Toll-Like Receptor Agonists in Immune Adjuvant Development: Molecular Mechanisms and Translational Challenges

Toll-like receptors (TLRs) are pattern recognition receptors which links the body’s innate and adaptive immune system, and have recently become central targets in modern vaccine adjuvant design. This review aims to investigate how TLR2, TLR3, TLR4, TLR5, TLR7/8, and TLR9 agonists can enhance antigen presentation and influence T-cell and antibody activity in conventional vaccines, which mostly exhibit low immunogenicity. Computational modeling and simulation studies have already illustrated ligand-receptor binding, signaling pathways, and resulting immune activation across antigen presenting cells, while cases such as MPLA and CpG-ODN, as well as licensed vaccines like Cervarix, Fendrix, and Heplisav-B have already utilized the potential translational application of TLR agonists. But despite these promising progress, inconsistencies between in silico and in vivo findings, species-specific responses, limitations in delivery method, and safety concerns persists. The review essentially highlights the potential of using multi-TLR strategies to support next generation vaccine adjuvant development.