Can MS Actually Be Prevented?

The evidence on EBV, smoking, vitamin D, obesity, and the challenges of designing trials targeting MS before it starts.

She was 42 when I first met her, one month after a bout of optic neuritis had led to her diagnosis. This was not her first encounter with MS. Her father had been diagnosed when she was a child, and as time went on, she saw how this disease slowly robbed him of his ability to walk and take care of himself. But she knew that much had changed since, that new treatments were now available, and she was optimistic. By the time she came to my clinic, she had already done the reading. She knew about the DMT options, she knew what she could do to help herself through this. She was composed, thoughtful, and had clearly processed a great deal in a short time.

Then, near the end of the visit, she said what she had really come to ask.

She had two daughters, ages 6 and 8. What was their risk of developing MS? And what, if anything, could she do to protect them?

I get some version of this question in clinic nearly every week. Sometimes it comes from a newly diagnosed mother like her. Sometimes from the adult sibling of a patient. Sometimes from a grandparent who noticed that MS “runs in the family” and wants to know what that means for a grandchild. The question is almost always the same underneath: is there something I can do, now, to change the odds?

For most of my career, the honest answer has been: not really. I’d offer reassurance that the absolute risk remained low even in first-degree relatives, and a few general suggestions about healthy lifestyle. But what my patients really want is a plan grounded in biology.

This is changing now. For the first time in the history of this disease, primary prevention of MS is no longer an esoteric notion but a serious scientific enterprise. A coherent story is forming about what causes MS to develop. There are modifiable risk factors with real causal evidence behind them. And there are now clinical trials designed to address those risk factors, opening the door to preventing the disease before it starts.

This column is about what we know, what we are testing, and what a mother of two girls can reasonably do today.

What We Learned from Watching the Families

The best way to understand what is happening before MS begins is to study people who are at high risk and follow them forward. That is what the Genes and Environment in Multiple Sclerosis (GEMS) study, launched by Philip De Jager and colleagues in 2011, was designed to do. GEMS recruited over 2,600 first-degree relatives of people with MS, collected biosamples, captured detailed environmental exposures, and followed them over time.

Two findings from this work are worth dwelling on.

The first is that first-degree relatives of people with MS develop MS at up to 30 times the rate of the general population. In absolute terms, this is still a low probability, most first-degree relatives will never develop MS, but it is substantially higher than the background rate, and it confirms what clinicians have long known from family history alone: shared genes and shared environments matter.

The second is that the prodromal phase of MS is measurable. Using a combined genetic and environmental risk score, the GEMS team could identify a subgroup of first-degree relatives at roughly twice the average family-member risk. These individuals are not destined to develop MS. But they are the population in whom preventive intervention might plausibly show a signal.

Running in parallel with GEMS has been a remarkable line of work using the US Department of Defense Serum Repository, a collection of over 60 million stored serum samples from active-duty military personnel. Because these samples were taken years before any clinical event and then archived, they allow us to look backward in time at the biology of people who went on to develop MS.

What those samples have shown is sobering. Serum neurofilament light chain, a marker of neuroaxonal injury, is elevated on average six years before the first clinical symptom of MS. Six years. In other words, neurons are being damaged and the immune system is dysregulated long before the first episode of optic neuritis or the first sensory symptom that prompts an MRI. By the time a person walks into a clinic with blurry vision, the disease has been underway, silently, for the better part of a decade.

The same repository gave us the most compelling evidence yet that Epstein-Barr virus is a cause, not a correlate, of MS. In the 2022 Bjornevik and Ascherio analysis, people who became infected with EBV had a 32-fold increased risk of developing MS compared to those who remained uninfected. This dramatic increase was specific to EBV, no other virus showed a similar effect. Even more striking: of the 35 people who developed MS and were initially EBV-negative, all but one became infected with EBV before their MS diagnosis. The timing, the specificity, and the sheer magnitude of the effect together make a compelling case that EBV infection is essentially a prerequisite for developing MS.

Put these findings together and a picture emerges. MS begins years before symptoms. It is preceded by measurable immune and neuroaxonal changes. And its biology is set in motion, at least in part, by an environmental exposure almost all of us encounter.

What Actually Drives MS Risk

If we are going to attempt to prevent MS before any sign of disease, we need to know which risk factors are causal, not merely associated. While there is much we still don’t know, four risk factors stand out right now.

