Concomitant Induction of CD4+ and CD8+ T Cell Responses in Volunteers Immunized with Salmonella enterica Serovar Typhi Strain CVD 908-htrA

Abstract

Type 1 cell-mediated immunity might play an important role in protection from typhoid fever. We evaluated whether immunization with Salmonella enterica serovar Typhi (S. Typhi) strain CVD 908-htrA (a ΔaroC ΔaroD ΔhtrA mutant), a leading live oral typhoid vaccine candidate, elicits specific CD4+ and CD8+ S. Typhi immune responses. Potent CTL responses and IFN-γ secretion by CD8+ T cells were detected following immunization with CVD 908-htrA in high (4.5 × 108 CFU) and low (5 × 107 CFU) dosages. S. Typhi-specific CTL were observed in six of eight vaccinees (four high and two low dose) after immunization. Mean increases in the frequency of IFN-γ spot-forming cells (SFC) in the presence of S. Typhi-infected targets were 221 ± 41 SFC/106 PBMC and 233 ± 87 SFC/106 PBMC, in the high and low dose groups, respectively. Strong CD4+ T cell responses were also observed. Increases in the IFN-γ production to soluble S. Typhi flagella (STF) occurred in 82 and 38% of the volunteers who received the high and low doses, respectively. Robust correlations were observed between volunteers that responded with IFN-γ SFC to stimulation with S. Typhi-infected cells and IFN-γ released in response to stimulation with STF Ags (r = 0.822, p < 0.001) and between CTL and IFN-γ production to STF (r = 0.818, p = 0.013). These data demonstrating the concomitant induction of both CD4- and CD8-mediated CMI are consistent with a significant role for type 1 immunity in controlling typhoid infection and support the continuing evaluation of CVD 908-htrA as a typhoid vaccine candidate.