Toll-like receptor 4 (TLR4) and NLR family pyrin domain containing 3 (NLRP3) inflammasome (TLR4/NLRP3)

The primary molecular targets engaged by the AS01E adjuvant system are Toll-like receptor 4 (TLR4) and the NLRP3 inflammasome. AS01E is a liposomal adjuvant containing two key immunostimulants: 3-O-desacyl-4'-monophosphoryl lipid A (MPL) and the saponin QS-21. MPL acts as a direct agonist of TLR4, triggering the production of pro-inflammatory cytokines such as IL-12 and TNF-alpha through the MyD88 and TRIF signaling pathways (Didierlaurent et al., 2014). QS-21 facilitates the activation of the NLRP3 inflammasome, likely via lysosomal destabilization and potassium efflux, leading to the maturation of IL-1beta and IL-18 (Coccia et al., 2017). The simultaneous engagement of these targets in innate immune cells, particularly monocytes and dendritic cells, results in a synergistic immune response characterized by high levels of IFN-gamma and enhanced antigen presentation. This mechanism is leveraged in modern subunit vaccines like Shingrix and Mosquirix to provide robust protection against viral and parasitic infections by inducing strong Th1-type cellular and humoral immunity (Burny et al., 2017). The coordinated activation of TLR4 and NLRP3 is essential for the adjuvant's ability to overcome low immunogenicity and provide durable protection in diverse patient populations (GSK, 2023).

Other names

Human innate immune receptors and cells engaged by AS01E adjuvantAS01E targetsMPL and QS-21 receptorsTLR4 and NLRP3 pathways

Synergistic activation of TLR4-mediated cytokine production and NLRP3-mediated inflammasome processing to enhance adaptive Th1-type immunity.