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
Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Cell. 2021 Jun 10;184(12):3205-3221.e24. doi: 10.1016/j.cell.2021.04.032. Epub 2021 Apr 24.
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.
单克隆抗体（mAb）是疫苗和治疗性设计的重点，用于对抗严重急性呼吸综合征冠状病毒2（SARS-CoV-2）及其变体。在此，我们将B细胞分选与单细胞VDJ和RNA测序（RNA-seq）以及单克隆抗体结构相结合，以表征针对SARS-CoV-2的B细胞反应。我们表明，SARS-CoV-2特异性B细胞库由转录上不同的B细胞群体组成，产生强效中和抗体（nAb）的细胞位于两个类似于记忆B细胞和活化B细胞的簇中。来自这两个簇的选定nAb与SARS-CoV-2刺突三聚体复合的冷冻电子显微镜结构显示了对各种受体结合域（RBD）表位的识别。其中一种单克隆抗体BG10-19将刺突三聚体锁定在封闭构象中，以有效中和SARS-CoV-2、最近出现的突变体B.1.1.7和B.1.351以及SARS-CoV，并与异源RBD发生交叉反应。总之，我们的结果表征了SARS-CoV-2特异性B细胞之间的转录差异，并揭示了交叉中和抗体靶点，这将为针对冠状病毒的免疫原和治疗设计提供信息。
