Lytic gammaherpesvirus-68 vaccination confers long-term, immune-mediated protection against severe experimental autoimmune encephalomyelitis

Research increasingly suggests that Epstein-Barr virus (EBV) plays an etiological role in multiple sclerosis (MS), a chronic autoimmune disease of the central nervous system (CNS). Current therapies help manage MS, however, there remains a need for preventative and curative therapies that address the disease etiology. Herein, a mouse model was developed to represent the sequence of events prior to MS onset and the mode of EBV transmission, using intranasal (IN) gammaherpesvirus-68 (𝛄HV68) infection, a murine homologue to EBV, prior to the induction of experimental autoimmune encephalomyelitis (EAE), a model of MS. The impact of administering a live 𝛄HV68 vaccine prior to 𝛄HV68 infection and EAE onset was then investigated. This work demonstrated that the virus-specific immune response elicited by the vaccination significantly attenuated paralysis and weight loss in mice. Moreover, clinical protection and circulating immunoglobulin (Ig)G was found to be maintained over time, with high 𝛄HV68 doses. Flow cytometry analyses revealed that the vaccine-induced protective immune response resulted from a reduction in pathogenic CD40⁺MHC-II⁺ dendritic cells (DCs). This change was accompanied by a protective shift in T cell phenotypes, wherein vaccinated mice had increased proportions of T regulatory cells (Tregs) and decreased proportions of interferon (IFN)-𝛄-producing T helper 1 cells (Th1) and effector memory T cells (TEMs). Subsequent analyses using enzyme-linked immunosorbent assays (ELISAs) further indicated that immune cells from vaccinated mice exhibited a reduced pro-inflammatory cytokines response but increased production of interleukin (IL)-2 when stimulated with a myelin peptide. Taken together, these data offer a proof of concept for a non-sterilizing EBV vaccine as a preventative therapy for MS and a novel model of study. Further, immune profiling demonstrated that the cellular mechanisms underlying attenuation were mediated by a protective shift in the DC and T cell response. This work lays the foundation for the development of new 𝛄HV68 vaccines and clinical trials investigating the efficacy of an EBV vaccine as a preventative therapy for MS.