부산대학교 도서관

Each year, 12.1 to 20.6 million typhoid fever infections occur globally, of which 1% result in death. Children are particularly susceptible to infection. As the causative bacterium Salmonella Typhi is transmitted via contaminated food or unsafe drinking water, typhoid fever has often been regarded as a disease of poverty or an infection of the returning traveller. However, increasing antimicrobial resistance and reduced treatment options have made typhoid fever a global threat. Interventions to reduce the burden of disease are urgently needed. Although vaccination has been recommended in endemic regions, uptake of pre-existing typhoid vaccines has been poor, particularly as these vaccines cannot be used in young children. While Vi-conjugate vaccines (TCV) can be used from infancy, a paucity of efficacy data has hindered their development. This phase IIb-observer blinded randomised controlled trial was conducted to evaluate the protective efficacy of a TCV using a controlled human infection model (CHIM) of typhoid fever in an effort to address this data gap, and to assist with the advancement of TCVs to control typhoid fever disease. Healthy typhoid naïve adult volunteers were randomised to receive control (n=34), Vi-TT (Vi-tetanus toxoid conjugate vaccine, n=41) or Vi-PS vaccine (licensed Vi-polysaccharide vaccine, n=37) one month prior to oral challenge with 104 CFUs of S. Typhi Quailes strain. Participants were diagnosed with typhoid fever over a two-week period if meeting the predefined composite definition (S. Typhi bacteraemia and/or fever ≥38°C for ≥12 hours). 103 participants completed challenge, of which 24/31 (77%) control, 13/37 (35%) Vi-TT and 13/35 (37%) Vi-PS were diagnosed with typhoid fever. The protective efficacies of Vi-TT and Vi-PS were 54.6% [95% CI: 26.8, 71.8] and 52.0% [23.2, 70.0], respectively. However, vaccine efficacy estimates differed depending on the definition of typhoid fever used. Clinical definitions resulted in higher efficacy estimates for Vi-TT, as vaccination appeared to reduce fever rates and symptom severity in diagnosed participants. An in-depth assessment of Vi-specific humoral immunity showed that Vi-TT was more immunogenic than Vi-PS, inducing higher anti-Vi IgG, IgA, IgM, IgG1, IgG2 and IgG3 antibody titres, higher frequencies of Vi-specific antibody secreting cells and greater Vi-antibody mediated functional responses than Vi-PS. Additional studies identified that Vi-TT induced circulating T follicular helper cells and Vi-specific IgG memory B cells, both features indicative of germinal centre responses, which were not detected in Vi-PS vaccinees. Evaluation of Vi-specific humoral responses to identify potential correlates of protection were conducted using logistic regression models. Anti-Vi IgG, IgA and IgG2 titres were found to significantly decrease the probability of typhoid fever diagnosis, however, a protective threshold (above which 100% of participants were protected) was not identified. The findings from this study represent the first efficacy results and comprehensive assessment of humoral immunity for the only WHO prequalified TCV - Vi-TT (Typbar-TCV, Bharat Biotech). These results contributed to a change in global health policies and funding prioritisation for TCVs. Towards the end of 2017, the WHO's Strategic Advisory Group of Experts on Immunisation recommended the use of TCVs in high burden typhoid endemic regions and importantly in children >6 months of age and the Global Vaccine Alliance pledged US$85 million to assist with the roll out of TCVs to areas of need. CHIM studies represent a platform to test and generate hypotheses. As such, more research is required to evaluate TCV efficacy in phase III trials conducted in endemic settings and to validate the preliminary humoral immunity results described in this thesis using observations from the field. For now, hopefully the action that has been set in motion with the introduction of TCVs will assist with the control of typhoid fever disease and help to improve the health of children living in high burden regions.