A vaccine used in some countries to prevent tuberculosis given very early in the course of multiple sclerosis (MS) appears to slow its development, preliminary results suggest.
In the study, published online December 4 in Neurology, individuals with clinically isolated syndrome (CIS) given the Bacille Calmette-Guérin (BCG) vaccine had fewer MS type lesions and a lower probability of developing clinically definite MS in the 5-year follow-up period.
Lead author, Giovanni Ristori, MD, University of Rome, Italy, explained to Medscape Medical News that a pilot study conducted in the 1990s had suggested reduced MRI activity in patients with MS given BCG vaccine. "As the vaccine is known to be safe, we thought it would be a good idea to test it in the very earliest stages of MS — in patients with CIS." "We did show an effect, with a reduction in MRI activity in the vaccinated group — mean of 3 lesions versus 7 lesions in the unvaccinated group," Dr. Ristori added. "And in addition, 58% of the vaccinated group remained relapse free over the 5-year follow-up versus 30% of unvaccinated controls. While these results must still be thought of as preliminary and no clinical recommendations can be made, they do justify further studies to look at this intriguing effect."
Mechanism Unclear
He noted that the mechanism behind the effects was not clear, but there appears to be a link between autoimmunity and infections.
"Our idea is that infections may increase the risk of MS development but benign microbial exposure may be protective. One theory on why there has been an increase in of immune disease and allergies in recent times is that the use of antibiotics and cleaner environments has reduced our exposure to microbes at an early age. Vaccines provide benign exposure to microbes, provoking an immune reaction without dangerous signals."
Dr. Ristori added that there has been some experience with type 1 diabetes in which the BCG vaccine has been associated with an improvement in the course of the disease over long-term follow-up. "We wanted to see if the same thing happened in MS."
For the study, 82 individuals with a first demyelinating episode and MRI lesions suggestive of MS were randomly assigned to BCG vaccine or placebo and were monitored monthly with brain MRI. Both groups then entered a preplanned phase with intramuscular interferon β-1a for 12 months. From month 18 onward, the patients took the disease-modifying therapies (DMTs) that their neurologist considered indicated in an open-label extension phase lasting up to 60 months.
A total of 73 patients completed the study: 33 vaccinated patients and 40 who received placebo. During the initial 6 months, the number of cumulative lesions was significantly lower in those who had received the BCG vaccine.
Table 1. Mean Number of Lesions on MRI by Treatment and Relative Risk
| Lesion Type | BCG Group (n = 33) | Placebo Group (n = 40) | Relative Risk (95% Confidence Interval) | P Value |
| Total gadolinium-enhancing (primary endpoint) | 3.09 | 6.62 | 0.541 (0.308 - 0.956) | .03 |
| New and enlarging T2 hyperintense | 3.21 | 7.67 | 0.364 (0.207 - 0.639) | .001 |
| New T1 hypointense | 0.18 | 0.90 | 0.149 (0.046 - 0.416) | .001 |
Clinical results showed that after 5 years of follow-up, the cumulative probability of clinically definite MS was lower in the BCG group, and more vaccinated people remained free of disease-modifying therapies.
Table 2. Risk for Clinically Definite MS or MS Treatment With Vaccination vs No Vaccination
| Outcome | Hazard Ratio (95% Confidence Interval) | P Value |
| Clinically definite MS | 0.52 (0.27 - 0.99) | .05 |
| Free of DMTs | 0.20 (0.04 - 0.93) | .04 |
The researchers conclude that "BCG vaccination appears to have early beneficial effects and possibly long-term action in persons with CIS, supporting previous observations in patients with MS."
They suggest that pleiotropic pathways may help explain the action of BCG in MS. These include "antigenic competition and traffic diversion of autoreactive T cells; the immunomodulatory action of effectors, which are usually associated with proinflammatory pathways; and the development of regulatory cells that are activated by adjuvant approaches and other microbial products, or by exposure to parasites, providing support to the view ('hygiene hypothesis') that 'Western' habits have facilitated the development of immune disorders in recent decades….
"Taken as a whole, our results warrant future phase 3 trials in people with CIS, with additional outcome measures (whole brain and gray matter atrophy, among others) especially aimed at verifying a potential neuroprotective effect. Moreover, our findings demonstrate the feasibility and possible benefit of safe, inexpensive, and handy approaches immediately after the first demyelinating episode," the authors comment.
In an accompanying editorial, Dennis Bourdette, MD, Oregon Health & Science University, and Robert T. Naismith, MD, Washington University, St. Louis, note that this study and others suggest that infections are not always deleterious for people with MS. "Some may be beneficial and even open doors to new therapies for MS."
They caution, however, that clinicians should not use BCG to treat CIS or MS off-label because its efficacy is not established and its safety with repeated dosing is unknown. They point out that this study provides Class I evidence based on design methods, but the sample size was small, the controlled part of the study was relatively short, and a larger trial demonstrating similar results with acceptable safety is needed to know whether BCG is truly effective.
"We should encourage investigations into understanding how BCG might induce immunoprotection and hope that this knowledge leads to the development of a 'safe, inexpensive, and handy' therapy for MS," they conclude.
Neurology. Published online December 4, 2013. Abstract Editorial
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