Multiple sclerosis has a common viral culprit, opening doors to new approachesEstablishing the link
In March 2000, epidemiologist Alberto Ascherio of the Harvard T.H. Chan School of Public Health published research exploring the link between Epstein-Barr virus and MS. With colleague Mette Munch of the University of Aarhus in Denmark, Ascherio analyzed data from eight studies suggesting that MS patients are more likely to have had an Epstein-Barr infection than those without MS. Studies over the next 20 years continued to hint that the virus plays a role, but “the problem is to go from a suggestion or suspicion to proof,” says Ascherio. Getting that proof is difficult, because nearly everyone has been infected with Epstein-Barr virus, or EBV, yet very few have MS.
“If it’s true that EBV causes MS, then you would expect to find that those individuals who are not infected with EBV, they will not get MS,” Ascherio says. “It’s very simple.” He and colleagues needed to follow a large group of young adults who had never been infected.
The researchers found such a group in the U.S. military. Through the Department of Defense Serum Repository, the team had access to repeated blood samples from more than 10 million individuals, taken when active-duty members were screened for diseases such as HIV at the start of their service and then every two years. Using blood samples taken between 1993 and 2013, Ascherio and colleagues could identify people who had never been infected with Epstein-Barr virus, track new infections and learn when people who developed MS started showing symptoms.
Over that 20-year span, 801 people whose blood was tested were diagnosed with MS. Thirty-five of those people had no signs of Epstein-Barr virus infection in their first blood sample. But all but one became infected before their MS diagnosis. People infected with the virus were 32 times as likely to develop MS as uninfected people. What’s more, the researchers found that blood concentrations of a nervous system protein that is a signal of nerve damage rose after Epstein-Barr virus infection, before an MS diagnosis. The results prompted Ascherio and his team to make a bold claim in Science in January: “These findings cannot be explained by any known risk factor for MS and suggest EBV as the leading cause of MS.”
It is still possible that infection with Epstein-Barr virus is a time stamp for something else, perhaps not yet identified, that’s also relevant for MS, says Mark Allegretta, vice president of research at the National Multiple Sclerosis Society. “The way we talk about it now is that it’s very strong evidence that it’s necessary for development of MS, but it’s insufficient on its own.”
Ascherio isn’t deterred. “After 20 years of talking about EBV and MS, it’s quite exciting that we’ve finally nailed it down,” he says. “There was a lot of skepticism until now and that is fading away.”
Epstein-Barr viruses (red) emerge from an immune system B cell in this colorized electron micrograph.Viral damage
Several studies support the idea that molecular mimicry causes MS damage. But other hypotheses are on the table.
Those B cells, for instance, where Epstein-Barr viruses hide out, produce antibodies. One possibility is that B cells infected with Epstein-Barr virus transform in ways that encourage the immune system to attack the body’s own tissues.
Aloisi, the neuroscientist in Rome, backs a different hypothesis: Perhaps the immune system’s attack on the virus itself is behind the damage.
“The biology of the virus is so similar to the biology of the disease,” Aloisi says. For some people, MS can go through phases of silence where the disease is stable, no better, no worse. The disease then reactivates, producing new brain lesions and worsening symptoms. Epstein-Barr virus can similarly come out of latency, perhaps causing a surge of problems before returning to hibernation inside host cells.
In 2007, Aloisi and colleagues discovered unexpected clusters of B cells within the membranes that cover and protect the brain. In all but one of 22 patients studied, some of those B cells were infected with Epstein-Barr virus.
The finding “was like a bomb in the field,” Aloisi says, “because nobody ever thought about this possibility.” Other researchers initially failed to replicate the results. But “little by little other work came out [in support],” she says. “It’s difficult to find these [clusters of B cells] in the brain because people with MS don’t have large, inflamed brains. It’s small spots here and there.”
Viral damage
Several studies support the idea that molecular mimicry causes MS damage. But other hypotheses are on the table.
Those B cells, for instance, where Epstein-Barr viruses hide out, produce antibodies. One possibility is that B cells infected with Epstein-Barr virus transform in ways that encourage the immune system to attack the body’s own tissues.
Aloisi, the neuroscientist in Rome, backs a different hypothesis: Perhaps the immune system’s attack on the virus itself is behind the damage.
“The biology of the virus is so similar to the biology of the disease,” Aloisi says. For some people, MS can go through phases of silence where the disease is stable, no better, no worse. The disease then reactivates, producing new brain lesions and worsening symptoms. Epstein-Barr virus can similarly come out of latency, perhaps causing a surge of problems before returning to hibernation inside host cells.
In 2007, Aloisi and colleagues discovered unexpected clusters of B cells within the membranes that cover and protect the brain. In all but one of 22 patients studied, some of those B cells were infected with Epstein-Barr virus.
The finding “was like a bomb in the field,” Aloisi says, “because nobody ever thought about this possibility.” Other researchers initially failed to replicate the results. But “little by little other work came out [in support],” she says. “It’s difficult to find these [clusters of B cells] in the brain because people with MS don’t have large, inflamed brains. It’s small spots here and there.”
A vaccine
Even better than stopping the infection once it starts would be to build defenses before the virus invades, or to stop it from reawakening. Enter vaccines.
The widespread impact of mono and Epstein-Barr virus’s links to cancer and autoimmune disease had already spurred vaccine research, so a few potential shots are already in the pipeline. But Epstein-Barr virus has a complex way of invading the body, says vaccinologist Javier Gordon Ogembo of City of Hope, a cancer care center in Duarte, Calif. The virus uses at least five viral proteins to invade both epithelial cells and B cells. A vaccine would need to drive an immune response that blocks the virus’s entry into both cell types to prevent infection. “This is the reason, I think, why there has not been a vaccine so far,” Ogembo says.
Vaccine options
Recent studies suggest that vaccines being developed to prevent diseases related to Epstein-Barr virus, or EBV, such as mononucleosis or cancer, might also work for multiple sclerosis.
Moderna mRNA vaccine:
Uses mRNA to teach the body to recognize four viral proteins that help EBV enter epithelial and B cells.
Developed for: Mononucleosis
Stage of development: Phase I clinical trial
NIH nanoparticles vaccine:
Teaches the body to attack a protein called gp350, which EBV uses to infect B cells
Developed for: Mono and cancer
Stage of development: Phase I clinical trial
City of Hope modified virus vaccine:
Delivers DNA to cells so the cells can make and teach the immune system to recognize five viral proteins that help EBV enter epithelial and B cells
Developed for: Mono and cancer
Stage of development: Animal studies
BioNTech mRNA vaccine:
Blocks myelin attack
Developed for: MS
Stage of development: Animal studies
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