Typhoidal Salmonella human challenge studies: ethical and practical challenges and considerations for low-resource settings.

Typhoidal Salmonella is a major global problem affecting more than 12 million people annually. Controlled human infection models (CHIMs) in high-resource settings have had an important role in accelerating the development of conjugate vaccines against Salmonella Typhi.The typhoidal Salmonella model has an established safety profile in over 2000 volunteers in high-income settings, and trial protocols, with modification, could be readily transferred to new study sites. To date, a typhoidal Salmonella CHIM has not been conducted in a low-resource setting, although it is being considered.Our article describes the challenges posed by a typhoidal Salmonella CHIM in the high-resource setting of Oxford and explores considerations for an endemic setting.Development of CHIMs in endemic settings is scientifically justifiable as it remains unclear whether findings from challenge studies performed in high-resource non-endemic settings can be extrapolated to endemic settings, where the burden of invasive Salmonella is highest. Volunteers are likely to differ across a range of important variables such as previous Salmonella exposure, diet, intestinal microbiota, and genetic profile. CHIMs in endemic settings arguably are ethically justifiable as affected communities are more likely to gain benefit from the study. Local training and research capacity may be bolstered.Safety was of primary importance in the Oxford model. Risk of harm to the individual was mitigated by careful inclusion and exclusion criteria; close monitoring with online diary and daily visits; 24/7 on-call staffing; and access to appropriate hospital facilities with capacity for in-patient admission. Risk of harm to the community was mitigated by exclusion of participants with contact with vulnerable persons; stringent hygiene and sanitation precautions; and demonstration of clearance of Salmonella infection from stool following antibiotic treatment.Safety measures should be more stringent in settings where health systems, transport networks, and sanitation are less robust.We compare the following issues between high- and low-resource settings: scientific justification, risk of harm to the individual and community, benefits to the individual and community, participant understanding, compensation, and regulatory requirements.We conclude that, with careful consideration of country-specific ethical and practical issues, a typhoidal Salmonella CHIM in an endemic setting is possible.

A Multicenter Cost-of-Illness and Long-term Socioeconomic Follow-up Study in the Severe Typhoid Fever in Africa Program: Study Protocol.

BACKGROUND: There are limited data on typhoid fever cost of illness (COI) and economic impact from Africa. Health economic data are essential for measuring the cost-effectiveness of vaccination or other disease control interventions. Here, we describe the protocol and methods for conducting the health economic studies under the Severe Typhoid Fever in Africa (SETA) program. METHODS: The SETA health economic studies will rely on the platform for SETA typhoid surveillance in 4 African countries-Burkina Faso, Ethiopia, Ghana, and Madagascar. A COI and long-term socioeconomic study (LT-SES) will be its components. The COI will be assessed among blood culture-positive typhoid fever cases, blood culture-negative clinically suspected cases (clinical cases), and typhoid fever cases with pathognomonic gastrointestinal perforations (special cases). Repeated surveys using pretested questionnaires will be used to measure out-of-pocket expenses, quality of life, and the long-term socioeconomic impact. The cost of resources consumed for diagnosis and treatment will be collected at health facilities. RESULTS: Results from these studies will be published in peer-reviewed journals and presented at scientific conferences to make the data available to the wider health economics and public health research communities. CONCLUSIONS: The health economic data will be analyzed to estimate the average cost per case, the quality of life at different stages of illness, financial stress due to illness, and the burden on the family due to caregiving during illness. The data generated are expected to be used in economic analysis and policy making on typhoid control interventions in sub-Saharan Africa.

Opportunities for Typhoid Vaccination in India.

Typhoid fever, an infection with potentially life threatening complications, is responsible for 11 to 21 million illness episodes and 145,000 to 161,000 deaths each year globally. India is a high burden country and also faces the challenge of antimicrobial resistance, which further narrows treatment options. This review analyzes the need for typhoid vaccination in India, and appraises the evidence on efficacy, immunogenicity and cost-effectiveness of currently available typhoid vaccines. In 2018, WHO prequalified the first typhoid conjugate vaccine Vi-TT and recommended it for children aged 6-23 months, along with measles vaccine at 9 or 15 months of age through the expanded programme on immunization. With the high endemicity of typhoid in India and the proven cost-effectiveness of the conjugate vaccine, a roll-out of typhoid vaccine should be considered at the earliest.

