Immune response to SARS-CoV-2 mRNA vaccination in multiple sclerosis patients after rituximab treatment interruption

Peripheral B cell depletion via anti-CD20 treatment is a highly effective disease-modifying treatment in multiple sclerosis (MS) patients. A drawback of anti-CD20 treatment is poor immune responses to vaccination. While this can be mitigated by treatment interruption of at least six months prior to vaccination, the timing to resume treatment while maintaining subsequent vaccine responses remains undetermined. We characterized SARS-CoV-2 S-directed antibody and B cell responses throughout three BNT162b2 doses in MS patients, where the first two doses were given during treatment interruption. The last anti-CD20 rituximab infusion was given 1.3 years (median) prior to the first vaccine dose and re-administered four weeks after the second vaccine dose. After two vaccine doses, antibody-mediated responses in SARS-CoV-2-naive MS patients were comparable to vaccinated healthy controls, albeit with greater variation. We could demonstrate that the response to the second dose of vaccination was predictive of a boost effect after a third dose, even after re-initiation of rituximab. MS patients also exhibited lower frequencies of Decay Accelerating Factor-negative memory B cells, a suggested proxy for germinal centre activity, than healthy individuals. Our findings also offer a first indication on the potential importance of antigenic stimulation of CD27-IgD- double negative B cells and the possible long-term impairment of germinal centre activity in rituximab-treated MS patients.