A diverse, naive-biased B cell compartment is associated with vaccine responsiveness in SOTR

Solid organ transplant recipients (SOTR) suffer increased morbidity and mortality due, in part, to chronic immunosuppression. The determination of an individual's immune competence is currently difficult but would improve risk assessment and inform medical decisions. We reasoned that correlating qualitative and quantitative measures of the B cell compartment with serologic responses to SARS-CoV-2 would reveal novel B cell-based predictors of immune competence. We performed an integrated analysis of B cell phenotypes, serology, and antibody repertoires in heart, lung, liver, kidney, and multi-organ transplant recipients and healthcare worker (HCW) controls (n=62 individuals total). We utilized K means clustering and correlation analyses to identify B cell features that correlated with vaccine serology. K means clustering identified three distinct B cell compartment-based groups in SOTR, which correlated with serum responses to SARS-CoV-2 vaccination. Group 1 SOTR had a naive-dominant circulating B cell pool and serologic responses closest to HCW. Group 2 SOTR had reduced naive but hyper-expanded memory B cells (MBC) and variable vaccine responses that segregated by immunosuppression. Group 3 SOTR had lymphopenia across B cell subsets and poor serologic responses. Antibody repertoire analysis showed reduced clonal diversity across SOTR, regardless of MBC numbers. Even in SOTR with the largest immune responses, vaccine-specific B cells showed evidence of reduced maturation and clonal diversity. These findings reveal a hierarchy of B cell impairment in SOTR that can be measured rapidly, with implications for immune monitoring and intervention in immunocompromised individuals.