New Data Suggest Epstein-Barr Virus May Be a Root Cause of Multiple Sclerosis

Alberto Ascherio, MD, DrPH

A newly published study in Science has grabbed the attention of the multiple sclerosis (MS) community as the longitudinal analysis suggests that Epstein-Barr virus (EBV), also known as herpesvirus 4, may be the leading cause for MS, lending credence to a long-held theory in the field.¹

Senior author Alberto Ascherio, MD, DrPH, professor of epidemiology and nutrition, Harvard University, and colleagues collected data on more than 10 million young adults on active duty in the US military, 995 of whom were diagnosed with MS during their period of service. The data suggested that those participants who were infected with EBV had a 32-fold increased risk of developing MS, with no increase observed after infection from other viruses, including the similarly transmitted cytomegalovirus.

When asked about the take-home points of the research for the clinical community, Ascherio told NeurologyLive^® "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."

EBV is a very common viral infection that often occurs in childhood, though most people will contract EBV at some point in their life. It does not usually cause symptoms aside from those that are not distinguishable from other mild, brief childhood illnesses. It is most commonly spread through bodily fluids, primarily saliva; however, it can be spread through blood and semen during sexual contact, blood transfusions, and organ transplantation.²

READ MORE: Age at MS Disease Onset Affects Pathophysiology, Gray and White Matter

For each MS case in the cohort, Ascherio and colleagues identified up to 3 serum samples collected before the date of MS onset. Cases were matched to 2 randomly selected individuals without MS of the same age, sex, race/ethnicity, branch of military service, and dates of collection of blood samples of who were on active military duty when the case was diagnosed. Among the 801 MS cases, only 1 individual was EBV-negative at last blood collection, which took place a median of 1 year before MS onset.¹

At baseline, 35 MS cases and 107 controls were EBV-negative. Thirty-four of those individuals became infected with EBV during the follow-up, and all seroconverted before the onset of MS. Furthermore, investigators recorded a median time of 5 years (range, 0 to 10 years) between the first EBV-positive sample to MS onset.

The connection between EBV and MS is not new, but these findings further establish and confirm years of musing on the relationship. A recent review by Tarlinton et al on the role of viruses in the pathogenesis of MS, which at the time, supported previous findings, concluded that EBV infection triggers the expression of human endogenous retroviruses (HERVs) that have been associated with MS pathogenesis; and for both the HERVs and herpesviruses, there was significant cross-reactivity between the viral protein epitopes, myelin oligodendrocyte protein, and myelin basic proteins—major targets in MS autoimmunity.⁴

Additionally, Amit Bar-Or, MD, FRCPC, FAAN, FANA, Melissa and Paul Anderson President’s Distinguished Professor; director, Center for Neuroinflammation and Neurotherapeutics; and chief, Multiple Sclerosis Division, department of neurology, Perelman School of Medicine, University of Pennsylvania, has also been at the forefront of this research. In a 2020 paper, he and colleagues concluded that ocrelizumab (Ocrevus; Genentech) represented a “breakthrough” treatment of MS because of its ability to substantially reduce annualize relapse rate while selectively targeting B-cells that would be consistent with the pathophysiologic role for EBV-infected B-cells in MS.⁵

"This is new in that we moved from suspicion to proof of causality—recognizing the cause of the disease is a critical step to reorient research. Although the role of EBV was suspected, most research on MS ignored until now the fact that MS is a complication of EBV infection," Ascherio added.

Most recently, Atara Biotherapeutics’ investigational agent ATA188, a novel agent that targets B-cells that have been infected with EBV, showed a sustained clinical benefit over 39 months in a phase 1/2 clinical trial of patients with progressive MS.³ 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.

The newly published data by Ascherio et al will hopefully open more realms of research into therapeutic approaches to MS, or even preventive measures. "In addition to a vaccine for prevention, the possibility of better and more radical treatments of MS by targeting EBV with antivirals," is more realistic, he said.

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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. About Epstein-Barr virus. CDC. https://www.cdc.gov/epstein-barr/about-ebv.html. Updated September 28, 2020. Accessed January 14, 2022.
3. 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.
4. Tarlinton RE, Martynova E, Rizvanov AA, Khaiboullina S, Verma S. Role of viruses in the pathogenesis of multiple sclerosis. Viruses. 2020;12(6):643.doi:10.3390/v12060643
5. Bar-Or A, Pender MP, Khanna R, et al. Epstein-Barr virus in multiple sclerosis: theory and emerging immunotherapies. Trends Mol Med. 2020;26(3); 296-310. doi:10.1016/j.molmed.2019.11.003