Andrea Espinosa

Background:  Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) characterized by immune-mediated myelin destruction, axonal injury, and progressive neurologic disability.^1,2 Although current disease-modifying therapies reduce relapse rates and lesion formation, they primarily target downstream inflammation rather than upstream disease initiation.¹ Epstein-Barr virus (EBV), a human herpesvirus that establishes lifelong latency in B lymphocytes, has emerged as one of the strongest environmental risk factors for MS.³ Longitudinal studies demonstrate that EBV infection precedes MS onset, and nearly all patients with MS show evidence of prior EBV infection.³ However, the mechanistic link between EBV infection and CNS autoimmunity remains unclear.

Objective:  To synthesize epidemiologic, mechanistic, and translational evidence linking EBV infection to MS pathogenesis and evaluate the potential role of EBV vaccination in disease prevention.

Search Methods:  A PubMed literature search was conducted using the keywords “multiple sclerosis,” “Epstein-Barr virus,” “EBV,” “B cells,” “T cells,” “molecular mimicry,” “EBNA1,” “GlialCAM,” “EBV vaccine,” “glycoprotein vaccine,” and “nanoparticle vaccine.” Primary research articles were prioritized, with review articles used for clinical background and context. Articles published between 2018 and 2024 were selected, with emphasis on epidemiologic, mechanistic, and translational vaccine studies.

Results:  Epidemiologic evidence strongly supports EBV as a potential upstream trigger of MS. In a longitudinal cohort study, EBV infection occurred before MS onset and was associated with a 32-fold increased risk of developing MS.³ Mechanistic studies further demonstrate that EBV-directed immune responses occur within the CNS. Gottlieb et al. analyzed paired blood and cerebrospinal fluid (CSF) samples from patients with relapsing-remitting MS. They identified shared EBV-specific T-cell receptor sequences in both the blood and CSF, suggesting that EBV-specific T-cell clones are present within the CNS.⁴ Lanz et al. provided evidence for molecular mimicry by showing that clonally expanded CSF B cells from patients with MS produced antibodies that bound both the EBV protein EBNA1 and the CNS protein GlialCAM.⁵ These findings suggest that immune responses initially directed against EBV may cross-react with CNS antigens and contribute to autoimmune demyelination. Translational vaccine studies further support the potential of EBV-targeted vaccination for disease prevention. Wei et al. demonstrated that EBV glycoprotein-based vaccines generate neutralizing antibodies capable of blocking viral entry into host cells.⁶ Malhi et al. demonstrated that a nanoparticle vaccine displaying EBV entry glycoproteins generated protective antibody responses and reduced viral infection in humanized mice.⁷

Conclusion:  Current evidence supports EBV as a biologically plausible and potentially modifiable environmental trigger of MS. Together, EBV-specific immune responses in the CNS, molecular mimicry involving EBNA1 and GlialCAM, and vaccine-mediated protection against EBV infection provide a mechanistic framework linking viral infection to autoimmune demyelination. Future studies should determine whether EBV vaccination can reduce MS incidence or alter disease development in humans. Targeting EBV may shift MS management from treating downstream inflammation toward preventing disease initiation.

Works Cited:

1. Ward M, Goldman MD. Epidemiology and Pathophysiology of Multiple Sclerosis. Continuum (Minneap Minn). Aug 1 2022;28(4):988–1005. doi:10.1212/con.0000000000001136
2. Filippi M, Bar-Or A, Piehl F, et al. Multiple sclerosis. Nature Reviews Disease Primers. 2018/11/08 2018;4(1):43. doi:10.1038/s41572-018-0041-4
3. Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. Jan 21 2022;375(6578):296–301. doi:10.1126/science.abj8222
4. Gottlieb A, Pham HPT, Saltarrelli JG, Lindsey JW. Expanded T lymphocytes in the cerebrospinal fluid of multiple sclerosis patients are specific for Epstein-Barr-virus-infected B cells. Proc Natl Acad Sci U S A. Jan 16 2024;121(3):e2315857121. doi:10.1073/pnas.2315857121
5. Lanz TV, Brewer RC, Ho PP, et al. Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature. Mar 2022;603(7900):321–327. doi:10.1038/s41586-022-04432-7
6. Wei CJ, Bu W, Nguyen LA, et al. A bivalent Epstein-Barr virus vaccine induces neutralizing antibodies that block infection and confer immunity in humanized mice. Sci Transl Med. May 4 2022;14(643):eabf3685. doi:10.1126/scitranslmed.abf3685
7. Malhi H, Homad LJ, Wan YH, et al. Immunization with a self-assembling nanoparticle vaccine displaying EBV gH/gL protects humanized mice against lethal viral challenge. Cell Rep Med. Jun 21 2022;3(6):100658. doi:10.1016/j.xcrm.2022.100658