نبذة مختصرة : International audience ; Disease-modifying therapies (DMT) administered to patients with multiple sclerosis (MS) can influence immune responses to SARS-CoV-2 and vaccine efficacy. However, data on the detailed phenotypic, functional and metabolic characteristics of antigen (Ag)-specific cells following the third dose of mRNA vaccine remain scarce. Here, using flow cytometry and 45-parameter mass cytometry, we broadly investigate the phenotype, function and the single-cell metabolic profile of SARS-CoV-2-specific T and B cells up to 8 months after the third dose of mRNA vaccine in a cohort of 94 patients with MS treated with different DMT, including cladribine, dimethyl fumarate, fingolimod, interferon, natalizumab, teriflunomide, rituximab or ocrelizumab. Almost all patients display functional immune response to SARS-CoV-2. Different metabolic profiles characterize antigen-specific-T and -B cell response in fingolimodand natalizumab-treated patients, whose immune response differs from all the other MS treatments. The immunosuppressive and immunomodulatory disease-modifying therapies (DMT) used for multiple sclerosis (MS) act at different levels, i.e., inhibiting the expansion of activated lymphocytes (teriflunomide), redirecting pathological immune cells away from the central nervous system [natalizumab, fingolimod (FTY)] or depleting immune cell subsets (B and T cells; anti-CD20, cladribine) 1 . In treated patients, DMT can introduce risk for increased infections, reduced vaccine effectiveness or reduce the duration of specific immunity. These aspects are of critical importance, especially in the course of a pandemic such as that due to SARS-CoV-2, where the host immune response is crucial 2-12 , and that was effectively fought by several different vaccines. In patients with MS, DMT such as interferon (IFN)-β, glatiramer acetate and dimethyl fumarate (DMF) are not expected to compromise
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