A recent study published in Science  supports the hypothesis that multiple sclerosis (MS) could be causally triggered by infection with the Epstein-Barr virus (EBV). The study evaluated longitudinally the Data from 10 million members of the US military. Infection with the pathogen from the herpes virus family increased the risk of MS among US soldiers by a factor of 32. The study group suggests that future vaccination against EBV could be an option to potentially reduce the incidence of MS. Moderna has developed an mRNA vaccine against EBV, which is currently in the first phase of clinical testing . But many questions remain unanswered.
“The results of the study published in Science are remarkable. Although these are ‘only’ observational data, the high number of participants, the exclusion of confounders and covariates, and the impressive result reinforce the hypothesis that infection with EBV can cause MS, a hypothesis that the scientific community already supports has been discussed for a long time,” explains Prof. Dr. Ralf Gold, Bochum, former President of the DGN. “The data now support the finding that EBV is most likely a trigger of MS, although perhaps not the only one.”
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The study examined over 10 million US service members between 1993 and 2013. All service members were screened for HIV before admission and these samples, if available, were used to detect prior EBV infection. As in the general population, the EBV prevalence was high, with only 5.3% of the samples being EBV negative. The researchers then evaluated how many people in the cohort developed MS and what their EBV status was. 955 people developed MS during their military service, serum samples were available from 801, most even up to three serum samples during the course before the MS diagnosis was made. Only one of the 801 cases was EBV negative – all other cases occurred in the group infected with EBV. Most MS cases emerged a median of five years after the first EBV-positive sample (all between one and 10 years).
This is a case-control study and for each person with MS, two matched controls were included who were comparable in terms of age, gender, ethnicity, etc., but did not have MS. What was interesting was that those suffering from MS had an extremely high seroconversion rate of 97%, ie they had many antibodies against EBV, while the healthy controls had a seroconversion rate of only 57% (p<0.001).
“These data suggest a causal relationship between EBV infection and MS and show that EBV is most likely not just a risk factor, but a trigger. The most important risk for MS to date, human leukocyte antigen (HLA)-DRB1*15:01, is associated with a three-fold increased risk of disease – and we now see a 32-fold risk for EBV, which is enormous and suggests a causal relationship indicates,” explains the MS expert from Bochum. “But we cannot say whether EBV is the only trigger, ultimately there was also a case in the group of EBV-negative people.” Although the authors discussed that an infection may already have been present in the case, but that the immune reaction could not have been measurable, they concede that it was also a “spontaneous”, non-EBV-associated case could.
To rule out bias because people predisposed to herpesviruses may also be predisposed to MS, levels of antibodies to cytomegalovirus (CMV), another common virus of the herpes family, were also measured how EBV is transmitted via saliva. However, there was no such correlation here, on the contrary: the CMV-positive people in this study had a lower risk of MS.
“Against the background of these data, vaccination against EBV is gaining in relevance, especially for population groups that are more at risk. For example, women are twice as likely to be affected by MS as men. Vaccination against EBV could also be interesting and efficient because it may not only prevent MS, but also various types of cancer,” adds Prof. Dr. Peter Berlit, Secretary General of the DGN. There is no approved EBV vaccine yet, but various companies are working on it, including Moderna. In addition to the effectiveness and safety of the EBV vaccine, there are also unanswered questions about when and how often vaccination must be carried out. Equally important is the development of criteria for the selection of people with a high risk of MS. “There is still a long way to go to a vaccination against MS – and if a vaccine is available, the question remains how high its acceptance in the population will be. Ultimately, Corona revealed a very high level of vaccination skepticism among the population.”
 Bjornevik K, Cortese M, Healy BC et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 13 Jan 2022. DOI: 10.1126/science.abj8222.
 A Study of an Epstein-Barr Virus (EBV) Candidate Vaccine, mRNA-1189, in 18- to 30-Year-Old Healthy Adults. ClinicalTrials.gov Identifier: NCT05164094.
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