Typhoid fever, caused by Salmonella enterica serovar Typhi (S. Typhi), remains a major public health problem worldwide. Ty21a is a licensed live-attenuated oral typhoid vaccine that has shown efficacy; however, it is modestly immunogenic and requires multiple doses. Because of the appearance of multiple antibiotic resistance S. Typhi strains there is renewed urgency for developing more effective typhoid vaccines. However, a major obstacle for the development of novel, more immunogenic, typhoid vaccines remains the lack of knowledge of the immunological correlates of protection (CoP) from S. Typhi infection in humans. This is due, in large measure, to the extreme difficulties associated with performing challenge studies with wild-type (wt) S. Typhi in volunteers and the lack of a small animal model that faithfully recapitulates human disease. Dr. Pollard (Oxford, UK) has recently reestablished, in collaboration with the CVD in Baltimore, the challenge model originally pioneered at UMB in the 1960's in which subjects were orally challenged with wt S. Typhi. Moreover, a follow up study in which subjects are being vaccinated with the M01ZH09 attenuated typhoid vaccine candidate and will be challenged with wt S. Typhi is already underway. These studies provide a truly unique opportunity to uncover the immunological CoP from S. Typhi infection and dramatically accelerate the development of novel, more effective vaccines. The immune responses to S. Typhi in humans are complex, involving antibodies (Ab) and cell-mediated immunity (CMI). We hypothesize that the induction of potent and sustained CMI and humoral immunity at the local and systemic levels is critical for the development of effective typhoid vaccines. Studies conducted by the PI over the past 20 years, largely supported by this R01, have shown that immunization with attenuated typhoid vaccines elicits memory B cells (BM), are well as potent CD4+ and CD8+ CMI responses, including multifunctional Tc17 memory T cells (TM). We propose to use specimens isolated from subjects (1) challenged with wt S. Typhi, (2) immunized with M01ZH09 or Ty21a followed by wt S. Typhi challenge and (3) immunized with one (non-protective) or four (protective) doses of Ty21a, to: (1) test the hypothesis that the kinetics of appearance, magnitude, characteristics, persistence and homing potential of defined specific multifunctional memory (TEM, TEMRA, TCM) and effector T cell (Teff) subsets and BM in circulation after challenge with wild-type S. Typhi predic whether the subjects will develop typhoid fever, (2) validate the findings in Aim 1 by evaluating in subjects immunized with attenuated S. Typhi strains whether similar responses can predict protection from the development of typhoid fever upon challenge with wt S. Typhi, and (3) test the hypothesis that protective MHC class II-, class Ia- and HLA-E-restricted CMI against S. Typhi is determined by a restricted set of epitopes derived from S. Typhi proteins.

Public Health Relevance

This project will provide unique insights into the immunological correlates of protection against the human- restricted pathogen S. Typhi which causes typhoid fever, a disease of great global public health importance. The proposed studies will be the first in over 30 years directed to uncover, using state-of-the-art immunological techniques, the correlates of protection from the development of typhoid fever using specimens from subjects challenged with wild-type S. Typhi or immunized with attenuated candidate typhoid vaccines followed by exposure to wild-type S. Typhi. This information will significantly advance the development of much needed improved typhoid vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
4R01AI036525-18
Application #
9020922
Study Section
Vaccines Against Microbial Diseases Study Section (VMD)
Program Officer
Alexander, William A
Project Start
1994-09-01
Project End
2018-02-28
Budget Start
2016-03-01
Budget End
2017-02-28
Support Year
18
Fiscal Year
2016
Total Cost
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
Zhang, Yan; Brady, Arthur; Jones, Cheron et al. (2018) Compositional and Functional Differences in the Human Gut Microbiome Correlate with Clinical Outcome following Infection with Wild-Type Salmonella enterica Serovar Typhi. MBio 9:
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:
Salerno-Gonçalves, Rosângela; Tettelin, Hervé; Lou, David et al. (2017) Use of a novel antigen expressing system to study the Salmonella enterica serovar Typhi protein recognition by T cells. PLoS Negl Trop Dis 11:e0005912
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
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
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

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