- Epstein–Barr virus (EBV) has long been linked to MS, but because the virus is extremely common and MS often develops years later, proving how the two are connected has been challenging.
- New research strengthens that link, showing that people with EBV‑related mononucleosis (glandular fever or “mono”) have a higher long‑term risk of MS, and that the immune response to EBV may help distinguish MS from similar neurological conditions.
- Together, the findings add to evidence that EBV plays a role in MS and support continued research into prevention, diagnosis, and treatment.
Epstein-Barr virus and MS
Epstein-Barr virus (EBV) infects most people worldwide, often during childhood, and can cause infectious mononucleosis – also known as glandular fever or “mono” – when infection occurs later in adolescence or adulthood.
For decades, scientists have suspected a link between EBV and MS. Nearly all people with MS show evidence of prior EBV infection, but because the virus is so widespread and MS often develops many years later, establishing a direct connection proved difficult.
Interest in the link intensified in 2022, when a large study of US military personnel showed that EBV infection almost always occurred before the onset of MS and was associated with a sharply increased risk of developing the disease. The study, which analysed stored blood samples from millions of service members, found no similar association with other common viruses, providing some of the strongest evidence to date that EBV plays a causal role in MS.
Two new studies add further detail to the growing evidence base, helping refine understanding of EBV’s role in MS, even as researchers continue to evaluate how the findings could be applied in clinical settings.
Study one: EBV-positive mononucleosis and MS risk
In the first study, published in Neurology Open Access, researchers examined whether people with laboratory-confirmed EBV‑positive glandular fever faced a higher risk of developing MS later in life.
Using medical records from the Rochester Epidemiology Project, the team from the Mayo Clinic and collaborators followed 4,721 people with confirmed EBV‑positive glandular fever (exposed group) and compared them with 14,163 individuals without EBV‑positive glandular fever (unexposed group).
What did the risk study find?
Over an average follow‑up of six to eight years, MS developed in 0.17% of those in the exposed group, compared with 0.07% of those in the unexposed group. After adjusting for factors such as smoking, socioeconomic status, and comorbidities (other medical conditions), people with EBV‑positive glandular fever were found to have just over a three‑fold higher risk of developing MS.
Although the absolute risk remained low, the researchers said the findings reinforce EBV as a key contributor to MS risk. Previous studies have suggested a two‑ to three‑fold increased risk, but many relied on self-reported histories of glandular fever or on billing/administrative diagnosis codes rather than confirmed clinical diagnoses. By using laboratory‑confirmed EBV‑positive glandular fever and expert review of MS diagnoses, the researchers aimed to reduce misclassification and strengthen confidence in the results.
This study adds to growing evidence that EBV infection appears to be necessary for MS to develop but alone is not enough to cause the disease. Most people infected with EBV never develop MS, indicating that genetic susceptibility and other environmental factors also play an important role.
Still, the findings have renewed interest in the potential long‑term impact of EBV prevention strategies, including vaccines currently under development.
Study two: EBV antibodies and MS diagnosis
In the second study, published online in JAMA Neurology, researchers approached the EBV-MS connection from a different angle, focusing not on future risk but on diagnosis after neurological symptoms emerge.
Led by researchers from the Medical University of Vienna, the study investigated whether antibodies to a specific EBV protein, called Epstein-Barr nuclear antigen 1 (EBNA‑1), could help distinguish MS from other inflammatory neurological diseases that can appear similar clinically.
Distinguishing MS from conditions such as myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and neuromyelitis optica spectrum disorder (NMOSD) can be challenging, particularly in people who test negative for established disease‑specific antibodies. Misclassification can have serious consequences, as some treatments commonly used for MS may worsen outcomes in NMOSD.
What did the antibody study find?
The researchers analysed blood samples from 2,091 people with neuroinflammatory diseases across multiple countries, along with 1,976 people without neuroinflammatory diseases. This included 184 people with MS, 65 with MOGAD, and 61 with NMOSD.
They found that while many people showed evidence of past EBV infection, persistently high levels of antibodies against a specific EBNA-1 peptide were strongly associated with MS.
When the researchers followed people over time, they found that 96% of those with MS had repeatedly high EBNA‑1 antibody levels. In contrast, fewer than 20% of people with MOGAD or NMOSD showed the same pattern. The results were confirmed in a separate group, suggesting that consistently high EBNA-1 antibody levels could help support an MS diagnosis.
The researchers found that tracking antibody levels over time was key. Although brief increases could occur in people without MS, sustained high levels were mainly seen in those with the disease.
Rather than replacing MRI scans or spinal fluid tests, the antibody test could provide an additional source of information when diagnosis is challenging.
Why do these studies matter?
Together, the studies highlight the role of EBV infection and the body’s immune response to EBV at different stages of MS – from increasing disease risk to helping distinguish MS from related conditions.
The researchers emphasise that while the findings do not change current care and most people infected with EBV will not develop MS, they deepen understanding of the disease.
The expanding evidence base has strengthened interest in the possibility of EBV‑focused MS prevention and treatment strategies.
In Australia, this evidence underpins MS Australia’s EBV in MS National Collaborative Platform, which brings researchers together to accelerate understanding of how EBV contributes to MS and the potential to target EBV to prevent or treat MS.
