Introduction <p>Sphingosine-1-phosphate receptor (S1PR) modulators are effective therapies for multiple sclerosis (MS) that block lymphocyte egress from secondary lymphoid organs. This migration inhibition carries the risk of reduced infection-control as reported for the non-selective S1PR modulator, fingolimod. CXCL13:CXCR5-associated immune activities play a key role in protective antibody-based immunity but are also linked to inflammation in MS. Utilizing the ongoing SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic, we aimed to determine whether selective S1PR modulation with ozanimod acts on the CXCL13:CXCR5 axis for modulating MS activity and whether this impacts anti-viral immune responses.</p> Methods <p>This 1-year observational study included 20 patients with MS receiving ozanimod and 10 healthy probands. CXCR5⁺ T cells, B cells, serum CXCL13, anti-SARS-CoV-2 serostatus, and SARS-CoV-2-spike protein (ProtS)-reactive T cell responses were measured at 3-month intervals.</p> Results <p>CXCR5⁺ T and B cell frequencies and serum CXCL13, but not anti-SARS-CoV-2 responses, declined after ozanimod initiation. Anti-SARS-CoV-2 antibody and ProtS-reactive T cell responses peaked after recall vaccinations and break-through infections. Notably, ProtS-reactive T cell frequencies shifted from CD4⁺ to CD8⁺ T cell responses in patients treated with ozanimod compared to controls.</p> Conclusion <p>Selective S1P receptor modulation with ozanimod affects the CXCL13:CXCR5 axis by reducing circulating CXCR5⁺ lymphocytes and serum CXCL13, which may contribute to reduce meningeal inflammation in MS. Moreover, the anti-SARS-CoV-2 immune defense appeared to be preserved during treatment with SARS-CoV-2-reactive CD8⁺ T cells, possibly compensating the lack of CD4⁺ T cell responses. Our immunological data may well apply to other viral infections and underscore the favorable safety and efficacy profile of ozanimod.</p>