Attenuated Salmonella typhi organisms which express genes encoding protective antigens of other pathogens have been developed for use as experimental oral vaccines. A Δasd S. typhi strain attenuated by deletions in cya, crp, and cdt which contains hepatitis B core (HBc) and pre-S genes encoded on an Asd+ pBR-based plasmid vector was constructed. Healthy adult volunteers ingested a single dose of 5 x 105 to 5 x 108 CFU of strain χ4073 (Δcya Δcrp Δcdt S. typhi Ty2), 6 x 107 or 1 x 109 CFU of strain χ4632(pYA3149), a further derivative of χ4073 deleted in asd and containing the Asd+ vector without the HBc-pre-S fusion, or 3 x 107 or 7 x 108 CFU of strain χ4632(pYA3167), a derivative containing the vector with the HBc-pre- S fusion. χ4073 was generally well tolerated by 22 volunteers. No volunteer had fever or positive blood cultures; 4 of 22 volunteers shed vaccine organisms in the stool in the first 48 h only. Two of 18 volunteers who received one of the plasmid-containing derivatives of χ4073 developed low- grade fevers on day 10 or 12 after ingestion. One of these volunteers had positive blood cultures on days 7 and 8. Seven of these 18 volunteers had vaccine organisms detected in their stools in the first 48 h only. Most volunteers developed S. typhi-specific serum responses and developed S. typhi-specific antibody-secreting cells. However, no volunteer developed serum antibody to hepatitis pre-S or pre-S-specific antibody-secreting cells. Although the parent strain χ4073 was well tolerated, induced immunoglobulin G seroconversion to S. typhi lipopolysaccharide in 80 to 100% of vaccinees and stimulated specific IgA-secreting lymphocytes in 80 to 100% of vaccinees given a single oral dose of 2 x 107 and 5 x 108 CFU, χ4073 derivatives containing the Asd+ vector with and without sequences encoding the HBc-pre- S fusion caused occasional febrile reactions at high doses and did not stimulate detectable immune responses to hepatitis B antigens.
ASJC Scopus subject areas
- Infectious Diseases