Targeted lipid A modification of Shigella vaccine strains reduced endotoxicity without compromising immunogenicity or invasiveness

Shigella infection contributes significantly to the global disease burden, especially affecting young children in developing countries. Currently, a vaccine against Shigella is unavailable and the prevalence of antibiotic resistance amongst Shigella species is continually rising. Live-attenuated Shigella vaccine candidates developed at Walter Reed Army Institute of Research have shown remarkable immunogenicity but exhibit adverse reactogenicity, most likely due to the highly toxic lipid A moiety present on the bacterial membrane. Previous attempts at reducing the endotoxicity have focused on deletion of intrinsic lipid A biosynthesis enzymes. In this study, we instead introduce exogenous lipid A modifying enzymes, generating targeted modifications in the lipid A structure, leading to a dampened TLR4 response within the host. In doing so, we generated vaccine candidates with detoxified lipid A and unaltered O-antigen structure thereby preserving the serotype-specific immunity while reducing endotoxicity.