Mucosal Immunity: The Key to Combating Enteroviruses and Beyond.

Enteroviruses (EVs) lead to 10-15 million symptomatic infections each year in the United States alone. EVs enter through either the gastrointestinal or respiratory mucosa, depending on the specific virus. Since these mucosal surfaces are the primary entry points for viruses, mucosal immunity serves as a crucial first line of defense. Nevertheless, the mechanisms that drive it are poorly understood for most EVs. Conventional intramuscular vaccines provide limited protection at these sites, leaving them unprotected; mucosal vaccination addresses this issue directly by generating local SIgA in GALT/NALT that neutralizes pathogens before they spread systemically, while also offering advantages in accessibility and cost. This is not merely theoretical; oral vaccines for polio and rotavirus have already shown the effectiveness of mucosal immunization at scale for enteric viral diseases. This review explores innate pattern recognition through TLR3, RIG-I, and MDA5 pathways, type I/III interferon (IFN) signaling, and mucosal SIgA responses across key EVs. It also assesses current mucosal vaccine candidates for EV-A71, CVA16, and EV-D68, most of which remain in preclinical stages. Understanding of these mechanistic gaps is important for advancing successful mucosal vaccine strategies into effective next-generation vaccines for EVs.