Structural basis of a shared antibody response to SARS-CoV-2
By M. Yuan, Hejun Liu, Nicholas C. Wu, C. D. Lee, Xueyong Zhu, Fangzhu Zhao, Deli Huang, Wenli Yu, Yuanzi Hua, H. Tien and 6 more. Science, 2020
606 citations recorded by the source corpus.
A common theme in antibody responses In the fight against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), antibodies are a key tool, both as potential therapeutics and to guide vaccine development. Yuan et al. focused on finding shared antibody responses, in which multiple individuals develop antibodies against the same antigen using the same genetic elements and modes of recognition. The authors identified the immunoglobulin heavy-chain variable region 3-53 gene as the most frequently used among 294 antibodies that target the receptor-binding domain (RBD) of the viral spike protein. These antibodies have few somatic mutations, and crystal structures of two neutralizing antibodies bound to the RBD show that mostly germline-encoded residues are involved in binding. The minimal affinity maturation and high potency of these antibodies is promising for vaccine design. Science, this issue p. 1119 IGHV3-53–encoded antibodies that display high-affinity germline binding to SARS-CoV-2 are a common response to COVID-19. 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.
Subfields: Immunology, Infectious Diseases, Radiology, Nuclear Medicine and Imaging
View Paper: https://www.semanticscholar.org/paper/8305815252bbc6e533fab75aae3be8909e105aa0
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In Infectious Diseases
Citations in the corpus
- Antibody escape of SARS-CoV-2 Omicron BA.4 and BA.5 from vaccine and BA.1 serum (2022, positive): “The second region of binding is on or in close proximity to the ACE2 binding surface of the RBD; most potently neutralizing antibodies bind this region and prevent the interaction of S with ACE2 on the host cell, blocking infection (Dejnirattisai et al., 2021a; Yuan et al., 2020a).”
- Comprehensive mapping of mutations to the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human serum antibodies (2021, background): “In particular, E484 is the site in the RBD where mutations usually have the largest effect on binding and neutralization—possibly because E484 is often targeted by antibodies that utilize heavy-chain germline genes that are common among anti-SARS-CoV-2 RBD antibodies, IGHV3-53 and IGHV3-66 (Barnes e”
- SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma (2021, neutral): “Class 1 antibodies are most frequently elicited by SARS-CoV-2 infection and are comprised almost entirely of immunoglobulin V-gene (VH3-53/66) germline restricted antibodies, forming a multi-donor class with highly similar epitopes only accessible in the RBD ‘up’ conformation 11,15,16 .”
- SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses (2022, positive): “Nineteen of the twenty most potent (FRNT50 < 100 ng/mL) neutralizing mAbs are mapped to the ACE2 binding site across the neck and shoulder epitopes of the RBD, and 5 of these are classified as public IGVH3-53 (immunoglobulin heavy chain variable gene family) antibodies (Dejnirattisai et al., 2021a; ”
- Reduced neutralization of SARS-CoV-2 B.1.617 by vaccine and convalescent serum (2021, positive): “Most potent neutralizing antibodies bind the RBD on or closely adjacent to the ACE2-interacting surface and function to block interaction of the virus with ACE2, preventing cellular adhesion and infection (Dejnirattisai et al., 2021a; Yuan et al., 2020; Kreye et al., 2020).”