Safety and immunogenicity in humans of an attenuated Salmonella typhi vaccine vector strain expressing plasmid-encoded hepatitis B antigens stabilized by the Asd-balanced lethal vector system

Attenuated Salmonella typhi organisms which express genes encoding protective antigens of other pathogens have been developed for use as experimental oral vaccines, A Delta asd 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 10(5) to 5 x 10(8) CFU of strain chi 4073 (Delta cya Delta crp Delta cdt S. typhi Ty2), 6 x 10(7) or 1 x 10(9) CFU of strain chi 4632(pYA3149), a further derivative of chi 4073 deleted in nsd and containing the Asd(+) vector without the HBc-pre-S fusion, or 3 x 10(7) or 7 x 10(8) CFU of strain chi 4632(pYA3167), a derivative containing the vector with the HBc-pre-S fusion, chi 4073 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 chi 4073 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 chi 4073 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 10(7) and 5 x 10(8) CFU, chi 4073 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.