B cell genomics behind cross-neutralization of SARS-CoV-2 variants and SARS-CoV

• Published in: Cell Vol. 184; no. 12; pp. 3205 - 3221.e24
• Main Authors: Scheid, Johannes F., Barnes, Christopher O., Eraslan, Basak, Hudak, Andrew, Keeffe, Jennifer R., Cosimi, Lisa A., Brown, Eric M., Muecksch, Frauke, Weisblum, Yiska, Zhang, Shuting, Delorey, Toni, Woolley, Ann E., Ghantous, Fadi, Park, Sung-Moo, Phillips, Devan, Tusi, Betsabeh, Huey-Tubman, Kathryn E., Cohen, Alexander A., Gnanapragasam, Priyanthi N.P., Rzasa, Kara, Hatziioanno, Theodora, Durney, Michael A., Gu, Xiebin, Tada, Takuya, Landau, Nathaniel R., West, Anthony P., Rozenblatt-Rosen, Orit, Seaman, Michael S., Baden, Lindsey R., Graham, Daniel B., Deguine, Jacques, Bieniasz, Paul D., Regev, Aviv, Hung, Deborah, Bjorkman, Pamela J., Xavier, Ramnik J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.06.2021
• Subjects: Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - immunology; Antibodies, Neutralizing - blood; Antibodies, Neutralizing - chemistry; Antibodies, Neutralizing - immunology; Antibodies, Viral - blood; Antibodies, Viral - chemistry; Antibodies, Viral - immunology; Antigen-Antibody Complex - chemistry; Antigen-Antibody Complex - metabolism; Antigen-Antibody Reactions; B-Lymphocytes - cytology; B-Lymphocytes - metabolism; B-Lymphocytes - virology; COVID-19; COVID-19 - pathology; COVID-19 - virology; cryo-electron microscopy; Cryoelectron Microscopy; Crystallography, X-Ray; disordered CDRH3; Gene Expression Profiling; Humans; Immunoglobulin A - immunology; Immunoglobulin Variable Region - chemistry; Immunoglobulin Variable Region - genetics; memory B cells; monoclonal antibodies; Protein Domains - immunology; Protein Multimerization; Protein Structure, Quaternary; SARS-CoV cross-neutralization; SARS-CoV-2 - immunology; SARS-CoV-2 - isolation & purification; SARS-CoV-2 - metabolism; Sequence Analysis, RNA; single B cell genomics; Spike Glycoprotein, Coronavirus - chemistry; Spike Glycoprotein, Coronavirus - genetics; Spike Glycoprotein, Coronavirus - immunology; Spike Glycoprotein, Coronavirus - metabolism; COVID-19; single B cell genomics; disordered CDRH3; memory B cells; SARS-CoV cross-neutralization; monoclonal antibodies; cryo-electron microscopy
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2021.04.032

Monoclonal antibodies (mAbs) are a focus in vaccine and therapeutic design to counteract severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants. Here, we combined B cell sorting with single-cell VDJ and RNA sequencing (RNA-seq) and mAb structures to characterize B cell responses against SARS-CoV-2. We show that the SARS-CoV-2-specific B cell repertoire consists of transcriptionally distinct B cell populations with cells producing potently neutralizing antibodies (nAbs) localized in two clusters that resemble memory and activated B cells. Cryo-electron microscopy structures of selected nAbs from these two clusters complexed with SARS-CoV-2 spike trimers show recognition of various receptor-binding domain (RBD) epitopes. One of these mAbs, BG10-19, locks the spike trimer in a closed conformation to potently neutralize SARS-CoV-2, the recently arising mutants B.1.1.7 and B.1.351, and SARS-CoV and cross-reacts with heterologous RBDs. Together, our results characterize transcriptional differences among SARS-CoV-2-specific B cells and uncover cross-neutralizing Ab targets that will inform immunogen and therapeutic design against coronaviruses. [Display omitted] •SARS-CoV-2-specific B cell repertoire includes transcriptionally distinct B cells•14 out of 15 potent neutralizers are from two clusters, memory and activated B cells•BG10-19 locks the spike trimer in a closed conformation to potently neutralize SARS-CoV-2•Several potent antibodies, including BG10-19, neutralize SARS-CoV-2 variants of concern B cell genomics reveals transcriptionally distinct populations that modulate antibody responses to SARS-CoV-2, with the identification of a monoclonal antibody that locks the virus spike trimer to neutralize recent variants, SARS and heterologous RBDs.