Part 1: Targeting a common virus to treat Multiple Sclerosis (MS)? Explaining the evidence for a link between Epstein-Barr Virus and MS.

Writer: Emily DiMaulo-Milk

Editor: Caryssa Drinkuth

            In April 2025, Moderna initiated a Phase II Clinical trial testing the investigational vaccine mRNA-1195 in patients with MS.¹ This vaccine targets the common virus, Epstein-Barr Virus (EBV), most well-known as the virus which causes “mono”.² In this two-part blog post, we will first explain how this widespread virus may contribute to the development and progression of MS before delving into the details of mRNA-1195 and Moderna’s Horizon Trial. 

What is Multiple Sclerosis (MS)? 

Who gets MS?

Multiple Sclerosis (MS) is a neurodegenerative disorder.³ While most neurodegenerative disorders, including Alzheimer’s disease and Parkinson’s disease, are prevalent in elderly populations, MS is usually diagnosed in early adulthood, with the average age of diagnosis for MS at 32 years old.³ MS affects 2.9 million people worldwide, or nearly 1 of every 3,000 people. The prevalence of MS varies greatly from region to region due to genetic variation among people or differences in climate. The United States has the third-highest MS prevalence worldwide, and approximately 1 million people in the United States are living with MS.⁴ There has been an estimated 30% increase in the number of people living with MS globally from 2013 to 2020. Within the United States, there has been a 50% increase in MS cases during that same period.⁵ This increase may be due to improvement in diagnosis and treatments for MS; however, there is no indication that MS is being diagnosed earlier, suggesting that other factors may play a role.³

What are the symptoms of MS?

It can take years to diagnose MS after symptoms first occur. Most people with MS have the relapsing-remitting form of the disease. In this stage of the disease, symptoms can be transient and non-specific, making misdiagnosis common. Initial symptoms of MS include fatigue, numbness/tingling, muscle weakness, blurry or double vision, vertigo, issues with coordination and balance, changes in mood and behavior such as depression, impaired bladder or bowel control, and cognitive problems. The symptoms and their severity can vary greatly from person to person. Symptoms can appear over the course of days to weeks, then improve or completely disappear into remission for months or even years. Eventually, 20-40% of people with relapsing-remitting MS develop secondary-progressive MS, where the symptoms of MS are constant.⁶ Over time, symptoms can worsen, and new symptoms can develop. During late stages of MS, people who are affected may have difficulty speaking and hearing, partial or complete paralysis, difficulty chewing and swallowing food, muscle spasms, pain, and difficulty controlling emotions.⁷ While MS itself is rarely fatal, there is no cure for MS, and significant disability can arise because of the disease.³ Additionally, the early onset of MS means that those who are diagnosed with the disease will spend decades managing their symptoms. 

What changes in the body cause MS?

            In neurodegenerative disorders, the destruction of nerve cells, or neurons, causes the disease to develop. In MS, it is the neurons of the brain and spinal cord that are primarily affected.³ Neurons are responsible for communication between the brain and the body. This communication is critical for sensation, control of movement, and feelings like hunger and thirst. Additionally, neurons within the brain communicate with each other to control emotions, speech, memory, and thought. Neurons signal to each other through special chemicals called neurotransmitters.⁸

Neurons consist of a cell body and an axon. In MS, it is the axon that is affected. The axon is a long, tail-like structure with neurotransmitters at its end that are released to allow communication between neurons. The release of neurotransmitters is triggered by an electrical signal that travels along the length of the axon. This electrical signal is slow over long distances and will weaken over time.⁸ To preserve the signal and speed up communication between neurons, healthy axons are typically coated with myelin sheaths. The myelin sheath also protects neurons from damage by serving as a physical barrier. It is composed of specialized fatty cells that discontinuously wrap around the neuron, acting like insulation on a wire to prevent the loss of an electrical signal. There are gaps along the myelin sheath, and the electrical signal “jumps” across these gaps as it travels along the axon to reduce travel time.⁹

In people living with MS, abnormal activity of immune cells destroys of the myelin sheath, a process called demyelination, which exposes the axon. This means MS is also an autoimmune disorder. A damaged myelin sheath results in a leaky electrical signal, causing delayed communication between neurons. Damage at the exposed axon can result in a complete inability to transmit signal to other neurons. These disruptions in neuronal communication cause the symptoms of MS to arise. As the disease progresses, demyelination continues to occur, causing symptoms to increase in severity and duration.³ Currently, there are no treatments available that can regenerate the myelin sheath.

