Dataset Information

Gut-Homing Conventional Plasmablasts and CD27(-) Plasmablasts Elicited after a Short Time of Exposure to an Oral Live-Attenuated Shigella Vaccine Candidate in Humans.

ABSTRACT: Currently, there is no licensed Shigella vaccine; however, various promising live-attenuated vaccine candidates have emerged, including CVD1208S (?guaBA, ?set, ?sen S. flexneri 2a), which was shown to be safe and immunogenic in Phase 1 clinical trials. Here, we report the immune responses elicited in an outpatient Phase 2 clinical trial in which subjects were vaccinated with CVD 1208S. Oral immunization with CVD 1208S elicited high anti-S. flexneri 2a LPS and IpaB antibody responses as well as an acute plasmablast (PB) infiltration in peripheral blood 7?days after immunization. PB sorted based on their expression of homing molecules confirmed that cells expressing integrin ?4?7 alone or in combination with CD62L were responsible for antibody production (as measured by ELISpot). Furthermore, using high-color flow-cytometry, on day 7 after immunization, we observed the appearance of conventional PB (CPB, CD19(dim) CD20(-) CD27(+high) CD38(+high) CD3(-)), as well as a PB population that did not express CD27 (CD27(-) PB; pre-plasmablasts). The pattern of individual or simultaneous expression of homing markers (integrin ?4?7, CD62L, CXCR3, and CXCR4) suggested that CPB cells homed preferentially to the inflamed gut mucosa. In contrast, ~50% CD27(-) PB cells appear to home to yet to be identified peripheral lymphoid organs or were in a transition state preceding integrin ?4?7 upregulation. In sum, these observations demonstrate that strong immune responses, including distinct PB subsets with the potential to home to the gut and other secondary lymphoid organs, can be elicited after a short time of exposure to a shigella oral vaccine.

SUBMITTER: Toapanta FR

PROVIDER: S-EPMC4138503 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

Gut-Homing Conventional Plasmablasts and CD27(-) Plasmablasts Elicited after a Short Time of Exposure to an Oral Live-Attenuated Shigella Vaccine Candidate in Humans.

Toapanta Franklin R FR Simon Jakub K JK Barry Eileen M EM Pasetti Marcela F MF Levine Myron M MM Kotloff Karen L KL Sztein Marcelo B MB

Frontiers in immunology 20140820

Currently, there is no licensed Shigella vaccine; however, various promising live-attenuated vaccine candidates have emerged, including CVD1208S (ΔguaBA, Δset, Δsen S. flexneri 2a), which was shown to be safe and immunogenic in Phase 1 clinical trials. Here, we report the immune responses elicited in an outpatient Phase 2 clinical trial in which subjects were vaccinated with CVD 1208S. Oral immunization with CVD 1208S elicited high anti-S. flexneri 2a LPS and IpaB antibody responses as well as a ...[more]

PMID: 25191323

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Project description:BACKGROUND: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; ?guaBA, ?set, ?sen) 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. METHODS: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-?, IL-2, IL-17A and TNF-?) and/or expression of the degranulation marker CD107a in 14 volunteers (11 vaccine and 3 placebo recipients). RESULTS: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 (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-? 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. CONCLUSIONS: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).

Dataset Information

Gut-Homing Conventional Plasmablasts and CD27(-) Plasmablasts Elicited after a Short Time of Exposure to an Oral Live-Attenuated Shigella Vaccine Candidate in Humans.

Publications

Gut-Homing Conventional Plasmablasts and CD27(-) Plasmablasts Elicited after a Short Time of Exposure to an Oral Live-Attenuated Shigella Vaccine Candidate in Humans.

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