The case for an Epstein-Barr virus vaccine: Lessons from its link to systemic lupus erythematosus.

Growing evidence has strengthened the longstanding hypothesis that Epstein-Barr virus (EBV) contributes directly to the development of systemic lupus erythematosus (SLE). While earlier work established epidemiologic associations and immune dysregulation in EBV-exposed individuals, recent multi-omic and single-cell studies now demonstrate mechanistic pathways that link viral infection to autoreactive B-cell activation. Notably, EBV has been shown to preferentially infect CD27+ CD21- memory B cells enriched for nuclear antigen-specific receptors, reprogramming them into potent antigen-presenting cells that drive T-cell activation and autoantibody formation. These findings align with genetic studies implicating EBNA2 binding at autoimmune risk loci and reinforce a credible causal model connecting EBV latency, lytic reactivation, and lupus pathogenesis. Together, these advances renew the urgency of developing a prophylactic EBV vaccine capable of blocking early infection, reducing viral latency, and limiting downstream autoimmune activation. Although no licensed vaccine currently exists, progress in multimeric antigen design, nanoparticle platforms, and adjuvants such as Matrix-M has created promising avenues for future clinical development. An effective EBV vaccine could not only reduce infectious mononucleosis and EBV-associated malignancies but also meaningfully lower the global burden of SLE. This review synthesizes emerging evidence supporting EBV vaccination as a preventive strategy for autoimmune disease.