Researchers believe that MS is caused by a combination of genetics, lifestyle and environmental factors. Epstein-Barr Virus (EBV), a virus that causes infectious mononucleosis and commonly referred to as the ‘kissing disease’, has long been suspected as a risk factor for MS.
Research has provided some evidence as to the link between EBV and MS. We know that people with clinically diagnosed infectious mononucleosis have a more than two-fold increased risk of developing MS, and those diagnosed with MS have higher levels of EBV antibodies as a result of infection than people who do not have MS (1). Prior to MS onset, people have an increased immune response to a specific protein of the EBV virus called EBNA1 (2-4). We also know that infection by EBV in adolescence, rather than in childhood, appears to be the critical time window that increases risk of MS (5). Given that 90% of adults are infected with EBV, it has been difficult to establish a causal relationship between EBV and MS onset. We also do not understand its mechanism of action.
In a landmark publication, a research team at Harvard provided the strongest evidence to-date that shows an association between EBV infection and the onset of MS. Following an analysis of blood samples and clinical data from 10 million young adults in the US military spanning 20 years, the researchers found that almost all MS cases were infected with EBV prior to MS onset. EBV infection increased risk of MS by 32-fold. This study suggests that EBV acts as an initial trigger or pre-condition required for MS onset (6). While EBV is likely necessary, it is not sufficient to trigger MS, and it is believed that other factors are needed. For more details, read this article.
To better understand the link between EBV infection and MS, a research group at Stanford University recently found that following EBV infection, people with MS developed antibodies to a specific part of the virus protein, EBNA1 protein. These EBNA1 antibodies are also able to detect a central nervous system protein called ‘glial cell adhesion molecule’ (or GlialCAM), a component of the myelin sheath – the protective coating surrounding nerve fibres that is often damaged in MS. This study suggests that EBV infection may lead to ‘molecular mimicry’ (7). After infection by EBV, the immune system produces antibodies against an invading virus and its proteins, and these antibodies also target the host’s myelin due to similarities between the proteins, triggering an autoimmune response. Molecular mimicry is one potential mechanism for how EBV infection may trigger MS.
These new findings have the potential to catalyze solutions that target EBV to help those currently living with MS, and those who may be diagnosed with MS in the future. For instance, would the development of an effective EBV vaccine prevent MS onset? Currently, we do not have an EBV vaccine, however there are a number of EBV vaccine candidates in development at various stages. For example, the National Institutes of Health in the US (NIH) is developing EBV vaccine candidates, and the biotechnology company, Moderna, recently announced their first subject in a Phase 1 EBV vaccine trial. Would antivirals that target EBV infected cells serve as an effective therapy for people living with MS? Antiviral therapies have potential to treat EBV infection and there are a number of existing antivirals already used in humans that could be re-purposed. Antiviral therapies have been successfully used to treat and manage other diseases like HIV and Hepatitis C. Atara Biotherapeutics is developing a T cell therapy currently in a Phase 2 trial called EMBOLD (ATA188) to assess the safety and efficacy of the therapy in people with progressive MS [UPDATE: read here]. The study is investigating the use of T cell immunotherapy to selectively target EBV antigens, which could play a role in the MS disease process. Insights as to how EBV plays a pathological role in MS will help optimize prevention and treatment strategies.
FREQUENTLY ASKED QUESTIONS:
Should I or a family member get tested to determine whether we have been infected with EBV?
Over 90% of adults will be infected with EBV, therefore it is not necessary to be tested. EBV infection appears to be necessary, but not sufficient for MS development. We do not fully understand why only a subset of people who are infected with EBV go on to develop MS – it is believed that other factors are needed in addition to EBV for MS development.
Is it possible to have MS, but not infectious mononucleosis?
Not everyone infected with EBV will go on to develop infectious mononucleosis. EBV infection during adolescence leads to infectious mononucleosis in more than half of affected individuals. Many people infected with EBV will never know they were infected. Therefore, it is possible to have MS, even if you never had infectious mononucleosis.
Is the MS Society of Canada supporting studies on EBV and MS?
The MS Society is funding several research studies to understand the role of EBV in initiating MS. Dr. Marc Horwitz and team at the University of British Columbia are developing mouse models with human-like immune systems to examine how EBV infection affects immune cell populations and increases the susceptibility and progression of MS. To date, they have shown that mice infected with EBV experience an earlier disease onset and a more severe MS-like disease course compared to uninfected mice. Refer to the MS Society’s ‘Research We Fund’ page for more information.
How will this new research on EBV as an initial trigger of MS support a cure for MS?
With evidence for EBV infection as an initial trigger for MS onset, the research community and industry can focus efforts to pursue MS prevention and therapeutics strategies targeting EBV.
When will the EBV vaccine be available?
All EBV trials for vaccines or treatments are in early phases of development (Phase 1 or 2) and will take several years to move forward to the next stage of development. Those interested in following the trials or participating in Canadian sites (where available) are encouraged to check the MS Society’s ‘Treatments in Development’ pages for more information.
REFERENCES:
1. Handel, A.E. et al. An updated meta-analysis of risk of multiple sclerosis following infectious mononucleosis. PLoS One. 2010 Sep 1;5(9):e12496. doi: 10.1371/journal.pone.0012496. PMID: 20824132; PMCID: PMC2931696.
2. Sundström, P. et al. Antibodies to specific EBNA-1 domains and HLA DRB1*1501 interact as risk factors for multiple sclerosis. J Neuroimmunol. 2009 Oct 30;215(1-2):102-7. doi: 10.1016/j.jneuroim.2009.08.004. Epub 2009 Sep 5. PMID: 19733917.
3. Sundqvist, E. et al. Epstein-Barr virus and multiple sclerosis: interaction with HLA. Genes Immun. 2012 Jan;13(1):14-20. doi: 10.1038/gene.2011.42. Epub 2011 Jul 21. PMID: 21776012.
4. Lünemann, J.D. et al. Elevated Epstein-Barr virus-encoded nuclear antigen-1 immune responses predict conversion to multiple sclerosis. Ann Neurol. 2010;67(2):159-169. doi:10.1002/ana.21886
5. Ascherio, A. & Munger K.L. Epidemiology of Multiple Sclerosis: From Risk Factors to Prevention-An Update. Semin Neurol. 2016 Apr;36(2):103-14. doi: 10.1055/s-0036-1579693. Epub 2016 Apr 26. PMID: 27116717.
6. Bjornevik, K. et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022 Jan 21;375(6578):296-301. doi: 10.1126/science.abj8222. Epub 2022 Jan 13. PMID: 35025605.
7. Lanz, T.V. et al. Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature. 2022 Jan 24. doi: 10.1038/s41586-022-04432-7. Epub ahead of print. PMID: 35073561.