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Salmonella Typhi (S. Typhi) has affected mankind for the last 50,000 years (Kidgell et al., 2002; Roumagnac et al., 2006), however the precise pathogenesis in humans has largely remained a mystery (Crump and Mintz, 2010). Typhoid fever, the systemic disease caused by S. Typhi infection, is responsible for an estimated 21 million new infections annually resulting in approximately 200,000–600,000 deaths world-wide (Crump et al., 2004; Buckle et al., 2012). If untreated, typhoid fever may result in severe illness including the complications of gastrointestinal bleeding, bowel perforation, and sometimes death. Transmission of S. Typhi occurs via ingestion of faecally-contaminated food or water (De Jong et al., 2012). Infection risk has been associated with household factors including contact with a recently infected relative, poor sanitation and hygiene infrastructure, which include spatial associations with contaminated public water sources (Vollaard et al., 2004; Sur et al., 2009; Baker et al., 2011).  Much of what we know about human Salmonella infection has been determined from historical human vaccine and, subsequently, challenge studies dating back to 1896 (Waddington et al., 2014a). Between 1952 and 1974, human challenge studies performed at the University of Maryland served as a unique tool by which to study host-pathogen interactions including mechanistic hypotheses regarding routes of infection, development of clinical symptomatology and evolution of host immune responses.  Initial improvements in sanitation infrastructure occurring during the last century in “western settings” and subsequently in the rest of the world resulted in a general reduction in the prevalence of typhoid fever. Infection is still highly prevalent in resource-limited countries and travelers. Reasons for this include the lack of effective vaccine campaigns, availability of accurate diagnostic tests and the emergence of antibiotic resistance, hindered by the incomplete understanding of bacterial pathogenesis and response to infection by the native host.  To address this, in 2011 we re-established controlled human infection studies of S. Typhi in Oxford. A model was developed using a sodium bicarbonate buffer to neutralize gastric acid and increase bacterial survival through the stomach; neutralization of stomach acid allows the use of lower challenge inocula and a smoother pattern of clinical infection (Waddington et al., 2014b). Ingestion with buffer resulted in a consistent pattern of typhoid infection with an attack rate of 65%, which developed after ingestion of 1–5 × 104 colony forming units. Participants were managed after challenge on an outpatient basis.  The development of this new challenge model will provide a standardized approach to study typhoid infection that will prove fundamental for the investigation of immunobiology in the relevant human host and the discovery, development and evaluation of novel vaccines, diagnostics and treatment modalities.

Why the development of effective typhoid control measures requires the use of human challenge studies