Structural engineering of flagellin as vaccine adjuvant: quest for the minimal domain of flagellin for TLR5 activation

Flagellin stimulates Toll-like receptor 5 (TLR5), triggering both innate and adaptive immune responses, making it a potential vaccine adjuvant. On mucosal surfaces, flagellin induces a strong release of cytokines, chemokines, and immunoglobulins. When used in its free monomeric form, flagellin has been shown to enhance immune responses when combined with vaccine antigens. Further research demonstrated that genetically linking flagellin to the antigen provides a more consistent immune boost. However, the bulky structure of flagellin presents challenges in designing the antigen-adjuvant construct, leading to ongoing research to determine the minimal flagellin domain necessary for its adjuvant effect. Early findings suggest that only the D0 and D1 domains are required for immune enhancement. Functional analysis revealed that the TLR5-binding region is located in the D1 domain, while TLR5 dimerization and signaling require the presence of D0. Further reductions in the size of the D0 and D1 domains may be possible as deeper studies aim to identify the key residues responsible for TLR5 activation and immune enhancement. Additionally, flagellin is being tested as a hapten carrier alongside its established adjuvant role. Recently, significant advancements in flagellin application have been observed as it progresses through clinical studies as an adjuvant, anti-radiation, and anti-cancer agent.