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Modern vaccines have largely shifted from using whole, killed or attenuated pathogens to being based on subunit components. Since this diminishes immunogenicity, vaccine adjuvants that enhance the immune response to purified antigens are critically needed. Further advantages of adjuvants include dose sparing, increased vaccine efficacy in immunocompromised individuals and the potential to protect against highly variable pathogens by broadening the immune response. Due to their ability to link the innate with the adaptive immune response, Toll-like receptor (TLR) agonists are highly promising as adjuvants in vaccines against life-threatening and complex diseases such as cancer, AIDS and malaria. TLRs are transmembrane receptors, which are predominantly expressed by innate immune cells. They can be classified into cell surface (TLR1, TLR2, TLR4, TLR5, TLR6) and intracellular TLRs (TLR3, TLR7, TLR8, TLR9), expressed on endosomal membranes. Besides a transmembrane domain, each TLR possesses a leucine-rich repeat (LRR) segment that mediates PAMP/DAMP recognition and a TIR domain that delivers the downstream signal transduction and initiates an inflammatory response. Thus, TLRs are excellent targets for adjuvants to provide a "danger" signal to induce an effective immune response that leads to long-lasting protection. The present review will elaborate on applications of TLR ligands as vaccine adjuvants and immunotherapeutic agents, with a focus on clinically relevant adjuvants.

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Department of Biochemistry, Magdalen College Oxford, University of Oxford, Oxford OX1 4AU, UK.