Multiple sclerosis (MS), a progressive disease that affects 2.8 million people worldwide and for which there is no definitive cure, is likely caused by infection with the Epstein-Barr virus (EBV), according to a study led by Harvard T.H. Chan School of Public Health researchers.

Their findings will be published online in Science on January 13, 2022.  

“The hypothesis that EBV causes MS has been investigated by our group and others for several years, but this is the first study providing compelling evidence of causality,” said Alberto Ascherio, professor of epidemiology and nutrition at Harvard Chan School and senior author of the study. “This is a big step because it suggests that most MS cases could be prevented by stopping EBV infection, and that targeting EBV could lead to the discovery of a cure for MS.”

MS is a chronic inflammatory disease of the central nervous system that attacks the myelin sheaths protecting neurons in the brain and spinal cord. Its cause is not known, yet one of the top suspects is EBV, a herpes virus that can cause infectious mononucleosis and establishes a latent, lifelong infection of the host. Establishing a causal relationship between the virus and the disease has been difficult because EBV infects approximately 95% of adults, MS is a relatively rare disease, and the onset of MS symptoms begins about ten years after EBV infection. To determine the connection between EBV and MS, the researchers conducted a study among more than 10 million young adults on active duty in the U.S. military and identified 955 who were diagnosed with MS during their period of service.

The team analyzed serum samples taken biennially by the military and determined the soldiers’ EBV status at time of first sample and the relationship between EBV infection and MS onset during the period of active duty. In this cohort, the risk of MS increased 32-fold after infection with EBV but was unchanged after infection with other viruses. Serum levels of neurofilament light chain, a biomarker of the nerve degeneration typical in MS, increased only after EBV infection. The findings cannot be explained by any known risk factor for MS and suggest EBV as the leading cause of MS.

Ascherio says that the delay between EBV infection and the onset of MS may be partially due the disease’s symptoms being undetected during the earliest stages and partially due to the evolving relationship between EBV and the host’s immune system, which is repeatedly stimulated whenever latent virus reactivates.  

“Currently there is no way to effectively prevent or treat EBV infection, but an EBV vaccine or targeting the virus with EBV-specific antiviral drugs could ultimately prevent or cure MS,” said Ascherio.

Genetic differences between the two main strains of the blood cancer-triggering virus have been shown to change the way the virus behaves when it infects white blood cells

Solution structures of type 1 and type EBV EBNA2-BS69 complexes determined by small angle X-ray scattering. Type 2 EBNA2 binds an extra BS69 molecule (dimer). CREDIT Michelle West, University of Sussex

Researchers at the University of Sussex have identified how differences in the genetic sequence of the two main strains of the cancer-associated Epstein-Barr virus (EBV) can alter the way the virus behaves when it infects white blood cells.

When EBV enters white blood cells it drives them to grow rapidly and continuously, making them ‘immortal’. In some cases this can lead to the development of lymphoma, a type of blood cancer.

There are two main strains of the virus worldwide and although they can both cause cancer, in the laboratory, one strain (type 1) is able to drive white blood cells to become immortal better than the other (type 2).

While scientists already knew that the different properties of the two strains were caused by a protein called EBNA2, which is produced by EBV, until now they didn’t know how it could cause the viruses to act so differently.

In a new research paper published in the journal PLOS Pathogens, Professor Michelle West together with Dr Erika Mancini at the University of Sussex and Professor Paul Farrell at Imperial College London, have identified a molecular reason for the difference in activity between the two strains.

Prof West said: “EBNA2 is kept in check by contact with a protein normally found in white blood cells; BS69. This contact damps down EBNA2 function but does not block it entirely.

“While type 1 has two contact points for BS69 the sequence changes in type 2 result in the creation of a third contact point.

“This additional contact damps down type 2 EBNA2 function to a greater extent, helping to explain why this strain of EBV is less efficient at driving white blood cell growth.”

The research, funded by the charity Bloodwise and the Medical Research Council helps shed light on how proteins already present in white blood cells can restrict some strains of the virus more than others.

Prof. West said: “It is assumed that because type 2 strains of EBV are less efficient in the laboratory, these strains of EBV might be less cancer promoting, but oddly there is no evidence to support this.

“We do know that type 2 strains of EBV are more common in certain parts of Asia and Africa, and we could speculate that immortalising white blood cells less efficiently may somehow be an advantage to the virus in infecting people in these parts of the world.

“New research also shows that type 2 strains of EBV are able to infect a different kind of white blood cell, the T cell, so it may be that type 2 strains use an alternative route to enter the body.”

Professor West’s team, in collaboration with Professor Farrell and Dr White at Imperial College, will now investigate the impact of strain variation on the biology of EBV further, thanks to recent funding for a 3-year project by the Medical Research Council.

This is a cryo-EM image of the gH/gL/gp45 candidate vaccine construct. NIAID.

A research team led by scientists from NIH’s National Institute of Allergy and Infectious Diseases (NIAID) has determined how several antibodies induced by Epstein-Barr virus (EBV), a herpesvirus that causes infectious mononucleosis and is associated with certain cancers, block infection of cells grown in the laboratory. They then used this information to develop novel vaccine candidates that, in animals, elicited potent anti-EBV antibody responses that blocked infection of cell types involved in EBV-associated cancers.

Currently, there is no licensed vaccine for EBV. The virus is associated with certain cancers (nasopharyngeal and gastric) of epithelial cells, which form the lining of the body’s surfaces, as well as Burkitt and Hodgkin lymphomas, which are cancers of the immune system’s B cells. Worldwide, about 200,000 cases of EBV-associated cancers occur annually, resulting in 140,000 deaths.

Jeffrey I. Cohen, M.D., and Wei Bu, Ph.D., both of NIAID, led the investigation. Prior efforts to develop an EBV vaccine focused on a viral surface protein, gp350, that the virus uses to enter B cells. However, EBV infects not only B cells, but also epithelial cells that line the mouth and upper throat. These cells are usually infected after contact with saliva from an EBV-infected individual. The new research helps define the contributions of virus-neutralizing antibodies other than those directed at gp350 on B cells. Among other findings, the team determined that antibodies to viral proteins called the gH/gL complex play a major role in inhibiting EBV fusion with epithelial cells.

The scientists developed two vaccine candidates, one designed to elicit antibodies to gH/gL on epithelial cells and another that included gH/gL and another viral protein, gp42. The team tested the vaccines in a series of experiments in mice and monkeys. In both animal models, each of the experimental vaccines induced antibodies that potently inhibited epithelial cell fusion. The vaccine containing gp42 induced stronger B cell fusion inhibitory antibodies than the one containing gH/gL alone.

Unlike the gp350 candidate EBV vaccine, which protects only B cells from infection, the candidate vaccines described in the new paper elicited antibodies that could prevent EBV from fusing with both epithelial cells and B cells and thus may provide protection independent of cell type, the authors note. The team is planning to further develop one of the vaccine constructs with an eye toward human trials.