How an EBV Vaccine Could Help Prevent MS
EBV lies dormant in most people, but its link to MS has led to increasing interest in the development of a vaccine.
Epstein-Barr virus (EBV) infects approximately 95% of the global population and usually causes no symptoms. However, the virus can cause infectious mononucleosis and has been associated with several cancers and autoimmune conditions, including multiple sclerosis (MS). Despite this substantial disease burden, there are currently no licensed or approved preventative or therapeutic EBV vaccines.
Prof. Lawrence Young, emeritus professor of molecular oncology at the University of Warwick, has spent decades investigating the role of EBV in tumor development. Here, he explains why the relationship between EBV and autoimmune disease is reinvigorating vaccine research, why preventing lifelong infection presents an unusual challenge, and how mRNA platforms, mucosal vaccines, and passive immunization could move the field forward.
The link between EBV and MS
What is driving the growing interest in an EBV vaccine?
EBV was discovered more than 60 years ago, but vaccine development has progressed slowly. Historically, research focused largely on the virus’s association with cancers, including lymphomas arising in people whose immune systems have been suppressed by HIV infection, immunodeficiency syndromes, organ transplantations, or medical treatments.
Interest has broadened as evidence has accumulated connecting EBV with autoimmune disease. “There's been increasing evidence that the virus drives autoimmunity in MS and in systemic lupus erythematosus,” said Young.
“It is the association of EBV with MS that has created a real enthusiasm for the development of EBV vaccines.” — Prof. Lawrence Young.
This evidence has encouraged researchers to consider both preventive and therapeutic interventions. A prophylactic vaccine could seek to prevent primary infection or infectious mononucleosis, while a therapeutic vaccine could strengthen immune control of EBV in people who are already infected.
Why interest in EBV vaccines is increasing:
- EBV has been linked to both malignant and autoimmune diseases.
- The relationship between EBV and MS has strengthened the case for vaccine development.
Could an EBV vaccine help prevent MS?
What impact could an EBV vaccine have on the prevention of autoimmune diseases?
EBV establishes lifelong infection in memory B cells. In MS, EBV-infected B cells may contribute to abnormal immune activity along with antigen mimicry, where immunity to EBV antigens cross-reacts with neuronal proteins. But the precise mechanisms remain under investigation.
One possible strategy to combat EBV-associated diseases is to suppress viral activity rather than eliminate EBV. A therapeutic vaccine could, for example, reduce viral replication or limit the infection of additional cells. However, stimulating immunity in someone with an existing autoimmune disease requires caution.
Preventing MS presents a different challenge. Delayed EBV infection—where primary exposure occurs during adolescence or early adulthood, rather than early childhood—can cause infectious mononucleosis, also called glandular fever. “Infectious mononucleosis increases the risk of developing MS by about threefold,” explained Young.
A vaccine that prevents infectious mononucleosis might therefore reduce subsequent MS risk, even if it does not provide sterilizing immunity and prevent EBV infection itself. Demonstrating this effect would be difficult, however, because MS can develop many years after primary infection.
Sterilizing immunity
Sterilizing immunity refers to the immune response's ability to prevent a pathogen from establishing any detectable infection in the body.
Potential routes to preventing EBV-associated diseases:
- Prevent primary EBV infection before the virus establishes lifelong persistence.
- Prevent infectious mononucleosis following delayed infection.
- Reduce EBV activity in people who are already infected.
Lifelong EBV persistence makes sterilizing immunity difficult
What features of EBV make it difficult to target with a vaccine?
EBV is particularly difficult to target with vaccinations because it persists inside the very immune cells that would ordinarily help coordinate antiviral protection. After entering through the mouth and oropharynx, the virus infects B cells and establishes a latent reservoir that can remain for life.
The virus can periodically reactivate, generate new viral particles, and infect other B cells. EBV replicates in epithelial cells in the nasopharynx and mouth, providing a continual source of B-cell infection. T cells usually keep this activity under control, which helps explain why EBV-associated disease becomes more likely following immunosuppression. “It's that intimate association—the fact that it is a virus, and it's the only virus that actually persists in our B lymphocytes—that makes it quite difficult to target,” Young said.
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Preventing infection entirely might require vaccination very early in life, potentially at birth, as the virus is transmitted via saliva and this predominantly occurs in childhood. This would create scientific, logistical, and economic challenges because nearly everyone would need to receive the vaccine.
An alternative could be vaccination in early adolescence. “If you could give a vaccine to everybody, irrespective of their EBV status, at the same time as they get their human papillomavirus vaccine, for instance, that might be sufficient,” stated Young. This approach might be valuable even in individuals who have already encountered EBV if it improves immune control or prevents infectious mononucleosis.
The central EBV vaccine-development challenges:
- EBV establishes a lifelong latent reservoir in memory B cells.
- Infection often occurs in early childhood without recognizable symptoms.
