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Title: Application of a challenge model to assess the protective efficacy of oral typhoid vaccines in humans
Author: Darton, Thomas C.
ISNI:       0000 0004 6060 6629
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2014
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Human infection by Salmonella Typhi has been occurring for the last 50,000 years and still accounts for ∼ 22million new cases each year worldwide. Through faeco-oral transmission, this human-restricted infection disproportionately affects the most impoverished sections of endemic communities where adequate sanitation infrastructure and effective vaccination approaches are lacking. Development of new control measures to accurately measure the burden of disease and to prevent infection with new vaccine candidates are hindered by an incomplete understanding of host-pathogen interactions and of what constitutes a protective human response after exposure. In this thesis I describe the practical application of a recently developed human challenge model of typhoid infection in assessing new control measures, including the evaluation of the oral single-dose vaccine candidate, M01ZH09. In performing a large, double-blind, placebo-controlled study, I was able to measure the direct protective efficacy (PE) of vaccination with either M01ZH09 or 3-dose Ty21a by performing human challenge with 104CFU Salmonella Typhi, Quailes strain, 28-days later. Using clinical and microbiological definitions to confirm typhoid diagnosis during a 14-day period after ingestion, I found insignificant levels of protection afforded by a single dose of M01ZH09 (12.9%), and a low PE after Ty21a vaccination (35%), demonstrating the stringency of the model and the endpoints used. Many additional insights into pathogen dynamics and host responses were found highlighting several important characteristics of oral vaccination. M01ZH09 was highly immunogenic, and both active vaccines significantly reduced bacterial burden (bacteraemia and stool shedding) while having no effect on symptomatic severity of infection in those diagnosed. M01ZH09 receipt resulted in a significantly longer incubation period, suggesting underlying protective responses were being generated. Further findings included the first objective demonstration of primary bacteraemia occurring after typhoid exposure, and frequent asymptomatic infection or stool shedding in those exposed but remaining well. Overall, these data also demonstrated significant protective effects against challenge by anti-Vi antibody status and age at baseline. Taking these factors into account, M01ZH09 and Ty21a vaccination did convey an overall protective advantage against developing typhoid infection, each reducing the risk of diagnosis by ~two-fold during the challenge period.
Supervisor: Angus, Brian ; Pollard, Andrew J. Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Vaccines ; Human challenge studies