What causes MS to develop? 

The exact factors that underlie the development of MS remain incompletely understood, and it is likely that a combination of factors are responsible for the development of MS. There are certain genetic risk factors that are known to increase the risk of developing MS. People with a family history of MS and those of Northern European ancestry are more likely to develop MS. Particularly, the HLA-DR15 haplotype is a known risk factor for MS. People assigned female at birth are two to three times more likely to develop MS for reasons which remain unclear, but may be due to differences in hormones or the immune system. Other factors, like smoking and obesity, may contribute to MS development by promoting inflammation, which can worsen the demyelination process.³ Recently, there has been much interest in a common virus, Epstein-Barr Virus (EBV), which may be linked to the development of MS. 

What is Epstein-Barr Virus (EBV), and what diseases does it cause?

What is EBV? 

            EBV is a type of herpesvirus. Nearly every adult has EBV, as the virus is detectable in 90-95% of adults. Most people are familiar with one of the diseases caused by EBV, infectious mononucleosis, or “mono,” but EBV is responsible for many different diseases. The virus is typically transmitted via saliva. It infects several types of cells, but primarily infects a special type of white blood cell called a B-cell. An initial infection with EBV usually occurs in childhood and causes no recognizable symptoms. Infection later in life, during adolescence, is much more likely to cause “mono.”²

Regardless of whether symptoms appear or not, infection with EBV is lifelong. Once infected with the virus, it stays in some B-cells in a latent form, hiding as a piece of DNA that appears similar to a person’s own genetic material.² This is similar to another, more familiar herpesvirus, Varicella-Zoster Virus, or chickenpox. People who had chickenpox as a child might experience periodic episodes of shingles. This itchy, uncomfortable rash isn’t caused by a new infection with chickenpox, but rather a reactivation of the latent virus that infected them when they were a child.¹⁰This reactivation of the virus is known as the lytic phase. During this time, the virus replicates, which enables the transmission of the virus from person to person. The lytic phase can be triggered by factors like an illness, inflammation, or stress. Usually, this phase lasts only a short time, from days to weeks. Unlike chickenpox, there is currently no vaccine for EBV. There are also no EBV-specific treatments available.²

What other diseases does EBV cause?

            In addition to “mono,” EBV has been demonstrated to cause several different cancers, including B-cell Lymphomas, NK/T-cell Lymphomas, Gastric Cancer, Nasopharyngeal Cancer, and may be linked to other cancers as well. In these tumors, the virus remains in the latent state, expressing a limited number of genes. In people with impaired immune systems, such as people living with HIV or transplant recipients, EBV can cause uncontrolled growth of infected cells, a disease called post-transplant lymphoproliferative disorder. In these people, the virus can also become uncontrollably lytic, causing lesions in the tongue in a disease called Oral Hairy Leukoplakia.²

Interestingly, EBV has also been linked to several autoimmune diseases in addition to MS, such as Rheumatoid Arthritis and Systemic Lupus Erythematosus.²

How did scientists identify a link between EBV and MS?

A potential link between EBV and MS was first proposed in the 1980s. Early work had identified that people living with MS had significantly higher rates of EBV infection than the general population.¹¹ Later epidemiological studies demonstrated that infection with EBV at adolescence, as opposed to infection during early childhood, elevated the risk for developing MS.¹² EBV has also been detected in MS lesions in the brain.¹¹ However, while suggestive, this hypothesis ultimately relied on correlational data. 