EBV infection is, as discussed, essentially a prerequisite. The risk of developing MS is roughly 32 times higher after EBV infection compared to those who remain EBV-negative, an effect not observed for any other virus tested.

Vitamin D insufficiency has long been linked to higher MS risk in observational studies. But observational studies can be misleading: people with low vitamin D might share other characteristics that actually explain the increased risk. To get around this problem, researchers have used a technique called Mendelian randomization, which looks at people who are genetically predisposed to have lower vitamin D levels. Because these genetic variants are randomly assigned at birth, they act like a natural experiment. These genetic studies support the idea that low vitamin D genuinely contributes to MS risk, rather than just being a statistical coincidence.

Adolescent obesity shows a similar pattern. Mendelian randomization studies have supported a causal relationship between elevated BMI in adolescence and adult MS risk.

Smoking (including passive exposure) increases MS risk meaningfully and also worsens the disease course once MS is established. The effect is dose-dependent. To my knowledge, e-cigarettes have not been studied with regard to MS. Theoretical concerns exist however, based on the lung irritation hypothesis and preclinical data showing e-cigarettes disrupt blood-brain barrier integrity and promote neuroinflammation.

What is notable about this list is that three of the four factors are modifiable, and the fourth, EBV, is becoming a vaccine-preventable exposure. This is the menu from which primary prevention strategies are being built.

The First Generation of Prevention Trials

The single most important development in MS prevention science is the arrival of EBV vaccines in clinical trials.

Two major EBV vaccine programs entered clinical testing in 2022. Moderna’s mRNA-1189 uses the same mRNA technology as the COVID-19 vaccines to teach the immune system to recognize the proteins EBV uses to break into cells. Early trials in people aged 12 to 30 showed the vaccine was safe and triggered a strong immune response, and it is now moving toward larger trials. The second program, developed by the National Institutes of Health (NIH), attaches a key EBV surface protein to tiny particles that help the immune system mount a stronger response. Both vaccines are still in early testing focused on safety and immune response, not yet on whether they actually prevent infection or disease.

The historical context here matters, and it is more encouraging than it might first appear. An earlier gp350 subunit vaccine tested in EBV-seronegative students did not prevent EBV infection, but it reduced symptomatic infectious mononucleosis by approximately 80%. At first glance, this may sound like a failure: the vaccine did not keep the virus out. But the distinction between asymptomatic EBV infection and symptomatic mononucleosis turns out to matter a great deal for MS.

Studies have consistently shown that people who develop symptomatic mono have a higher MS risk than those who are infected with EBV without ever getting sick. It’s not just whether you were infected, it’s how your body responded. People infected as young children, who typically never notice it, appear to have lower MS risk than those infected as teenagers or adults who develop full-blown mono. The leading theory is that mono’s intense immune response with high levels of virus and widespread inflammation creates conditions that make the immune system more likely to later attack the body’s own tissues.

If this theory is correct, a vaccine doesn’t necessarily need to block EBV infection entirely. A vaccine that prevents mono, turning what would have been a severe infection into a silent one, could still meaningfully reduce MS risk, even if the virus quietly takes up residence in the body. Partial protection may be enough.

Moderna is also developing a second vaccine, mRNA-1195, which takes a different approach. Rather than preventing EBV infection in the first place, this “therapeutic vaccine” is designed for people who are already infected, aiming to help their immune system keep the dormant virus under tighter control. It is now being tested in people with relapsing MS in an international Phase 2 study called the Horizon trial (clinicaltrials.gov), to see whether strengthening the body’s control over EBV can slow MS disease activity and progression. This isn’t about preventing MS, it’s about treating it. But the trial also serves as a critical test of the EBV-MS connection: if suppressing EBV helps control MS, it would be powerful evidence that the virus is truly driving the disease.

Beyond vaccines, researchers are exploring other ways to target EBV. Antiviral drugs already used for other viral infections are being evaluated for future MS trials. EBV-specific T-cell therapies take a different approach: patients receive laboratory-trained immune cells designed to find and destroy EBV-infected cells that may be driving their MS. One such therapy, ATA188, was tested in progressive MS but did not meet its primary goal of improving disability; earlier small-scale trials of similar approaches showed benefit in some patients. EBNA-1 inhibitors, originally developed for EBV-related cancers, are also being considered. None of these is yet a proven MS treatment, but together they represent a pipeline that didn’t exist five years ago.

