Abstract
BackgroundShigellosis persists as a public health problem worldwide causing ~ 165,000 deaths every year, of which ~ 55,000 are in children less than 5 years of age. No vaccine against shigellosis is currently licensed. The live-attenuated Shigella flexneri 2a vaccine candidate CVD 1208S (S. flexneri 2a; ΔguaBA, Δset, Δsen) demonstrated to be safe and immunogenic in phase 1 and 2 clinical trials. Earlier reports focused on humoral immunity. However, Shigella is an intracellular pathogen and therefore, T cell mediated immunity (T-CMI) is also expected to play an important role. T-CMI responses after CVD 1208S immunization are the focus of the current study.MethodsConsenting volunteers were immunized orally (3 doses, 108 CFU/dose, 28 days apart) with CVD 1208S. T-CMI to IpaB was assessed using autologous EBV-transformed B-Lymphocytic cell lines as stimulator cells. T-CMI was assessed by the production of 4 cytokines (IFN-γ, IL-2, IL-17A and TNF-α) and/or expression of the degranulation marker CD107a in 14 volunteers (11 vaccine and 3 placebo recipients).ResultsFollowing the first immunization, T-CMI was detected in CD8 and CD4 T cells obtained from CVD 1208S recipients. Among CD8 T cells, the T effector memory (TEM) and central memory (TCM) subsets were the main cytokine/CD107a producers/expressors. Multifunctional (MF) cells were also detected in CD8 TEM cells. Cells with 2 and 3 functions were the most abundant. Interestingly, TNF-α appeared to be dominant in CD8 TEM MF cells. In CD4 T cells, TEM responses predominated. Following subsequent immunizations, no booster effect was detected. However, production of cytokines/expression of CD107a was detected in individuals who had previously not responded. After three doses, production of at least one cytokine/CD107a was detected in 8 vaccinees (73%) in CD8 TEM cells and in 10 vaccinees (90%) in CD4 TEM cells.ConclusionsCVD 1208S induces diverse T-CMI responses, which likely complement the humoral responses in protection from disease.Trial registration This study was approved by the Institutional Review Board and registered on ClinicalTrials.gov (identifier NCT01531530)
Highlights
Shigellosis persists as a public health problem worldwide causing ~ 165,000 deaths every year, of which ~ 55,000 are in children less than 5 years of age
IpaB‐induced necrosis in B‐LCL is reduced when IpaB is delivered by LPS‐nanoparticles To evaluate T cell mediated immune responses (T-CMI), we used autologous B-lymphocytic cell lines (B-LCL) as antigen presenting cells
We investigated whether the cell death induced by IpaB in B-LCL was due to necrosis or apoptosis using a dual staining method with a viability dye (YeVID) and Annexin V (Fig. 1a)
Summary
Shigellosis persists as a public health problem worldwide causing ~ 165,000 deaths every year, of which ~ 55,000 are in children less than 5 years of age. No vaccine against shigellosis is currently licensed. The liveattenuated Shigella flexneri 2a vaccine candidate CVD 1208S (S. flexneri 2a; ΔguaBA, Δset, Δsen) demonstrated to be safe and immunogenic in phase 1 and 2 clinical trials. T-CMI responses after CVD 1208S immunization are the focus of the current study. Shigella causes ~ 165,000 deaths worldwide every year, of which ~ 55,000 are in children younger than 5 years of age [1, 2]. Phases 1 and 2 clinical trials of this vaccine candidate have demonstrated the safety of this strain as well as its ability to induce humoral responses [9, 10]
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