Recent advancements in our understanding of the association between Epstein-Barr virus (EBV) and multiple sclerosis (MS), along with progress in EBV vaccine development, warrant serious considerations of future EBV vaccine-based MS-prevention studies. The clinical, financial, logistical, and technological considerations for designing and conducting retrospective and/or prospective prevention studies with the primary objective of evaluating the effectiveness of EBV vaccines in preventing MS and other EBV-associated sequelae are presented here. As implementation of these studies may require hundreds of thousands of participants, millions of dollars, and decades to observe if meaningful reductions in MS incidence occur, alternative approaches using pragmatic phase IV, post-licensure study designs focused on either the prevention of MS or infectious mononucleosis (IM), a common clinical manifestation of EBV infection that has been associated with increased risk of MS, are also explored. Current knowledge gaps in technology, funding, and research that must be addressed for a study protocol to be successfully designed and implemented are also discussed.
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