Identification of a novel Th1 promoting vaccine adjuvant from natural products (P4451)

Abstract

Abstract One of the great obstacles to vaccine development is the lack of adjuvants that can safely and appropriately stimulate human immune cells. There are a limited number of adjuvants that have been approved for use in human vaccines. In the USA, all but one of the adjuvanted vaccines uses aluminum salts (alum) and these promote T helper (TH) 2 but not TH1 immunity. For this screen we have utilized Eskitis's Nature Bank library as a source of compounds. This library consists of over 200,000 natural product fractions derived from a collection of over 45,000 samples of plants and marine invertebrates from Australia, China, and Papua New Guinea. Mice on a C57BL/6 background that express the IL-12p40 promoter linked to yellow fluorescent protein (YFP) have been utilized as a source of dendritic cells (DCs). Splenic DCs were cultured in the presence of Nature Bank fractions or with toll like receptor-9 (TLR9) agonist CpG 1826. Cultures were assayed for IL-12 production by measuring YFP using a Perkin Elmer Operetta high content screening system and analyzed with Harmony software. Only a single compound was identified in our screen of over 20,000 fractions and it robustly activated DCs (86% compared to 11% for CpG positive controls) to become IL-12 positive. We have preliminary structural data on the compound and are subsequently testing “compound A” for immunogenicity and adjuvant activity utilizing in vitro and in vivo assays with mice, as well as human monocyte derived DC cultures.