A history of infection with Epstein-Barr virus (EBV) has been shown to be a strong risk factor for developing multiple sclerosis (MS) — but is targeting the virus a viable strategy for MS prevention or treatment?
This question was the subject of a debate, "How To and Should We Target EBV in MS?," that was held at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, which took place last week in California.
EBV is one of the most common viruses that infects humans. It's best-known as the cause of infectious mononucleosis, or mono, but EBV more commonly causes childhood infections that don't lead to symptoms at all, or it causes unremarkable cold- or flu-like symptoms that are mild and resolve without the need for medical intervention.
In total, about 90% to 95% of people around the world are infected with EBV at some point in their lives.
Previous study found greater MS risk in those with EBV infection history
Epidemiological studies have shown that EBV infection is a risk factor for developing MS. In particular, a study published last year that assessed more than 10 million people in the U.S. military found that the risk of MS was more than 30 times higher among people with a history of EBV infection.
While it's not entirely understood how EBV could cause MS, several potential mechanisms have been proposed. For example, EBV can infect immune B-cells and alter their activity, which may be involved in the autoimmune attack that causes MS.
Additionally, certain EBV proteins are structurally similar to proteins in the myelin sheath that are targeted by the autoimmune attack in MS. Researchers have proposed that, when the immune system attacks EBV to fight off the infection, this structural similarity may cause it to erroneously target the myelin sheath as well, which could ultimately result in MS.
In the ACTRIMS debate, Jeffrey Cohen, MD, from the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health (NIH), stressed that there isn't enough data yet to say with certainty that EBV can directly cause MS — but this idea can be tested in future studies.
Cohen argued that, if EBV can indeed increase MS risk, then preventing EBV with a vaccine or similar therapy should reduce the incidence of MS.
No vaccines are currently approved for EBV, though the NIH recently began clinical testing of an experimental EBV nanoparticle vaccine, and another NIH-developed EBV vaccine is expected to enter trials later this year. These vaccines primarily aim to prevent mono, but if testing shows that they are safe and can effectively prevent EBV infection, they could be valuable tools to test the connection between EBV and MS, Cohen said.
He noted that "an effective EBV vaccine that reduces the incidence of MS might have additional benefits," since EBV can cause mono and has also been linked with certain cancers, particularly a blood cancer called Hodgkin's lymphoma.
"An effective EBV vaccine should reduce infectious mononucleosis and reduce MS and EBV-associated cancers," Cohen said.
Based on statistical data on the incidence of MS, a theoretical trial testing of whether an EBV vaccine could reduce the incidence of the neurodegenerative disease would need to be very large, with about 100,000 total participants. Still, Cohen said that such a study could feasibly done if an EBV vaccine becomes available.
"A Phase 4 case-control study of vaccinated vs. unvaccinated persons could be done to determine if there is a lower incidence of MS in the vaccinated population," Cohen wrote in the abstract to the debate.
There's nothing more important [than safety] when you're immunizing healthy individuals, particularly children.
Majority of people who've been infected with EBV do not develop MS
Arguing against Cohen, Peter Calabresi, MD, a professor of neurology at Johns Hopkins University, said that although the enthusiasm about potentially preventing MS through a vaccine is understandable, "caution regarding over exuberance is urged."
For one thing, Calabresi stressed that, as over 90% of people are infected with EBV, the vast majority of people with a history of the viral infection don't go on to develop MS — so it's clear that, while EBV may increase MS risk, other factors are also at play.
Calabresi also urged caution about the possibility of an approved EBV vaccine any time in the near future, noting that these vaccines would have to be given during early childhood, when most cases of EBV infection take place — which "makes prevention a daunting task," he said.
These vaccines could also "have untoward side effects" by delaying EBV infections to adolescence, when they are more likely to cause infectious mononucleosis and contribute to MS. "Individuals may become susceptible to natural infection at an age where the consequences of infection are more severe," Calabresi said.
Additionally, he noted that vaccines work by activating the immune system against the virus. So, if it's indeed true that the immune system's attack against EBV could be involved in the development of MS, special care is needed in the design of EBV vaccines to ensure they don't promote an immune response that could trigger or worsen MS.
Cohen said he "completely agrees" with Calabresi that it will be absolutely critical to take rigorous steps to ensure that a potential EBV vaccine is safe before distributing it widely. "There's nothing more important [than safety] when you're immunizing healthy individuals, particularly children," Cohen said.
Cohen noted that, for other viruses that have been associated with autoimmune diseases — such as hepatitis B or varicella zoster (which causes chicken pox and shingles) — vaccinations have actually been shown to reduce the risk of virus-associated autoimmune complications.
"I think that safety is a concern," he said. "We do not know the long-term effects of an EBV vaccine. But there are vaccines … for viruses that have been associated with autoimmune disease, and we've not seen issues."
Some experimental therapies targeting EBV being developed for MS
Both Cohen and Calabresi said there is currently not much data to suggest that targeting EBV could be effective for people who already have MS, as most available data has specifically focused on the risk of developing the disease. Some investigational therapies targeting EBV are being developed for MS patients.
Calabresi argued that these therapies are unlikely to be effective, because once the immune system starts attacking healthy nervous system tissue, other biological mechanisms become activated to drive this attack. As such, by the time clinical MS is diagnosed, it's probably too late to target EBV: "The proverbial 'horse is out of the barn,' " Calabresi wrote.
Instead of focusing on EBV itself as a treatment target in MS, Calabresi said he favors further work to understand the biological mechanisms by which EBV may lead to the neurological disorder. Better understanding of these mechanisms could pave the way toward more targeted therapies, he argued.
"For now, I think that the MS community should focus more on downstream immunological events where we've had great success already," he said.
Note: The Multiple Sclerosis News Today team is providing in-depth coverage of the ACTRIMS Forum 2023 Feb. 23–25. Go here to see the latest stories from the conference. Follow along on Facebook, Twitter, and Instagram for live updates using the hashtag #actrims2023.
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