Summary: A large, population-based study strengthens the association between infectious mononucleosis (mono), caused by the Epstein-Barr virus (EBV), and a later increased risk of developing multiple sclerosis (MS). Analyzing more than two decades of medical records, researchers found that people who experienced laboratory-confirmed EBV-positive mono as adolescents or adults had roughly a threefold higher risk of MS compared with matched individuals who did not have mono.
Although MS remains uncommon in the general population, these findings highlight EBV infection—particularly clinically apparent mono—as a potential target for prevention strategies, including vaccines, that could reduce the future burden of MS worldwide.
Key Facts
- Threefold increase in relative risk: After adjusting for factors such as smoking, race and ethnicity, and chronic conditions like diabetes and depression, the analysis found an adjusted hazard ratio of approximately 3, indicating a near tripling of MS risk among people with EBV-positive mono.
- Absolute rates observed:
- Mono group: 8 of 4,721 people (0.17%) developed MS, equivalent to 2.25 cases per 10,000 person-years.
- Control group: 10 of 14,163 people (0.07%) developed MS, equivalent to 0.77 cases per 10,000 person-years.
- Age matters: EBV infects most people, often in childhood without symptoms. When primary infection occurs in adolescence or adulthood, it more commonly causes symptomatic mono, which appears to be the form of infection associated with higher MS risk.
- Vaccine relevance: The study received support from ModernaTX, Inc., which is developing EBV-targeted vaccines that could ultimately reduce EBV-associated conditions, including MS.
Source: AAN
A study published April 1, 2026, in Neurology Open Access examined whether laboratory-confirmed Epstein-Barr virus–positive infectious mononucleosis (EBV-positive IM, commonly called mono) is linked to a greater chance of later developing multiple sclerosis. The Epstein-Barr virus is a ubiquitous herpesvirus that is typically asymptomatic when contracted in childhood but often causes mononucleosis when infection occurs in the teenage years or adulthood.
“These results emphasize the importance of continuing research into methods to prevent Epstein-Barr virus infection,” said study author Jennifer L. St. Sauver, PhD, of the Mayo Clinic in Rochester, Minnesota. “Reducing EBV infections that produce symptomatic mono could lower the number of MS cases in the future. MS often leads to significant disability and substantial treatment costs, and it most commonly begins when people are in the prime of their working and family lives.”
The investigators used records from the Rochester Epidemiology Project to identify people with serologic evidence of EBV infection and a concurrent diagnosis of infectious mononucleosis between 1998 and 2022. They identified 4,721 people with EBV-positive mono and matched each to three age- and sex-matched individuals without evidence of mono, yielding 14,163 referents. Incident MS cases were confirmed by blinded expert chart review and analyzed using multivariable Cox proportional hazards models that controlled for demographic and health-related confounders.
Participants with mono were followed for a median of six years, while referents were followed for a median of eight years. During follow-up, 8 individuals in the exposed group (0.17%) and 10 in the referent group (0.07%) were diagnosed with MS. These incidences correspond to 2.25 and 0.77 cases per 10,000 person-years, respectively. After adjusting for variables such as race, ethnicity, smoking status, diabetes, depression, and substance use disorders, EBV-positive mono remained associated with a more than threefold increased risk of developing MS (adjusted hazard ratio 3.14, 95% CI: 1.18–8.34).
The authors caution that an association does not prove causation: the study demonstrates a strong link between symptomatic EBV infection and subsequent MS but cannot definitively show that mono causes MS. Another limitation is the follow-up duration; with median follow-up of six to eight years, some MS cases that develop later in life could have been missed.
“Mononucleosis is relatively uncommon, but if preventing EBV infection or symptomatic mono can reduce future MS cases, that would support prioritizing EBV vaccine development and other preventive measures,” St. Sauver said.
Funding: The study received support from ModernaTX, Inc., which is working on vaccines against Epstein-Barr virus–associated conditions.
Key Questions Answered:
A: No. In this study only 0.17% of people with a documented history of mono developed MS. While the relative risk was higher, the absolute risk remains low—most people who have had mono will not develop neurological disease.
A: One leading explanation is molecular mimicry: EBV persists in B cells, and in some individuals the immune response to the virus may cross-react with components of the central nervous system, including myelin, triggering autoimmune damage.
A: Preventing primary EBV infection or stopping the development of symptomatic mono through vaccination is a plausible strategy to reduce MS risk. This is an active area of research, and vaccine candidates are in development.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The full journal paper was reviewed as part of reporting.
- Additional context and clarification were provided by editorial staff.
About this multiple sclerosis research news
Author: Natalie Conrad
Source: AAN (American Academy of Neurology)
Contact: Natalie Conrad – ANN
Image: The image is credited to Neuroscience News
Original Research: Open access. “Risk of Multiple Sclerosis Among Persons With Epstein-Barr Virus–Positive Mononucleosis: A Population-Based Study” by Jennifer L. St. Sauver et al., Neurology Open Access. DOI: 10.1212/WN9.0000000000000082
Abstract
Risk of Multiple Sclerosis Among Persons With Epstein-Barr Virus–Positive Mononucleosis: A Population-Based Study
Background and Objectives
Previous research linking Epstein-Barr virus–positive infectious mononucleosis (EBV-positive IM) to multiple sclerosis (MS) often lacked laboratory confirmation or relied on administrative codes. This study aimed to determine whether laboratory-confirmed EBV-positive mono is associated with a higher risk of clinically verified MS.
Methods
Using the Rochester Epidemiology Project, investigators conducted a retrospective cohort study identifying individuals with serologic evidence of EBV infection and an accompanying diagnosis of IM between 1998 and 2022. Each exposed individual was matched by age and sex to three unexposed individuals without evidence of IM. MS diagnoses were confirmed by blinded expert chart review, and multivariable Cox proportional hazards models adjusted for potential confounders.
Results
The exposed cohort included 4,721 people (55% female; 70% younger than 20 years at infection). The referent cohort included 14,163 people with similar demographic distribution. Over median follow-up periods of 6 years for the exposed group and 8 years for referents, MS developed in 8 exposed individuals (0.17%) versus 10 referents (0.07%). EBV-positive IM was associated with an adjusted >3-fold increased risk of MS (adjusted hazard ratio 3.14, 95% CI: 1.18–8.34).
Discussion
Laboratory-confirmed EBV-positive mononucleosis was associated with a substantially higher risk of developing MS in this population-based study. These results align with prior evidence and support preventive strategies targeting EBV—including vaccination—to potentially reduce the long-term public health impact of multiple sclerosis.