New typhoid vaccines have been sought to replace the reactogenic parenteral whole cell vaccines. Both Ty21a, a live oral attenuated Vi-negative Salmonella typhi vaccine strain, and parenteral Vi polysaccharide vaccine are safe and efficacious in field trials. To achieve potentially greater protective efficacy, a derivative of Ty21a that expresses Vi polysaccharide was prepared and its safety and immunogenicity assessed in 27 adult volunteers. The volunteers received either one dose of 5 x 10(5), 5 x 10(7), or 5 x 10(9) cfu or three doses of 5 x 10(9) cfu of lyophilized vaccine and were observed for adverse effects on a research isolation ward. The vaccine was well tolerated; however, at the highest dose, 13% of volunteers had mild diarrhea. Serial blood cultures were negative for the vaccine strain. Vaccine was shed in the stool of most volunteers at the higher doses for 1-4 days. No serum antibodies to Vi, circulating cells secreting antibody to Vi, or jejunal fluid antibodies to Vi were detected in any volunteer.