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

Montague, Zachary; Lv, Huibin; Otwinowski, Jakub; DeWitt, William S.; Isacchini, Giulio; Yip, Garrick K.; Ng, Wilson W.; Tsang, Owen Tak-Yin; Yuan, Meng; Liu, Hejun; Wilson, Ian A.; Peiris, J. S. Malik; Wu, Nicholas C.; Nourmohammad, Armita; Mok, Chris Ka Pun

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.