Autoimmunity is often thought of as a genetic malady that will require a genetic route for cure and prevention. Many of us have relatives and friends suffering from an autoimmune disease, from rheumatoid arthritis and multiple sclerosis to Crohn and celiac disease — after all, autoimmunity affects 8-10% of the world’s population, by some estimates.
Sufferers are often found in familial clusters, and current treatments, generally focused on inhibiting the autoimmune response, are often ineffective and come with severe side-effects. Advances in CRISPR and stem cell techniques have given hope for future prevention, but progress in application to autoimmunity is slow and fraught with risks. What if there was another way?
The Epstein-Barr virus (EBV) infects more than 90% of the people on the planet before the age of 40. Infection is often asymptomatic — many people are even unaware that they have been infected. For others, the virus manifests as a childhood ear infection or, for adolescents, as a case of infectious mononucleosis. These illnesses are not pleasant, but within days or weeks, those affected fully recover… or do they? As for all herpes viruses, EBV infection is life-long. For 5-10 % of the infected population, EBV will cause autoimmunity or cancer later in life. The virus takes an enormous human toll, and most of those affected are women.
A growing body of evidence suggests that most autoimmune diseases are caused by EBV. Multiple sclerosis, rheumatoid arthritis, and lupus have all been directly associated with the virus. A recent publication in the journal Nature Genetics showed an unqualified relationship between EBV proteins and transcription factors and various human gene loci associated with seven autoimmune diseases. EBV works, after the initial infection, by disrupting gene expression in the B cells that it infects. This gives these cells a survival advantage, allowing EBV to make more copies of itself. In many cases, the host develops autoimmunity or cancer.
EBV is also associated with over 1% of cancer cases. Endemic Burkitt’s lymphoma, Hodgkin’s lymphoma, and nasopharyngeal carcinomas are all linked to the virus, as are approximately 10% of gastric carcinomas. The cancers are thought to result from EBV interfering with cell apoptosis. The virus infects epithelial cells in addition to B cells, so the havoc that it wreaks extends to epithelial cells even in the absence of B-cell mediation. However, evidence suggests that viral multiplication in B cells is necessary for the large viral loads associated with acute infection stages, such as the loads present during infectious mononucleosis.
The good news is that vaccine development against EBV is in its advanced stages. It was shown in a Phase 2 trial that reported in 2004 that a vaccine based on the EBV antigen glycoprotein 350 (gp350) protected against infectious mononucleosis. gp350 is used by the virus to attach itself to B cells to facilitate infection. Those vaccinated still became latently infected, even though no one got sick. Nevertheless, it is infectious mononucleosis, not an asymptomatic infection that is a risk factor for multiple sclerosis and Hodgkin’s lymphoma, so sterilizing immunity might not be necessary. A number of other vaccine development efforts are ongoing. Also, research to establish a genetic understanding of how the virus operates has exposed a number of potential vulnerabilities.
The vaccine development effort based on gp350 continues. The rights to the antigen are owned by AstraZeneca and its R&D company MedImmune. Researchers at the University of Minnesota are working in cooperation with MedImmune. Mouse models are being used, and preparations for additional human trials are underway. Vaccine development is moving forward.
The problem is that the pace of vaccine development is inconsistent with the public health emergency that EBV represents. If the situation was similar to that surrounding universal influenza or Zika vaccines, the pace would be understandable. For those vaccines, there remain outstanding fundamental scientific questions related to safety and efficacy that need to be resolved. For EBV, it appears that the fundamental questions have already been answered as of 2004. What is needed is the completion of appropriate Phase 3 trials to ensure the vaccine is as safe and effective as it appears.
We recently witnessed how fast vaccine development can move when Ebola vaccine was taken from animal studies to human Phase 3 and use in an emergency in under a year. Phase 3 trials are expensive, costing tens of millions of dollars, and they require regulatory approval. What is needed is the commitment of the global community to push this forward, perhaps coordinated by the World Health Organization, as was done in the case of Ebola.
These findings are described in the article entitled The time has come for a Phase 3 trial of an Epstein-Barr virus vaccine, recently published in the journal Vaccine. This work was written by Jeffrey T. Paci and Irina Paci of the Department of Chemistry at the University of Victoria in British Columbia, Canada.
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