- Viral reactivation can continue at low levels throughout life.
Multivalent mRNA vaccines could target several stages of EBV infection
What are some of the current strategies being investigated in EBV vaccine trials?
Researchers have historically investigated subunit vaccines containing selected EBV antigens. Newer mRNA platforms could make it easier to include multiple antigens within a single formulation.
This capacity is important because EBV has both lytic and latent stages. “There are two approaches that are being looked at, both targeting the so-called latent antigens and/or those antigens on the surface of the virus that are important in mediating infection into other cells,” explained Young.
Lytic vs latent phase
The lytic phase involves a virus taking control of a host cell and using it to produce its viral progeny, killing the host in the process to release new viruses. In the latent phase, the viral genome remains silent within host cells until reactivation after the appropriate conditions have occurred.
Combining antigens from different stages of the viral life cycle could produce broader protection than a vaccine targeting a single viral component.
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Moderna is embarking on a clinical trial of an investigational mRNA vaccine, mRNA-1189, that targets four glycoprotein antigens on the virus particle, which the virus uses to enter cells. The goal of the vaccine is to raise robust immune responses to a broad range of EBV proteins utilized in cell entry to protect against infectious mononucleosis.
A separate program by Moderna is underway to evaluate the safety and reactogenicity of another mRNA vaccine, mRNA-1195, in participants with MS. The vaccine contains glycoproteins and latent antigens and is designed to induce antibody and T-cell responses simultaneously to prevent EBV reactivation.
“We've seen recently that the way that you formulate viruses, particularly in terms of encapsulating either antigens or RNA, is also very important,” Young said.
Eli Lilly recently acquired Vaccine Company, which is developing in vivo nanoparticle technologies designed to elicit durable immune responses associated with virus-like particle vaccines. The lead program from Vaccine Company is applying this technology to EBV with a five-antigen prophylactic vaccine candidate.
How newer vaccine platforms could help combat EBV infection:
- mRNA technology can encode several EBV antigens in one vaccine.
- Multivalent designs could address both primary infection and lifelong persistence.
- New vaccine formulation technologies could provide more durable immune responses.
Mucosal vaccines and passive immunity offer additional paths forward
What new or emerging vaccine technology could bring an EBV vaccine closer to reality?
Most EBV vaccine research has concentrated on systemic immune responses, but the virus first encounters the body at mucosal surfaces in the mouth, nose, and throat, where it continues to replicate throughout life.
“You can actually detect the virus at low levels all the time in the throats of infected individuals,” explained Young. “If you could dampen that or prevent that in the first place with a mucosal vaccine generating immunity in the tissues and linings of the head and neck, that would be quite interesting.”
iosBio, for example, has leveraged its oral vaccine technology to develop OraPro-EBV, which is designed to generate mucosal immunity by targeting both B cells and the epithelial cells lining the nose and throat.
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Passive immunization provides another option. Instead of prompting the body to generate its own antibodies, this approach administers monoclonal antibodies that block EBV infection. Post-transplant lymphoproliferative disease (PTLD), an EBV-associated complication of immunosuppression following organ transplantation, could provide an important setting for testing these antibodies.
AbVir Biotherapeutics is developing an antibody, ABV-010, that targets a vulnerable site on the EBV entry protein. In preclinical models, the antibody completely blocked EBV infection and prevented PTLD development.
Such studies could act as clinical stepping stones, showing whether control of EBV changes disease outcomes without requiring researchers to wait 10 or 20 years for possible cases of MS.
Researchers are also investigating EBV-specific antiviral drugs and cell-based therapies.
“Some of the therapies that have been used in the past to treat PTLD and EBV-associated lymphomas involved growing EBV-specific T cells in the lab and putting them back into patients, and actually that acted as a precursor to all the work that's gone on in T-cell immunity for cancer,” Young said.
CAR T-cell technologies may eventually support more targeted approaches. “CAR T-cell technology is very exciting and is also being looked at in the context of developing better approaches to treating EBV-associated tumors, and that could be extended to these autoimmune diseases,” stated Young. He cautioned, however, that “immune-cell therapies must be evaluated carefully in people who already have autoimmune disease.”
Emerging opportunities for combating EBV-associated diseases:
- Oral vaccines that generate mucosal immunity.
- Monoclonal antibodies that provide immediate passive protection.
- EBV-specific antiviral drugs.
- CAR T-cell therapies for selected EBV-associated diseases.
EBV vaccine research is shifting from the pursuit of complete infection prevention toward a broader range of clinically meaningful goals.
Key takeaways:
- Stronger evidence linking EBV to MS has created new scientific and commercial momentum.
- Multivalent mRNA and mucosal vaccines could target different stages and anatomical sites of infection.
- Preventing infectious mononucleosis or suppressing viral activity may deliver health benefits even without sterilizing immunity.
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