Dynamics of B-cell repertoires and emergence of cross-reactive responses in COVID-19 patients with different disease severity

COVID-19 patients show varying severity of the disease ranging from asymptomatic to requiring intensive care. Although a number of monoclonal antibodies against SARS-CoV-2 have been identified, we still lack an understanding of the overall landscape of B-cell receptor (BCR) repertoires in COVID-19 patients. Here, we used high-throughput sequencing of BCR repertoires collected over multiple time points during an infection to characterize statistical and dynamical signatures of the B-cell response to SARS-CoV-2 in 19 patients with different disease severities. Based on principled statistical approaches, we determined differential sequence features of BCRs associated with different disease severity. We identified 34 significantly expanded rare clonal lineages shared among patients as candidates for a specific response to SARS-CoV-2. Moreover, we identified natural emergence of a BCR with cross-reactivity to SARS-CoV and SARS-CoV-2 in a number of patients. Overall, our results provide important insights for development of rational therapies and vaccines against COVID-19. This work was supported by DFG grant (SFB1310) on Predictability in Evolution (A.N., Z.M., J.O., G.I.), the Max Planck Society through MPRG funding (A.N., Z.M., J.O., G.I.), Department of Physics at the University of Washington (A.N., Z.M.), NIH NIAID F31AI150163 (WSD), Calmette and Yersin scholarship from the Pasteur International Network Association (H.L.), Bill and Melinda Gates Foundation OPP1170236 (I.A.W.), NIH K99 AI139445 (N.C.W.), US National Institutes of Health (contract no. HHSN272201400006C) (J.S.M.P), National Natural Science Foundation of China (NSFC)/Research Grants Council (RGC) Joint Research Scheme (N_HKU737/18) (C.K.P.M. and J.S.M.P) and the Research Grants Council of the Hong Kong Special Administrative Region, China (Project no. T11-712/19-N) (J.S.M.P).