Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19

A wide spectrum of clinical manifestations has become a hallmark of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) COVID-19 pandemic, although the immunological underpinnings of diverse disease outcomes remain to be defined. We performed detailed characterization of B cell responses through high-dimensional flow cytometry to reveal substantial heterogeneity in both effector and immature populations. More notably, critically ill patients displayed hallmarks of extrafollicular B cell activation and shared B cell repertoire features previously described in autoimmune settings. Extrafollicular activation correlated strongly with large antibody-secreting cell expansion and early production of high concentrations of SARS-CoV-2-specific neutralizing antibodies. Yet, these patients had severe disease with elevated inflammatory biomarkers, multiorgan failure and death. Overall, these findings strongly suggest a pathogenic role for immune activation in subsets of patients with COVID-19. Our study provides further evidence that targeted immunomodulatory therapy may be beneficial in specific patient subpopulations and can be informed by careful immune profiling. Include: COVID, age 18 to 80 years; exclude: immunocompromised, oral or intravenous corticosteroids within preceding 14 days National Institutes of Health grants UL TR000424 (Emory Library IT), R01-AG054991 (to W.T.H.), U19-AI110483 Emory Autoimmunity Center of Excellence (to I.S.), P01-AI125180-01 (to I.S. and F.E.-H.L.), R37−AI049660 (to I.S.), 1R01AI121252 (to F.E.-H.L.), 1U01AI141993 (to F.E.-H.L.), R01 AI127828 (to J.E.C. and M.S.D.) and T32-HL116271-07 (to R.P.R.); HHS/NIAID/NIH contract 75N93019C00074 (to J.E.C.); Defense Advanced Research Project Agency grant HR001117S0019 (to J.E.C.); the Dolly Parton COVID-19 Research Fund at Vanderbilt; and a Fast Grants Award (to J.E.C.)