Background: Evidence on SARS-CoV-2 mRNA vaccination under siponimod treatment is rare. Methods: AMA-VACC is a prospective, open-label clinical study on SARS-CoV-2 mRNA vaccination during ongoing siponimod treatment (cohort 1), during siponimod interruption (cohort 2), or during treatment with other disease-modifying therapies or without therapy (cohort 3). SARS-CoV-2-specific antibodies and T-cell reactivity were measured six months after the initial vaccination and one month after the booster. Results: 41 patients were recruited into cohort 1 (n = 17), cohort 2 (n = 4), and cohort 3 (n = 20). Seroconversion for SARS-CoV-2 neutralizing antibodies was reached by 50.0%, 100.0%, and 90.0% of patients at month 6 and by 81.3%, 100.0%, and 100.0% one month after booster (cohorts 1, 2, and 3, respectively). Antibody levels in cohort 1 increased after the booster compared to month 6 but remained lower compared to cohorts 2 and 3. T-cell responses were seen in 28.5%, 25.0%, and 73.7% at month 6 and in 28.6%, 50.0%, and 83.3% after the booster (cohorts 1, 2, and 3, respectively). In cohort 1, the extent of T-cell response was lower at month 6 compared to cohorts 2 and 3 but reached almost similar levels after the booster. Conclusions: The antibody and T-cell responses support SARS-CoV-2 (booster) vaccines in siponimod-treated patients.