The science of vaccine adjuvants: advances in TLR4 ligand adjuvants

TLR ligands are used in modern vaccine adjuvants, TLR4 ligand-based adjuvants are the most advanced in commercial vaccines. Increased understanding of TLR4 receptor-ligand interactions enables chemical synthesis and modification of new leads and our understanding of the biological/immunological mechanisms of combination adjuvants enables formulation of potent and safe vaccine compositions. Characterization of non-glycolipid TLR4 ligands provided new mechanistic information that could lead to new formulations. This review discusses advances in TLR4 agonist design - both glycolipid and non-glycolipid based TLR4 ligands - as well as CD14 activation as options to activate or synergize with TLR4 signaling. Finally, we review the molecular and cellular mechanisms that are elicited by formulated TLR4 targeted combination adjuvants during the initiation of innate immune responses leading to quality adaptive responses.