Humoral and cell-based responses following SARS-CoV-2 mRNA vaccination of patients with multiple sclerosis on B-cell depleting therapy

Introduction: Anti-CD20 treated MS patients may have higher risk of severe SARS-CoV-2. Early reports indicate they mount attenuated antibody responses to SARS-CoV-2 vaccines, raising significant concerns about their protection, and the merit of aCD20 infusion delay to enable more robust vaccine responses. Little is known about cellular responses (particularly spike-antigen-specific T-cell responses) to these vaccines in B cell-depleted state. Aims: To characterize the magnitude and kinetics of both antibody-and cell-based responses to SARS-CoV-2 mRNA vaccines in aCD20 treated MS patients, compared to healthy controls (HC). Methods: Both humoral IgG responses to Spike (S) protein and its receptor-binding-domain (RBD), as well as Spike-reactive B cells (flow cytometry) and S-protein-specific CD4+ and CD8+ T-cell responses (activation-induced marker/AIM assays), were serially assessed in 21 MS patients on aCD20 therapy and 10 HC, pre-and post-SARS-CoV-2 mRNA vaccination (pre-vaccine-T1;10 days post primary-T2, pre-booster-T3;10-day post-booster-T4 and 30 days post-booster-T5). Results: Antibodies to both S-protein and RBD were induced in 100% of HC by T4 and, with some lag (by T5), in 89% and 50% of MS patients, respectively. Mean Spike-IgG concentrations for HC and MS patients at T5 were 165.3± 201.9 units/mL (u/ml) and 22.3± 58.2 u/mL respectively (p=0.0004);and 97± 136 u/ mL(HC) and 10.2± 29 u/mL (MS) (p<0.0001) for RBD-IgG. All 6 patients vaccinated longer than 20 weeks after the last aCD20 treatment exhibited partial B-cell reconstitution, and all had measurable spike-specific memory B-cells at T5. All MS patients and HC mounted CD4+ and CD8+ T-cell responses to vaccine. Expansion of activated (Ki67+CD38+) CD4+ T-cells was robust in HC and somewhat attenuated in MS patients (p= 0.03), while expansion of activated (Ki67+CD38+) CD8+ T cells was robust in both cohorts. In AIM assays, spike-antigen-specific responses of CD4+ T-cells of patients were similarly mildly attenuated compared to HC, while those of CD8+ T cells were similarly robust for both patients and HC. Conclusion: In spite of attenuated humoral SARS-CoV-2 mRNA vaccine responses, aCD20 treated patients mount robust CD8+ and mildly attenuated CD4+ T-cell responses. Longer time from last aCD20 infusion may enable more robust humoral and cell-based responses. It will be important to study how cell-based responses relate to protection, complications and risk of infecting others.