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Research Project 3

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Effect of Oral Immunization with Ty21a Typhoid Vaccine On Local & Systemic Immune Responses & the Gut Microbiota in Children, Adults & Elderly

Project Leader: Claire M. Fraser-Liggett, PhD 

This study will explore whether oral immunization with the licensed Ty21a typhoid vaccine results in perturbations of the microbiota measured in terminal ileum biopsies and stools, as well as to evaluate in depth the systemic and local immune responses elicited following immunization in children, adults and the elderly.

Live oral typhoid vaccine Ty21a is one of the safest and best tolerated of all licensed vaccines. However, the modest immunogenicity of this vaccine, which requires that three or four spaced doses be administered (at an interval of 48 hours between doses) in order to confer credible protection, constitutes an important practical shortcoming. Thus, the development of improved typhoid vaccines is a high global public health priority to aid in the prevention antibiotic-resistant typhoid fever in developing countries and against the potential use of S. Typhi (a category B priority pathogen) as a bioterror agent.

The pioneering studies proposed in this application will be the first to explore the interactions between the microbiota and immunogenicity elicited by a bacterial oral vaccine in humans. As described above, the lessons learned in these studies might have implications for the introduction of other attenuated vaccines in developing countries. The in-depth immunological studies to be performed in these studies include measurements of serum and local (Secretory IgA in stool) antibodies and specific antibody secreting cells (ASC), memory B cells (BM) and memory T cell subsets both locally and systemically.

These important studies should markedly accelerate the development of improved vaccines, which has been hampered by a lack of information of the specific determinants of protective immunity to S. Typhi infection and contribute much needed information on local mucosal immunity in humans.