Longitudinal Study Suggests Epstein-Barr Virus as a Leading Cause and Trigger of MS

Researchers at Harvard T. H. Chan School of Public Health and Harvard Medical School examined a cohort of over 10 million young adults in the US military, 955 of whom were diagnosed with multiple sclerosis (MS) over a 20-year period to understand the causes of MS. Following examination of blood samples and clinical data, researchers found that the risk of MS increased 32-fold after infection with Epstein-Barr virus (EBV), a virus that causes infectious mononucleosis and has long been suspected to be a risk factor for MS. This study provides the strongest evidence to-date showing the association between EBV infection and the development of MS.

Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease of the central nervous system. While the exact cause of MS is unknown, it is believed to be a combination of genetic and environmental factors such as vitamin D, obesity, smoking, and viral infection with Epstein-Barr virus (EBV). This study aims to test the hypothesis that EBV is a leading risk factor and potential cause of MS.

The research team examined blood samples taken from a racially diverse population of over 10 million adults serving in the US military over a 20-year period. The team assessed blood samples for EBV status at time of first sample and found 5.3% of individuals in the cohort were negative for the virus. In total, there were 955 MS cases in the cohort. Three blood samples were assessed for evidence of EBV infection in each MS case and in matched controls, including the first available sample, the last one collected before MS disease onset and one in between. A total of 801 MS cases and 1566 controls without MS (age-, sex-, and race/ethnicity- matched controls) were included in the study. Most of the individuals in the cohort were less than 20 years of age at the time of first blood sample and those who developed MS had symptom onset a median of 10 years after time of first sample.

A total of 35 MS cases and 107 controls were negative for EBV in the initial sample, and all but one of these MS cases eventually tested positive for EBV antibodies, which means that almost all MS cases were infected with EBV prior to MS onset. The researchers found that other viruses were not associated with MS cases, including cytomegalovirus (CMV), a virus like EBV that is transmitted through the saliva, is part of the same family of viruses, and has high rates of infection in the general population. They also examined a biomarker of neurodegeneration, neurofilament light chain (sNfL), in the blood samples of MS cases and controls who were EBV negative in the initial samples. No signs of sNfL were found before and around EBV infection similar to those without MS, but sNfL increased after EBV infection, indicating that EBV infection preceded MS symptom onset.

Overall, this study provides the strongest evidence for EBV as a trigger for MS, indicating a 32-fold increase in MS risk. Given that most of the population is infected with EBV, we need to understand why only a fraction of individuals infected with EBV go on to develop MS. It might mean that other genetic and environmental factors are needed to initiate MS onset. Understanding the biological mechanisms for how EBV triggers MS will be key and could lead to targeted interventions that might prevent MS before it starts, for example through vaccination, or modify disease course through antivirals. Currently, there are ongoing efforts to develop and test EBV vaccines.