Background & Objectives: Epstein–Barr virus (EBV) establishes lifelong infection, presenting either silently as asymptomatic seroconversion (ASC) or symptomatically as infectious mononucleosis (IM). EBV is linked to multiple malignancies and strongly associated with autoimmune diseases, particularly multiple sclerosis (MS)1. IM further increases MS and lymphoma risk2, suggesting that immune responses during symptomatic infection may shape long-term outcomes. However, how clinical presentation imprints long-term antibody immunity remains unclear. We performed the first proteome-wide analysis of EBV-specific humoral responses across the full clinical spectrum of infection.
Methods: IgG and IgA responses were profiled using a custom EBV proteome microarray spanning latent, lytic, and structural antigens3. Cohorts included IM patients followed longitudinally (acute, 6 weeks, 6 months, 1 year), ASC, EBV-seropositive adults with or without prior IM, and EBV-seronegative controls.
Results: ASC elicited modest but broad and durable recognition of viral antigens, including mucosal responses. In contrast, IM induced rapid IgG expansion with a transient IgA burst that contracted after the acute phase. Early IM responses revealed an “immune gap,” with reduced IgG recognition of latent and structural proteins compared with ASC and long-term seropositives. Over one year, IM antibody profiles matured and converged with those of established seropositive individuals, but only after this initial deficit. AI-driven analytics further identified distinct immune signatures of symptomatic infection and durable long-term memory.
Conclusions: Clinical presentation during primary EBV infection strongly influences long-term humoral imprinting. Asymptomatic infection promotes durable and broad systemic and mucosal immunity, while symptomatic IM leaves an early “immune gap” marked by delayed IgG maturation and short-lived IgA activity. Although convergence eventually occurs, this transient deficit may compromise early viral control and contribute to EBV-associated autoimmunity, such as multiple sclerosis. By integrating proteome-wide profiling with AI, this study identifies immune signatures of protection and nominates novel antigen targets for rational EBV vaccine development.