Persistent Immunity from Historic Smallpox Vaccination and Its Limited Cross-Neutralization of Monkeypox Virus: A Population-Based Serological Study in Taiwan

Background Understanding the extent of cross-protection conferred by the historic smallpox vaccination and the immunogenicity of Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN) after the 2022 global mpox outbreak is essential to inform current prevention strategies. In this study, we assessed the seropositivity and neutralizing capacities of the vaccinia virus (VACV)- and monkeypox virus (MPXV)-specific antibodies in 260 Taiwanese patients. Methods We analyzed serum samples from 260 individuals in Taiwan, stratified by their birth year, before or after 1979, the year of smallpox vaccination cessation. ELISA and plaque reduction neutralization tests were conducted to assess VACV- and MPXV-specific antibody responses. Furthermore, we evaluated an additional cohort of MVA-BN vaccines (n = 9) before and after vaccination. Results Over 80% of individuals born before 1979 retained VACV-reactive antibodies, with 84% of this seropositive subgroup exhibiting neutralizing activity. We detected cross-reactive MPXV antibodies in 69% of individuals who were VACV-seropositive; however, only 65% had MPXV-neutralizing capacity, with titers significantly lower than those against VACV. MVA-BN vaccination enhanced VACV and MPXV antibody levels; however, MPXV-neutralizing titers remained low, particularly in individuals without prior smallpox immunization. Conclusion Historical smallpox vaccination induces long-lasting humoral immunity, and a correlation between VACV and MPXV antibody levels further suggests that it provides some degree of cross-protection against MPXV infection. MVA-BN boosted orthopoxvirus immunity; however, it may be limited in MPXV neutralization in vaccine-naïve populations. These findings offer useful insights for future mpox vaccination strategies and public health planning in regions with varying smallpox vaccination histories.