Accelerating Typhoid Conjugate Vaccine Introduction: What Can Be Learned From Prior New Vaccine Introduction Initiatives?

The health consequences of typhoid, including increasing prevalence of drug-resistant strains, can stress healthcare systems. While vaccination is one of the most successful and cost-effective health interventions, vaccine introduction can take years and require considerable effort. The Typhoid Vaccine Acceleration Consortium (TyVAC) employs an integrated, proactive approach to accelerate the introduction of a new typhoid conjugate vaccine to reduce the burden of typhoid in countries eligible for support from Gavi, the Vaccine Alliance. TyVAC and its partners are executing a plan, informed by prior successful vaccine introductions, and tailored to the nuances of typhoid disease and the typhoid conjugate vaccine. The iterative process detailed herein summarizes the strategy and experience gained from the first 2 years of the project.

A Review of the Economic Evidence of Typhoid Fever and Typhoid Vaccines.

Typhoid places a substantial economic burden on low- and middle-income countries. We performed a literature review and critical overview of typhoid-related economic issues to inform vaccine introduction. We searched 4 literature databases, covering 2000-2017, to identify typhoid-related cost-of-illness (COI) studies, cost-of-delivery studies, cost-effectiveness analyses (CEAs), and demand forecast studies. Manual bibliographic searches of reviews revealed studies in the gray literature. Planned studies were identified in conference proceedings and through partner organization outreach. We identified 29 published, unpublished, and planned studies. Published COI studies revealed a substantial burden in Asia, with hospitalization costs alone ranging from $159 to $636 (in 2016 US$) in India, but there was less evidence for the burden in Africa. Cost-of-delivery studies are largely unpublished, but 1 study found that $671 000 in government investments would avert $60 000 in public treatment costs. CEA evidence was limited, but generally found targeted vaccination programs to be cost-effective. This review revealed insufficient economic evidence for vaccine introduction. Countries considering vaccine introduction should have access to relevant economic evidence to aid in decision-making and planning. Planned studies will fill many of the existing gaps in the literature.

A Global Agenda for Typhoid Control-A Perspective from the Bill & Melinda Gates Foundation.

Recognizing that enteric fever disproportionately affects the poorest and the most vulnerable communities that have limited access to improved sanitation, safe water sources, and optimal medical care, the Bill & Melinda Gates Foundation has funded efforts to augment global understanding of the disease since the foundation's inception. At the turn of the century, early efforts focused on characterizing the burden of disease in Asia and evaluating use of the available Vi-polysaccharide vaccines through the Diseases of the Most Impoverished projects at the International Vaccine Institute (IVI). More recent efforts have centered on supporting development of typhoid conjugate vaccines and expanding disease surveillance efforts into Africa, as well as generating a greater understanding of the clinical severity and sequelae of enteric fever in Africa, Asia, and India. The Typhoid Vaccine Accelerator Consortium is playing a critical role in coordinating these and other global efforts for the control of typhoid fever. Here, we outline the scope of support and strategic view of the foundation and describe how, by working through strong partnerships, we can realize a radical reduction of the significance of enteric fever as a global public health problem in the next 10 to 15 years.

Modelling the cost-effectiveness of a rapid diagnostic test (IgMFA) for uncomplicated typhoid fever in Cambodia.

