Naive human B cells engage the receptor binding domain of SARS-CoV-2, variants of concern, and related sarbecoviruses

Initial exposure to a pathogen elicits an adaptive immune response to control and eradicate the threat. Interrogating the abundance and specificity of the naive B cell repertoire drives understanding of how to mount protective responses. Here, we isolated naive B cells from eight seronegative human...

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Bibliographic Details
Published in:Science immunology 2021-12, Vol.6 (66), p.eabl5842-eabl5842
Main Authors: Feldman, Jared, Bals, Julia, Altomare, Clara G, St Denis, Kerri, Lam, Evan C, Hauser, Blake M, Ronsard, Larance, Sangesland, Maya, Moreno, Thalia Bracamonte, Okonkwo, Vintus, Hartojo, Nathania, Balazs, Alejandro B, Bajic, Goran, Lingwood, Daniel, Schmidt, Aaron G
Format: Article
Language:English
Subjects:
Antibodies, Neutralizing - immunology
Antigens, Viral - immunology
B-Lymphocytes - cytology
B-Lymphocytes - immunology
B-Lymphocytes - metabolism
Coronavirus - immunology
COVID-19 - immunology
COVID-19 Vaccines - immunology
Epitopes
Humans
Lymphocyte Activation
SARS-CoV-2 - classification
SARS-CoV-2 - immunology
SARS-CoV-2 - metabolism
Spike Glycoprotein, Coronavirus - chemistry
Spike Glycoprotein, Coronavirus - metabolism
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Summary:Initial exposure to a pathogen elicits an adaptive immune response to control and eradicate the threat. Interrogating the abundance and specificity of the naive B cell repertoire drives understanding of how to mount protective responses. Here, we isolated naive B cells from eight seronegative human donors targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain (RBD). Single-cell B cell receptor (BCR) sequencing identified diverse gene usage and no restriction on complementarity determining region length. A subset of recombinant antibodies produced by naive B cell precursors bound to SARS-CoV-2 RBD and engaged circulating variants including B.1.1.7, B.1.351, and B.1.617.2, as well as preemergent bat-derived coronaviruses RaTG13, SHC104, and WIV1. By structural characterization of a naive antibody in complex with SARS-CoV-2 spike, we identified a conserved mode of recognition shared with infection-induced antibodies. We found that representative naive antibodies could signal in a B cell activation assay, and by using directed evolution, we could select for a higher-affinity RBD interaction, conferred by a single amino acid change. The minimally mutated, affinity-matured antibodies also potently neutralized SARS-CoV-2. Understanding the SARS-CoV-2 RBD–specific naive repertoire may inform potential responses capable of recognizing future SARS-CoV-2 variants or emerging coronaviruses, enabling the development of pan-coronavirus vaccines aimed at engaging protective germline responses.
ISSN:2470-9468
2470-9468
DOI:10.1126/sciimmunol.abl5842