The Impact of Orthopoxvirus Vaccination and Mpox Infection on Cross-Protective Immunity 2917

Abstract Description Immunological memory mediates rapid protection following infection or vaccination, including against heterologous exposure. However, cross-reactive memory responses in humans remain poorly characterized. We explored the longevity and specificity of cross-protective responses to orthopoxviruses through smallpox vaccination and Mpox virus (MPXV) infection. We assessed systemic and mucosal responses in four human cohorts, including smallpox vaccine recipients along with Mpox-infected individuals. Smallpox vaccines elicited strong VACV- and MPXV-reactive antibodies. Despite high levels of anti-MPXV antibodies in the plasma, cross-neutralization activity correlated with viral antigenic distance. Higher neutralization was observed for the cowpox virus than for MPXV, which has lower antigenic conservation with VACV. Complement-mediated neutralization effectively enhanced MPXV neutralization, highlighting the crucial role of antibody effector functions in controlling more distantly related viruses. Neutralizing capacity against VACV is sustained for more than 80 years. Cross-reactive responses wane rapidly within a year. In contrast to humoral responses, Tcell cross-reactivity is long-lasting, detected up to 70 years post-vaccination. While smallpox vaccines target less conserved antigens, Fc functions are crucial in overcoming the limitations of antigenic distance. These mechanisms, coupled with T-cell responses, contribute to effective/long-lasting immunity against orthopoxviruses. Funding Sources Supported by Yale University and Stavros Niarchos Foundation Institute for Global Infectious Disease. Topic Categories Viral Immunology (VIR)