This study is the first to provide compelling evidence of a causal link between EBV and MS, principal investigator Alberto Ascherio, MD, DrPH, professor of epidemiology, Harvard T. H. Chan School of Public Health, and professor of medicine, Harvard Medical School, told Medscape Medical News.
The “prevailing” view has been that MS is “an autoimmune disease of unknown etiology,” said Ascherio. “Now we know MS is a complication of a viral infection.” With this knowledge, he added, “we can redirect research” to find antiviral drugs to treat the disease.
The study was published online January 13 in Science.
A chronic disease of the central nervous system, MS involves an inflammatory attack on the myelin sheath and the axons it insulates. The disease affects 2.8 million people worldwide.
EBV is a human herpesvirus that can cause infectious mononucleosis. After infection, it persists in latent form in B-lymphocytes.
EBV is common and infects about 95% of adults. Most individuals are already infected with the virus by age 18 or 20 years, making it difficult to study uninfected populations, said Ascherio.
However, access to a “huge” database of more than 10 million active-duty US service personnel made this possible, he said.
Service members are screened for HIV at the start of their service care and biennially thereafter. The investigators used stored blood samples to determine the relation between EBV infection and MS over a 20-year period from 1993 to 2013.
Researchers examined 801 MS case patients and 1566 matched controls without MS. Most individuals were under 20 at the time of their first blood collection. Symptom onset for those who developed MS was a median of 10 years after the first sample was obtained.
Only one of the 801 MS case patients had no serologic evidence of EBV. This individual may have been infected with the virus after the last blood collection, failed to seroconvert in response to infection, or was misdiagnosed, the investigators note.
The hazard ratio (HR) for MS between EBV seroconversion vs persistent EBV seronegative was 32.4 (95% CI, 4.3 – 245.3; P < .001).
An MS Vaccine?
MS risk was not increased after infection with cytomegalovirus, a herpesvirus that is transmitted through saliva, as is EBV.
Researchers measured serum concentrations of neurofilament light chain (sNflL), a biomarker of neuroaxonal degeneration, in samples from EBV-negative individuals at baseline. There were no signs of neuroaxonal degeneration before EBV seroconversion in subjects who later developed MS.
This indicates that “EBV infection preceded not only symptom onset but also the time of the first detectable pathological mechanisms underlying MS,” the investigators note.
The very magnitude of increased MS risk of MS observed EBV almost completely rules out confounding by known risk factors. Smoking and vitamin D deficiency double the risk, and genetic predisposition and childhood obesity also only raise the risks of MS to a “moderate” degree, said Ascherio.
It’s not clear why only some people infected with EBV go on to develop MS, he said.
The idea that reverse causation ― that immune dysregulation during the preclinical phase of MS increases susceptibility to EBV infection ― is unlikely, the investigators note. For instance, EBV seroconversion occurs before elevation of sNfL levels, an early marker of preclinical MS.
Since most MS cases appear to be caused by EBV, a suitable vaccine might thwart the disease. “A vaccine could, in theory, prevent infection and prevent MS,” said Ascherio, adding there’s ongoing work to develop such a vaccine.
Another approach is to target the virus driving MS disease progression. Developing appropriate antivirals might treat and even cure MS, said Ascherio.
In an accompanying commentary, William H. Robinson, MD, PhD, professor, Division of Immunology and Rheumatology, Department of Medicine, Stanford University, and a colleague said the study findings “provide compelling data that implicate EBV as the trigger for the development of MS.”
The mechanism or mechanisms by which EBV leads to MS “remain elusive,” the commentary authors write.
“Possibilities include molecular mimicry, through which EBV viral protein sequences mimic human myelin proteins and other CNS proteins and thereby induce autoimmunity against myelin and CNS antigens,” they note.
As other factors, including genetic susceptibility, are important to MS, EBV infection is likely necessary but not sufficient to trigger MS, said the commentary. “Infection with EBV is the initial pathogenic step in MS, but additional fuses must be ignited for the full pathophysiology.”
The commentary authors query whether there may be “new opportunities” for therapy with vaccines or antivirals. “Now that the initial trigger for MS has been identified, perhaps MS could be eradicated.”
In a statement from the Science Media Center, an independent venture promoting views from the scientific community, two other experts offered their take on the study.
Also commenting Paul Farrell, PhD, professor of tumor virology, Imperial College London, United Kingdom, said the paper “provides very clear confirmation of a causal role for EBV in most cases of MS.”
While there’s evidence that a vaccine can prevent the EBV disease infectious mononucleosis, no vaccine candidate has yet prevented the virus from infecting and establishing long-term persistence in people, noted Farrell.
“So, at this stage it is not clear whether a vaccine of the types currently being developed would be able to prevent the long-term effects of EBV in MS,” he said.
Daniel Davis, PhD, professor of immunology, University of Manchester, United Kingdom, commented that the value of this new discovery is not an immediate medical cure or treatment but is “a major step forward” in understanding MS.
The study “sets up new research working out the precise details of how this virus can sometimes lead to an autoimmune disease,” said Davis. “There is no shortage of ideas in how this might happen in principle and hopefully the correct details will emerge soon.”
The study received funding from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, National Multiple Sclerosis Society, the German Research Foundation, the National Institutes of Health, and the Howard Hughes Medical Institute. Ascherio reports no relevant financial relaitonships.Robinson is a coinventor on a patent application filed by Stanford University that includes antibodies to EBV.Farrell reports serving on an ad hoc review panel for GSK on EBV vaccines in 2019 as a one off. He has a current grant from MRC on EBV biology including some EBV sequence variation, but the grant is not about MS. Davis reports no relevant financial relationships.