Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis

Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system whose underlying cause has long been uncertain. Epstein-Barr virus — a near-ubiquitous human herpesvirus that infects more than 95% of adults — has been epidemiologically linked to MS for decades, but until now no study had been able to demonstrate the necessary temporal sequence: that EBV infection actually precedes the onset of MS rather than being a coincident or downstream finding. The challenge is that MS is rare and EBV is common, so a study large enough to capture EBV-negative individuals who later seroconvert and later still develop MS is logistically extraordinary.

The authors solved this by leveraging serum samples banked by the US military as part of routine HIV surveillance, which provided more than 10 million young adults with longitudinal serology over two decades of active service. From this cohort they identified 955 individuals diagnosed with MS during their period of service, and they retrieved up to three pre-diagnosis serum samples per case — the earliest typically collected years before clinical onset. Each MS case was matched to two controls who did not develop MS. Antibody profiling against EBV (and against cytomegalovirus and other viruses as comparators) was performed on the pre-diagnosis samples using both standard ELISA and the VirScan phage-display platform.

The signal was unambiguous. Among the small subset of individuals who were EBV-seronegative at their first sample, only one of the 801 future MS cases remained EBV-negative before MS onset; the rest had seroconverted to EBV in the years preceding their MS diagnosis. The risk of MS rose 32-fold after EBV infection (95% CI 4.3–245.3) but was unchanged after infection with cytomegalovirus — a virus transmitted similarly to EBV — ruling out a generic "any viral infection" explanation. Serum neurofilament light chain, a sensitive marker of axonal damage that rises before clinical MS symptoms appear, increased only after EBV seroconversion, locating the neuroaxonal injury downstream of the viral exposure rather than coincident with it. Together, these findings cannot be explained by any other established MS risk factor (HLA genotype, smoking, vitamin D status, EBV-MS reverse causation) and identify EBV as the leading cause of MS — with direct implications for prevention, including the rationale for prophylactic EBV vaccines and EBV-targeted therapies now under development.