CD56 bright NK cells are negatively associated with antibody response to vaccination in people with multiple sclerosis on B‐cell‐depleting therapy

Abstract Objectives We sought to identify determinants of vaccine response in people with multiple sclerosis (pwMS) receiving B‐cell‐depleting therapies. Methods This was a prospective single‐centre cohort study (ACTRN12623001249640). Peripheral blood samples were collected from pwMS receiving ocrelizumab ( n = 38) before and after a third dose of COVID‐19 mRNA vaccine. Immunogenicity was measured by T‐cell IFN‐γ ELISpot, antibody titres and live virus neutralisation. Humoral immunity was benchmarked against pwMS receiving natalizumab ( n = 15), and against a correlate of real‐world protection (50% reduction in incidence of infection). The peripheral immune phenotype was assessed by high‐parameter flow cytometry and tested for association with vaccine response. Results CD20 + T cells, natural killer (NK) cells and B cells were lower in pwMS receiving ocrelizumab, while CD27 + CD38 + T‐cell and CD8 + NK cell frequencies were elevated relative to natalizumab. Following a third dose, 51% of pwMS on ocrelizumab were seropositive for SARS‐CoV‐2 receptor‐binding domain Ig, and 25% and 14% met the threshold for effective neutralisation of live ancestral and omicron BA.5 virus, respectively. B‐cell frequency at the time of vaccination, but not time since ocrelizumab infusion, positively correlated with antibody response. Immunomodulatory CD56 bright NK cells were negatively associated with antibody response. CD3 − CD20 + B cells (% of lymphocytes) and CD56 bright NK cells (% of NK cells) were associated with effective virus neutralisation in prior non‐responders. Conclusion Time since ocrelizumab infusion was not associated with protective vaccination. Evaluation of B‐cell and CD56 bright NK cell frequencies may provide a personalised strategy to stratify pwMS for vaccination and prophylaxis.