Chemical synthesis of synbiotic bacterial lipid A for the development of vaccine adjuvants

Abstract

 Lipopolysaccharide (LPS), one of the cell surface components of Gram-negative bacteria, is recognized through receptorial complex TLR4/MD2 to activate innate immunity. LPS and its active principle lipid A are candidates for vaccine adjuvants which enhance the effectiveness of vaccines. On the other hand, most of bacterial LPS have inflammatory effects, for example, canonical Escherichia coli LPS has strong immune stimulative functions but it also shows lethal toxicity.

 Here, we focused on symbiotic bacterial lipid A as a pool of safe immune modulators. Alcaligenes faecalis inhabits in the human Peyer's patches without harmful effects and was suggested to be involved in the host immune system. Thus, we assumed that A. faecalis LPS and lipid A should not be toxic to the host. Kiyono et al. and we previously clarified that A. faecalis LPS has antibody-producing activity comparable to that of E. coli LPS without excessive inflammatory effect. In this study, we synthesized three types of A. faecalis lipid A with different acylation patterns via common disaccharide intermediate. After introduction of corresponding fatty acids to the disaccharide intermediate, two phosphate groups were simultaneously introduced and all protecting groups were removed to afford A. faecalis lipid A. Next, we evaluated their immunological function to identify hexa-acylated A. faecalis lipid A as active principle of A. faecalis LPS. Furthermore, hexa-acylated A. faecalis lipid A enhanced antigen-specific IgA antibody production without toxicity, and thus was found to be a promising adjuvant.