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

Jared Feldman,Nathania Hartojo,Kerri St Denis,Goran Bajic,Blake M Hauser,Aaron G Schmidt,Larance Ronsard,Daniel Lingwood,Julia Bals,Maya Sangesland,Thalia Bracamonte Moreno,Alejandro B Balazs,Clara G Altomare,Evan C Lam,Vintus Okonkwo

doi:10.1126/sciimmunol.abl5842

Abstract

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.

Highlights

Initial exposure to viral antigens by natural infection or vaccination primes an immune response and often establishes immune memory which can prevent or control future infections
We showed that coronavirus-specific naive B cells are present across distinct seronegative donors, are of unrestricted gene usage and when recombinantly expressed as IgGs, have affinity for SARS-CoV2 receptor binding domain (RBD), circulating variants of concern, and at least four related coronaviruses
These data suggest that RBD-specific precursors are likely present across a large fraction of individual human naive repertories, consistent with longitudinal studies of SARS-CoV-2 infected individuals in which most convalescent individuals seroconverted with detectable RBD serum antibodies and neutralization titers [9, 36]

Summary

Introduction

Initial exposure to viral antigens by natural infection or vaccination primes an immune response and often establishes immune memory which can prevent or control future infections. For SARS-CoV-2, the etiological agent of COVID-19, the development of a neutralizing antibody response after primary infection or vaccination is associated with protection against reinfection in non-human primates [4, 5]. The presence of neutralizing antibodies can predict disease severity and survival after primary SARS-CoV-2 infection [6] or vaccination [7]. The two arms of humoral immune memory, long-lived bone marrow plasma cells [8] and circulating memory B cells [9, 10], are induced by natural infection in humans and may persist for at least 8 months after primary infection, providing potentially durable long-term protection. Comparable levels of neutralizing antibody titers are present in convalescent COVID-19 subjects and vaccine recipients [11] further supporting the role of adaptive immune responses in helping to control and prevent disease severity

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