Epstein-Barr virus in depth
A virus almost everyone carries
The Epstein-Barr virus (EBV) is a herpesvirus that infects more than nine in ten adults worldwide. It spreads in saliva and infects B cells, where it stays for life in a quiet, latent form inside memory B cells, held in check by T cells. Infection in early childhood usually passes unnoticed. Infection in adolescence or early adulthood more often causes glandular fever, also called infectious mononucleosis.
The evidence that EBV comes first
For decades, studies found that almost everyone with MS carries antibodies against EBV, and that people who have had glandular fever have about twice the risk of MS. A meta-analysis of 18 studies put the relative risk at 2.17. But these studies could not show which came first.
A study published in 2022 settled much of that question. It followed more than 10 million young adults in the US military, whose blood was stored regularly, and identified 955 who developed MS during their service. Among those who started without EBV, the risk of MS rose 32-fold after infection with EBV, but not after infection with cytomegalovirus, a related virus spread in a similar way. Blood levels of neurofilament light, a marker of damage to nerve fibres (lesson 7.2), rose only after infection with EBV. The authors concluded that EBV is the leading cause of MS. This finding cannot be explained by any other known risk factor, but it also leaves open why so few infected people develop MS.
32 times
Bjornevik 20222.17 times
Handel 2010More than 9 in 10
Soldan 2022How could a common virus cause MS?
Several explanations are under study. They are not mutually exclusive, and each has some direct evidence.
EBV hypotheses
Step 1 of 7 · Infection
Molecular mimicry. Antibodies made inside the nervous system of people with MS were traced to the B cells that made them. One of these antibodies bound both a protein of the virus, EBNA1, and a protein of the brain's support cells, GlialCAM, with high affinity. Structural studies and experiments in mice supported the idea that an immune response to the virus can cross-react with the brain.
Genes and virus working together. HLA-DRB1*15:01, the strongest genetic risk factor for MS, can act as a co-receptor that helps EBV infect B cells in the laboratory. A viral protein, EBNA2, binds DNA near many genetic risk variants for MS and other autoimmune diseases, which suggests the virus may switch on the same genes that raise risk.
Infected B cells as drivers. EBV changes the behaviour of the B cells it infects. In lupus, another autoimmune disease linked to EBV, infected B cells were reprogrammed into cells that present self-proteins to T cells and drive autoimmunity. Whether the same happens in MS is being studied. It would fit with the strong effect of medicines that remove B cells, which also remove many of the memory B cells where EBV lives.
Poor control of the virus. Another idea is that in people who develop MS the immune system controls EBV-infected B cells less well, so that infected cells survive in larger numbers and reach the brain. This is the reasoning behind trials of T cells trained to recognise the virus.
Why most infected people never get MS
Since almost everyone is infected and few develop MS, EBV is close to necessary but far from sufficient. Genes, infection at an older age, low vitamin D, smoking and obesity in adolescence all add to the risk (lesson 8.1). The virus may set the stage, with these factors deciding whether the immune response turns against the nervous system.
What this means for prevention and treatment
If EBV is a cause, two strategies follow: prevent infection, or target the virus or the cells that carry it in people who already have MS.
- Vaccines. Vaccines designed to prevent EBV infection or glandular fever are in early trials in healthy young people, for example an mRNA vaccine (NCT05164094). Proving that a vaccine prevents MS would take many years and very large numbers of people, because MS appears years after infection and in few of those infected.
- Antiviral medicines. Medicines that act on EBV, such as tenofovir and famciclovir, are being tested in small trials in MS, mostly measuring the virus or MRI activity. Their effect on the latent virus, which does not copy itself, is likely to be limited.
- T-cell therapy. ATA188, donated T cells primed against EBV, was tested in progressive MS. Its phase 2 trial, EMBOLD, did not meet its main goal of improving disability, as the company announced in November 2023.
The live box below lists every EBV trial in the Trial Bank. The fact check "If Epstein-Barr virus causes MS, will an EBV vaccine cure it?" answers the most common question.If Epstein-Barr virus causes MS, will an EBV vaccine cure it?
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What we know
- EBV infection precedes MS and raises its risk about 32-fold in the largest study so far.
- People who have had glandular fever have about twice the risk of MS.
- Antibodies in MS can cross-react between a viral protein and a brain protein, and the main risk gene interacts with the virus.
What we don't know
- Which of the proposed mechanisms matters most, or whether they differ between people.
- Why only a small minority of infected people develop MS.
- Whether preventing or treating EBV infection can prevent or stop MS.
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Key terms
- Glandular fever (infectious mononucleosis)
- An illness caused by first infection with EBV in adolescence or adulthood, with fever, sore throat and tiredness. It doubles the risk of MS.
- EBNA1
- A protein of the Epstein-Barr virus. Some antibodies against it also bind a brain protein, GlialCAM.
- Cytomegalovirus
- A common herpesvirus related to EBV and spread in a similar way. Infection with it did not raise MS risk.
- Axon (nerve fibre)
- The long extension of a nerve cell that carries its signal. Losing axons, rather than myelin alone, is thought to cause most lasting disability.
- T cell
- A white blood cell that recognises a specific target and directs or carries out an immune attack.
- B cell
- A white blood cell that can present targets to T cells, release inflammatory signals and mature into antibody-making cells. Some B-cell-targeting medicines are highly effective MS treatments.
- Neurofilament light (NfL)
- A protein released when nerve fibres are damaged. Blood levels can rise with new inflammation and fall on effective treatment. Other conditions can also affect its level.
- Epstein-Barr virus (EBV)
- A common herpes virus that causes glandular fever. Infection appears to be almost necessary for MS, but most infected people never develop it.
- Molecular mimicry
- When the immune response to a microbe also recognises a similar-looking protein of the body.
- HLA-DRB1*15:01
- A version of an immune gene that is the strongest single genetic risk factor for MS.
- Phase 1, 2 and 3
- The stages of testing in people: safety and dose, then an early sign of effect, then a large test of benefit.
References
- Soldan SS, Lieberman PM. Epstein-Barr virus and multiple sclerosis. Nat Rev Microbiol 2022.https://doi.org/10.1038/s41579-022-00770-5
- Handel AE, et al. An updated meta-analysis of risk of multiple sclerosis following infectious mononucleosis. PLoS One 2010.https://doi.org/10.1371/journal.pone.0012496
- Bjornevik K, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science 2022.https://doi.org/10.1126/science.abj8222
- Lanz TV, et al. Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature 2022.https://doi.org/10.1038/s41586-022-04432-7
- Menegatti J, et al. HLA-DRB1*15:01 is a co-receptor for Epstein-Barr virus, linking genetic and environmental risk factors for multiple sclerosis. Eur J Immunol 2021.https://doi.org/10.1002/eji.202149179
- Harley JB, et al. Transcription factors operate across disease loci, with EBNA2 implicated in autoimmunity. Nat Genet 2018.https://doi.org/10.1038/s41588-018-0102-3
- Younis S, et al. Epstein-Barr virus reprograms autoreactive B cells as antigen-presenting cells in systemic lupus erythematosus. Sci Transl Med 2025.https://doi.org/10.1126/scitranslmed.ady0210
Next · Lesson 3 of 3
Genetics of susceptibility and severity
MS is not inherited in a simple way, but genes shape who develops it and, separately, how severe it becomes. This lesson explains what the largest genetic studies have found and what they mean for families.
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