Safety of live oral Salmonella typhi vaccine strains with deletions in htrA and aroC aroD and immune response in humans

Carol O. Tacket, Marcelo B. Sztein, Genevieve A. Losonsky, Steven S. Wasserman, James P. Nataro, Robert Edelman, Derek Pickard, Gordon Dougan, Stephen N. Chatfield, Myron M. Levine

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Abstract

A single-dose, oral Salmonella typhi vaccine strain has been sought as a carrier or vector of cloned genes encoding protective antigens of other pathogens. Such a hybrid vaccine, administered orally, would stimulate immune responses both at the mucosal surface and in the systemic compartment and would potentially provide protection against multiple pathogens. S. typhi CVD 908 and CVD 906, which harbor deletions in aroC and aroD, were further engineered by deletion in htrA to produce strains CVD 908-htrA and CVD 906- htrA, which are unable to sustain growth and are severely impaired in their ability to survive in host tissues. These strains were red to humans at doses of 5 x 107 to 5 x 109 CFU with buffer, and safety and immune responses were assessed. CVD 908-htrA and CVD 906-htrA were well tolerated in volunteers: mild diarrhea in 3 of 36 volunteers and mild fever in 1 volunteer were the only notable adverse responses. The vaccine strains were not detected in blood cultures and only transiently detected in stool. Serum immune responses to S. typhi lipopolysaccharide and H antigens were observed in 75 to 100% of volunteers who received 5 x 108 to 5 x 109 CFU, and cells secreting S. typhi-specific antibodies were found in all volunteers alter ingestion of either strain. Sixty-three percent to 83% of volunteers developed lymphoproliferative responses to S. typhi flagellar and particulate antigens after the higher doses. These studies demonstrate the potential of CVD 908- htrA as a live vector for the delivery of heterologous genes, and a clinical trial of such a construct is planned.

Original languageEnglish
Pages (from-to)452-456
Number of pages5
JournalInfection and Immunity
Volume65
Issue number2
Publication statusPublished - 1 Feb 1997
Externally publishedYes

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