Multiple sclerosis (MS) is almost always a delayed response to infection with the Epstein-Barr virus, a study of 10 million former military personnel in the US indicates. The findings could provide clues on how to treat the disease – which is hallmarked by the immune system attacking the myelin sheath that protects the brain and spinal nerves – and raise the urgency of preventing the common virus in the first place. More broadly, it serves as a reminder that even when people appear asymptomatic or recover quickly from viral infections, there can be serious consequences down the track.

The Epstein-Barr virus is part of the herpes family of double-stranded DNA viruses. Its high transmissibility through kissing, spitting, or sharing food means the overwhelming majority of the population has been infected by their late 20s. Its most common effect is infectious mononucleosis, better known as glandular fever, which can leave people feeling exhausted for weeks and, in rarer cases damage the liver or spleen.

Epstein-Barr has also been linked to much rarer, but far more serious, conditions such as certain blood cancers. For decades medical researchers have suspected it may be a cause of MS, but have struggled to prove or disprove the theory. Access to the serum samples taken from more than 10 million Americans serving in the military has led to publication in Science of powerful evidence supporting the idea.

The US Military takes blood serum from its soldiers every two years. Harvard Chan Professor Alberto Ascherio led a team that tested 62 million samples collected from 1993 to 2013 for the presence of Epstein-Barr antibodies. Military records revealed 955 people among those tested who were diagnosed with MS while serving.

Almost all those with MS tested positive for Epstein-Barr antibodies. That alone would have been limited evidence since the virus is so widespread, but among the few who got MS after testing negative for Epstein-Barr antibodies on admission, almost all had caught the virus while on duty.

This is consistent with the theory that infection as an adult is much riskier than as a child, just as is true for the diseases already linked to the virus, which seldom affect those who catch it young.

Notably, the authors also tested for other viral infections in the same sample and did not find any increased MS risk.

“The hypothesis that EBV causes MS has been investigated by our group and others for several years, but this is the first study providing compelling evidence of causality,” Ascherio said in a statement. That's partly because Epstein-Barr is so common (95 percent of Americans get it), it takes a large sample size to find enough people who have never been infected to gain a useful comparison. Other studies have also often not been able to establish the age at which infection occurred, something the military's longitudinal data addressed.

Although MS can still occur in the uninfected, the risk is 32 times higher after an adult infection than among the few who dodged the virus entirely, suggesting Epstein-Barr is easily the major cause.

“This is a big step because it suggests that most MS cases could be prevented by stopping EBV infection, and that targeting EBV could lead to the discovery of a cure for MS,” Ascherio said. 

Although the mechanism is not fully understood, an accompanying editorial notes the common presence of Epstein-Barr infected B cells in the brains of MS patients. The reason why most people avoid MS, even after infection, is unknown.

Epstein-Barr has the vaccine-friendly attribute of not reinfecting people who have already had it, but neither a vaccine nor a treatment currently exist. However, a phase I trial has been announced using mRNA technology accelerated to fight COVID-19.