Date of Award

Fall 10-1-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Public Health

First Advisor

Pitzer, Virginia

Abstract

Background: Typhoid fever is a major source of morbidity and mortality in developing countries, accounting for approximately 12-21 million infections, 119,000-269,000 deaths, and 2-23 million disability-adjusted life years (DALYs) annually. Typhoid fever is caused by infection with the bacteria Salmonella enterica serovar Typhi, which is mainly transmitted through fecal contamination of food or water. Due to these modes of transmission, most cases occur in low- and middle-income countries (LMICs) where sanitary conditions are poor and access to clean water and sanitation is not common. However, the scale of disease incidence is uncertain. Studies suggest that facility-based laboratory-confirmed estimates, the numbers used for reporting and decision-making, are considerably lower than the actual numbers. As a result, typhoid likely has an even higher global burden than is reported.While typhoid remains a major cause of morbidity and mortality, it is preventable. Interventions against typhoid exist, with varying degrees of efficacy and costs. Investments in water and sewer systems in the early 20th century are thought to have been responsible for the decline of typhoid in many developed countries; however, no economic evaluations have quantified the costs and impact of improvements in sanitation. Additionally, a typhoid conjugate vaccine (TCV) has been approved, but research regarding its long-term efficacy and use in outbreak settings is limited. Cost-effectiveness evaluations of TCVs recommend their use in endemic settings, but modelling suggests that vaccination alone will not eliminate disease. Methods & Results: Before we can evaluate the impact of interventions, we need accurate estimates of baseline disease incidence. Therefore, in Chapter 1, we developed a Bayesian framework to combine multiple data sources to estimate the population-based typhoid incidence based on passive surveillance data from Blantyre, Malawi; Kathmandu, Nepal; and Dhaka, Bangladesh. The ratio of observed to adjusted incidence rates was 7.7 (95% credible interval (CrI): 6.0-12.4) in Malawi, 14.4 (95% CrI: 9.3-24.9) in Nepal, and 7.0 (95% CrI: 5.6-9.2) in Bangladesh. Adjusted incidence rates were within or below the seroincidence rate limits of typhoid infection. Estimates of blood-culture-confirmed typhoid fever without these adjustments results in considerable underestimation of the true incidence of typhoid fever.In Chapter 2, we evaluated the cost-effectiveness of typhoid conjugate vaccine use in response to outbreaks of typhoid fever. We fit a modified version of an existing dynamic compartmental model of typhoid fever to Malawi outbreak data and evaluated preventive and reactive vaccination strategies. We then conducted a cost-effectiveness analysis using the net-benefits framework to compare no vaccination to routine vaccination at 9 months of age with and without a catch-up campaign up to 15 years old. We examined variations in outbreak definitions, delays in implementation of reactive vaccination, and the timing of preventive vaccination relative to the outbreak. We estimated that vaccination would prevent 15-60% of disability-adjusted life-years (DALYs) in the outbreak scenarios. Some form of routine vaccination with a catch-up campaign was preferred over no vaccination for willingness-to-pay (WTP) values of at least $110 per DALY averted. Countries where outbreaks of typhoid fever due to introduction of antimicrobial resistant strains are likely to occur should consider TCV introduction. Reactive vaccination can be a cost-effective strategy, but only if delays in vaccine deployment are minimal; otherwise, introduction of preventive routine immunization with a catch-up campaign should be considered. Lastly, in Chapter 3, we quantified the relationship between investments in water and sanitation infrastructure and long-term typhoid transmission rates using historical data from 16 U.S. cities. We fit two models for each city: (1) we modified a Time-series Susceptible-Infectious-Recovered (TSIR) model and extracted long-term transmission rates, and (2) we measured the association between the transmission rates and financial variables using hierarchical regression models. Overall historical $1 per capita ($16.13 in 2017) investments in the water supply were associated with approximately 5% (95% confidence interval: 3-6%) decreases in typhoid transmission, while $1 increases in the overall sewer system investments were associated with estimated 6% (95% confidence interval: 4-9%) decreases. Conclusions: A combination of statistical and mathematical modeling permits us to evaluate the cost-effectiveness of typhoid interventions across settings. We are able to estimate the true population-based incidence of typhoid fever in Africa and Asia, weigh the costs and effects of vaccination strategies in an outbreak setting, and estimate the impact of water and sanitation investments in an endemic setting. These findings can help to inform decision-making regarding typhoid control and prevention. The results can play an essential role in making the case for improvements in water and sanitation and/or vaccination to reduce the global burden of typhoid fever.

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