Humoral correlates of protection in a mouse model of echovirus infection

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, and produce chimeric IgG1 (mouse Fab, human IgG1 Fc) to maintain functional IgG transport. Primary echovirus infection caused acute disease and elicited virus-specific neutralizing antibodies (nAbs), IgG, and IgM only in hFc mice but not in parental Tg32 mice, which lack chimeric IgG1 and IgG transport. These humoral responses correlated with protection against a homologous lethal-dose challenge, with survival in approximately 75% and 55% of previously infected males and females, respectively. The protective role of these antibodies was confirmed by passive transfer of immune serum, which conferred complete, sterilizing protection. Statistical modeling identified anti-E5 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.