Abstract
Echoviruses commonly infect humans and can cause severe outcomes, including meningitis and liver failure, especially in neonates and immunocompromised individuals. Although recent progress has been made in understanding acute pathogenesis and innate immunity to echoviruses, adaptive immune responses remain poorly defined, in part due to the lack of an appropriate small animal model of infection. Here, we developed a translational mouse model of echovirus infection using hFc mice, which express human FcRn, the echovirus receptor, while maintaining functional IgG circulation. Primary echovirus infection caused acute disease and elicited virus-specific nAbs, IgG, and IgM only in hFc mice, which express human FcRn and support IgG transport, but not in parental Tg32 mice that lack IgG transport. These humoral responses correlated with protection against a homologous lethal-dose challenge. The protective role of these antibodies was confirmed by passive transfer of immune serum, which conferred complete, sterilizing protection. Statistical modeling identified E5-specific nAb, total IgG, and IgG1 titers as the strongest predictors of survival following infection, identifying novel correlates of protection. These findings establish hFc mice as a robust translational model for dissecting echovirus adaptive immunity, define the humoral response to infection, and identify correlates of protection to guide future vaccine development and preclinical evaluation.