Characterization of Salmonella enterica Derivatives Harboring Defined aroC and Salmonella Pathogenicity Island 2 Type III Secretion System ( ssaV ) Mutations by Immunization of Healthy Volunteers

Abstract

The attenuation and immunogenicity of two novel Salmonella vaccine strains, Salmonella enterica serovar Typhi (Ty2 ⌬aroC ⌬ssaV, designated ZH9) and S. enterica serovar Typhimurium (TML ⌬aroC ⌬ssaV, designated WT05), were evaluated after their oral administration to volunteers as single escalating doses of 10 7 , 10 8 , or 10 9 CFU. ZH9 was well tolerated, not detected in blood, nor persistently excreted in stool. Six of nine volunteers elicited anti-serovar Typhi lipopolysaccharide (LPS) immunoglobulin A (IgA) antibody-secreting cell (ASC) responses, with three of three vaccinees receiving 10 8 and two of three receiving 10 9 CFU which elicited high-titer LPS-specific serum IgG. WT05 was also well tolerated with no diarrhea, although the administration of 10 8 and 10 9 CFU resulted in shedding in stools for up to 23 days. Only volunteers immunized with 10 9 CFU of WT05 mounted detectable serovar Typhimurium LPS-specific ASC responses and serum antibody responses were variable. These data indicate that mutations in type III secretion systems may provide a route to the development of live vaccines in humans and highlight significant differences in the potential use of serovars Typhimurium and Typhi.

Regulation of Vi Capsular Polysaccharide Synthesis in Salmonella enterica Serotype Typhi

“…The rpoS mutation could affect the immunogenicity in recombinant vaccines [63]. In fact, live typhoid vaccines derived from Ty2 (RpoS − ) have yielded poor results when used as a live recombinant S. Typhi vaccine (RAStyVs) expressing protective antigens from a diversity of pathogens [64,65,66,67,68,69]. It is thus possible that the poor immunogenicity observed for Ty21a may be the result of the rpoS mutation rather than Vi antigen deletion.…”

Vaccines against typhoid fever

“…Finally, the recently developed strain ZH9 lacks the aroC and ssvA genes; the latter encodes a protein involved in protein secretion via a type III secretion system. This strain was also shown to be safe and immunogenic in a phase I clinical study [63].…”

Immunological responses against Salmonella enterica serovar Typhimurium Braun lipoprotein and lipid A mutant strains in Swiss-Webster mice: Potential use as live-attenuated vaccines

“…Strains of S. Typhimurium with mutations in the Salmonella pathogenicity island-2 (SPI-2) are also attenuated in mice [62][63][64][65]. Further, the phoP/phoQ and the ΔaroC ΔssaV S. Typhimurium mutant strains have been reported to be safe and elicit specific antibodies and IgA antibody-secreting cell responses to the heterologous antigens as well as to the carriers LPS [56,66,67] in human volunteers. The ssaV gene codes for a protein involved in protein secretion via the type 3 secretion system (T3SS) on the SPI-2.…”