Journal
SCIENCE IMMUNOLOGY
Volume 6, Issue 66, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.abl5842
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Funding
- NIH [R01AI146779, R01AI124378, R01AI137057, R01AI153098, R01AI155447, DP2DA042422, DP2DA040254, T32 AI007245]
- Massachusetts Consortium on Pathogen Readiness (MassCPR) grant
- MGH Transformative Scholars Program
- Charles H. Hood Foundation
- Public Health Service Institutional Research Training Award [AI07647]
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Exposure to pathogens triggers adaptive immune responses; understanding the naive B cell repertoire aids in mounting protective responses; naive antibodies can recognize and neutralize SARS-CoV-2.
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 higheraffinity 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.
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