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

doi:10.1126/science.abh1139

. 2021 Aug 13;373(6556):818-823.

doi: 10.1126/science.abh1139. Epub 2021 May 20.

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

Meng Yuan^#¹, Deli Huang^#², Chang-Chun D Lee^#¹, Nicholas C Wu^#^{3

4}, Abigail M Jackson¹, Xueyong Zhu¹, Hejun Liu¹, Linghang Peng², Marit J van Gils⁵, Rogier W Sanders^{5

6}, Dennis R Burton^{2

7}, S Momsen Reincke^{8

9}, Harald Prüss^{8

9}, Jakob Kreye^{8

9}, David Nemazee², Andrew B Ward¹, Ian A Wilson^{10

11}

Affiliations

¹ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
² Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
³ Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
⁴ Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
⁵ Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, Netherlands.
⁶ Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
⁷ Ragon Institute of MGH, Harvard, and MIT, Cambridge, MA 02139, USA.
⁸ German Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, Germany.
⁹ Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Berlin, Germany.
¹⁰ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. wilson@scripps.edu.
¹¹ Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.

^# Contributed equally.

PMID: 34016740
PMCID: PMC8284396
DOI: 10.1126/science.abh1139

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

Meng Yuan et al. Science. 2021.

. 2021 Aug 13;373(6556):818-823.

doi: 10.1126/science.abh1139. Epub 2021 May 20.

Authors

Affiliations

¹ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
² Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
³ Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
⁴ Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
⁵ Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, Netherlands.
⁶ Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
⁷ Ragon Institute of MGH, Harvard, and MIT, Cambridge, MA 02139, USA.
⁸ German Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, Germany.
⁹ Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Berlin, Germany.
¹⁰ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. wilson@scripps.edu.
¹¹ Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.

^# Contributed equally.

PMID: 34016740
PMCID: PMC8284396
DOI: 10.1126/science.abh1139

Abstract

Neutralizing antibodies (nAbs) elicited against the receptor binding site (RBS) of the spike protein of wild-type severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are generally less effective against recent variants of concern. RBS residues Glu⁴⁸⁴, Lys⁴¹⁷, and Asn⁵⁰¹ are mutated in variants first described in South Africa (B.1.351) and Brazil (P.1). We analyzed their effects on angiotensin-converting enzyme 2 binding, as well as the effects of two of these mutations (K417N and E484K) on nAbs isolated from COVID-19 patients. Binding and neutralization of the two most frequently elicited antibody families (IGHV3-53/3-66 and IGHV1-2), which can both bind the RBS in alternative binding modes, are abrogated by K417N, E484K, or both. These effects can be structurally explained by their extensive interactions with RBS nAbs. However, nAbs to the more conserved, cross-neutralizing CR3022 and S309 sites were largely unaffected. The results have implications for next-generation vaccines and antibody therapies.

PubMed Disclaimer

Figures

**Fig. 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 P.1 lineages are mapped onto a structure of SARS-CoV-2 RBD (white) in complex with ACE2 (green) (PDB ID: 6M0J) (90). Binding affinities of Fc-tagged human ACE2 against SARS-CoV-2 RBD wild type and mutants were assayed by biolayer interferometry (BLI) experiments. Detailed sensorgrams are shown in fig. S1. (B) Distribution of IGHV gene usage. Numbers of RBD-targeting antibodies encoded by each IGHV gene are shown as solid bars. The frequently used IGHV3-53 and IGHV3-66 genes are highlighted in blue, and IGHV1-2 in orange. The IGHV gene usage in 1,593 SARS-CoV-2 RBD-targeting antibodies (, –44) compared to healthy individuals (baseline) (76) (fold-enrichment) is shown as black lines. ^#: IGHV gene frequencies in healthy individuals that were not reported in (76) are shown with hashtags (^#). *: IGHV genes that are significantly enriched over the baseline repertoire (76) (p < 0.05, one-sample proportion test with Bonferroni correction) are shown with an asterisk (*). A fold-enrichment of one (red dashed line) represents no difference over baseline. (C) Effects of single mutations on the neutralization activity and binding affinity of each neutralizing antibody. IC₅₀ or K_D increase 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 or binding was detected at the highest amount of IgG used. 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 17 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). The discrepancy between CV05-163 neutralizing SARS-CoV-2 pseudotyped virus (IC₅₀ = 0.47 μg/ml) and authentic virus (IC₅₀ = 0.02 μg/ml) reported in our previous study (17) is possibly due to different systems (pseudovirus vs. authentic virus) and host cells (Hela cells vs. Vero E6 cells) used in these experiments.

**Fig. 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 (9) with an additional epitope RBS-D that maps to a region in the RBS above or slightly overlapping with the S309 site. Details of the epitope classifications are shown in fig. S3A. Structures of RBD-targeting antibodies that were isolated from patients are analyzed (91). (B and 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 6XC3), CC12.3 (PDB 6XC4) (13), and COVA2-04 (PDB 7JMO) (75)] and (C) binding mode 2 [COVA2-39 (PDB 7JMP) (75)]. 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.

