B cell genomics behind cross-neutralization of SARS-CoV-2 variants and SARS-CoV.
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.
['Scheid|Johannes F|JF|', 'Barnes|Christopher O|CO|', 'Eraslan|Basak|B|', 'Hudak|Andrew|A|', 'Keeffe|Jennifer R|JR|', 'Cosimi|Lisa A|LA|', 'Brown|Eric M|EM|', 'Muecksch|Frauke|F|', 'Weisblum|Yiska|Y|', 'Zhang|Shuting|S|', 'Delorey|Toni|T|', 'Woolley|Ann E|AE|', 'Ghantous|Fadi|F|', 'Park|Sung-Moo|SM|', 'Phillips|Devan|D|', 'Tusi|Betsabeh|B|', 'Huey-Tubman|Kathryn E|KE|', 'Cohen|Alexander A|AA|', 'Gnanapragasam|Priyanthi N P|PNP|', 'Rzasa|Kara|K|', 'Hatziioanno|Theodora|T|', 'Durney|Michael A|MA|', 'Gu|Xiebin|X|', 'Tada|Takuya|T|', 'Landau|Nathaniel R|NR|', 'West|Anthony P|AP|', 'Rozenblatt-Rosen|Orit|O|', 'Seaman|Michael S|MS|', 'Baden|Lindsey R|LR|', 'Graham|Daniel B|DB|', 'Deguine|Jacques|J|', 'Bieniasz|Paul D|PD|', 'Regev|Aviv|A|', 'Hung|Deborah|D|', 'Bjorkman|Pamela J|PJ|', 'Xavier|Ramnik J|RJ|']
D000911:Antibodies, Monoclonal D057134:Antibodies, Neutralizing D000914:Antibodies, Viral D000936:Antigen-Antibody Complex D000937:Antigen-Antibody Reactions D001402:B-Lymphocytes D000086382:COVID-19 D020285:Cryoelectron Microscopy D018360:Crystallography, X-Ray D020869:Gene Expression Profiling D006801:Humans D007070:Immunoglobulin A D007135:Immunoglobulin Variable Region D000072417:Protein Domains D055503:Protein Multimerization D020836:Protein Structure, Quaternary D000086402:SARS-CoV-2 D017423:Sequence Analysis, RNA D064370:Spike Glycoprotein, Coronavirus
monoclonal antibodies cryo-electron microscopy COVID-19 SARS-CoV cross-neutralization disordered CDRH3 memory B cells single B cell genomics