Vaccinations in Multiple Sclerosis and Risk of Relapse

Abstracts & Commentary

Sources: Ascherio A, et al. Hepatitis B vaccination and the risk of multiple sclerosis. N Engl J Med. 2001;344:327-332. Confavreux C, et al. Vaccinations and the risk of relapse in multiple sclerosis. N Engl J Med. 2001;344:319-326.

Ascherio and colleagues performed a case-control study in 2 large cohorts of nurses in the United States consisting of more than 230,000 women followed for 11 to 24 years. For each person with multiple sclerosis (MS), 5 healthy controls and 1 person with breast cancer were selected as controls. The analyses included 192 women with MS and 645 matched controls, whose hepatitis B vaccination status was confirmed by vaccination certificates. The multivariate relative risk of MS associated with exposure to the hepatitis vaccine at any time before the onset of disease was 0.9 (95% confidence interval, 0.5-1.6), and within 2 years before onset of disease was 0.7 (95% confidence interval, 0.3-1.8). Thus, there was no association between hepatitis B vaccination and the development of MS.

Confavreux and associates conducted a case-crossover study in a European database for MS to assess if vaccinations for hepatitis B, tetanus, or influenza increased the risk of relapse in MS. Patients with an index relapse confirmed by a visit to a neurologist and preceded by a 12-month relapse-free period were included in the study. Of 643 patients with MS attacks, 15% reported having been vaccinated during the preceding 12 months (94% confirmed by medical records). In these patients, 2.3% had been vaccinated during the preceding 2-month period, vs. 2.8-4.0% that were vaccinated in the 3- to 12-month period prior to the index attack. The relative risk of relapse associated with exposure to any vaccine was 0.71 (95% confidence interval 0.4-1.2), indicating that vaccination did not increase the short-term risk of relapse in MS.


The safety of vaccinations in patients with MS has been debated for decades, with many reports of relapses and clinical onset of disease after vaccination. Small studies of influenza vaccination in MS patients have been reassuring (Neurology. 1997;49:312-314), yet clinicians remain reluctant to vaccinate persons with MS. Concerns increased following a mass hepatitis B vaccination program in France between 1995 and 1997, where several reports of new onset of MS were described a few weeks following immunization. However, as these carefully conducted case-controlled studies above appear to indicate, a significant increase in MS relapses with vaccination cannot be confirmed. One shortcoming of the European study by Confavreux et al is that the study design did not allow the index relapse to be the "first attack", or clinical onset of disease. Since only patients with established MS were retrospectively analyzed, they could not capture persons whose first episode might have been temporarially associated with vaccination.

Some clinicians may be convinced by their own anectdotal experiences with MS relapses following vaccination that there is cause and effect. Indeed, if MS attacks appear to correlate with a variety of viral infectious illness, it is a reasonable extrapolation that the viral antigenic stimulation of a vaccine could specifically or nonspecifically activate immune responses to trigger a relapse. However, the very unpredictable nature of this poorly understood relapsing disease makes it impossible to draw such conclusions. As the above reports indicate, the risk of relapse in MS with vaccination is small, and the public health benefits of mass immunization are great. —Brian R. Apatoff