Importance: Scientific literature is sparse about the association of vaccination with the onset of multiple sclerosis (MS) flare-ups. Immunization by vaccines of the entire population is crucially important for public health.

Objective: To evaluate the risk of hospitalization for severe MS flare-ups after vaccination in patients with MS.

Design, setting, participants: This cohort study included patients diagnosed with MS between January 1, 2007, and December 31, 2017, who were included in the System of National Health Databases, a national health claims database in France. In a nested case-crossover analysis, cases were defined by vaccine exposure prior to the onset of hospitalization due to an MS flare-up, and flare-up rates were compared with those that occurred prior to vaccine exposure in up to 4 control time windows immediately preceding the at-risk time window (ie, the MS flare-up) for each patient. Data were analyzed from January 2022 to December 2022.

Exposure: Receipt of at least 1 vaccination, including the diphtheria, tetanus, poliomyelitis, pertussis, or Haemophilus influenzae (DTPPHi) vaccine, influenza vaccine, and pneumococcal vaccine, during follow-up.

Main outcomes and measures: The primary outcome was the risk of hospitalization for an MS flare-up after receipt of a vaccine. Adjusted odds ratios (AORs) and 95% CIs were derived using conditional logistic regression to measure the risk of hospitalization for an MS flare-up associated with vaccination.

Results: A total of 106 523 patients constituted the MS cohort (mean [SD] age, 43.9 [13.8] years; 76 471 females [71.8%]; 33 864 patients [31.8%] had incident MS and 72 659 patients [68.2%] had prevalent MS) and were followed up for a mean (SD) of 8.8 (3.1) years. Of these patients, 35 265 (33.1%) were hospitalized for MS flare-ups during the follow-up period for a total of 54 036 MS-related hospitalizations. The AORs of hospitalization for an MS flare-up and vaccine exposure in the 60 days prior to the flare-up were 1.00 (95% CI, 0.92-1.09) for all vaccines, 0.95 (95% CI, 0.82-1.11) for the DTPPHi, 0.98 (95% CI, 0.88-1.09) for the influenza vaccine, and 1.20 (95% CI, 0.94-1.55) for the pneumococcal vaccine.

Conclusions and relevance: A nationwide study of the French population found no association between vaccination and the risk of hospitalization due to MS flare-ups. However, considering the number of vaccine subtypes available, further studies are needed to confirm these results.