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Title: Investigating enteric fever : application of controlled human infection models to understand enteric fever pathogenesis and immunity
Author: Gibani, Malick Mahdi Mabruk
ISNI:       0000 0004 8507 2088
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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The development of novel vaccines for typhoidal Salmonella is hampered, in part, by a limited understanding of protective host immune responses to infection, the absence of reliable immunological correlates of protection, and uncertainties relating to disease pathogenesis. Controlled human infection models (CHIM) for Salmonella Typhi and Paratyphi have recently been re-established. In this thesis, I describe the application of two controlled human infection studies (CHIM), designed to offer insights into enteric fever pathogenesis and immunity. In the first study, I investigate a recently identified virulence factor encoded by S. Typhi and Paratyphi, termed the typhoid toxin. Following generation, manufacture and characterisation of challenge strains, I compared the response to challenge with either wild type S. Typhi or typhoid toxin-deficient isogenic mutant strain in 40 healthy volunteers using a novel challenge protocol. There was no significant difference in the rate of infection after challenge with wild type or typhoid toxin deficient strains, although there was a trend toward a more severe clinical syndrome in participants challenged with the typhoid toxin deficient strain. Collectively these data suggest that expression of the typhoid toxin is not an absolute requirement for the establishment of acute typhoid fever. In a second study, I recruited naïve volunteers with no prior exposure to Salmonella Typhi or Paratyphi and compared the response to challenge with a cohort of previously-exposed volunteers. Homologous re-challenge with S. Typhi or Paratyphi A was associated with a 37% and 56% relative reduction in attack rates, respectively and a prolonged time to disease. These are the first data indicating prior Salmonella Paratyphi exposure confers protection against re-challenge. In contrast, heterologous re-challenge was not associated with significant reduction in attack rates. Protection from the disease on re-challenge was most pronounced in older participants and in individuals who did develop disease on primary exposure. Baseline serum antibody and memory B-cell measurements did not correlate with protection after re-challenge, and previous exposure was not associated with a demonstrable boosting of humoral immune responses. Further studies identified that previous exposure and Vi-vaccination were significantly associated with reduced shedding of S. Typhi after challenge. Collectively, these studies demonstrate the expanding application and potential of controlled human infection models to understand of enteric fever pathogenesis and immunity. It is hoped that the data presented herein will ultimately aid efforts aimed at disease control, by identifying correlates of protection and to provide a platform for further vaccine studies.
Supervisor: Rollier, Christine ; Pollard, Andrew J. Sponsor: Bill and Melinda Gates Foundation ; Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available