Typhoid fever is a common cause of fever in Cambodian children but diagnosis and treatment are usually presumptive owing to the lack of quick and accurate tests at an initial consultation. This study aimed to evaluate the cost-effectiveness of using a rapid diagnostic test (RDT) for typhoid fever diagnosis, an immunoglobulin M lateral flow assay (IgMFA), in a remote health centre setting in Cambodia from a healthcare provider perspective. A cost-effectiveness analysis (CEA) with decision analytic modelling was conducted. We constructed a decision tree model comparing the IgMFA versus clinical diagnosis in a hypothetical cohort with 1000 children in each arm. The costs included direct medical costs only. The eligibility was children (≤14 years old) with fever. Time horizon was day seven from the initial consultation. The number of treatment success in typhoid fever cases was the primary health outcome. The number of correctly diagnosed typhoid fever cases (true-positives) was the intermediate health outcome. We obtained the incremental cost effectiveness ratio (ICER), expressed as the difference in costs divided by the difference in the number of treatment success between the two arms. Sensitivity analyses were conducted. The IgMFA detected 5.87 more true-positives than the clinical diagnosis (38.45 versus 32.59) per 1000 children and there were 3.61 more treatment successes (46.78 versus 43.17). The incremental cost of the IgMFA was estimated at $5700; therefore, the ICER to have one additional treatment success was estimated to be $1579. The key drivers for the ICER were the relative sensitivity of IgMFA versus clinical diagnosis, the cost of IgMFA, and the prevalence of typhoid fever or multi-drug resistant strains. The IgMFA was more costly but more effective than the clinical diagnosis in the base-case analysis. An IgMFA could be more cost-effective than the base-case if the sensitivity of IgMFA was higher or cost lower. Decision makers may use a willingness-to-pay threshold that considers the additional cost of hospitalisation for treatment failures.

Urban Slums: A Supportive Ecosystem for Typhoidal Salmonellae.

The typhoidal Salmonellae were controlled in cities in North America and Europe in the late 19th and early 20th century by development of centralized water treatment systems. In the early 21st century, large urban centers where drinking water routinely mixes with human feces have the highest burden of typhoid fever. Although improving municipal drinking water quality is the most robust approach to reduce enteric fever burden, the high costs and managerial capacity that such systems require and decreasing per capita water availability requires new approaches to reach the highest risk communities. The spread of antimicrobial resistance threatens to increase the burden of enteric fever much sooner than the extension of safe reliable water service delivery can be implemented. Thus, vaccination is an important interim measure.

Economic evaluation of typhoid - a review.

INTRODUCTION: To evaluate the potential economic value and likely impact of a hypothetical rapid test in its early stages of development requires the use of models. The model structure and the type of model (dynamic/static) to employ are key considerations. The aim of the review was to explore the literature on typhoid economic evaluations and to explore the types of models that have been previously adopted in this setting for test-treat evaluations and to capture data on model inputs that may be useful for a de novo model. AREAS COVERED: A systematic review was conducted to identify economic evaluations focused on typhoid in established literature databases. Eight studies were identified and included for narrative synthesis. The review has revealed that there have been relatively few economic evaluations that have focused on typhoid fever, all of which have focused on the impact of interventions at the population level (vaccination) but not the individual level (test-treat strategies). EXPERT COMMENTARY: Under certain circumstances, either a static model or a transmission dynamic model may be appropriate in the evaluation of an intervention for typhoid fever. Typhoid test-treat modeling represents a gray area where further work is needed.

Integrating Qualitative Techniques in Model Development: A Case Study Using the Framework Approach.

BACKGROUND: Despite their potential, there is limited uptake of formal qualitative methods in model development by modellers and health economists. The aim of this case study was to highlight in a real-world context how a qualitative approach has been applied to gain insight into current practice (delineating existing care pathways) for typhoid fever in Ghana, which can then assist in model structure conceptualisation in a model-based cost-effectiveness analysis. METHODS: The perspectives of a range of healthcare professionals working in different settings and across different practices in the Eastern region of Ghana were captured with a self-administered survey using open-ended questions and analysed using the framework method. RESULTS: A total of 51 completed questionnaires were retrieved representing a 73% response rate. It was found that two main care pathways for typhoid fever exist in Ghana and there was no consensus on how a new test might be applied to the existing pathways. CONCLUSION: The two settings in Ghana have different care pathways and any cost-effectiveness analysis should consider the alternative pathways separately. This study demonstrated that framework analysis is a qualitative methodology that is likely to be accessible and feasible across a wide range of health economic settings.

