The goal of this project is to fully characterize at the local and systemic levels T cell-mediated immune responses (CMI) induced by oral immunization with new generation attenuated S. typhi strains and to identify the cellular and molecular mechanisms that best correlate with protection against challenge with wild-type S. typhi. The development of improved typhoid vaccines has been hampered by a considerable lack of information on the specific determinants of protective CMI to S. typhi infection. Moreover, insufficient information is available regarding human mucosal immune responses to S. typhi, likely to be a key defense mechanism. Our central hypothesis is that the induction of potent and sustained CMI at both the local (e.g., the gut microenvironment) and systemic levels is critical for the development of an effective typhoid vaccine. Specifically, using peripheral blood mononuclear cells (PBMC) and mucosal biopsy specimens obtained from volunteers vaccinated with attenuated strains of S. typhi or challenged with wild-type S. typhi we propose. 1) To test the hypothesis that protective CMI responses against S. typhi will be determined by a set of immunodominant epitopes derived from S. typhi antigens. We will study the fine specificity of anti-S. typhi T cell responses by identifying immunodominant S. typhi proteins and T cell epitopes using a panel of T cell clones obtained from blood of immunized volunteers. 2) To test the hypothesis that CTL induced by immunization kills infected target cells by a combination of perforin and FAS ligand-mediated mechanisms. 3) To test the hypothesis that dendritic cells (DC) play a key role in the induction of protective immune responses in humans following oral immunization with attenuated strains of S. typhi. 4) To test the hypothesis that challenge with wild-type S. typhi or immunization with attenuated strains elicits the appearance in the gut mucosa of specific CTL effectors and T lymphocytes that produce Type-1 cytokines, and that these responses correlate with protection following challenge with wild-type S. typhi.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI036525-05
Application #
6193505
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Project Start
1994-09-01
Project End
2005-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
5
Fiscal Year
2000
Total Cost
$334,125
Indirect Cost
Name
University of Maryland Baltimore
Department
Pediatrics
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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Sztein, Marcelo B (2018) Is a Human CD8 T-Cell Vaccine Possible, and if So, What Would It Take? CD8 T-Cell-Mediated Protective Immunity and Vaccination against Enteric Bacteria. Cold Spring Harb Perspect Biol 10:
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Cong, Yu; McArthur, Monica A; Cohen, Melanie et al. (2016) Characterization of Yellow Fever Virus Infection of Human and Non-human Primate Antigen Presenting Cells and Their Interaction with CD4+ T Cells. PLoS Negl Trop Dis 10:e0004709
Darton, Thomas C; Jones, Claire; Blohmke, Christoph J et al. (2016) Using a Human Challenge Model of Infection to Measure Vaccine Efficacy: A Randomised, Controlled Trial Comparing the Typhoid Vaccines M01ZH09 with Placebo and Ty21a. PLoS Negl Trop Dis 10:e0004926
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