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Risk of multiple sclerosis (MS) increased 32-fold after infection with Epstein-Barr virus (EBV) but was unchanged after other viral infections, a longitudinal analysis showed.

Data from more than 10 million U.S. military recruits monitored over a 20-year period -- 955 of whom were diagnosed with incident MS during their service -- showed that MS had a hazard ratio of 32.4 (95% CI 4.3-245.3, P<0.001) with EBV seroconversion compared with persistent EBV seronegativity, reported Alberto Ascherio, MD, DrPH, of the Harvard T.H. Chan School of Public Health, and co-authors in .

The findings point to MS as a complication of EBV infection, the researchers noted. "The hypothesis that EBV causes MS has been investigated by our group and others for several years, but this is the first study providing compelling evidence of causality," Ascherio said in a statement.

"This is a big step because it suggests that most MS cases could be prevented by stopping EBV infection, and that targeting EBV could lead to the discovery of a cure for MS," he added.

Multiple strands of evidence indicate the association of EBV infection with MS is causal, noted Gavin Giovannoni, MBBCh, PhD, an academic neurologist at Queen Mary University of London in England, who wasn't involved with the research.

"Now Alberto Ascherio and colleagues show in a large cohort study of young adults in the U.S. military that the risk of multiple sclerosis increased 32-fold after infection with EBV, which was unchanged after infection with other viruses, including cytomegalovirus, a closely related herpesvirus with similar patterns of transmission," Giovannoni told MedPage Today.

"In a new and exciting finding, blood neurofilament light chain levels, a marker of neurodegeneration, were seen to increase in study subjects, but only after EBV infection indicating presymptomatic MS disease onset," he added. "These findings strengthen the causal link between EBV and MS and make a compelling case for an MS prevention study using an EBV vaccine. They also support ongoing trials targeting EBV as a therapeutic strategy to treat MS."

Prior research has found increased serum antibodies to EBV in 99.5% of MS patients and 94% of healthy individuals, observed William Robinson, MD, PhD, and Lawrence Steinman, MD, both of Stanford University, in an .

"Nearly everyone is infected with EBV, but only a small fraction develop MS," Robinson and Steinman wrote. "Thus, other factors, such as genetic susceptibility, are important in MS pathogenesis."

Mechanisms linking EBV and MS remain elusive, the editorialists pointed out. Molecular mimicry is a possibility, as is EBV transformation of B cells. "In addition, EBV might mediate bystander damage to the axon and its surrounding sheath, or defective clearance of infected B cells," they wrote. "CD8+ T cells specific for EBV lytic proteins are present in MS brain lesions, and a persistent EBV infection in the CNS [central nervous system] might stimulate CD8+ T cell responses that mediate CNS injury."

In their study, Ascherio and colleagues analyzed serum samples taken biennially by the Department of Defense. They determined EBV status at the time of the first sample and the relationship between EBV infection and MS onset during the period of active duty.

Samples came from a racially diverse U.S. military population from 1993 to 2013. Most participants were under 20 at the time of their first blood collection. No participants had an MS diagnosis at baseline. Those who developed MS had symptom onset a median of 5 years after their first EBV-positive sample.

Each incident MS case was matched with two controls without MS of the same age, sex, race or ethnicity, and branch of military service. In total, 801 MS cases and 1,566 controls had samples available to assess EBV status over time.

EBV seropositivity was nearly ubiquitous at the time MS developed; only one of 801 MS cases was EBV seronegative at the time of MS onset.

Levels of serum neurofilament light, an axonal injury biomarker that's not disease-specific, rose after EBV infection in people who were EBV-negative at baseline and went on to develop MS. "There were no signs of neuroaxonal degeneration before EBV seroconversion in individuals who later developed MS, indicating that EBV infection preceded not only symptom onset but also the time of the first detectable pathological mechanisms underlying MS," Ascherio and co-authors wrote.

To assess predispositions to both infections and MS, the researchers also measured antibodies against cytomegalovirus (CMV), a herpesvirus that, like EBV, is transmitted through saliva. Among people who were CMV-negative at baseline, CMV seroconversion occurred at a similar rate in those who later developed MS and those who didn't.

"To explain a 32-fold increase in MS risk, any confounder would have to confer a >60-fold increase in risk of EBV seroconversion and a >60-fold risk of MS," Ascherio and co-authors noted.

"None of the known or suspected risk factors for MS has such strong associations," they added. "The next strongest known risk factor for MS, homozygosity for the HLA-DR15 allele, which confers a threefold increase in MS risk, is not associated with EBV positivity and thus cannot explain the EBV-MS association."

Currently, there's no way to effectively infection, but vaccines against EBV are actively being studied. Last week, Moderna in the of its mRNA EBV vaccine candidate. The phase I study will enroll approximately 270 people from around 15 U.S. centers.

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