodies over baseline is shown as black lines. A fold enrichment of one (red dashed line) represents no difference over baseline. The frequently used IGHV3–53 and IGHV3–66 genes are highlighted in blue, and IGHV1–2 in orange. Numbers of RBD-targeting antibodies encoded by each IGHV gene is shown as black lines. (C) Effect of single mutations on the neutralization activity of each neutralizing antibody. IC50 increases that are less than 10-fold are represented by “−”, between 10- and 100-fold as “+”, and greater than 100-fold as “++”. Results in red with “✕” indicate no neutralization activity was detected at 10 μg/ml of IgG. N.C.: not categorized in the original studies. N.S.: No structure available. (D) Neutralization of pseudotyped SARS-CoV-2 virus and variants carrying K417N or E484K mutations. A panel of 18 neutralizing antibodies were tested, including four mode-1 IGHV3–53 antibodies (blue), two mode-2 IGHV3–53 antibodies (purple), and two IGHV1–2 antibodies (orange).CC BY-NC · PubMed Central
Figure 2. Antibody binding and structures to the wild-type SARS-CoV-2 RBS. (A) Antibodies making contact with RBD residues K417, E484 and N501 are represented by blue, red and yellow boxes, respectively (cutoff distance = 4 Å). Antibodies encoded by the most frequently elicited IGHV3–53/3–66 and IGHV1–2 in convalescent patients are shown in green and orange boxes, respectively. Antibodies are ordered by epitopes originally classified in (46) with an additional epitope RBS-D. Details of the epitope classifications are shown in Figure S2A. All available structures of RBD-targeting antibodies that were isolated from patients are analyzed. (B-C) Residues that are mutated in recently circulating variants are integral to the binding sites of IGHV3–53 antibodies. Representative structures are shown for (B) IGHV3–53 binding mode 1 [CC12.1 (PDB ID: 6XC3), CC12.3 (PDB ID: 6XC4) (11), and COVA2–04 (PDB ID: 7JMO) (47)] and (C) binding mode 2 [COVA2–39 (PDB ID: 7JMP) (47)]. The SARS-CoV-2 RBD is in white and Fabs in different colors. Residues K417 and E484 are represented by blue and red spheres, respectively. Hydrogen bonds and salt bridges are represented by black dashed lines.
Figure 2. Antibody binding and structures to the wild-type SARS-CoV-2 RBS. (A) Antibodies making contact with RBD residues K417, E484 and N501 are represented by blue, red and yellow boxes, respectively (cutoff distance = 4 Å). Antibodies encoded by the most frequently elicited IGHV3–53/3–66 and IGHV1–2 in convalescent patients are shown in green and orange boxes, respectively. Antibodies are ordered by epitopes originally classified in (46) with an additional epitope RBS-D. Details of the epitope classifications are shown in Figure S2A. All available structures of RBD-targeting antibodies that were isolated from patients are analyzed. (B-C) Residues that are mutated in recently circulating variants are integral to the binding sites of IGHV3–53 antibodies. Representative structures are shown for (B) IGHV3–53 binding mode 1 [CC12.1 (PDB ID: 6XC3), CC12.3 (PDB ID: 6XC4) (11), and COVA2–04 (PDB ID: 7JMO) (47)] and (C) binding mode 2 [COVA2–39 (PDB ID: 7JMP) (47)]. The SARS-CoV-2 RBD is in white and Fabs in different colors. Residues K417 and E484 are represented by blue and red spheres, respectively. Hydrogen bonds and salt bridges are represented by black dashed lines.CC BY-NC · PubMed Central
Figure 3. E484 is critical for RBD recognition of IGHV1–2 antibodies. Heavy and light chains of antibody 2–4 (PDB 6XEY) (26) are shown in pink and light pink, respectively, S2M11 (PDB 7K43) (29) in orange and yellow, and C121 (PDB 7K8X) (44) in dark and light green, and CV05–163 in cyan and light cyan. The RBD is shown in white. E484 and K417 are highlighted as red and blue spheres, respectively. Hydrogen bonds are represented by dashed lines. Hydrogen bonds are not shown in the panel of C121 due to the limited resolution (3.9 Å).
Figure 3. E484 is critical for RBD recognition of IGHV1–2 antibodies. Heavy and light chains of antibody 2–4 (PDB 6XEY) (26) are shown in pink and light pink, respectively, S2M11 (PDB 7K43) (29) in orange and yellow, and C121 (PDB 7K8X) (44) in dark and light green, and CV05–163 in cyan and light cyan. The RBD is shown in white. E484 and K417 are highlighted as red and blue spheres, respectively. Hydrogen bonds are represented by dashed lines. Hydrogen bonds are not shown in the panel of C121 due to the limited resolution (3.9 Å).CC BY-NC · PubMed Central
Figure 4. Antibodies targeting other major antigenic sites are differentially affected by mutations in recent variants. (A) Interactions between RBS-C antibodies and SAR-SCoV-2 RBD. The RBD is shown in white with E484, K417 represented as red and blue spheres, respectively. The various antibodies illustrated are in different colors. Only the variable domains are shown for clarity. Hydrogen bonds and salt bridges to E484 are represented by dashed lines. Published structures with PDB IDs 6XKP (16), 7CHF (37), 7BWJ (17), 7K8U (44), and 7CWN (50) are used to depict structures of SARS-CoV-2 RBD with CV07–270, BD-368–2, P2B-2F6, C104, and P17, respectively. The electron density for the full side chain of VH N52 was not well resolved in the 3.8-Å structure of C104 in complex with SARS-CoV-2 S. The full side chain is modeled here and shown as transparent sticks to illustrate a possible interaction with E484. (B) Cross-neutralizing antibodies to the RBD are not affected by E484 and K417 mutations. COVA1–16 targets the CR3022 cryptic site (yellow) (51) and CV38–142 targets the S309 proteoglycan site (blue) (52) to the RBD. Glycans at the N343 glycosylation site are represented by sticks. The RBS surface is shown in green. E484 and K417 are highlighted as red and blue spheres, respectively. (C) Neutralization of CV38–142 and COVA1–16 against SARS-CoV-2 wild type, K417N or E484K pseudoviruses.
Figure 4. Antibodies targeting other major antigenic sites are differentially affected by mutations in recent variants. (A) Interactions between RBS-C antibodies and SAR-SCoV-2 RBD. The RBD is shown in white with E484, K417 represented as red and blue spheres, respectively. The various antibodies illustrated are in different colors. Only the variable domains are shown for clarity. Hydrogen bonds and salt bridges to E484 are represented by dashed lines. Published structures with PDB IDs 6XKP (16), 7CHF (37), 7BWJ (17), 7K8U (44), and 7CWN (50) are used to depict structures of SARS-CoV-2 RBD with CV07–270, BD-368–2, P2B-2F6, C104, and P17, respectively. The electron density for the full side chain of VH N52 was not well resolved in the 3.8-Å structure of C104 in complex with SARS-CoV-2 S. The full side chain is modeled here and shown as transparent sticks to illustrate a possible interaction with E484. (B) Cross-neutralizing antibodies to the RBD are not affected by E484 and K417 mutations. COVA1–16 targets the CR3022 cryptic site (yellow) (51) and CV38–142 targets the S309 proteoglycan site (blue) (52) to the RBD. Glycans at the N343 glycosylation site are represented by sticks. The RBS surface is shown in green. E484 and K417 are highlighted as red and blue spheres, respectively. (C) Neutralization of CV38–142 and COVA1–16 against SARS-CoV-2 wild type, K417N or E484K pseudoviruses.CC BY-NC · PubMed Central