More direct evidence for a link between EBV and MS was provided by a study published in the journal Sciencein 2022. This study, led by Dr. Kjetil Bjornevik, was a twenty-year-long effort involving over 10 million people who provided over 60 million blood samples. Researchers were able to determine if a person was infected with EBV using blood serum samples that were taken every six months. By analyzing the samples collected over time, the researchers were able to determine not only who was infected with the virus, but also when people who were uninfected became infected, termed seroconversion. Importantly, all these samples were taken from adults, meaning that any seroconversion represented a late-life infection with EBV.¹³

From this population, 801 people who went on to develop MS were identified, all but one of whom were infected with EBV. Being infected with EBV resulted in a 26-fold increase in developing MS. Interestingly, seroconversion was significantly more common in people who went on to develop MS compared to the control group, and increased the risk of developing MS by 34-fold. Importantly, seroconversion also consistently preceded the development of MS, suggesting viral infection was a prerequisite for the development of MS. These associations were not true for a related herpesvirus, Human Cytomegalovirus. The authors also used a panel that would recognize antibodies against hundreds of viruses to determine which viruses a person had developed an immune response against. By doing this, the authors could rule out a general association between viral infection and MS. Overall, there were similar antibodies in the serum of people who developed MS and those who did not- except for antibodies against EBV proteins, which were much higher in the group with MS.¹³ Ultimately, this paper was a landmark in demonstrating a specific link between EBV and MS.

How might EBV contribute to the development of MS?

How can the identified link between EBV and MS be explained?

Altogether, while this work tracking people’s EBV and MS status over time strengthened the argument for a link between late-life EBV infection and MS, it did not explain how EBV could contribute to the development of MS. However, at the same time, another group of researchers led by Dr. Tobias V. Lanz was investigating an EBV protein called EBNA1. Their paper was published in the journal Nature just eleven days after the Science paper and provided mechanistic evidence for a link between EBV and MS. The research published in Nature suggested that molecular mimicry of EBNA1 may explain how infection with EBV results in demyelination and, thus, the development of MS.¹⁴

What is molecular mimicry?

Autoimmune disorders are caused by immune cells killing a person’s own healthy cells because it mistakes them for cells that are dangerous. There are many kinds of immune cells, each of which has a specialized job in the multi-step process of recognizing and killing dangerous cells. Immune cells called T-cells identify dangerous cells infected with a virus by looking at a sample of the proteins being expressed in this cell, called antigens. A different kind of immune cell called B-cells support this process by producing antibodies which “flag” a cell expressing antigen so that other immune cells recognize and kill them.¹⁵

Immune cells that recognize proteins normally produced by cells- self-antigens– are autoreactive and typically killed during their development, though some survive. Cells infected with a virus start making new proteins that are different from cell proteins, called foreign antigens. If a foreign antigen is recognized by a T-cell during presentation or an antibody produced by a B-cell, the antigen will be “remembered” by these cells. Then, the next time that a foreign antigen shows up, these immune cells are ready to work together to attempt to kill cells expressing the foreign antigen.¹⁵

But what happens when a self-antigen and a foreign antigen are so similar that an immune cell can’t tell them apart?

In this case, immune cells will target not just dangerous cells, but also healthy cells that express the self-antigen. This is molecular mimicry, and it is the driving force behind many different autoimmune diseases.¹⁵

How could molecular mimicry in EBV cause MS symptoms?

In the case of EBV, the critical viral protein EBNA1 has molecular mimicry for several of the proteins that compose the myelin sheath.^{11, 14} In this model, immune cells mistake the healthy cells that make up the myelin sheath for dangerous cells infected with EBV, leading to the destruction of the myelin sheath and the development of MS. Antibodies that recognize both EBNA1 and components of the myelin sheath have been detected at high levels in patients with MS and may even serve as an early diagnostic marker. ^14,16 However, there is still much debate as to how cross-reactive antibodies against EBNA1 and the myelin sheath are generated and if they are truly the cause of MS.

Could other properties of the virus contribute to MS genesis and progression?

There are several other hypotheses that have been proposed regarding how EBV would result in the development of MS, and more than one may be true.