**Fig. 3. E484 is critical for RBD recognition of IGHV1-2 antibodies.**
Heavy and light chains of antibody 2-4 (PDB 6XEY) (27) are shown in pink and light pink, respectively, S2M11 (PDB 7K43) (30) in orange and yellow, and C121 (PDB 7K8X) (10) 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).

**Fig. 4. Antibodies targeting other major antigenic sites are differentially affected by mutations in recent variants.**
(A) Interactions between RBS-C antibodies and SARS-CoV-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 (17), 7CHF (38), 7BWJ (18), 7K8U (10), and 7CWN (78) 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 V_H 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) (80) and CV38-142 targets the S309 proteoglycan site (blue) (81) 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.

See this image and copyright information in PMC

Update of

Structural and functional ramifications of antigenic drift in recent SARS-CoV-2 variants.
Yuan M, Huang D, Lee CD, Wu NC, Jackson AM, Zhu X, Liu H, Peng L, van Gils MJ, Sanders RW, Burton DR, Reincke SM, Prüss H, Kreye J, Nemazee D, Ward AB, Wilson IA. Yuan M, et al. bioRxiv [Preprint]. 2021 Feb 17:2021.02.16.430500. doi: 10.1101/2021.02.16.430500. bioRxiv. 2021. Update in: Science. 2021 Aug 13;373(6556):818-823. doi: 10.1126/science.abh1139 PMID: 33619487 Free PMC article. Updated. Preprint.

Cited by

SARS-CoV-2 Delta and Omicron variants evade population antibody response by mutations in a single spike epitope.
He P, Liu B, Gao X, Yan Q, Pei R, Sun J, Chen Q, Hou R, Li Z, Zhang Y, Zhao J, Sun H, Feng B, Wang Q, Yi H, Hu P, Li P, Zhang Y, Chen Z, Niu X, Zhong X, Jin L, Liu X, Qu K, Ciazynska KA, Carter AP, Briggs JAG, Chen J, Liu J, Chen X, He J, Chen L, Xiong X. He P, et al. Nat Microbiol. 2022 Oct;7(10):1635-1649. doi: 10.1038/s41564-022-01235-4. Epub 2022 Sep 23. Nat Microbiol. 2022. PMID: 36151403 Free PMC article.
The emergence and ongoing convergent evolution of the N501Y lineages coincides with a major global shift in the SARS-CoV-2 selective landscape.
Martin DP, Weaver S, Tegally H, San EJ, Shank SD, Wilkinson E, Lucaci AG, Giandhari J, Naidoo S, Pillay Y, Singh L, Lessells RJ; NGS-SA; COVID-19 Genomics UK (COG-UK); Gupta RK, Wertheim JO, Nekturenko A, Murrell B, Harkins GW, Lemey P, MacLean OA, Robertson DL, de Oliveira T, Kosakovsky Pond SL. Martin DP, et al. medRxiv [Preprint]. 2021 Jul 25:2021.02.23.21252268. doi: 10.1101/2021.02.23.21252268. medRxiv. 2021. Update in: Cell. 2021 Sep 30;184(20):5189-5200.e7. doi: 10.1016/j.cell.2021.09.003 PMID: 33688681 Free PMC article. Updated. Preprint.
Immunization with synthetic SARS-CoV-2 S glycoprotein virus-like particles protects macaques from infection.
Sulbaran G, Maisonnasse P, Amen A, Effantin G, Guilligay D, Dereuddre-Bosquet N, Burger JA, Poniman M, Grobben M, Buisson M, Dergan Dylon S, Naninck T, Lemaître J, Gros W, Gallouët AS, Marlin R, Bouillier C, Contreras V, Relouzat F, Fenel D, Thepaut M, Bally I, Thielens N, Fieschi F, Schoehn G, van der Werf S, van Gils MJ, Sanders RW, Poignard P, Le Grand R, Weissenhorn W. Sulbaran G, et al. Cell Rep Med. 2022 Jan 24;3(2):100528. doi: 10.1016/j.xcrm.2022.100528. eCollection 2022 Feb 15. Cell Rep Med. 2022. PMID: 35233549 Free PMC article.
A CNN model for predicting binding affinity changes between SARS-CoV-2 spike RBD variants and ACE2 homologues.
Chen C, Boorla VS, Chowdhury R, Nissly RH, Gontu A, Chothe SK, LaBella L, Jakka P, Ramasamy S, Vandegrift KJ, Nair MS, Kuchipudi SV, Maranas CD. Chen C, et al. bioRxiv [Preprint]. 2022 Mar 23:2022.03.22.485413. doi: 10.1101/2022.03.22.485413. bioRxiv. 2022. PMID: 35350198 Free PMC article. Preprint.
A Pre-Vaccination Baseline of SARS-CoV-2 Genetic Surveillance and Diversity in the United States.
Capoferri AA, Shao W, Spindler J, Coffin JM, Rausch JW, Kearney MF. Capoferri AA, et al. Viruses. 2022 Jan 7;14(1):104. doi: 10.3390/v14010104. Viruses. 2022. PMID: 35062308 Free PMC article.