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Metadata

Authors
Yuan, M., Huang, D., Lee, C.-C. D., Wu, N. C., Jackson, A. M., Zhu, X., Liu, H., Peng, L., van Gils, M. J., Sanders, R. W., Burton, D. R., Reincke, S. M., Prüss, H., Kreye, J., Nemazee, D., Ward, A. B., & Wilson, I. A.
Affiliations
  • Scripps Research Institute (US)
  • University of Illinois Urbana-Champaign (US)
  • Cornell University (US)
  • German Center for Neurodegenerative Diseases (DE)
Corresponding author
Wilson, Ian A.
ORCID
Venue
Science
Publisher
openRxiv
Published
2021-02-17
Volume
373
Issue
6556
Pages
818-823
ISSN
0036-8075 (ISSN-L)
DOI
10.1101/2021.02.16.430500
PMC
PMC7899451
OpenAlex
W3160471157
Cited by
364
References
112
Citations by year
2026: 11 · 2025: 27 · 2024: 35 · 2023: 60 · 2022: 138 · 2021: 92
FWCI
25.73
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Science (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by-nc)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
  • DZNE Pub (submittedVersion)
Funders
  • U.S. Department of Energy (DE‐ AC02‐06CH11357, COVID-19, Contract No. DE-AC02-06CH11357., AC02‐06CH11357, 06CH11357, No. DE-AC02-06CH11357, DE-AC02-)
  • Bill and Melinda Gates Foundation (INV-004923, OPP1170236, OPP1170236 and INV-004923)
  • Helmholtz-Gemeinschaft (HIL-A03 and SO-097)
  • Deutsche Forschungsgemeinschaft (PR1274/5–1, and PR 1274/5-1, DE-AC02-06CH11357, PR1274/3–1, PR 1274/3-1, and PR 1274/5-1)
  • Bundesministerium für Bildung und Forschung (01GM1908D)
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek
  • National Institutes of Health (COVID-19, DE-AC02–06CH11357, AI110657)
  • Office of Science (Contract No. DE-AC02-06CH11357, AC02‐06CH11357, DE-AC02, No. DE-AC02-06CH11357., 06CH11357, DE-AC02-06CH11357)
  • National Institute of Allergy and Infectious Diseases (R01AI142945, R01AI132317, P01AI110657, R00AI139445)
  • Argonne National Laboratory (DE- AC02-06-CH11357, DE-AC02, AC02–06CH11357, No. DE-AC02-06CH11357, 06CH11357, Contract No. DE-AC02-06CH11357.)
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, antigenic drift, Beta variant, P.1, spike protein mutations, K417N, E484K, receptor binding sites, ACE2 binding, neutralizing antibodies, CR3022, vaccine design, antibody therapy

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