Current vaccines against typhoid fever have limited efficacy and cannot be used in young children, posing a significant challenge for infection control in endemic areas. The lack of knowledge regarding disease pathogenesis, alongside the absence of suitable correlates of protection, hinders the development of improved vaccines. To address this, the EU-funded MCF_IIF BLOHMKE 2012 (Identification of novel correlates of protection to accelerate the introduction of vaccines against typhoid into populations with high disease burden) project used an established model of controlled human typhoid fever infection established by the Oxford Vaccine Group (OVG) at the University of Oxford. Healthy, consenting adult volunteers are infected with S. Typhi and subsequently treated with a course of antibiotics. The goal of MCF_IIF BLOHMKE 2012 was to establish analyses pipelines for transcriptional data in participants of the acute typhoid challenge model. This data was compared with participants vaccinated with two life attenuated oral vaccines against typhoid fever, the Ty21a and M01ZH09. Specific focus was given on molecular host response at several time points after vaccination and the profiles were correlated to immunogenicity and outcome. Using this challenge model, they found host responses to oral challenge 12 hrs after ingestion of the pathogen. To validate the challenge model with respect to real life scenarios, researchers compared the data from the model participants with the transcriptional profiles from patients in the field. Interestingly, gene expression analysis indicated a potential impact of the host’s metabolism on the immune response to typhoid. Using sensitive computational methods, the research team went on to interrogate the subtle host responses to vaccination. The two vaccines, M01ZH09 and Ty21a, exhibited marked differences in the magnitude of immunogenicity with a variable expression of over 110 genes. However, detailed gene set enrichment analysis (GSEA) of NK cell transcripts and cell cycle genes indicated distinct differences between the two vaccines. Collectively, the study established a robust analysis platform for generating molecular data on the outcome of vaccination against typhoid fever. The insight into disease pathogenesis and responses to live attenuated oral vaccines will further support vaccine development and increase treatment opportunities.
Systems Biology, Enteric Fever, Systems Vaccinology, Transcriptomics, Biomarkers discovery, enteric fever, vaccine, Salmonella Typhi, challenge model, Ty21a, M01ZH09, systems biology, systems vaccinology