Pattern recognition receptors on dendritic cells and other innate immune cells engaged by AS03

AS03 is an oil-in-water emulsion adjuvant composed of squalene, alpha-tocopherol, and polysorbate 80, primarily used in pandemic influenza vaccines such as Pandemrix and Arepanrix (Morel et al., 2011). While many adjuvants function by directly stimulating Toll-like receptors (TLRs), AS03's mechanism of action is notably independent of classical pattern recognition receptors (PRRs) such as TLR2, TLR4, TLR7, and TLR9, as well as their signaling adaptors MyD88 and TRIF (Morel et al., 2011). Instead, research has identified the endoplasmic reticulum (ER) stress sensor kinase Inositol-requiring enzyme 1 alpha (IRE1α) as a critical molecular target in myeloid cells, including dendritic cells and macrophages (Givord et al., 2018). Activation of the IRE1α pathway by AS03 triggers the production of pro-inflammatory cytokines, most notably Interleukin-6 (IL-6), which facilitates the recruitment of innate immune cells and the induction of T follicular helper (Tfh) cells (Givord et al., 2018). This localized inflammatory environment enhances the magnitude, quality, and breadth of the subsequent adaptive antibody response. Additionally, AS03 may indirectly engage the NLRP3 inflammasome through the induction of danger-associated molecular patterns (DAMPs) like extracellular ATP, and its alpha-tocopherol component has been shown to modulate Protein Kinase C alpha (PKCα) signaling to influence dendritic cell development (Morel et al., 2011; Vono et al., 2013). The use of AS03-adjuvanted vaccines has been associated with a rare but significant risk of narcolepsy in certain populations, highlighting the complexity of its interaction with the host immune system (Ahmed et al., 2016).

Other names

AS03-engaged innate sensorsIRE1α signaling pathwayNLRP3 inflammasomeInositol-requiring enzyme 1 alpha (IRE1α)NLR family pyrin domain containing 3 (NLRP3)Protein kinase C alpha (PKCα)

AS03 activates the ER stress sensor IRE1α in myeloid cells, leading to IL-6 production and enhanced T follicular helper (Tfh) cell responses. It also induces the release of DAMPs like ATP, which can activate the NLRP3 inflammasome. Alpha-tocopherol in AS03 modulates PKCα activity.