T cell mediated immunity induced by the live-attenuated Shigella flexneri 2a vaccine candidate CVD 1208S in humans

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 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.

Consenting 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).

Following 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 (T_EM) and central memory (T_CM) subsets were the main cytokine/CD107a producers/expressors. Multifunctional (MF) cells were also detected in CD8 T_EM cells. Cells with 2 and 3 functions were the most abundant. Interestingly, TNF-α appeared to be dominant in CD8 T_EM MF cells. In CD4 T cells, T_EM 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 T_EM cells and in 10 vaccinees (90%) in CD4 T_EM cells.

CVD 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).