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Persistently reduced humoral and cellular immune response following third SARS-CoV-2 mRNA vaccination in anti-CD20-treated multiple sclerosis patients

Objective: To examine humoral and cellular response in multiple sclerosis patients on anti-CD20 therapy after third BNT162b2 mRNA SARS-CoV-2 vaccination. Methods A prospective longitudinal study design from first throughout third vaccination in Danish and American MS centers. All participants were treated with ocrelizumab. Antibody (Ab) levels were assessed before and after third vaccination using SARS-CoV-2 IgG II Quant assay (Abbott Laboratories). B- and T-lymphocytes enumeration was done with BD Multitest(TM)6-color TBNK reagent. Spike-specific T-cell responses were measured through PBMC stimulation with spike peptide pools (JPT Peptide Technologies). Results: We found that 14.0%, 37.7%, and 33.3% were seropositive after first, second and third vaccination. The median Ab-levels were 74.2 BAU/mL (range: 8.5-2427), 43.7 BAU/ml (range: 7.8-366.1) and 31.3 BAU/mL (range: 7.9-507.0) after first, second and third vaccination, respectively. No difference was found in levels after second and third vaccination (p=0.1475). Seropositivity dropped to 25.0% of participants before the third vaccination, a relative reduction of 33.3% (p=0.0020). No difference was found between frequencies of spike reactive CD4+ and CD8+ T-cells after second (0.65 +/- 0.08% and 0.95 +/- 0.20%, respectively) and third vaccination (0.99 +/- 0.22% and 1.3 +/- 0.34%), respectively. Conclusion: In this longitudinal cohort we found no significant increased humoral or cellular response with administration of a third SARS-CoV-2 mRNA vaccination. These findings suggest the need for clinical strategies to include allowance of B cell reconstitution before repeat vaccination and/or provision of pre-exposure prophylactic monoclonal antibodies.