Abstract Text: The effects of immunomodulation on the immune response to COVID-19 vaccination and the consequences for patients have not yet been conclusively determined. We here examined the effects of disease-modifying therapies (DMTs) on the immunogenicity of the SARS-CoV-2 mRNA vaccine in patients with multiple sclerosis (MS) in a prospective cohort study. We enrolled 126 MS patients of which 105 received either anti-CD20-based B cell depletion (aCD20-BCD), fingolimod, interferon-β, dimethyl fumarate, glatiramer acetate, teriflunomide or natalizumab, and 21 were untreated MS patients for comparison. In contrast to all other treated and untreated MS patients, a proportion of patients treated with aCD20-BCD or fingolimod exhibited defects and/or lack of any humoral response. In aCD20-BCD patients, the absence of humoral responses correlated with peripheral blood B cell numbers prior to the first vaccination and consequently with the last aCD20-BCD treatment time point. CD4+ T-cell responses were intact. However, in patients who received long-term treatment with fingolimod, we did not detect spike-reactive CD4+ T-cell responses, a defect that could not be dissolved by repeated booster vaccinations. The duration of fingolimod treatment (>29 months), rather than peripheral blood B and T cell counts prior to each vaccination, correlated with whether a humoral immune response was elicited. Our results suggest that patients treated long-term with fingolimod are at risk for severe SARS-CoV-2 infection despite booster vaccinations, which is important for clinical decision making and adapted protective measures.
