Multiple sclerosis, immunomodulation, and immunizations: balancing the benefits.

Our patients with multiple sclerosis (MS) frequently inquire about the safety and efficacy of an annual influenza vaccination. Influenza remains a leading cause of mortality in the United States, with an estimated 20,000 deaths or more annually. Approximately 40% of all adults in the United States are vaccinated annually. The necessity of vaccination is particularly compelling for those with MS, who are twice as likely to be admitted for influenza compared to those without MS. What should we tell our patients regarding vaccinations and their diseasemodifying therapy? In 1965, Drs. Sibley and Foley reported that the immunologic response to the influenza vaccine was similar between patients with MS and healthy controls. Over the ensuing decades, much debate revolved around the safety of immunizations for patients with MS, particularly with regards to the risk of relapse or disease worsening. In 2002, the American Academy of Neurology published evidence-based guidelines that the benefit of immunizations was greater than the risk in individuals with MS, recommending that Centers for Disease Control and Prevention guidelines should be followed for the administration of ageand riskappropriate vaccinations. Further recommendations stressed the safety of inactivated vaccines and avoiding vaccination during a relapse. Presently, the National MS Society recommends the standard influenza vaccination and not the live-attenuated virus nasal spray. The high-dose, inactivated influenza vaccine (Fluzone) has not yet been studied sufficiently to recommend for those with MS. The efficacy of vaccines in providing clinical protection must take into account other therapeutic agents that alter the immune system. Since the publication of the American Academy of Neurology guidelines, there have been more than 5 new Food and Drug Administration–approved MS therapies. One study of interferon-b-treated and untreated patients with MS demonstrated a similar seroprotective response (titers $40) to influenza vaccination in 93% and 90.9%, respectively. In a more recent study comparing interferon-b and teriflunomide (7and 14-mg doses), the proportion of patients with seroprotective titers ($40) was .90% in all treatment groups (interferonb and teriflunomide), with one exception: among those patients taking teriflunomide 14 mg daily, only 76.9% demonstrated seroprotection to the specific H3N2 vaccine strain at 28 days postvaccination. These data suggest that for these MS therapies, patients demonstrate an expected titer response to vaccines. In this issue ofNeurology®, Kappos et al. report on the postvaccination response rate in fingolimodtreated patients with MS. This study was a placebocontrolled randomized study to assess the responder rate to seasonal influence vaccine and tetanus toxoid (TT) booster at 3 and 6 weeks postvaccination in 138 participants (95 in fingolimod and 43 in placebo group). Participants received either fingolimod 0.5 mg or placebo daily. The responder rate was defined as the proportion of patients demonstrating seroconversion or a substantial postvaccination increase ($4fold) in antibody titer from prevaccine in at least 1 of the 3 strains contained in the seasonal influenza vaccine or TT booster dose. The responder rate at 3 weeks postinfluenza vaccination was lower in fingolimod-treated patients compared to controls (54% vs 84%). The antibody response varied depending upon the specific strain, particularly for the novel California strain, for which few participants had high circulating titers at baseline (48.4% seroprotection for fingolimod vs 72.1% for controls). Finally, post-TT booster response rates were 57% in fingolimod and 75% in placebo groups, with similar rates,.90%, for seroprotection within both groups. If fingolimod is associated with decreased responder rates to influenza virus, how frequent is this a problem for our patients? Whereas postmarketing data specific to immunization are not known, the clinical development program included 3,916 patients, of whom 1,437 were on fingolimod, 866 on placebo, and 431 on interferon-b 1a. Upper respiratory tract infections (not otherwise specified) were similar in fingolimod and placebo groups (15.8% for fingolimod 0.5 mg vs 24.6% for placebo). The incidence of influenza during the clinical trial