New study looks into causal link between Epstein-Barr virus and Multiple Sclerosis

Compelling evidence suggests that many MS cases could be prevented by stopping EBV infection.

Multiple sclerosis and the Epstein-Barr virus 

A new study published in Science magazine provides compelling evidence of causality between the Epstein-Barr virus and Multiple sclerosis. It suggests that most cases of MS could be prevented by stopping the Epstein-Barr virus infection, and that targeting the virus could lead to the discovery of a cure for multiple sclerosis. Experts in the United Kingdom believe that this study is important, but that there is still a long way to go in order to prevent and cure the disease of multiple sclerosis.

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Multiple sclerosis or MS, a progressive disease that affects 2.8 million people worldwide and for which there is no definitive cure, is likely caused by infection with the Epstein-Barr virus or EBV, according to a recent study from the Harvard T.H. Chan School of Public Health.

"For years, our group and others have been studying the hypothesis that EBV causes multiple sclerosis. This is the first study to provide convincing evidence of causality," said Alberto Ascherio, professor of epidemiology and nutrition at the Harvard Chan School and senior author of the study. "This is a big step as it is suggested that most cases of MS could be prevented by stopping EBV infection, and that targeting EBV could lead to the discovery of a cure for multiple sclerosis", he added.

Establishing a causal relationship between the virus and the disease has been difficult because EBV infects about 95% of adults, MS is a relatively rare disease, and the onset of MS symptoms begins about ten years after EBV infection. To determine the link between EBV and MS, researchers conducted a study among more than 10 million young adults on active duty in the U.S. military and identified 955 individuals diagnosed with multiple sclerosis during their time of service.

The team analyzed serum samples taken every two years and determined EBV infection in soldiers at the time of the first sample and the relationship between EBV infection and the onset of MS during active duty. In this cohort, the risk of multiple sclerosis increased 32-fold after an Epstein-Barr virus infection but was unchanged after infection with other viruses. Serum levels of neurofilament light chain, a biomarker of MS-typical nerve degeneration, increased only after EBV infection. According to the authors, the findings cannot be explained by any known risk factor for MS and suggest EBV as a major cause of MS.

Study of geographic/ethnic variants of Epstein-Barr virus may reveal more precise findings

Paul Farrell, Professor of cancer virology at Imperial College London,  stated that "the epidemiological links between Epstein-Barr virus and multiple sclerosis have been known for many years and this study provides very clear evidence for a causal role of EBV in the majority of MS cases." He explained the process as follows:

"An auto-immune cross-reactivity of EBV protein epitopes with cellular proteins of neurons or glial cells presents the most likely mechanism. Specific examples of this phenomenon are mentioned in the supporting article in Perspectives, and there may be several EBV targets involved. However, the current specific examples of cross-reactivity explain only some of the MS cases."

"One aspect that should be looked at more specifically when interpreting the data is EBV sequence variation. Laboratory assays for immunologic responses normally use the EBV reference sequence, but it is now clear that there are variations in EBV in different geographic and ethnic groups, particularly in some of the proteins that are the primary candidates for cross-reactivity epitopes. We speculate that this type of geographic variation may be important in the incidence of one of the types of cancer associated with EBV infection. Further research should therefore include sequencing of EBV in MS cases in comparison to controls to determine if this might explain more individual cases."

"This would also be important for the development of vaccines or targeted therapies against EBV that may be able to prevent or treat MS.An EBV vaccine would seem to be the obvious solution. There is evidence that an EBV vaccine could prevent the EBV infectious mononucleosis. However, no potential EBV vaccine has yet prevented the virus from infecting and establishing long-term persistence in humans. Thus, it remains unclear at this stage whether a vaccine of the types currently in development would be able to prevent the long-term effects of EBV regarding the development of MS."

The Epstein-Barr virus may not be the only factor causative in the development of multiple sclerosis

Immunology Professor Daniel Davis, (University of Manchester) proposed that "by retrospectively analyzing blood samples from US military personnel collected between 1993 and 2013, it has been shown that the onset of multiple sclerosis is associated with Epstein Barr virus infection. However, well over 9 in 10 people are infected with this virus worldwide, usually in childhood, and only very rarely does multiple sclerosis then develop. We already knew that this virus increases the risk of certain types of cancer, and now we know that it is also a possible factor in multiple sclerosis. It is important to note, however, that for most people infected with the virus, there will be no serious consequences."

Prof. Davis explained that "essentially, we don't know why only a small fraction of people infected with this virus ever develop multiple sclerosis. There must be other factors involved, including heredity of certain genes. Overall, the value of this finding may not lie in having identified a cure or an immediate medical treatment, but it does represent an important step forward in understanding MS. It also establishes new research that will work on the precise details of how this virus can sometimes lead to an auto-immune disease. There is no shortage of ideas about how this might happen in principle, and we hope that the right specifics will emerge soon."

  1. Bjornevik K, Cortese M, Healy BC, Kuhle J, Mina MJ, Leng Y, Elledge SJ, Niebuhr DW, Scher AI, Munger KL, Ascherio A. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022 Jan 21. doi: 10.1126/science.abj8222. Epub ahead of print. PMID: 35025605.
  2. Rura N. Epstein-Barr virus may be leading cause of multiple sclerosis. Harvard Chan School Press Release. January 13, 2022
  3. Science Media Centre. Expert reaction to study looking at Epstein-Barr virus infection and multiple sclerosis. January 13, 2022