Bridget A. Bagert, MD, MPH, on Epstein-Barr Virus and Multiple Sclerosis

Following the publication of data suggesting that EBV is a leading cause of MS, the director of the Ochsner MS Center and an investigator in an EBV-specific therapy clinical trial offered her reaction to the data.

Recently, new findings from a longitudinal analysis that included data on more than 10 million young adults on active duty in the US military suggest that infection with herpesvirus 4, also known as Epstein-Barr virus (EBV), may be the leading cause of multiple sclerosis (MS).1

The data lend weight to a theory that has circulated discussions in the community for almost a decade. Infection with EBV translated to a 32-fold increased risk of developing MS in the analysis of the 995 individuals in the cohort diagnosed with the demyelinating disease during service. No increase was observed after infection from other viruses, including the similarly transmitted cytomegalovirus.

Study author Alberto Ascherio, MD, DrPH, professor of epidemiology and nutrition, Harvard University, told NeurologyLive® that the findings suggest "that multiple sclerosis, a condition until now described as ‘an autoimmune disease of unknown etiology’ is in fact, a complication of infection of the Epstein-Barr virus."

Many have theorized and collected data about the role of EBV in MS over the last decade, with some even exploring it as a therapeutic target. At the 37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), October 13-15, 2021, data from a small, open-label extension (OLE) portion of the phase 1 study of the Atara Biotherapeutics’ investigational agent, ATA188, in progressive multiple sclerosis (MS) were presented, suggesting that the therapy offered a sustained clinical benefit over 39 months based on magnetization transfer ratio (MTR), while being safe and tolerable.2

Ultimately, those data showed that the magnetization transfer ratio (MTR) for unenhancing T2 lesions showed a correlation with Expanded Disability Status Scale (EDSS) at 6 months (n = 21; ρ = –0.4180; P = .0594) and at 12 months (n = 23; ρ = –0.3539; P = .1062), with the findings suggesting evidence of a potential remyelination effect based on the increases in MTR associated with EDSS scores.

Bridget A. Bagert, MD, MPH, is among those who have advocated about the role of EBV in MS. At ECTRIMS 2021, NeurologyLive® spoke with Bagert, who is the director of the Ochsner Multiple Sclerosis Center and one of the investigators of the ATA188 trial, to find out more about the therapy’s performance. After the publication of data from Ascherio et al, we followed up with Bagert to find out her reaction to the data.

NeurologyLive®: What was your immediate reaction to, or takeaway from, these data?

Bridget A. Bagert, MD, MPH: I was thrilled to see these data. The combination of a very large sample size, long-term follow-up, and neurofilament light measures made for an extraordinarily robust study design.

How does this add to what we already understood about the relationship between EBV and MS?

The sheer magnitude of the effect size (32-fold increase in MS risk after infection with EBV) is extraordinary and makes the possibility of confounding by other factors very unlikely.Also, the observation that EBV seroconversion occurred before the elevation in neurofilament light—a marker of early MS damage—in patients who developed MS years later weakens the reverse causation argument; it is the EBV infection that leads to MS and not the other way around.

What clinical implications might further assessments of this relationship have, especially with the consideration of EBV-targeted therapies?

We must continue to invest in EBV-specific therapeutics for MS including the EBV-specific T-cell trials and antiviral trials. And given the high prevalence of MS around the world, this study highlights the urgent need to create a safe and effective EBV vaccine so that we can one day prevent MS from developing in people altogether.

Is the MS or larger neurology community fully aware of EBV and its possible role in demyelinating disorders?

No, unfortunately. Many MS experts are still reluctant to say confidently that “MS results from a failure of individuals to effectively manage EBV.”My hope is that this study will finally change this reluctance, and lead to a much broader acceptance of the fact that MS is caused by EBV infection.

Transcript edited for clarity.

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REFERENCES
1. Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. Published online January 13, 2022. doi:10.1126/science.abj8222
2. Bar-Or A, Pender MP, Hodgkinson SJ, et al. Updated open-label extension clinical data and new magnetization transfer ratio imaging data from a Phase I study of ATA188, an off-the-shelf, allogeneic Epstein-Barr virus-targeted T-cell immunotherapy for progressive multiple sclerosis. Presented at ECTRIMS Congress; October 13-15, 2021; Poster P638.