Typhoid Fever: Way Forward.

The Tackling Typhoid supplement shows that typhoid fever continues to be a problem globally despite socioeconomic gains in certain settings. Morbidity remains high in many endemic countries, notably in sub-Saharan Africa and South Asia. In addition, antimicrobial resistance is a growing issue that poses a challenge for clinical management. The findings from this supplement revealed that outside of high-income countries, there were few reliable population-based estimates of typhoid and paratyphoid fever derived from surveillance systems. This indicates the need for monitoring systems that can also characterize the effectiveness of interventions, particularly in low- and middle-income settings. The country case studies indicated that gains in economic conditions, education, and environmental health may be associated with reductions in typhoid fever burden. Over the study period, the effect is mainly notable in countries with higher baseline levels of economic development, female literacy, and investments in public sanitation. High burden countries must continue to invest in strategies at the local level to address environmental factors such as access to safe drinking water and improved public sanitation that are known to interrupt transmission or diminish the risk of acquiring typhoid. Developing more effective vaccines and incorporating appropriate immunization strategies that target populations with the greatest risk could potentially alleviate disease burden.

Global Trends in Typhoidal Salmonellosis: A Systematic Review.

Typhoid and paratyphoid fever continue to significantly contribute to global morbidity and mortality. Disease burden is higher in low-and middle-income settings where surveillance programs are rare and little systematic information exists at population level. This review evaluates national, regional, and global trends in the incidence of typhoid fever and of related morbidity and mortality. A literature search in Medline, Embase, and Web of Science was conducted in June 2016, followed by screening and data extraction in duplicate. Studies reporting blood culture estimates of typhoid or paratyphoid morbidity and mortality were included in the analysis. Our search yielded 5,563 unique records, of which 1978 were assessed for relevance with 219 records meeting the eligibility criteria. Salmonella enterica serotype Typhi was the most commonly reported organism (91%), with the occurrence of typhoidal Salmonella (either incidence or prevalence) being the most commonly reported outcome (78%), followed by typhoid fever mortality, ileal perforation morbidity, and perforation mortality, respectively. Fewer than 50% of studies stratified outcomes by age or urban/rural locality. Surveillance data were available from 29 countries and patient-focused studies were available from 32 countries. Our review presents a mixed picture with declines reported in many regions and settings but with large gaps in surveillance and published data. Regional trends show generally high incidence rates in South Asia, sub-Saharan Africa, and East Asia and Pacific where the disease is endemic in many countries. Significant increases have been reported in certain countries but should be explored in the context of long-term trends and underlying at-risk populations.

Implementation of Interventions for the Control of Typhoid Fever in Low- and Middle-Income Countries.

Past research has focused on typhoid fever surveillance with little attention to implementation methods or effectiveness of control interventions. This study purposefully sampled key informants working in public health in Chile, India, Pakistan, Bangladesh, Thailand, Vietnam, South Africa, and Nigeria to 1) scope typhoid-relevant interventions implemented between 1990 and 2015 and 2) explore contextual factors perceived to be associated with their implementation, based on the Consolidated Framework for Implementation Research (CFIR). We used a mixed methods design and collected quantitative data (CFIR questionnaire) and qualitative data (interviews with 34 public health experts). Interview data were analyzed using a deductive qualitative content analysis and summary descriptive statistics are provided for the CFIR data. Despite relatively few typhoid-specific interventions reportedly implemented in these countries, interventions for diarrheal disease control and regulations for food safety and food handlers were common. Most countries implemented agricultural and sewage treatment practices, yet few addressed the control of antibiotic medication. Several contextual factors were perceived to have influenced the implementation of typhoid interventions, either as enablers (e.g., economic development) or barriers (e.g., limited resources and habitual behaviors). Consolidated Framework for Implementation Research factors rated as important in the implementation of typhoid interventions were remarkably consistent across countries. The findings provide a snapshot of typhoid-relevant interventions implemented over 25 years and highlight factors associated with implementation success from the perspective of a sample of key informants. These findings can inform systematic investigations of the implementation of typhoid control interventions and contribute to a better understanding of the direct effects of implementation efforts.

