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, Boston, told this news organization.
The “prevailing” view has been that MS is “an autoimmune disease of unknown etiology,” said Dr. 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 Jan. 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 Dr. Ascherio.
However, access to a “huge” database of more than 10 million active-duty U.S. 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 1,566 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 for MS between EBV seroconversion versus 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 Dr. 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 Dr. Ascherio, adding that 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 Dr. Ascherio.