Abstract
Broadly protective vaccines against known and preemergent human coronaviruses (HCoVs) are urgently needed. To gain a deeper understanding of cross-neutralizing antibody responses, we mined the memory B cell repertoire of a convalescent severe acute respiratory syndrome (SARS) donor and identified 200 SARS coronavirus 2 (SARS-CoV-2) binding antibodies that target multiple conserved sites on the spike (S) protein. A large proportion of the non-neutralizing antibodies display high levels of somatic hypermutation and cross-react with circulating HCoVs, suggesting recall of preexisting memory B cells elicited by prior HCoV infections. Several antibodies potently cross-neutralize SARS-CoV, SARS-CoV-2, and the bat SARS-like virus WIV1 by blocking receptor attachment and inducing S1 shedding. These antibodies represent promising candidates for therapeutic intervention and reveal a target for the rational design of pan-sarbecovirus vaccines.
Highlights
I n December 2019, a novel pathogen emerged in the city of Wuhan in China’s Hubei province, causing an outbreak of atypical pneumonia [a disease known as coronavirus disease 2019 (COVID-19)]
Cognate antibody heavy- and light-chain pairs were amplified from 315 individual SARSCoV-2–reactive B cells by single-cell reverse transcription polymerase chain reaction (RT-PCR) and subsequently cloned and expressed as fulllength immunoglobulin Gs (IgGs) in an engineered strain of Saccharomyces cerevisiae [14]
To map the antigenic sites recognized by the severe acute respiratory syndrome (SARS)-CoV and SARS-CoV-2 cross-reactive antibodies isolated from donor 84, we performed binding experiments using a panel of recombinant S protein subunits and individual domains
Summary
More than 80% of the low-affinity (KDApps > 10 nM) SARS-CoV and SARS-CoV-2 crossreactive antibodies reacted with one or more of the HCoV S proteins, suggesting that SARSCoV infection may have boosted a preexisting MBC response induced by circulating HCoVs (Fig. 2B). Consistent with this hypothesis, the broadly cross-reactive antibodies showed significantly higher levels of SHM and clonal expansion compared with those that only recognized SARS-CoV and SARS-CoV-2 (Fig. 2, B to D). To map the antigenic sites recognized by the SARS-CoV and SARS-CoV-2 cross-reactive antibodies isolated from donor 84, we performed binding experiments using a panel of recombinant S protein subunits and individual domains. Antibodies. (A) Apparent binding affinities (KDApps) of SARS-CoV-2 S-specific IgGs p.f
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