Structural basis of a shared antibody response to SARS-CoV-2

• Published in: Science (American Association for the Advancement of Science) Vol. 369; no. 6507; pp. 1119 - 1123
• Main Authors: Yuan, Meng, Liu, Hejun, Wu, Nicholas C., Lee, Chang-Chun D., Zhu, Xueyong, Zhao, Fangzhu, Huang, Deli, Yu, Wenli, Hua, Yuanzi, Tien, Henry, Rogers, Thomas F., Landais, Elise, Sok, Devin, Jardine, Joseph G., Burton, Dennis R., Wilson, Ian A.
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 28.08.2020; AAAS; American Association for the Advancement of Science
• Subjects: ACE2; Affinity; Angiotensin; Angiotensin I; Angiotensin-converting enzyme 2; Antibodies; Antibodies, Neutralizing - chemistry; Antibodies, Neutralizing - genetics; Antibodies, Neutralizing - immunology; Antibodies, Viral - chemistry; Antibodies, Viral - genetics; Antibodies, Viral - immunology; Antibody Formation; Antibody response; Antigens; BASIC BIOLOGICAL SCIENCES; Betacoronavirus - immunology; Binding Sites; Biochem; Chains; Complementarity Determining Regions - chemistry; Complementarity Determining Regions - genetics; Complementarity Determining Regions - immunology; Complementarity-determining region; Coronaviridae; Coronavirus Infections - genetics; Coronavirus Infections - immunology; Coronavirus Infections - prevention & control; Coronaviruses; COVID-19; COVID-19 Vaccines; Crystal structure; Crystallography, X-Ray; Design; Drug development; Feedback (Response); Humans; IgG antibody; Immunoglobulin G; Immunoglobulin Heavy Chains - chemistry; Immunoglobulin Heavy Chains - genetics; Immunoglobulin Heavy Chains - immunology; Immunoglobulins; Immunology; Maturation; Mutation; Neutralizing; Pandemics - prevention & control; Pneumonia, Viral - immunology; Pneumonia, Viral - prevention & control; Protein Domains; Proteins; Receptors; Recognition; Residues; Respiratory diseases; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Spike protein; Vaccine development; Vaccines; Variable region; Viral diseases; Viral Vaccines - chemistry; Viral Vaccines - genetics; Viral Vaccines - immunology
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abd2321

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.