See all "Cited by" articles

References

1. M. Chand et al., Investigation of Novel SARS-CoV-2 Variant: Variant of Concern 202012/01. Technical Briefing 5. Public Health England (2020); https://assets.publishing.service.gov.uk/government/uploads/system/uploa....
1. H. Tegally et al., Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa. medRxiv [preprint]. 22 December 2020. - PubMed
1. N. R. Faria et al., “Genomic characterisation of an emergent SARS-CoV-2 lineage in Manaus: preliminary findings” (2021); https://virological.org/t/genomic-characterisation-of-an-emergent-sars-c....
1. V. Tchesnokova, H. Kulakesara, L. Larson, V. Bowers, E. Rechkina, D. Kisiela, Y. Sledneva, D. Choudhury, I. Maslova, K. Deng, K. Kutumbaka, H. Geng, C. Fowler, D. Greene, J. Ralston, M. Samadpour, E. Sokurenko, Acquisition of the L452R mutation in the ACE2-binding interface of Spike protein triggers recent massive expansion of SARS-Cov-2 variants. bioRxiv [preprint]. 22 February 2021. - PMC - PubMed
1. Yadav P. D., Sapkal G. N., Abraham P., Ella R., Deshpande G., Patil D. Y., Nyayanit D. A., Gupta N., Sahay R. R., Shete A. M., Panda S., Bhargava B., Mohan V. K., Neutralization of variant under investigation B.1.617 with sera of BBV152 vaccinees. Clin. Infect. Dis. ciab411 (2021). 10.1093/cid/ciab41110.1093/cid/ciab411 - DOI - DOI - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
Medical
- MedlinePlus Health Information
Research Materials
- Addgene Non-profit plasmid repository
Miscellaneous
- NCI CPTAC Assay Portal

[1] M. Chand et al., Investigation of Novel SARS-CoV-2 Variant: Variant of Concern 202012/01. Technical Briefing 5. Public Health England (2020); https://assets.publishing.service.gov.uk/government/uploads/system/uploa....

[2] M. Chand et al., Investigation of Novel SARS-CoV-2 Variant: Variant of Concern 202012/01. Technical Briefing 5. Public Health England (2020); https://assets.publishing.service.gov.uk/government/uploads/system/uploa....

[3] H. Tegally et al., Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa. medRxiv [preprint]. 22 December 2020. - PubMed

[4] H. Tegally et al., Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa. medRxiv [preprint]. 22 December 2020. - PubMed

[5] N. R. Faria et al., “Genomic characterisation of an emergent SARS-CoV-2 lineage in Manaus: preliminary findings” (2021); https://virological.org/t/genomic-characterisation-of-an-emergent-sars-c....

[6] N. R. Faria et al., “Genomic characterisation of an emergent SARS-CoV-2 lineage in Manaus: preliminary findings” (2021); https://virological.org/t/genomic-characterisation-of-an-emergent-sars-c....

[7] V. Tchesnokova, H. Kulakesara, L. Larson, V. Bowers, E. Rechkina, D. Kisiela, Y. Sledneva, D. Choudhury, I. Maslova, K. Deng, K. Kutumbaka, H. Geng, C. Fowler, D. Greene, J. Ralston, M. Samadpour, E. Sokurenko, Acquisition of the L452R mutation in the ACE2-binding interface of Spike protein triggers recent massive expansion of SARS-Cov-2 variants. bioRxiv [preprint]. 22 February 2021. - PMC - PubMed

[8] V. Tchesnokova, H. Kulakesara, L. Larson, V. Bowers, E. Rechkina, D. Kisiela, Y. Sledneva, D. Choudhury, I. Maslova, K. Deng, K. Kutumbaka, H. Geng, C. Fowler, D. Greene, J. Ralston, M. Samadpour, E. Sokurenko, Acquisition of the L452R mutation in the ACE2-binding interface of Spike protein triggers recent massive expansion of SARS-Cov-2 variants. bioRxiv [preprint]. 22 February 2021. - PMC - PubMed

[9] Yadav P. D., Sapkal G. N., Abraham P., Ella R., Deshpande G., Patil D. Y., Nyayanit D. A., Gupta N., Sahay R. R., Shete A. M., Panda S., Bhargava B., Mohan V. K., Neutralization of variant under investigation B.1.617 with sera of BBV152 vaccinees. Clin. Infect. Dis. ciab411 (2021). 10.1093/cid/ciab41110.1093/cid/ciab411 - DOI - DOI - PubMed

[10] Yadav P. D., Sapkal G. N., Abraham P., Ella R., Deshpande G., Patil D. Y., Nyayanit D. A., Gupta N., Sahay R. R., Shete A. M., Panda S., Bhargava B., Mohan V. K., Neutralization of variant under investigation B.1.617 with sera of BBV152 vaccinees. Clin. Infect. Dis. ciab411 (2021). 10.1093/cid/ciab41110.1093/cid/ciab411 - DOI - DOI - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Figures

Update of

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials

Miscellaneous

Abstract

Figures

Update of

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials

Miscellaneous