Structural Basis of a Shared Antibody Response to SARS-CoV-2

Overview

Journal Science

Specialty Science

Date 2020 Jul 15

PMID 32661058

Citations 378

Authors

Meng Yuan

Hejun Liu

Nicholas C Wu

Chang-Chun D Lee

Xueyong Zhu

Fangzhu Zhao

Deli Huang

Wenli Yu

Yuanzi Hua

Henry Tien

Thomas F Rogers

Elise Landais

Devin Sok

Joseph G Jardine

Dennis R Burton

Ian A Wilson

Affiliations

Soon will be listed here.

Abstract

Molecular understanding of neutralizing antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could accelerate vaccine design and drug discovery. We analyzed 294 anti-SARS-CoV-2 antibodies and found that immunoglobulin G heavy-chain variable region 3-53 (IGHV3-53) is the most frequently used IGHV gene for targeting the receptor-binding domain (RBD) of the spike protein. Co-crystal structures of two IGHV3-53-neutralizing antibodies with RBD, with or without Fab CR3022, at 2.33- to 3.20-angstrom resolution revealed that the germline-encoded residues dominate recognition of the angiotensin I converting enzyme 2 (ACE2)-binding site. This binding mode limits the IGHV3-53 antibodies to short complementarity-determining region H3 loops but accommodates light-chain diversity. These IGHV3-53 antibodies show minimal affinity maturation and high potency, which is promising for vaccine design. Knowledge of these structural motifs and binding mode should facilitate the design of antigens that elicit this type of neutralizing response.

Citing Articles

Generation of antigen-specific paired chain antibody sequences using large language models.

Wasdin P, Johnson N, Janke A, Held S, Marinov T, Jordaan G bioRxiv. 2025; .

PMID: 40027781 PMC: 11870394. DOI: 10.1101/2024.12.20.629482.

Structures and functions of the limited natural polyclonal antibody response to parvovirus infection.

Adu O, Lee H, Fruh S, Schoenle M, Weichert W, Flyak A Proc Natl Acad Sci U S A. 2025; 122(8):e2423460122.

PMID: 39951487 PMC: 11873831. DOI: 10.1073/pnas.2423460122.

Retrospective SARS-CoV-2 human antibody development trajectories are largely sparse and permissive.

Kirby M, Petersen B, Faris J, Kells S, Sprenger K, Whitehead T Proc Natl Acad Sci U S A. 2025; 122(4):e2412787122.

PMID: 39841142 PMC: 11789010. DOI: 10.1073/pnas.2412787122.

Structural Immunology of SARS-CoV-2.

Yuan M, Wilson I Immunol Rev. 2024; 329(1):e13431.

PMID: 39731211 PMC: 11727448. DOI: 10.1111/imr.13431.

Structural and Functional Insights into the Evolution of SARS-CoV-2 KP.3.1.1 Spike Protein.

Feng Z, Huang J, Baboo S, Diedrich J, Bangaru S, Paulson J bioRxiv. 2024; .

PMID: 39713475 PMC: 11661143. DOI: 10.1101/2024.12.10.627775.

References

Burton D, Walker L . Rational Vaccine Design in the Time of COVID-19. Cell Host Microbe. 2020; 27(5):695-698. PMC: 7219357. DOI: 10.1016/j.chom.2020.04.022. View

Shi R, Shan C, Duan X, Chen Z, Liu P, Song J . A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2. Nature. 2020; 584(7819):120-124. DOI: 10.1038/s41586-020-2381-y. View

Cao Y, Su B, Guo X, Sun W, Deng Y, Bao L . Potent Neutralizing Antibodies against SARS-CoV-2 Identified by High-Throughput Single-Cell Sequencing of Convalescent Patients' B Cells. Cell. 2020; 182(1):73-84.e16. PMC: 7231725. DOI: 10.1016/j.cell.2020.05.025. View

Pinto D, Park Y, Beltramello M, Walls A, Tortorici M, Bianchi S . Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Nature. 2020; 583(7815):290-295. DOI: 10.1038/s41586-020-2349-y. View

