Disease-modifying therapies (DMTs) are known to impact cellular and humoral immune response in persons with multiple sclerosis (pwMS). In this study, we performed in-depth SARS-CoV-2-specific T-cell profiling using flow cytometry. T-cell immunity in pwMS with or without DMTs was evaluated before a first SARS-CoV-2 messenger ribonucleic acid (mRNA) vaccination and at one-, two- and six-month follow-up. T-cell stimulation without SARS-CoV-2-specific antigens was used as a control. T-cell response was compared to B-cell response by evaluating SARS-CoV-2-specific antibodies. We observed an upregulation of specific subpopulations of SARS-CoV-2 spike-specific CD4+ T cells. Thus, our results demonstrate the induction of a broad and distinct CD4+ T-cell response in pwMS even on anti-CD20 treatment and sphingosine-1-phosphate receptor modulation after SARS-CoV-2 mRNA vaccination. This was particularly seen in CD4+high and CD4+CD154+ T cells. Our results do not support the induction of a CD8+ T-cell immune response. While humoral immune response was impaired in pwMS during ocrelizumab and fingolimod treatment, there was evidence of a compensatory upregulation of subpopulations of SARS-CoV-2-specific CD4+ T cells at low levels of seroconversion in pwMS. In conclusion, our results provide important insights into the mechanisms of the adaptive immune response in pwMS following SARS-CoV-2 mRNA vaccination.