Human in vitro modeling reveals age- and formulation-specific mechanism of action of AS01 9236

Abstract Description Although AS01™ (a liposomal formulation of MPLA+QS-21) is used in licensed vaccines, there is a limited understanding of its mechanism of action (MOA). To gain further insight into AS01™ MOA, we used a series of complementary human in vitro assays termed MEMPHIS (Modular Evaluation of immunogenicity using Multi-Platform Human In vitro Systems). Peripheral blood mononuclear cells (PBMCs) were used from young adults (YAs,18–64 years; n = 9) and older adults (OAs, >65 years; n = 9). Formulations tested included AS01B™ and liposomal MPLA or QS-21. In PBMCs, AS01B™ demonstrated a reduction of pro-inflammatory cytokines IFNα, IFNγ, IL-1α, and TNFα in YAs, as compared to liposomal MPLA or QS-21 alone, suggesting a potentially favorable reactogenicity profile. This synergistic reduction of pro-inflammatory cytokines was not observed in OAs. In striking contrast, MPLA and QS-21 co-formulated within AS01B™ synergistically induced robust production of IL-1β and IL-12p70 in YAs and OAs in monocyte-derived dendritic cells (MoDCs), compared to MPLA and QS-21 formulations alone, as well as IL1α and TNFα in YAs. AS01B™ significantly activated autologous antigen-specific CD4+ and CD8+ T cells in YAs in a MoDC:T-cell co-culture assay. In a human tissue construct, AS01B™ induced the secretion of CXCL10 by monocytes and enhanced differentiation of DCs. These human in vitro platforms shed light on age-specific MOA of AS01™, informing its application for population-specific adjuvanted vaccines. Funding Sources This study was funded by GSK with additional support to the Precision Vaccines Program provided by NIH/NIAID. Topic Categories Vaccines and Immunotherapy (VAC)