Social and Economic Burden Associated With Typhoid Fever in Kathmandu and Surrounding Areas: A Qualitative Study.

Typhoid fever is a significant contributor to infectious disease mortality and morbidity in low- and middle-income countries, particularly in South Asia. With increasing antimicrobial resistance, commonly used treatments are less effective and risks increase for complications and hospitalizations. During an episode of typhoid fever, households experience multiple social and economic costs that are often undocumented. In the current study, qualitative interview data from Kathmandu and surrounding areas provide important insights into the challenges that affect those who contract typhoid fever and their caregivers, families, and communities, as well as insight into prevention and treatment options for health providers and outreach workers. When considering typhoid fever cases confirmed by blood culture, our data reveal delays in healthcare access, financial and time costs burden on households, and the need to increase health literacy. These data also illustrate the impact of limited laboratory diagnostic equipment and tools on healthcare providers' abilities to distinguish typhoid fever from other febrile conditions and treatment challenges associated with antimicrobial resistance. In light of these findings, there is an urgent need to identify and implement effective preventive measures including vaccination policies and programs focused on at-risk populations and endemic regions such as Nepal.

Modelling and Optimal Control of Typhoid Fever Disease with Cost-Effective Strategies.

We propose and analyze a compartmental nonlinear deterministic mathematical model for the typhoid fever outbreak and optimal control strategies in a community with varying population. The model is studied qualitatively using stability theory of differential equations and the basic reproductive number that represents the epidemic indicator is obtained from the largest eigenvalue of the next-generation matrix. Both local and global asymptotic stability conditions for disease-free and endemic equilibria are determined. The model exhibits a forward transcritical bifurcation and the sensitivity analysis is performed. The optimal control problem is designed by applying Pontryagin maximum principle with three control strategies, namely, the prevention strategy through sanitation, proper hygiene, and vaccination; the treatment strategy through application of appropriate medicine; and the screening of the carriers. The cost functional accounts for the cost involved in prevention, screening, and treatment together with the total number of the infected persons averted. Numerical results for the typhoid outbreak dynamics and its optimal control revealed that a combination of prevention and treatment is the best cost-effective strategy to eradicate the disease.

Integration of enteric fever surveillance into the WHO-coordinated Invasive Bacterial-Vaccine Preventable Diseases (IB-VPD) platform: A low cost approach to track an increasingly important disease.

BACKGROUND: Lack of surveillance systems and accurate data impede evidence-based decisions on treatment and prevention of enteric fever, caused by Salmonella Typhi/Paratyphi. The WHO coordinates a global Invasive Bacterial-Vaccine Preventable Diseases (IB-VPD) surveillance network but does not monitor enteric fever. We evaluated the feasibility and sustainability of integrating enteric fever surveillance into the ongoing IB-VPD platform. METHODOLOGIES: The IB-VPD surveillance system uses WHO definitions to enroll 2-59 month children hospitalized with possible pneumonia, sepsis or meningitis. We expanded this surveillance system to additionally capture suspect enteric fever cases during 2012-2016, in two WHO sentinel hospitals of Bangladesh, by adding inclusion criteria of fever ≥102°F for ≥3 days, irrespective of other manifestations. Culture-positive enteric fever cases from in-patient departments (IPD) detected in the hospital laboratories but missed by the expanded surveillance, were also enrolled to assess completion. Costs for this integration were calculated for the additional personnel and resources required. PRINCIPAL FINDINGS: In the IB-VPD surveillance, 5,185 cases were enrolled; 3% (N = 171/5185) were positive for microbiological growth, of which 55% (94/171) were culture-confirmed cases of enteric fever (85 Typhi and 9 Paratyphi A). The added inclusion criteria for enteric fever enrolled an additional 1,699 cases; 22% (358/1699) were positive, of which 85% (349/358) were enteric fever cases (305 Typhi and 44 Paratyphi A). Laboratory surveillance of in-patients of all ages enrolled 311 additional enteric fever cases (263 Typhi and 48 Paratyphi A); 9% (28/311) were 2-59 m and 91% (283/311) >59 m. Altogether, 754 (94+349+311) culture-confirmed enteric fever cases were found, of which 471 were 2-59 m. Of these 471 cases, 94% (443/471) were identified through the hospital surveillances and 6% (28/471) through laboratory results. Twenty-three percent (170/754) of all cases were children <2 years. Additional cost for the integration was USD 44,974/year, a 27% increase to the IB-VPD annual expenditure. CONCLUSION: In a setting where enteric disease is a substantial public health problem, we could integrate enteric fever surveillance into the standard IB-VPD surveillance platform at a modest cost.

