The Humoral Response against Salmonella Typhi Protein Antigens During Acute, Convalescent, and Chronic Typhoid Fever

Tran, Vu Thieu Nga (2019). The Humoral Response against Salmonella Typhi Protein Antigens During Acute, Convalescent, and Chronic Typhoid Fever. PhD thesis The Open University.



Enteric (typhoid) fever is a life-threatening disease caused by the Salmonella enterica subspecies enterica serovars Typhi (S. Typhi) and Paratyphi A, B, and C (S. Paratyphi A, B, and C). The disease still causes major public health problems in low- and middle-income countries, principally in Asia and Africa. The increasing frequency of multi-drug resistant (MDR) and extended-drug resistant isolates (XDR) of S. Typhi and an increasing incidence of S. Paratyphi A mean that the international dynamics of enteric fever are changing. These changes add urgency to the demand for more efficient enteric fever control campaigns. The aim of this thesis was to assess control measures for enteric fever in Vietnam and to develop techniques that can be used as further control methods. I firstly systemically reviewed retrospective information regarding enteric fever in Vietnam and combined these data with data on economic development. This investigation revealed that national economic growth, the provision of improved quality drinking water, and better sanitation were likely the greatest contributors to the decline and ultimate elimination of enteric fever in Vietnam. My work then evaluated the serodiagnostic potential of a panel of novel S. Typhi protein antigens and the Vi capsular polysaccharide (Vi) in a group of patients with febrile diseases in Bangladesh. These data demonstrated the utility of serology for typhoid diagnostics when exploiting a combination of Vi and at least one protein antigen. I then assessed the acquisition of antibody against typhoid toxin during natural S. Typhi and S. Paratyphi A infections and measured the capability of these antibodies to neutralise the toxin. The data provided supporting evidence for generating an antitoxin treatment for enteric fever (caused by both S. Typhi and S. Paratyphi A), and potentially encourages the use of typhoid toxin in vaccine formulations. Within the scope of searching for vaccine novel candidates, my work further identified a panel of immunogenic antigens shared between S. Typhi and S. Paratyphi A that can stimulate an antibody response which can instigate bactericidal killing during natural infection. Finally, by exploiting the unique immunological profiles of S. Typhi carriers (cytokines and antibody), I developed a method of identifying S. Typhi carriers and estimating the prevalence of S. Typhi carriage in a typhoid endemic population. My findings will potentially lead to the development of novel enteric fever control strategies. I conclude that improved case detection and widespread vaccination campaigns using polyvalent Salmonella vaccines should be initiated for reducing the burden of enteric fever in endemic areas.

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