Salmonella enterica serovar Typhi (S. Typhi) is a major human pathogen causing approximately 22 million new infections and 600,000 deaths annually posing a significant challenge for strategies to control the infection in endemic areas. Current vaccines are of limited efficacy and cannot be used in young children. Development of new alternatives has stalled due to the high costs associated with performing large field trials as no reliable correlates of protection exist. Using a novel human challenge model recently established by the Oxford Vaccine Group, this research aims to identify easy-to-measure gene expression signatures predictive of vaccine-conferred protection (correlates of protection). Microarray technology will be used to determine the longitudinal gene expression levels in whole blood from individuals vaccinated against typhoid and subsequently challenged with S. Typhi. In order to identify the molecular events underlying the host-response to vaccination and infection with S. Typhi, transcriptional patterns will be identified using computational approaches such as network analysis and pathway and gene ontology over-representation analysis. Furthermore, gene expression signatures correlating with clinical and immunobiological data will indicate the mechanisms governing vaccine-derived protection. These data will facilitate the identification of reliable correlates of protection to accelerate the development and deployment of novel typhoid vaccines.