Novel B cell epitope discovery against human coronaviruses

PROJECT SUMMARY Human coronaviruses have caused devastating global pandemics and epidemics and continue to threaten global public health. Coronaviruses are highly variable, which has led evasion of most neutralizing antibodies and reduction in vaccine effectiveness. Many potent antibodies to coronaviruses have very limited breadth, while some of the broadest neutralizing antibodies described to date exhibit notably lower neutralization potency. Thus, the exigency to capitalize on what we have learned during the SARS-CoV-2 pandemic to find novel epitopes that elicit broad and potent antibodies against the coronavirus family and enhance pandemic preparedness. We have developed a highly integrated platform for identification of B cell epitopes against coronaviruses. Our previous studies revealed over ten B cell epitopes on the SARS-CoV-2 spike, through comprehensive characterization and high-resolution structure determination. This project aims to identify novel B cell epitopes on SARS-CoV-2 and other human coronaviruses, focusing on conserved and cryptic epitopes that elicit broadly neutralizing antibodies. Specifically, we will (1) identify unexplored epitopes on the SARS-CoV-2 spike protein, (2) uncover cryptic epitopes that have been largely understudied, and (3) identify pan-sarbecovirus, pan- betacoronavirus, and pan-coronavirus epitopes. Collectively, utilizing diverse donor samples, state-of-the-art multi-bait B cell isolation strategies, and high-throughput structural biology, this research aims to uncover novel B cell epitopes that inform on the design of next-generation vaccines and therapeutics, enhancing our preparedness for future coronavirus pandemics.