Blood EBV Activity Biomarkers May Predict Multiple Sclerosis Relapse Months Ahead

Although many people harbor latent Epstein-Barr virus (EBV), growing evidence has linked the virus to MS pathobiology. Current indicators often emerge only after inflammation is already underway, leaving a need for earlier markers of disease activity. New findings now show that EBV reactivation in circulating immune cells can precede MS relapse by as much as three months.

Investigators at Mass General Brigham (Boston, MA, USA) profiled peripheral blood to track EBV activity and immune gene-expression changes before relapse. Using single-cell RNA sequencing alongside complementary molecular assays, the team analyzed hundreds of thousands of immune cells to determine which cell populations and pathways shift ahead of clinical events. Particular attention was given to B lymphocytes, which can harbor latent EBV, as well as viral lytic activity and host pathways associated with genetic risk for MS.

The analysis included samples from 114 people with MS and 21 healthy participants enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis (CLIMB) study at Brigham and Women’s Hospital. Serial blood samples collected up to 90 days before relapse were compared with samples obtained during remission from the same patients, allowing investigators to identify pre-relapse immune changes relative to periods of quiescent disease.

The researchers detected increased EBV lytic activity in immune cells as early as three months before relapse, accompanied by higher expression of genes associated with MS risk. B cells showed some of the strongest changes, activating antiviral and inflammatory pathways and displaying an increase in ABC-like B cells, a subset associated with viral infection and autoimmune disease. EBV-derived proteins also activated MS risk genes before relapse, a pattern that was not observed during remission or in healthy controls.

The study was published in Nature Medicine on September 16, 2026, and was conducted within the Mass General Brigham system, including Brigham and Women’s Hospital. If validated in larger, prospective studies, blood biomarkers of EBV activity could help identify patients at increased risk of relapse and complement MRI scans and existing blood biomarkers that typically detect disease activity only after inflammation has begun. The authors also note that future work is needed to determine whether these patterns extend to early-stage and progressive MS.

“These findings open a new avenue for targeted therapeutics,” said senior author Tanuja Chitnis, M.D., director of the Translational Neuroimmunology Research Center and chief of the Division of Neuroimmunology at Mass General Brigham.

“Currently, most MS treatments work by broadly suppressing the immune system. Our results suggest there’s an opportunity to be more precise and develop approaches that target EBV or the immune cells involved in relapse,” added Chitnis.

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