Epstein-Barr Virus May Be Leading Cause of MS, Raising Risk by 32 Times

Infection with the common Epstein-Barr virus (EBV) increases the risk of developing multiple sclerosis (MS) by 32 times — the strongest link yet — according to a study looking at two decades of data from more than 10 million U.S. military members.

“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,” Alberto Ascherio, MD, the study’s senior author and a professor of epidemiology and nutrition at Harvard T.H. Chan School of Public Health, said in a university press release.

“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,” Ascherio added.

The study, “Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis,” was published in the journal Science.

Multiple sclerosis, a neurodegenerative disease characterized by abnormal immune attacks in the brain and spinal cord, is thought to be caused by a combination of genetic and environmental factors.

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An increasing number of studies have supported EBV, a herpes virus, as a major environmental risk factor of MS. EBV is one of the most common viruses, infecting about 95% of the adult population at some point in their lives.

The virus is mostly known for causing infectious mononucleosis, or mono, but its symptoms may be minor and unnoticeable in most people. After infection, it remains in the body throughout life in a dormant form inside B-cells — a type of immune cell implicated in MS.

However, evidence of causality, or a cause-and-effect relationship, has yet to be established in MS. This is mainly due to the high frequency of EBV, the rarity of MS, and the fact that 10 years appear to separate EBV infection and MS onset.

To establish causality, a study would have to identify a large number of people before they get infected and follow them over time to see who develops MS and to compare the risk of MS between those who were infected with the virus and those who were not.

In a nutshell, a study would have to show that some people who developed MS after EBV infection would not have developed the disease if they were not first infected with the virus.

Now, Ascherio and his colleagues seem to have accomplished just that.

Thanks to a 20-year collaboration with the U.S. military, the team of researchers was able to track the long-term health of more than 10 million service members on active duty. They had their blood screened for HIV at the start of their service, and every two years afterward, allowing the researchers to test those blood samples for EBV as well.

EBV infection was assessed through the presence of antibodies against the virus.

A total of 955 service members eventually developed MS during their time in the military, of whom 801 had at least three blood samples collected prior to MS — the first available, the last collected before MS onset, and one in between — and were subsequently included in the analysis. These service members were matched, based on age, sex, race, military branch, and dates of sample collection, to 1,566 who did not develop MS and served as a control group.

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Results showed that only one of the 801 people with MS had not been infected with EBV before the disease’s onset. This patient, whose last sample was obtained three months before MS onset, may have been infected after the sample was taken, or failed to develop antibodies against the virus, the team noted.

When the researchers looked at the 35 MS cases and the 107 controls who were EBV-negative at the start of service, they found that, again, MS was preceded by EBV infection in all but one of the military personnel (97%). In turn, 57% of those who did not develop MS had been infected with the virus, highlighting that EBV was associated with a 32.4 times higher risk of MS.

The median time from estimated EBV infection — defined as the midpoint between the last negative sample and the first positive sample — to MS onset was 7.5 years (range: two to 15 years).

Ascherio noted that this delay may be partially related to the disease’s symptoms being undetected during the earliest stages, and to the evolving relationship between the virus and the host’s immune system, which is repeatedly stimulated every time the dormant virus reactivates.

The researchers also analyzed the blood levels of neurofilament light chain (NfL), a biomarker of nerve cell damage, in the two groups of patients. NfL levels are known to “increase as early as 6 years before clinical MS onset and may be a more accurate marker of the time of initiation of the disease process,” the researchers wrote.

Data showed that NfL levels increased in service members who later developed MS — but not in controls — only after they became infected with Epstein-Barr, “indicating that EBV infection preceded not only symptom onset but also the time of the first detectable [damaging] mechanisms underlying MS,” the researchers wrote.

Notably, the risk of developing MS was unchanged after infection with the similarly transmitted cytomegalovirus. These and additional analyzes of the service members’ immune responses to most of the viruses that infect humans suggested that the link between EBV and MS was not due to a higher general predisposition to viral infection.

“These findings cannot be explained by any known risk factor for MS and suggest EBV as the leading cause of MS,” the researchers wrote.

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Still, infection alone is insufficient to cause the disease, and its combination with genetic predisposition and/or other environmental factors, such as smoking, may lead to the development of MS.

“The extremely low MS risk in EBV-negative individuals suggests that by far most MS cases are caused by EBV and could thus potentially be prevented by a suitable vaccine,” the researchers wrote.

“Currently there is no way to effectively prevent or treat EBV infection, but an EBV vaccine or targeting the virus with EBV-specific antiviral [medications] could ultimately prevent or cure MS,” Ascherio said.

Directly targeting EBV “could have major advantages” relative to B-cell-depleting therapies used for MS — such as rituximab and Ocrevus (ocrelizumab) — which involve long intravenous (into-the-vein) infusions and “may increase the risk of infections,” the team wrote.

Funding for the study was provided by the National Institute of Neurological Disorders and Stroke, the National Institutes of Health, the National Multiple Sclerosis Society, the German Research Foundation, and the Howard Hughes Medical Institute.