BackgroundMost commercial foot-and-mouth disease (FMD) vaccines have various disadvantages, such as low antibody titers, short-lived effects, compromised host defense, and questionable safety.ObjectivesTo address these shortcomings, we present a novel FMD vaccine containing Dectin-1 agonist, β-D-glucan, as an immunomodulatory adjuvant. The proposed vaccine was developed to effectively coordinate innate and adaptive immunity for potent host defense against viral infection.MethodsWe demonstrated β-D-glucan mediated innate and adaptive immune responses in mice and pigsin vitroandin vivo. The expressions of pattern recognition receptors, cytokines, transcription factors, and co-stimulatory molecules were promotedviaFMD vaccine containing β-D-glucan.Resultsβ-D-glucan elicited a robust cellular immune response and early, mid-, and long-term immunity. Moreover, it exhibited potent host defense by modulating host’s innate and adaptive immunity.ConclusionOur study provides a promising approach to overcoming the limitations of conventional FMD vaccines. Based on the proposed vaccine’s safety and efficacy, it represents a breakthrough among next-generation FMD vaccines.