- A new study provides strong evidence that multiple sclerosis (MS) can be caused by the Epstein-Barr virus. The findings bring scientists one step closer to understanding the causes of autoimmune diseases.
- Of the 801 subjects in the study who developed MS, all but one were infected with EBV prior to the onset of MS.
- EBV vaccines and antiviral drugs can help prevent cases of multiple sclerosis and other diseases.
Scientists have long searched for the cause of multiple sclerosis (MS), an autoimmune disease that affects an estimated 2.8 million people worldwide each year.
Certain factors, including genetics, lifestyle, and immune system health, are known to play a role, but nothing has been found to support all cases of MS. Previous studies have shown a link between MS and the highly common Epstein-Barr virus (EBV), but none have shown that the virus causes the condition.
In a comprehensive study published last week, a team of researchers presented strong evidence that EBV is a trigger for MS.
What is the Epstein-Barr virus?
EBV is a member of the herpes family. About 95% of adults worldwide carry the virus. Although it is usually dormant, in some cases, exposure to EBV can lead to mononucleosis (mono) or other rare complications.
In a 20-year collaboration with the U.S. military, researchers at Harvard University analyzed blood samples from more than 10 million active-duty military members to see if EBV or other infectious agents could induce MS.
Their latest report shows that people infected with EBV have a 32-fold higher risk of developing MS. After accounting for other risk factors, the authors say the findings suggest that EBV is a major cause of MS.
“The main takeaway from our study is that EBV does appear to be a cause of MS,” Kassandra Munger, a senior research scientist at Harvard’s TH Chan School of Public Health and senior co-author of the study, told VigorTip. “This is the strongest evidence to date to establish a temporal association between EBV and any pathological process in MS.”
Research that examines causality
Earlier studies have linked EBV to MS. Some have pointed out that individuals with EBV monoclonal antibodies and antibodies have a higher risk of developing MS. Others have reported traces of EBV in the brain tissue of some MS patients.
But to prove that EBV causes MS, researchers not only have to establish a link between the virus and the disease, but also demonstrate that viral infection precedes all MS cases.
“We knew it was important to determine whether this EBV infection itself occurred before any evidence of MS. That turned out to be an even bigger challenge,” Munger said.
In this case, a randomized clinical study—the gold standard for proving cause and effect in medicine—is unethical because researchers cannot simply infect people with a virus.
Instead, they analyzed serum samples collected between 1993 and 2013 from more than 10 million young men on active duty in the U.S. military. Every two years, the military screens active-duty members for HIV and stores the samples in a repository. The team tested the samples for evidence of viral infection in people with and without multiple sclerosis.
The researchers analyzed three samples from each person: the first sample collected, the last sample before the MS diagnosis, and the samples in between. They identified 801 MS cases with sufficient available samples for EBV evaluation. The vast majority of MS cases (all but one) tested positive for EBV before the onset of MS.
People who had EBV antibodies detected in the third sample had a 32-fold higher risk of developing MS than those who didn’t.
Timing and importance of specific pathogens
The disease process of MS can begin years before a person is diagnosed. To test that EBV infection occurs before the onset of MS, rather than the other way around, the researchers tracked a biomarker called neurofilament light chain (NfL). This protein can indicate damage to the nervous system six years before multiple sclerosis develops clinical symptoms.
Subjects with MS had significantly higher levels of NfL than subjects without MS. Importantly, the researchers saw signs of EBV infection in these people before any NfL was detected.
The Harvard team also tested other viruses, such as cytomegalovirus, to verify that EBV was a unique factor in MS cases. When the team tested some of the samples for about 200 other pathogens, MS patients had significantly higher antibodies against EBV than against other pathogens.
“What we do know is that it’s not an overall increase in the immune response to everything. It’s very specific to EBV,” Munger said. “In terms of current environmental factors, EBV has by far the strongest association with MS, so much so that we do think it’s a causal relationship.”
piece of the puzzle
The virus alone may not be enough to cause multiple sclerosis, said John Corboy, MD, a professor of neurology at the University of Colorado School of Medicine who was not associated 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 are exposed to Epstein Barr virus, but most people — the vast majority — don’t get MS,” Corboy said.
Low Vitamin D Levels Linked to Increased MS Risk, Study Shows Smokers are 1.5 times more likely to develop MS than non-smokers. In some parts of the world, people are more likely to develop MS, although scientists aren’t sure what causes these clusters.
Corby added that while the Harvard study provides strong evidence for the idea that EBV may support MS, there may be other key drivers of MS that are caused by some EBV infections and not others. Therefore, he says the term “causality” is too strong a description of the association between EBV and MS.
“It’s harder to call it causation when it doesn’t explain all the puzzles,” he said.
The Case for Boosting EBV Vaccines
Current treatments for MS, such as monoclonal antibody infusions, can help reduce the number and severity of relapses and slow disease progression.
When dormant, EBV lingers in B cells, a type of immune cell that protects the body from infection. EBV can alter cells over time and cause them to become disease-causing. Treatments currently under study could use healthy T cells to expel EBV-infected B cells from the brain, Corboy said.
The vaccine effectively protects against other herpes viruses, such as the varicella virus, which causes chickenpox and shingles. The chickenpox vaccine essentially eliminates the neurological disease shingles, Corboy said.
“If we had a vaccine that was widely available and effective against Epstein-Barr virus, I think it would have important implications for many aspects of medicine, including the development of multiple sclerosis,” Corboy said.
Moderna recently launched a Phase 1 clinical trial of an mRNA vaccine against EBV. In addition to its links with MS, EBV has also been linked to certain cancers, such as certain types of lymphoma and stomach cancer.
“The next step is really to see if the EBV vaccine can prevent the disease — which may actually be the final proof that if we can prevent EBV infection, we can prevent MS from developing,” Munger said. “It will be exciting to see how this all develops over the next few years.”
what does this mean to you
EBV infects nearly everyone, but very few people go on to develop MS. Certain behavioral and environmental factors, such as smoking and vitamin D deficiency, may increase the risk of developing MS.