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.

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.

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.

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.

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.

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.

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.

Cost of illness due to typhoid Fever in pemba, zanzibar, East Africa.

The aim of this study was to estimate the economic burden of typhoid fever in Pemba, Zanzibar, East Africa. This study was an incidence-based cost-of-illness analysis from a societal perspective. It covered new episodes of blood culture-confirmed typhoid fever in patients presenting at the outpatient or inpatient departments of three district hospitals between May 2010 and December 2010. Cost of illness was the sum of direct costs and costs for productivity loss. Direct costs covered treatment, travel, and meals. Productivity costs were loss of income by patients and caregivers. The analysis included 17 episodes. The mean age of the patients, was 23 years (range=5-65, median=22). Thirty-five percent were inpatients, with a mean of 4.75 days of hospital stay (range=3-7, median=4.50). The mean cost for treatment alone during hospital care was US$ 21.97 at 2010 prices (US$ 1=1,430.50 Tanzanian Shilling─TSH). The average societal cost was US$ 154.47 per typhoid episode. The major expenditure was productivity cost due to lost wages of US$ 128.02 (83%). Our results contribute to the further economic evaluation of typhoid fever vaccination in Zanzibar and other sub-Saharan African countries.

The cost of typhoid illness in low- and middle-income countries, a scoping review of the literature.

Typhoid fever is responsible for a substantial health burden in low- and middle-income countries (LMICs). New means of prevention became available with the prequalification of typhoid conjugate vaccines (TCV) by the World Health Organization (WHO) in 2018. Policymakers require evidence to inform decisions about TCV. The economic burden related to typhoid fever can be considerable, both for healthcare providers and households, and should be accounted for in the decision-making process. We aimed to understand the breadth of the evidence on the cost of typhoid fever by undertaking a scoping review of the published literature. We searched scientific databases with terms referring to typhoid fever cost of illness to identify published studies for the period January 1st 2000 to May 24th 2024. We also conferred with stakeholders engaged in typhoid research to identify studies pending completion or publication. We identified 13 published studies reporting empirical data for 11 countries, most of them located in Asia. The total cost of a typhoid episode ranged from $23 in India to $884 in Indonesia (current 2022 United States Dollar [USD]). Household expenditures related to typhoid fever were characterized as catastrophic in 9 studies. We identified 5 studies pending completion or publication, which will provide evidence for 9 countries, most of them located in Africa. Alignment in study characteristics and methods would increase the usefulness of the evidence generated and facilitate cross-country and regional comparison. The gap in evidence across regions should be mitigated when studies undertaken in African countries are published. There remains a lack of evidence on the cost to treat typhoid in the context of increasing antimicrobial resistance. Decision-makers should consider the available evidence on the economic burden of typhoid, particularly as risk factors related to antimicrobial resistance and climate change increase typhoid risk. Additional studies should address typhoid illness costs, using standardized methods and accounting for the costs of antimicrobial resistance.

Modelling typhoid risk in Dhaka metropolitan area of Bangladesh: the role of socio-economic and environmental factors.

BACKGROUND: Developing countries in South Asia, such as Bangladesh, bear a disproportionate burden of diarrhoeal diseases such as cholera, typhoid and paratyphoid. These seem to be aggravated by a number of social and environmental factors such as lack of access to safe drinking water, overcrowdedness and poor hygiene brought about by poverty. Some socioeconomic data can be obtained from census data whilst others are more difficult to elucidate. This study considers a range of both census data and spatial data from other sources, including remote sensing, as potential predictors of typhoid risk. Typhoid data are aggregated from hospital admission records for the period from 2005 to 2009. The spatial and statistical structures of the data are analysed and principal axis factoring is used to reduce the degree of co-linearity in the data. The resulting factors are combined into a quality of life index, which in turn is used in a regression model of typhoid occurrence and risk. RESULTS: The three principal factors used together explain 87% of the variance in the initial candidate predictors, which eminently qualifies them for use as a set of uncorrelated explanatory variables in a linear regression model. Initial regression result using ordinary least squares (OLS) were disappointing, this was explainable by analysis of the spatial autocorrelation inherent in the principal factors. The use of geographically weighted regression caused a considerable increase in the predictive power of regressions based on these factors. The best prediction, determined by analysis of the Akaike information criterion (AIC) was found when the three factors were combined into a quality of life index, using a method previously published by others, and had a coefficient of determination of 73%. CONCLUSIONS: The typhoid occurrence/risk prediction equation was used to develop the first risk map showing areas of Dhaka metropolitan area whose inhabitants are at greater or lesser risk of typhoid infection. This, coupled with seasonal information on typhoid incidence also reported in this paper, has the potential to advise public health professionals on developing prevention strategies such as targeted vaccination.

