Epstein-Barr Virus Is Likely the Leading Cause of Multiple Sclerosis, Study Finds

Scientists have long sought the cause of multiple sclerosis (MS), an autoimmune disease that affects some 2.8 million people worldwide each year.

Certain factors including genetics, lifestyle, and immune system health are known to play a role, but none have been found to underpin all MS cases. Prior studies have indicated a linkage between MS and the highly common Epstein-Barr virus (EBV), but none could show that the virus causes the condition.

In a sweeping study published last week, a team of researchers presented strong evidence suggesting that EBV is a trigger for MS.

Throughout a 20-year collaboration with the U.S. military, researchers at Harvard analyzed blood samples from more than 10 million active-duty service members to understand whether EBV, or a different infectious agent, induced MS.

Their latest report showed that the risk of developing MS was 32-fold higher for people infected with EBV. After accounting for other risk factors, the authors said that the findings suggested that EBV is the leading cause of MS.

“The main takeaway from our study is that EBV does appear to be a cause of MS,” Kassandra Munger, ScD, senior research scientist at the Harvard T.H. Chan School of Public Health and senior co-author on the study, told Verywell. “This is the strongest evidence to date of this association establishing the temporality between EBV and any pathological process for MS.”

A Study to Test Causation

Earlier studies have linked EBV to MS. Some noted a higher risk of MS in individuals with mono and antibodies to EBV. Others reported traces of EBV in the brain tissue of some people with MS.

But to prove that EBV causes MS, researchers would have to not only establish an association between the virus and the disease but also show that the viral infection precedes all cases of MS.

“We knew it was really important to establish whether this infection with EBV itself occurred prior to any evidence of MS existing. That proved to be a bigger challenge,” Munger said.

A randomized clinical study—the gold standard for proving causation in medicine—is unethical in this case because researchers couldn’t simply infect people with the virus.

Instead, they analyzed serum samples collected from more than 10 million young adults on active duty in the U.S. military between 1993 and 2013. Every two years, the military screened active-duty members for HIV and stored the samples in a repository. The team tested these samples for evidence of viral infections in people who developed MS and those who did not.

The researchers analyzed three samples per person: the one first collected, the last one before MS diagnosis, and one in between. They identified 801 MS cases that had enough available samples for the EBV assessment. A supermajority of the MS cases—all but one—tested positive for EBV before the onset of MS.

The risk of developing MS was 32 times greater for those who had detectable EBV antibodies in their blood by the third sample, compared to those who did not.

The Importance of Timing and the Particular Pathogen

The disease process for MS can begin years before a person is diagnosed. To test that EBV infection occurred before the onset of MS, and not the other way around, the researchers tracked a biomarker called neurofilament light chain (NfL). This protein can indicate damage to the nervous system as much as six years before MS becomes clinically apparent.

The subjects who developed MS showed significantly higher levels of NfL than those who remained MS free. Importantly, researchers saw signs of EBV infection in these individuals before any NfL was detected.

The Harvard team also tested other viruses like cytomegalovirus to verify that EBV was a unique factor contributing to MS cases. When the team tested a portion of the samples for about 200 other pathogens, antibodies against EBV were exceptionally higher in MS patients than antibodies against other pathogens.

“What we do know is that it’s not some blanket increase in an immune response to everything. It’s very targeted towards EBV,” Munger said. “In terms of environmental factors right now, EBV by far has the strongest association with MS to the point where we do believe it is a causal association.”

One Piece of the Puzzle

The virus alone may not be sufficient to cause MS, according to John Corboy, MD, MA, a professor of neurology at the University of Colorado School of Medicine who’s not affiliated with the study.

Changes in the immune system, the expression of certain genes, and environmental factors may also play a role, Corby explained.

“Many people get exposed to the Epstein Barr virus but most—the vast majority—do not develop MS,” Corboy said.

Studies have shown that low vitamin D levels are associated with an increased risk of MS and people who smoke are 1.5 times more likely to develop MS than nonsmokers. In certain parts of the world, people are more likely to develop MS, though scientists aren’t yet sure what causes these clusters.

While the Harvard study offered strong evidence for the idea that EBV may underpin MS, there are likely other key drivers that cause MS to arise from some EBV infections and not others, Corby added. He said the word “causation,” therefore, is too strong a descriptor for the association between EBV and MS.

“It’s harder to call it causation when it can’t account for all the pieces of the puzzle,” he said.

Strengthening the Case for EBV Vaccines

Current treatments for MS, such as monoclonal antibody infusions, can help reduce the number and severity of relapses and slow the disease progression.

When dormant, EBV lingers in B cells, a type of immune cells that protects the body from infections. EBV possibly alters the cells over time and causing them to become pathogenic. Treatments currently under investigation could use healthy T cells to oust EBV-infected B cells in the brain, Corboy said.

Vaccines have effectively protected against other herpesviruses like varicella, the virus that causes chickenpox and shingles. The varicella vaccine has essentially eliminated shingles as a neurological disease, Corboy said.

“If we had a vaccine, widely used and effective against the Epstein-Barr Virus, I would think that that would have an important impact on many aspects of medicine, including the development of multiple sclerosis,” Corboy said.

Moderna recently launched a phase one clinical trial of an mRNA vaccine against EBV. Beyond its connection to MS, EBV is associated with certain cancers such as some types of lymphoma and stomach cancer.

“The next step really is to see if EBV vaccines can prevent the disease—that would actually be the perhaps ultimate proof that if we can prevent EBV infection, we prevent MS from occurring,” Munger said. “It’s going to be exciting to watch all of that unfold in the next few years.”