Residual immune responses after historical smallpox vaccination and exploratory outbreak modeling in immunocompromised populations

Following the discontinuation of routine smallpox vaccination and the emergence of mpox outbreaks, immunity against orthopoxviruses has received renewed attention. This study characterized immune responses among individuals with historical smallpox vaccination. Separately, an exploratory mathematical model was used to assess hypothetical transmission scenarios among immunocompromised populations. Cellular and humoral immune responses following historical smallpox vaccination were assessed using enzyme-linked immunosorbent assay and enzyme-linked immunospot assay. Associations between clinical characteristics, laboratory markers, and immune responses were evaluated using regression analyses. An exploratory susceptible-infected-recovered-dead model based on published epidemiological parameters was used to assess hypothetical transmission scenarios among immunocompromised populations. Analysis included 112 peripheral blood mononuclear cell and 3,202 serum samples. Cellular immune responses were limited among individuals with historical smallpox vaccination, with no significant differences observed between healthy and disease groups. Vaccinated individuals with comorbidities had lower vaccinia virus Tianan strain-specific immunoglobulin G titers than the healthy group ( P < 0.001), with variations observed across chronic disease subgroups. The proportion of individuals with negative neutralizing antibody responses decreased with age but was higher among disease groups than in the healthy group. Chronic disease (odds ratio [OR], 0.67; 95% CI, 0.44–0.98) and cancer (OR, 0.58; 95% CI, 0.37–0.90) were associated with lower odds of high antibody positivity. High-density lipoprotein cholesterol and aspartate aminotransferase levels were positively associated with antibody levels, whereas cholinesterase showed an inverse association. Exploratory modeling under hypothetical scenarios suggested differences in simulated infection and mortality patterns among immunocompromised populations, with higher simulated infection proportions in individuals aged 15–19 years and higher mortality proportions in those aged ≥ 70 years. Individuals with historical smallpox vaccination showed detectable residual immune responses, with variations observed across comorbidity groups and in association with laboratory markers. Immunocompromised individuals may warrant further evaluation for potential orthopoxvirus susceptibility. These findings may inform future orthopoxvirus preparedness and prevention strategies.