The overall objective of this project is to fully characterize short and long-term effector and memory humoral and T cell-mediated immune responses (CMI) induced by oral immunization with attenuated S. Typhi live oral vaccines in US subjects, and to identify the cellular and molecular mechanisms that best correlate with protection. Our central hypothesis is that the induction of potent and sustained CMI and humoral immunity at both the local and systemic levels is critical for the development of effective typhoid vaccines, a high public health priority. Specifically, using serum, peripheral blood mononuclear cell (PBMC) and mucosal mononuclear cells (MMC) isolated from terminal ileum biopsies obtained from subjects immunized with one dose of new generation attenuated S. Typhi vaccine candidates or one (low protective efficacy) or four (high protective efficacy) doses of the licensed S. Typhi attenuated vaccine strain Ty21a, we propose to test the following hypotheses: (1) protective HLA class II, classical HLA class la and HLA-E-restricted CMI against S. Typhi depends on immunodominant epitopes derived from S. Typhi antigens. A secondary aim is to evaluate the hypothesis that classical and HLA-E-restricted CD8+ effector responses play complementary roles in protection;(2) the longevity, magnitude and characteristics of CMI to S. Typhi in immunized subjects can be predicted by measuring the magnitude and persistence of specific effector memory (TEM) and central memory (TCM) T cell populations in circulation soon after immunization;(3) the longevity, magnitude and characteristics of antibody responses to LPS and S. Typhi proteins in immunized subjects can be predicted by measuring the avidity of these antibodies in serum, as well as by the magnitude and duration of specific memory B cell populations (BM) in circulation soon after immunization;and (4) that oral immunization with S. Typhi strains elicits the appearance in the gut mucosa of S. Typhi-specific responses mediated by B (e.g., BM) and T (e.g., CTL, Th) cells that correlate with protection. Relevance. The development of improved vaccines to prevent antibiotic-resistant typhoid fever in developing countries is a high global public health priority. The potential use of S. Typhi, the causative agent of typhoid fever, as a bioterror agent has added a new sense of urgency. The goal of this project is to accelerate the development of improved typhoid fever vaccines by uncovering the immunological mechanisms that best correlate with protection in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI036525-13
Application #
7740150
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
Alexander, William A
Project Start
1994-09-01
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
13
Fiscal Year
2010
Total Cost
$456,230
Indirect Cost
Name
University of Maryland Baltimore
Department
Pediatrics
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Booth, Jayaum S; Patil, Seema A; Ghazi, Leyla et al. (2017) Systemic and Terminal Ileum Mucosal Immunity Elicited by Oral Immunization With the Ty21a Typhoid Vaccine in Humans. Cell Mol Gastroenterol Hepatol 4:419-437
Salerno-Goncalves, Rosângela; Luo, David; Fresnay, Stephanie et al. (2017) Challenge of Humans with Wild-type Salmonella enterica Serovar Typhi Elicits Changes in the Activation and Homing Characteristics of Mucosal-Associated Invariant T Cells. Front Immunol 8:398
Wahid, Rezwanul; Fresnay, Stephanie; Levine, Myron M et al. (2016) Cross-reactive multifunctional CD4+ T cell responses against Salmonella enterica serovars Typhi, Paratyphi A and Paratyphi B in humans following immunization with live oral typhoid vaccine Ty21a. Clin Immunol 173:87-95
Toapanta, Franklin R; Bernal, Paula J; Fresnay, Stephanie et al. (2016) Oral Challenge with Wild-Type Salmonella Typhi Induces Distinct Changes in B Cell Subsets in Individuals Who Develop Typhoid Disease. PLoS Negl Trop Dis 10:e0004766
Salerno-Goncalves, R; Safavie, F; Fasano, A et al. (2016) Free and complexed-secretory immunoglobulin A triggers distinct intestinal epithelial cell responses. Clin Exp Immunol 185:338-47
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
Blohmke, Christoph J; Darton, Thomas C; Jones, Claire et al. (2016) Interferon-driven alterations of the host's amino acid metabolism in the pathogenesis of typhoid fever. J Exp Med 213:1061-77
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
Fresnay, Stephanie; McArthur, Monica A; Magder, Laurence et al. (2016) Salmonella Typhi-specific multifunctional CD8+ T cells play a dominant role in protection from typhoid fever in humans. J Transl Med 14:62
Salerno-Goncalves, Rosangela; Fasano, Alessio; Sztein, Marcelo B (2016) Development of a Multicellular Three-dimensional Organotypic Model of the Human Intestinal Mucosa Grown Under Microgravity. J Vis Exp :

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