Persistent Classical and Atypical Memory B Cells Underlie Heterogeneous Vaccine Responses in Ocrelizumab-Treated Multiple Sclerosis

Patients with multiple sclerosis (pwMS) treated with ocrelizumab (OCR), a B-cell-depleting therapy, exhibit heterogeneous humoral responses to SARS-CoV-2 mRNA vaccination. The mechanisms underlying this heterogeneity remain poorly understood. We performed a longitudinal analysis of antigen-specific T and B cell responses in OCR-treated pwMS and non-MS healthy controls following vaccination. Based on post-vaccination anti-Spike IgG titers, pwMS were categorized as ‘super-responders’ (SR), ‘responders’ (R), or ‘non-responders’ (NR). We investigated how immune cell composition, timing of OCR infusion, and lymphocyte subset dynamics influenced humoral response outcomes. While CD4 ⁺ and CD8 ⁺ T cell populations were largely preserved across all OCR-treated pwMS, distinct differences in the representation of residual B cell composition distinguished responders from non-responders. Notably, CD19 ⁺ CD27 ⁺ classical memory B cells and CD19 ⁺ CD27-IgD-T-bet ⁺ CD11c ⁺ CXCR5-DN2-like B cells persisted following OCR infusion and were enriched in the SR group compared to the NR group. Our findings identify persistent memory B cell subsets that escape OCR depletion as key immune correlates and mechanistic mediators of vaccine responsiveness in OCR-treated pwMS, highlighting potential targets to enhance vaccine efficacy in this population. All participating patients were enrolled in clinical trials NCT04843774 and NCT04682548 .