Another EBV protein, EBNA2, interacts with host proteins to manipulate the processes that regulate the expression of a gene. The genes with which EBNA2 interacts are abundantly autoimmune genetic risk factors- including nearly half of the genetic risk factors for MS. Therefore, EBV infection could simultaneously affect the expression of many different genes, which could have different impacts dependent upon the genetic background of the person who is infected.¹⁷

Additionally, as infection with EBV is lifelong, there will be a persistent presence of foreign antigens. This could cause continuous low-grade inflammation that broadly promotes the activity of immune cells with numerous effects, including promoting the survival and activation of autoreactive cells.¹² Consistent with this, there is evidence that activation of the lytic phase, when more EBV antigens are present, may correlate with MS symptom flare-ups.¹⁸

EBV is also known to manipulate the processes that normally select against cells that recognize self-antigens and may promote their survival. In a different autoimmune disorder that has been linked to EBV, Systemic Lupus Erythematosus, researchers found that EBV-infected cells in people living with Lupus were responsive to the self-antigen that is aberrantly targeted in patients with Lupus. Further, these EBV-infected autoreactive B-cells could initiate a cascade that caused even uninfected autoreactive T- and B-cells to activate.¹⁹ In this way, EBV can act as the “spark” for a larger inflammatory “fire.”

Is it definite that EBV causes MS?

Given that EBV is present in most people, but most people do not get MS, being infected with EBV is not sufficient to cause MS. Rather, a combination of factors, one of which is EBV, may drive the development of MS. While exceedingly rare, some patients are EBV negative yet develop MS, suggesting that EBV is not required for the development of MS. While preclinical studies have revealed that mice which are prone to autoimmune disease develop brain lesions and neurological symptoms when injected with a segment of EBNA1,²¹ as of right now, there is no direct proof of EBNA1 causing demyelination in humans. The antibodies against EBNA1 that are suspected of promoting demyelination are not always detectable in patients with MS and have also been detected in people who do not have MS,²² complicating matters. Again, there are likely other factors, such as the genetic background of the virus and person, the character of the autoreactive cells, and if the cells migrate to the brain, which dictate whether demyelination occurs. There may also be other autoreactive antibodies that are produced in response to EBV infection which have not yet been identified. Overall, while it is generally well accepted that EBV plays a role in the development of MS, it remains unclear exactly how this occurs, and why only a small proportion of people with EBV develop MS. Therefore, it is important that researchers continue their investigation in this area.

Could a vaccine against EBV protect or treat MS?

            Here, we describe the evidence for a link between the common virus EBV and the rare neurodegenerative and autoimmune disorder, MS. While there are treatments available for MS, there are no cures, and these treatments are not always effective or tolerable. Further, once demyelination occurs, the myelin sheath cannot be regenerated.³Therefore, there is a need to develop better methods to help people living with MS. In the next post, we will describe one of these attempts- a vaccine against EBV created by scientists at Moderna.¹

Glossary:

Multiple Sclerosis (MS): A neurodegenerative disorder driven by autoimmune destruction of the myelin sheath. It is typically diagnosed in early adulthood. Symptoms are impaired motor and sensory function and are progressive. There is no cure for MS. 

Neurodegenerative disorder: A disease caused by the destruction of neurons.

Neurons: Specialized nerve cells that sense the environment, control muscle movement, and are responsible for communication between the brain and the body.

Axon: The part of the neuron along which an electrical signal travels to enable communication between neurons.

Myelin Sheath: The fatty coating along the axon that protects the axon from damage and allows the electrical signal to travel quickly without degradation.

Demyelination: The destruction of the myelin sheath and the physiological change that causes MS symptoms.

Autoimmune disorder: A disease caused by abnormal activity of the immune system, negatively impacting healthy cells.

HLA-DR15: A well-established genetic risk factor for MS that affects a protein involved in antigen presentation.

Epstein-Barr Virus (EBV): A common virus that causes a lifelong infection and has been linked to many different cancers and autoimmune disorders. There are no EBV vaccines or specific treatments available.

B-cell: A type of immune cell that produces antibodies and plays a supportive role in immunity. Also, the type of cell that EBV primarily infects.

Latent: The phase in the viral lifecycle where the virus is largely inactive. EBV spends the majority of its lifecycle in this phase.

Lytic: The phase of the viral lifecycle during which most viral proteins are produced and which, if successfully completed, results in the production of more virus. This phase is essential for the transmission of virus from person to person. 

