Salmonella typhi Ty800, deleted for the SalmonellaphoP/phoQ virulence regulon has been shown to be a safe and immunogenic single dose oral typhoid fever vaccine in volunteers. This promising vaccine strain was modified to constitutively express a heterologous protein of Gram negative bacterial origin, Helicobacter pylori urease subunits A and B, yielding S. typhi strain Ty1033. Seven volunteers received single oral doses of ≥10¹⁰ colony forming units of Ty1033; an eighth volunteer received two doses 3 months apart. Side effects were similar to those observed previously in volunteers who received the unmodified vector Ty800. All volunteers had strong mucosal immune responses to vaccination as measured by increases in IgA-secreting cells in peripheral blood directed against S. typhi antigens. Seven of eight volunteers had convincing seroconversion as measured by increases in serum IgG directed against S. typhi flagella and lipopolysaccharide antigens by ELISA. No volunteer had detectable mucosal or humoral immune responses to the urease antigen after immunization with single doses of Ty1033. A subset of three volunteers received an oral booster vaccination consisting of recombinant purified H. pylori urease A/B and E. coli heat labile toxin adjuvant 15 days after immunization with Ty1033. None of three had detectable humoral or mucosal immune responses to urease. Expression of a stable immunogenic protein in an appropriately attenuated S. typhi vector did not engender detectable mucosal or systemic antibody responses; additional work will be needed to define variables important for immunogenicity of heterologous antigens carried by live S. typhi vectors in humans.