PROJECT SUMMARY / ABSTRACT Typhoid fever is a major global health concern, with ongoing occurring outbreaks in some developing countries. The causative agent of typhoid fever is the gram-negative bacterium, Salmonella Typhi. It has been recently discovered that S. Typhi produces an unusual toxin known as typhoid toxin. The goal of this research program is to generate typhoid fever vaccines targeting both the bacterium and its secreted virulence factor typhoid toxin, and to design and specify the right-intrinsic-adjuvant system of those vaccines. In Specific Aim 1 we will genetically engineer the Ty21a vaccine strain to make it express inactive typhoid toxin, and in Specific Aim 2 we will generate Ty21a expressing the toxin’s receptor binding subunit without its two enzymatic subunits. In Specific Aim 3, we will survey PltB variants to define their specific glycan binding preference, in order to specify the adjustment on the PltB sequence, aimed at maximizing immunoreactivities of targeted age groups. The modified Ty21a vaccines generated as part of this study are expected to be more effective and may even have potential applications for uses in humans.