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

Cell
Authors
Keywords
Abstract

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.

Year of Publication
2021
Journal
Cell
Volume
184
Issue
12
Pages
3205-3221.e24
Date Published
2021 06 10
ISSN
1097-4172
DOI
10.1016/j.cell.2021.04.032
PubMed ID
34015271
PubMed Central ID
PMC8064835
Links
Grant list
R33 AI122390 / AI / NIAID NIH HHS / United States
P30 DK043351 / DK / NIDDK NIH HHS / United States
K08 AI120898 / AI / NIAID NIH HHS / United States
P01 AI138938 / AI / NIAID NIH HHS / United States
R21 AI122390 / AI / NIAID NIH HHS / United States
P50 AI150464 / AI / NIAID NIH HHS / United States
U19 AI142784 / AI / NIAID NIH HHS / United States
DP1 DA046100 / DA / NIDA NIH HHS / United States