Wu N, Grande G, Turner H, Ward A, Xie J, Lerner R . In vitro evolution of an influenza broadly neutralizing antibody is modulated by hemagglutinin receptor specificity. Nat Commun. 2017; 8:15371. PMC: 5440694. DOI: 10.1038/ncomms15371. View

Chi X, Yan R, Zhang J, Zhang G, Zhang Y, Hao M . A neutralizing human antibody binds to the N-terminal domain of the Spike protein of SARS-CoV-2. Science. 2020; 369(6504):650-655. PMC: 7319273. DOI: 10.1126/science.abc6952. View

Parameswaran P, Liu Y, Roskin K, Jackson K, Dixit V, Lee J . Convergent antibody signatures in human dengue. Cell Host Microbe. 2013; 13(6):691-700. PMC: 4136508. DOI: 10.1016/j.chom.2013.05.008. View

Ekiert D, Friesen R, Bhabha G, Kwaks T, Jongeneelen M, Yu W . A highly conserved neutralizing epitope on group 2 influenza A viruses. Science. 2011; 333(6044):843-50. PMC: 3210727. DOI: 10.1126/science.1204839. View

Yuan M, Wu N, Zhu X, Lee C, So R, Lv H . A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV. Science. 2020; 368(6491):630-633. PMC: 7164391. DOI: 10.1126/science.abb7269. View

10.

Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q . Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science. 2020; 367(6485):1444-1448. PMC: 7164635. DOI: 10.1126/science.abb2762. View

11.

Ye J, Ma N, Madden T, Ostell J . IgBLAST: an immunoglobulin variable domain sequence analysis tool. Nucleic Acids Res. 2013; 41(Web Server issue):W34-40. PMC: 3692102. DOI: 10.1093/nar/gkt382. View

12.

Briney B, Inderbitzin A, Joyce C, Burton D . Commonality despite exceptional diversity in the baseline human antibody repertoire. Nature. 2019; 566(7744):393-397. PMC: 6411386. DOI: 10.1038/s41586-019-0879-y. View

13.

Brouwer P, Caniels T, van der Straten K, Snitselaar J, Aldon Y, Bangaru S . Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability. Science. 2020; 369(6504):643-650. PMC: 7299281. DOI: 10.1126/science.abc5902. View

14.

Lan J, Ge J, Yu J, Shan S, Zhou H, Fan S . Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature. 2020; 581(7807):215-220. DOI: 10.1038/s41586-020-2180-5. View

15.

Boyd S, Gaeta B, Jackson K, Fire A, Marshall E, Merker J . Individual variation in the germline Ig gene repertoire inferred from variable region gene rearrangements. J Immunol. 2010; 184(12):6986-92. PMC: 4281569. DOI: 10.4049/jimmunol.1000445. View

16.

Lurie N, Saville M, Hatchett R, Halton J . Developing Covid-19 Vaccines at Pandemic Speed. N Engl J Med. 2020; 382(21):1969-1973. DOI: 10.1056/NEJMp2005630. View

17.

Robbiani D, Gaebler C, Muecksch F, Lorenzi J, Wang Z, Cho A . Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Nature. 2020; 584(7821):437-442. PMC: 7442695. DOI: 10.1038/s41586-020-2456-9. View

18.

Zhou P, Yang X, Wang X, Hu B, Zhang L, Zhang W . A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020; 579(7798):270-273. PMC: 7095418. DOI: 10.1038/s41586-020-2012-7. View

19.

Wrapp D, Wang N, Corbett K, Goldsmith J, Hsieh C, Abiona O . Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020; 367(6483):1260-1263. PMC: 7164637. DOI: 10.1126/science.abb2507. View

20.

Wu N, Wilson I . Structural insights into the design of novel anti-influenza therapies. Nat Struct Mol Biol. 2018; 25(2):115-121. PMC: 5930012. DOI: 10.1038/s41594-018-0025-9. View