Toll-like receptor 5 agonist is a potent adjuvant for intradermal vaccination

Flagellin, the key structural protein of bacterial flagella, is known to stimulate Toll-like receptor 5 (TLR5) signaling, making it an effective adjuvant for nasal, intramuscular, or subcutaneous routes of vaccination. Here, we investigate the potential of intradermal flagellin delivery to enhance adaptive immunity in mouse and pig models. Our study shows that intradermal administration of flagellin enhances systemic antibody responses to co-administered antigens in a TLR5-dependent manner. Transcriptional analysis of mouse and pig skin revealed that flagellin induces an early pro-inflammatory response associated with pathways essential for adjuvant activity, such as dendritic cell maturation or communication between innate and adaptive immune cells. This immune activation is swiftly detected in the bloodstream of vaccinated animals. Furthermore, our investigation reveals flagellin's capacity to activate innate immunity of structural skin cells including human keratinocytes and fibroblasts. Collectively, our findings underscore flagellin' potential to improve the efficacy of intradermal vaccine formulations by engaging skin structural cells, thus advancing the landscape of vaccination strategies.