The Design Problem

Imagine you want to run a trial to prevent MS. You would enroll people who have never had MS, randomize them to either an intervention (a vaccine, say, or a behavioral intervention, or a drug), and follow them forward to see whether they develop MS at different rates.

The problem is immediately obvious. Most people, even most at-risk first-degree relatives, will never develop MS. Background incidence is low. To detect a preventive effect, you need either a very large population, a very long follow-up, or a very high-risk subgroup, ideally all three. A traditional trial of this design, powered to show a meaningful effect on MS incidence, would need tens of thousands of participants followed for years or decades. The costs are enormous. The scientific patience required is extraordinary.

There are several ways the field is trying to make this tractable.

The first is to enrich the study population. GEMS and similar cohorts show us how to identify first-degree relatives at the highest end of the genetic-and-environmental risk distribution. Studying these individuals rather than the general population could dramatically improve statistical power at a manageable sample size.

The second is to use intermediate biomarker endpoints rather than clinical MS as the outcome. If we have a biomarker that reliably predicts eventual MS, and that biomarker responds to a preventive intervention, we may be able to demonstrate biological efficacy without waiting a decade for clinical events to accrue. Serum NfL is at this time the most serious candidate, given that elevations precede clinical onset by six years. Subclinical MRI lesion development is another. Refined immune biomarkers, especially EBV-related immune signatures, are under active investigation.

The third is to focus on interventions where the bar for demonstrating net benefit is lower, because the intervention is safe, inexpensive, and carries its own independent health benefits. An EBV vaccine that prevents infectious mononucleosis does not need to demonstrate a reduction in MS incidence to be clinically useful. The MS benefit, if it emerges, is essentially a bonus. This lowers the activation energy for the first generation of primary prevention strategies considerably.

The fourth is to accept that the field will need to run these trials in stages, starting with the populations most at risk, gathering biomarker evidence first, then moving to larger populations once the preliminary signals are solid. The ethical calculus of who to enroll in a prevention trial, how much baseline risk justifies exposure to an experimental intervention, is itself a serious conversation that is only now beginning to happen in a structured way.

None of this is easy. But the tools are assembling. The risk-stratification methods are in development. The biomarkers are maturing. The vaccine platform is functional. Whether future trials will succeed is genuinely unknown. That they are now serious scientific enterprises, rather than distant aspirations, is already a considerable change.

What I Told Her

I want to go back to the mother with her two daughters. As a mom and a doctor, I see her strength in confronting her own diagnosis and I want to bring her the best answers we have because I know her daughters are everything to her just like my kids are everything to me. Here is what I would tell her.

First, the absolute risk to her daughters is low, even with a first-degree relative with MS. Most children of mothers with MS will never develop the disease.

Second, there are concrete things she can do, grounded in real evidence, to reduce that risk further. Support a healthy weight through adolescence, because adolescent obesity is one of the most robust modifiable risk factors for adult MS. Make sure they never smoke (or even vape), and minimize their exposure to smoke from others. Encourage regular physical activity, not as a specific MS prevention measure but as part of the broader health picture that reduces inflammation and supports overall metabolic health. Ensure reasonable sun exposure and dietary vitamin D intake through childhood and adolescence; I do not recommend routine vitamin D level monitoring in children, but insufficiency should be avoided.

Third, keep an eye on the EBV vaccine space. If and when an EBV vaccine becomes licensed, she should have a serious conversation with her daughters’ pediatrician about vaccination before adolescence, the period when EBV infection is most likely to become clinically manifest and when MS risk begins its slow climb. Even if the MS benefit takes decades to prove, the vaccine would prevent infectious mononucleosis, which is itself worth preventing.

Fourth, be attentive, but not hypervigilant. If either daughter ever has unexplained neurological symptoms, especially those consistent with demyelination, optic neuritis, unexplained numbness or weakness, Lhermitte’s sign, it should be evaluated promptly. But the goal is not to generate MS anxiety in children. The goal is to raise informed, healthy young adults.

And finally, I told her what I am telling you, the reader. The landscape is changing. What we can offer at-risk families today is more than what we could offer five years ago, and in another five or ten years, it will be more than what we can offer today. The path to primary prevention is shorter than it was, and the work to walk that path is actively underway.

For a mother sitting in my office asking what she can do for her children, that is not nothing. It is, in fact, quite a lot.

References:

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