The Impact of Orthopoxvirus Vaccination and Mpox Infection on Cross-Protective Immunity 2402

Abstract Description Immunological memory provides rapid protection post-infection or vaccination, yet cross-reactive memory in humans is not well understood. We examined cross-protective responses to orthopoxviruses via smallpox/mpox vaccination and Mpox virus (MPXV) infection, analyzing systemic and mucosal responses in four cohorts: first- (Dryvax) and/or third-generation (JYNNEOS) vaccine recipients (vaccinated 1 week to 80 years ago) and Mpox-infected individuals. The vaccines elicited strong VACV- and MPXV-reactive antibodies; VACV-neutralizing antibodies persisted for decades and were enhanced by JYNNEOS boost. Direct cross-neutralization correlated with viral antigenic distance, showing higher neutralization for cowpox virus (CWPXV) than MPXV. Non-vaccinated Mpox-convalescents also had lower VACV neutralization than CWPXV. Complement-mediated neutralization enhanced the MPXV response, emphasizing antibody effector functions. Boosters provided robust, diverse, extended cross-neutralizing responses. Long-term memory analysis showed sustained VACV neutralization across ages, with strong responses even in 80-year-olds. T-cell reactivity to VACV and MPXV epitopes was detected decades later, underscoring lasting cross-reactive T-cell memory in vaccine efficacy. These findings highlight the enduring cross-neutralizing antibodies and T-cell responses from vaccination, demonstrating long-term defense against orthopoxviruses reinforced by complement-mediated neutralization and T-cell responses. Funding Sources Supported by T32AI055403-20; Stavros Niarchos Foundation (SNF) Topic Categories Viral Immunology (VIR)