Live Attenuated Measles-Mumps-Rubella and Varicella Vaccinations and Multiple Sclerosis Activity

Importance Live attenuated measles-mumps-rubella (MMR) and varicella vaccines are recommended for immunocompetent people with multiple sclerosis (MS) lacking immunity. However, concerns about postvaccination relapses may contribute to vaccine hesitancy, and robust data addressing this risk remain limited. Objective To assess whether the risk of MS relapse within 1 year after MMR or varicella vaccination is not unacceptably worse than risk after no such vaccination based on a predefined noninferiority margin. Design, Setting, and Participants This cohort study used prospectively collected data from July 2016 to October 2024 for people with MS at a tertiary MS center in Barcelona, Spain, who received at least 1 dose of live attenuated MMR and/or varicella vaccine due to serologic susceptibility. Vaccinated patients were matched 1:2 with unvaccinated control individuals with MS by sex, age, and epoch of first demyelinating event. Exposures Live attenuated MMR and/or varicella vaccine. Main Outcomes and Measures Primary outcomes were relapse count and time to first relapse within 1 year of time 0, analyzed using Poisson and Cox proportional hazards regression models with inverse probability weighting based on a propensity score including treatment category, Expanded Disability Status Scale score, and annualized relapse rate in the prior year. Noninferiority was predefined as an annualized relapse rate ratio with an upper bound of the 95% CI less than 1.4. Results A total of 369 people with MS were included, of whom 123 were vaccinated (mean [SD] age, 28.75 [8.72] years; 85 females [69.1%]) and matched to 246 unvaccinated controls (mean [SD] age, 28.66 [8.60] years; 170 females [69.1%]). Overall, 36 relapse events were observed (15 [41.7%] among vaccinated patients and 21 [58.3%] among unvaccinated controls). In the weighted Poisson model, although relapse incidence was not significantly different between vaccinated and unvaccinated individuals (incidence rate ratio, 0.52; 95% CI, 0.23-1.06), the noninferiority criterion was met. Similarly, weighted Cox proportional hazards regression models showed no difference in hazard of relapse between groups (hazard ratio [HR], 0.55; 95% CI, 0.25-1.17) but the noninferiority criterion was met. Sensitivity and exploratory analyses, including time-dependent adjustment for postbaseline treatment exposure (HR, 0.60; 95% CI, 0.27-1.33), restriction to the high-risk period (n = 15 events), and comparisons of magnetic resonance imaging before (n = 43 events) and after (n = 21 events) exposure in vaccinated patients, revealed findings consistent with those of the primary analysis. Conclusions and Relevance In this cohort study of nonimmunosuppressed people with MS, vaccination with live attenuated MMR or varicella vaccine was not associated with increased risk of postvaccination relapse. The results support the administration of these vaccines when indicated and may help reassure clinicians and patients, reducing vaccine hesitancy.