Study Reveals Higher EBNA1 Antibodies Associated With Reduced Disability Progression in MS

A population-based study of patients with multiple sclerosis (MS) reported that higher serum levels of Epstein-Barr virus nuclear antigen 1 (EBNA1) antibodies were associated with a reduced risk of disability progression, with the strongest association observed among patients carrying both HLA-A02:01* and HLA-DRB115:01*. The findings suggest that the relationship between Epstein-Barr virus (EBV)-related immune responses and MS progression may depend on an individual's underlying immunogenetic profile.¹

Published in Journal of Neurology, Neurosurgery & Psychiatry, the study examined whether EBV-related immune responses remain relevant after disease onset and potentially influence long-term disability accumulation. Previous studies evaluating EBV antibody responses and disease course have produced inconsistent findings and have rarely accounted for modification by HLA genotype, despite the strongly implicated EBV infection in MS susceptibility,

Investigator Anna Karin Hedström, MD, PhD, of the Department of Clincal Neuroscience at Karolinska Institutet in Sweden, and colleagues analyzed data from 2 population-based Swedish MS studies, the Epidemiologic Investigation of Multiple Sclerosis (EIMS) and Genes and Environment in Multiple Sclerosis (GEMS). Participants had longitudinal disability data available through the Swedish MS Registry.

The analysis included patients aged 16 to 70 years with neurologist-confirmed MS who had provided blood samples and had longitudinal Expanded Disability Status Scale (EDSS) assessments. EBNA1 immunoglobulin G (IgG) antibody levels were measured using multiplex serology targeting the EBNA1 peptide segment spanning amino acids 385 to 420, a region previously associated with MS susceptibility.

The primary outcome was confirmed disability worsening (CDW), defined as a sustained increase in EDSS for at least 6 months. Investigators used Cox proportional hazards models to examine the association between EBNA1 antibody levels and time to CDW, adjusting for sex, age, calendar year of diagnosis, disease phenotype, disease duration, and baseline EDSS. The researchers also evaluated whether HLA-A02:01* and HLA-DRB115:01* modified the association.

Higher EBNA1 Levels Associated With Lower Risk of Disability Worsening

Across the full cohort, higher EBNA1 antibody levels were associated with a lower risk of CDW. For each 1-SD increase in EBNA1 antibody levels, the hazard ratio (HR) for CDW was 0.93 (95% CI, 0.90-0.96).¹

The association varied according to HLA status. The strongest inverse association was observed in patients carrying both HLA-A02:01* and HLA-DRB115:01, in whom each 1-SD increase in EBNA1 antibody levels was associated with a 13% lower risk of CDW (HR, 0.87; 95% CI, 0.81-0.93).

By comparison, associations were weaker or not clearly evident among patients in the other HLA-defined subgroups. Statistical analyses provided evidence for effect modification by HLA-DRB115:01* (P for interaction = .04), with additional evidence of a 3-way interaction involving HLA-A02:01* (P = .03).

Investigators also examined EBNA1 levels after dichotomizing participants according to the cohort median. In the overall population, higher EBNA1 levels remained associated with reduced risk of CDW (HR, 0.91; 95% CI, 0.85-0.97).

Among carriers of both HLA alleles, higher EBNA1 levels were associated with reduced risks of several disability outcomes. The HR for CDW was 0.88 (95% CI, 0.77-1.00), while the HRs for reaching EDSS 3 and EDSS 4 were 0.76 (95% CI, 0.61-0.94) and 0.79 (95% CI, 0.64-0.98), respectively. Among patients lacking either HLA-DRB115:01* or HLA-A02:01*, point estimates were generally closer to 1, with CIs including 1 across the evaluated outcomes.

Findings Consistent Across Sensitivity Analyses

The researchers performed several analyses to determine whether treatment exposure or the timing of EBNA1 measurement could account for the findings. 

The inverse association persisted when analyses were restricted to patients treated exclusively with platform therapies, including interferon beta, glatiramer acetate, or teriflunomide. Similar findings were observed after restricting analyses to treated patients and accounting for disease-modifying therapy (DMT) exposure as a time-varying covariate, as well as afteradditional adjustment for DMT status at the time of blood sampling.

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A delayed-entry analysis, in which follow-up began at the time of EBNA1 sampling, attenuated the overall association. However, the inverse association among patients carrying both HLA-DRB115:01* and HLA-A02:01* remained evident.¹

Additional adjustment for educational attainment, autoimmune disease, infectious mononucleosis, smoking, alcohol consumption, body mass index, sun exposure, and physical activity did not materially change the estimates. The association also remained after adjustment for ancestry-informative principal components.

Investigators found no meaningful correlation between the time from study baseline to blood sampling and EBNA1 antibody levels (r = 0.01; P = .24). Adjusting for the most recent EDSS score before blood sampling slightly attenuated the estimates but did not materially change the overall pattern.

Interpreting the EBV-MS Relationship

Investigators emphasized that EBNA1 antibody levels may reflect different biological processes during MS susceptibility compared with the period following disease onset.Researchers also noted that serum EBNA1 antibody levels are unlikely to directly capture immune processes occurring within the central nervous system. If EBV contributes to MS progression through compartmentalized CNS inflammation, circulating antibody levels may instead serve as an indirect marker of broader systemic immune activity.¹

The stronger association observed in patients carrying both HLA-DRB115:01* and HLA-A02:01* further supports the possibility that host genetics influence how EBV-related immune markers relate to MS outcomes. HLA-DRB115:01* is the strongest established genetic risk allele for MS, whereasHLA-A02:01* has been consistently associated with reduced MS risk.

Because several DMTs can affect humoral immune responses, treatment was an important potential confounder. B-cell-directed and lymphocyte-trafficking therapies, for example, may alter EBNA1 antibody levels through effects on B-cell populations, antigen presentation, or broader immune regulation. Investigators noted the consistency of the findings across multiple treatment-related analyses reduced, but did not eliminate, the possibility that treatment exposure explained the observed associations.

Limitations and Next Steps

The study's authors acknowledged several limitations, including the measurement of EBNA1 antibodies at a single time point and the use of a single EBNA1 epitope. Consequently, the study could not evaluate changes in antibody responses over time or responses to other EBV antigens.¹

Researchers also could not determine whether EBNA1 antibody levels directly reflect viral antigen burden, immune competence, or treatment-related changes in B-cell biology. Antibodies are not generally considered directly pathogenic in MS and may instead function as markers of underlying immune processes, including T-cell-mediated mechanisms.

In addition, although analyses accounted for numerous potential confounders, residual confounding cannot be excluded. The investigators also noted that EBNA1 levels measured after MS onset could partly reflect prior immune trajectories associated with both serological responses and disease progression.

Ultimately, the findings suggest that EBV-related immune responses may have relevance beyond the development of MS, but that their relationship with disability progression is not uniform across patients. Rather, the prognostic association appears to be influenced by HLA background, particularly the combination of HLA-A02:01* and HLA-DRB115:01*.

The authors concluded that these findings support greater consideration of host immunogenetic context in studies evaluating EBV-related biomarkers and MS progression, while emphasizing the need for mechanistic and longitudinal research to clarify how host-virus interactions may contribute to long-term disability accumulation.

REFERENCES
1. Hedström AK, Thomas O, Strid P, et al. HLA-dependent association between EBNA1 antibody levels and disability progression in multiple sclerosis. J Neurol Neurosurg Psychiatry. Published Online First: 31 July 2026. doi: 10.1136/jnnp-2026-338964