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

• DOI: 10.1016/j.cell.2021.04.032
• Publication Date: 2021-04-24T04:16:00Z
• Authors: Johannes F. Scheid; Christopher O. Ba...; Basak Eraslan; Andrew Hudak; Jennifer R. Keeffe; Lisa A. Cosimi; Eric M. Brown; Frauke Muecksch; Yiska Weisblum; Shuting Zhang; Toni Delorey; Ann E. Woolley; Fadi Ghantous; Sung-Moo Park; Devan Phillips; Betsabeh Tusi; Kathryn E. Huey-T...; Alexander A. Cohen; Priyanthi N.P. Gn...; Kara Rzasa; Theodora Hatziioanno; Michael A. Durney; Xiebin Gu; Takuya Tada; Nathaniel R. Landau; Anthony P. West; Orit Rozenblatt-R...; Michael S. Seaman; Lindsey R. Baden; Daniel B. Graham; Jacques Deguine; Paul D. Bieniasz; Aviv Regev; Deborah Hung; Pamela J. Bjorkman; Ramnik J. Xavier
• Keywords: 0301 basic medicine; 570; Immunoglobulin Variable Region; 610; cryo-electron microscopy; Antigen-Antibody Complex; Antibodies, Viral; Crystallography, X-Ray; Article; Antigen-Antibody Reactions; 03 medical and health sciences; disordered CDRH3; Protein Domains; memory B cells; Humans; Protein Structure, Quaternary; B-Lymphocytes; SARS-CoV cross-neutralization; SARS-CoV-2; Sequence Analysis, RNA; Gene Expression Profiling; Cryoelectron Microscopy; Antibodies, Monoclonal; COVID-19; Antibodies, Neutralizing; Immunoglobulin A; 3. Good health; single B cell genomics; Spike Glycoprotein, Coronavirus; monoclonal antibodies; Protein Multimerization

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.