Getting vaccinated wasn’t tied to an uptick in multiple sclerosis (MS) flare-ups in a large national Study from France.

Hospitalization for an MS flare showed no hint of increased likelihood in the 60 days after exposure to any vaccine (adjusted odds ratio [aOR] 1.00, 95% CI 0.92-1.09), researchers led by Lamiae Grimaldi, PharmD, PhD, of the Assistance Publique-Hôpitaux de Paris, reported in JAMA Neurology.

That was true for common vaccines: the combination diphtheria, tetanus, poliomyelitis, pertussis, and Haemophilus influenzae (DTPPHi) vaccine used in France (aOR 0.95, 95% CI 0.82-1.11), the influenza vaccine (aOR 0.98, 95% CI 0.88-1.09), and the pneumococcal vaccine (aOR 1.20, 95% CI 0.94-1.55).

The findings reinforce American Academy of Neurology guidelines recommending routine vaccinations for most MS patients. Other than patients with contraindications, only those in the midst of an MS relapse were recommended to delay vaccination and those getting immunosuppressive or immunomodulating drugs were recommended to skip live-attenuated vaccines.

“Vaccines represent one of the greatest advances in medicine for preventing morbidity and mortality. Therefore, it is essential that patients with MS benefit from them,” Grimaldi’s group wrote. “Vaccination is particularly suitable in this population since infections are known to increase the risk of MS flare-ups and exacerbate the severity of symptoms.”

The decade-long debate about whether vaccination sparks flares in MS, though, has “spurred doubts and potentially detrimental vaccination hesitancy, highlighting the need for well-conducted large-scale studies to examine the association,” Grimaldi’s group wrote.

Notably, most prior literature on vaccines and risk of MS flare-ups had focused on flu shots, “whereas this study examined the risk of flare-ups associated with several other vaccines,” the researchers noted.

Their study utilized the System of National Health Databases registry, which covers some 65 million people — more than 99% of French residents — along with claims linked to the national hospital discharge database (covering acute, long-term, and emergency visits) and death records. Patients were included if they were diagnosed from January 1, 2007, through December 31, 2017, or had a record of care during that period if diagnosed earlier.

The 106,523 MS patients (mean age 43.9 years, 71.8% females) were followed a mean of 8.8 years. During the overall 11 years of the study, 54.6% of the patients were vaccinated at some point, including 45.3% after entry in the MS cohort. The most common vaccination was DTPPHi (30.3%, mainly in those under age 34), followed by the flu shot (19.2%) and pneumococcus (7.0%, mainly in those over age 70).

MS flare-ups were defined by hospitalization of at least 1 day and night with either a principle discharge diagnosis code of a specific MS disorder or including one. Flares had to be more than 12 months either after disease onset in the incident MS group with known disease onset (“to avoid a misclassification of medical procedures related to the new MS diagnosis as flare-ups”) or at any time during follow-up for preexisting cases included into the dataset. Flare-ups were considered separate events when separated by at least 120 days.

The study design used a nested case-crossover analysis whereby cases were used as their own controls, comparing vaccine exposure in 60-day time windows before a flare-up versus the most recent four windows prior to that at-risk period to boost statistical power.

The same proportion — 2.3% — was found to have been vaccinated during a 60-day at-risk time window immediately preceding the index flare-up hospitalization as had been vaccinated during at least one of the control windows that didn’t precede a flare.

Sensitivity analyses using 30-day and 90-day time windows didn’t materially change the results, except that the slight increase in adjusted odds ratio for the pneumococcal vaccine when using the 90-day time window made it statistically significant (aOR 1.59, 95% CI 1.27-1.99).

“Information on the pneumococcal vaccine is of paramount importance as it is recommended before initiation of the biotherapies used in MS,” Grimaldi’s group pointed out. “Considering the number of vaccine subtypes available, further studies are needed to confirm these observed results.”

They also cautioned that their study could not completely rule out a small vaccine-related risk, “particularly in the case of the pneumococcal vaccine,” and had lower power for vaccines uncommonly used in the largely adult study cohort, such as the human papillomavirus, hepatitis, and measles vaccines.

On the other hand, the group noted the strength of their study in eliminating multiple individual confounders by using patients as their own controls. Also, they added: “Because health insurance in France is universal and access to care is basically unlimited, we are confident that the study identified virtually all hospitalizations occurring in all patients with MS in France over 11 years (67 million patients registered).”