Cost-effectiveness analysis of typhoid conjugate vaccines in five endemic low- and middle-income settings.

BACKGROUND: Typhoid fever remains endemic in low- and middle-income countries. Programmatic use of existing vaccines is limited, but upcoming typhoid conjugate vaccines (TCVs) could warrant wider use. We evaluated the cost-effectiveness of five TCV delivery strategies in three urban areas (Delhi and Kolkata, India and Nairobi, Kenya) and two rural settings (Lwak, Kenya and Dong Thap, Vietnam) with varying incidence. METHODS AND FINDINGS: We evaluated routine infant vaccination with and without catch-up campaigns among older individuals. We used a dynamic model of typhoid transmission to simulate cases, hospitalizations, deaths, disability-adjusted life-years (DALY) lost, treatment and intervention costs. We estimated cost-effectiveness (in terms of cost in international dollars (I$) per DALY averted) from the healthcare payer perspective, and assessed how it was influenced by uncertain model parameters. Compared to no vaccination, routine infant vaccination at I$1/dose was cost-saving in Delhi and Dong Thap, "very cost-effective" in Kolkata and Nairobi, and "cost-effective" in Lwak according to World Health Organization thresholds. However, routine vaccination was not the optimal strategy compared to strategies that included a catch-up campaign, which yielded the highest probability of being cost-saving in Delhi and Dong Thap and were most likely to provide a return on investment above a willingness-to-pay threshold of I$1440 in Kolkata, I$2300 in Nairobi, and I$5360 in Lwak. Vaccine price impacted the optimal strategy, and the number of doses required and rate of hospitalization were the primary sources of uncertainty. CONCLUSION: Routine vaccination with TCV would be cost-effective in most settings, and additional one-time catch-up campaigns would also be economically justified.

Geographical distribution of typhoid risk factors in low and middle income countries.

BACKGROUND: While the global burden of typhoid fever has been often brought up for attention, the detailed surveillance information has only been available for the limited number of countries. As more efficacious vaccines will be available in the near future, it is essential to understand the geographically diverse patterns of typhoid risk levels and to prioritize the right populations for vaccination to effectively control the disease. METHODS: A composite index called the typhoid risk factor (TRF) index was created based on data with the Global Positioning System (GPS). Demographic and Health Surveys (DHS) and National Geographical Data Center (NGDC) satellite lights data were used for this analysis. A count model was adopted to validate the TRF index against the existing surveillance burden data. The TRF index was then re-estimated for 66 countries using the most recent data and mapped out for two geographical levels (sub-national boundary and grid-cell levels). RESULTS: The TRF index which consists of drinking water sources, toilet facility types, and population density appeared to be statistically significant to explain variation in the disease burden data. The mapping analysis showed that typhoid risk levels vary not only by country but also by sub-national region. The grid-cell level analysis highlighted that the distribution of typhoid risk factors is uneven within the sub-national boundary level. Typhoid risk levels are geographically heterogeneous. CONCLUSIONS: Given the insufficient number of surveillance studies, the TRF index serves as a useful tool by capturing multiple risk factors of the disease into a single indicator. This will help decision makers identify high risk areas for typhoid as well as other waterborne diseases. Further, the study outcome can guide researchers to find relevant places for future surveillance studies.