Seroconversion: The development of an antibody response, here used as a measure of going from uninfected with EBV to infected with EBV.

EBNA1: A critical viral protein that enables the replication of the virus and the maintenance of the virus in a cell. Antibodies against this viral protein have been implicated in the development of MS.

Molecular mimicry: The phenomenon of a foreign antigen from an infectious agent having structural similarity to a protein normally produced in healthy cells. 

T-cells: A specialized immune cell, most well-known as the cells that monitor for dangerous cells, like a cancer cell or a virus-infected cell, by checking the proteins expressed in that cell.

Antigens: A substance that produces an immune response. In this context, an antigen is a segment of a protein that is expressed by a cell.

Self-antigens: Antigens that are normally expressed by healthy cells in a person and  should not normally trigger a robust immune response.

Autoreactive: A descriptor for immune cells that recognize and react to self-antigen. They are associated with autoimmune diseases.

Foreign antigens: Antigens that are not normally expressed by healthy cells, but may instead be expressed by an infectious agent like a virus. 

References:

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2. Damania B, Kenney SC, Raab-Traub N. Epstein-Barr virus: Biology and clinical disease. Cell. 2022;185(20):3652-3670. doi:10.1016/j.cell.2022.08.026
   
3. Boutitah-Benyaich I, Eixarch H, Villacieros-Álvarez J, et al. Multiple sclerosis: molecular pathogenesis and therapeutic intervention. Signal Transduct Target Ther. 2025;10(1):324. Published 2025 Oct 2. doi:10.1038/s41392-025-02415-4
   
4. The Multiple Sclerosis International Federation, Atlas of MS, 3rd Edition; 2020
   
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6. Mayo Clinic. Multiple Sclerosis. Mayo Clinic. Published 2024. https://www.mayoclinic.org/diseases-conditions/multiple-sclerosis/symptoms-causes/syc-20350269
   
7. Caring for someone with multiple sclerosis at end of life. Marie Curie. Published 2023.
   https://www.mariecurie.org.uk/professionals/palliative-care-knowledge-zone/multiple-sclerosis
   
8. Neurons: How the Brain Communicates. Mhanational.org. Published 2025. https://mhanational.org/resources/neurons-how-the-brain-communicates/
   
9. Cleveland Clinic. Myelin Sheath: What It Is, Purpose & Function. Cleveland Clinic. Published May 9, 2022. https://my.clevelandclinic.org/health/body/22974-myelin-sheath
   
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16. Vietzen H, Kühner LM, Berger SM, et al. Early identification of individuals at risk for multiple sclerosis by quantification of EBNA-1_381-452-specific antibody titers. Nat Commun. 2025;16(1):6416. Published 2025 Jul 14. doi:10.1038/s41467-025-61751-9
    
17. Hong T, Parameswaran S, Donmez OA, et al. Epstein-Barr virus nuclear antigen 2 extensively rewires the human chromatin landscape at autoimmune risk loci. Genome Res. 2021;31(12):2185-2198. doi:10.1101/gr.264705.120
    
18. Soldan SS, Su C, Monaco MC, et al. Multiple sclerosis patient-derived spontaneous B cells have distinct EBV and host gene expression profiles in active disease. Nat Microbiol. 2024;9(6):1540-1554. doi:10.1038/s41564-024-01699-6
    
19. Younis S, Moutusy SI, Rasouli S, et al. Epstein-Barr virus reprograms autoreactive B cells as antigen-presenting cells in systemic lupus erythematosus. Sci Transl Med. 2025;17(824):eady0210. doi:10.1126/scitranslmed.ady0210
    
20. Jog NR, McClain MT, Heinlen LD, et al. Epstein Barr virus nuclear antigen 1 (EBNA-1) peptides recognized by adult multiple sclerosis patient sera induce neurologic symptoms in a murine model. J Autoimmun. 2020;106:102332. doi:10.1016/j.jaut.2019.102332
    
21. Vietzen H, Berger SM, Kühner LM, et al. Ineffective control of Epstein-Barr-virus-induced autoimmunity increases the risk for multiple sclerosis. Cell. 2023;186(26):5705-5718.e13. doi:10.1016/j.cell.2023.11.015