Cost of illness due to typhoid fever in five Asian countries.

OBJECTIVE: To generate community-based estimates of the public (paid by the government) and private (paid by households) costs of blood culture-confirmed typhoid fever in Hechi, China; North Jakarta, Indonesia; Kolkata, India; Karachi, Pakistan and Hue, Vietnam. METHODS: To measure out-of-pocket costs of illness and lost earnings, families with culture-proven cases were surveyed 7, 14 and 90 days after onset of illness. Public costs of treatment were measured at local health facilities using a micro costing (bottom-up) method. RESULTS: The costs of hospitalized cases ranged from USD 129 in Kolkata to USD 432 in North Jakarta (hospitalization rates varied from 2% in Kolkata to 40% in Hechi) and the costs of non-hospitalized cases ranged from USD 13 in Kolkata to USD 67 in Hechi. Where costs were highest (Hechi, North Jakarta and Karachi), the bulk of the costs of hospitalized cases was borne by families, comprising up to 15% of annual household income. CONCLUSION: Although these estimates may understate true costs due to the fact that higher quality treatment may have been provided earlier-than-usual, this multi-country community-based study contributes to evidence on the public and private costs of typhoid fever in developing countries. These cost estimates were used in a cost-effectiveness analysis of typhoid vaccines and will help policymakers respond to World Health Organization's updated typhoid fever immunization recommendations.

Typhoid vaccine: a case for inclusion in national program.

Typhoid has been reported to be a common and significant cause of morbidity in pre-school and school-age children in the endemic countries like India. The incidence of typhoid has been reported to be as high as 27.3 per 1000 person-years in children less than 5 years of age. Serious complications occur in about 10% of cases requiring hospitalization. The mean cost of treatment per episode of blood culture-confirmed typhoid fever has been calculated as INR 3,597 (1996 prices) in an outdoor setting, whereas in case of hospitalization, the cost of illness increases by several folds (INR 18,131). Vi polysaccharide vaccine is safe, efficacious and affordable for use as a cost-effective public health tool to protect children from typhoid and related complications, when given at 2 and 5 years of age as a part of National Immunization Schedule.

Financial barrier against access to diagnostic procedures among enteric fever suspects in highly-endemic areas of China.

There is currently no public financial system that fully covers enteric fever suspects in China. This study aimed at documenting the level of access to definitive diagnostic procedures, especially haemoculture, for these patients and examining the effect of health insurance on access to such care. A hospital-based cross-sectional study was conducted in six counties of Yunnan province, using a structured questionnaire and data extraction from medical records. In total, 714 subjects were recruited. Chi-square test and logistic regression were employed for analysis of data. The majority of the subjects were young adults (52%) and farmers (55%) from low-income families (49%). Only 407 (57%) could afford haemoculture routinely advised by their doctors. Of these, 123 (30%) had haemoculture positive for Salmonella Typhi. After adjustment for income, not getting haemoculture was marginally associated with percentage of reimbursement from the insurance (p value for trend=0.047). Illiteracy was also an independent risk factor for this outcome. The poor coverage of haemoculture for patients suspected of having enteric fever in this endemic area was due to financial barrier. The current health-insurance system inadequately relieved the problem. Further financial reform to help patients suspected with enteric fever is required.

Treatment cost for typhoid fever at two hospitals in Kolkata, India.

The purpose of this study was to estimate treatment cost for typhoid fever at two hospitals in Kolkata, India. This study was an incidence-based cost-of-illness analysis from the providers' perspective. Micro-costing approach was employed for calculating patient-specific data. Unit costs of medical services used in the calculation were directly measured from the study hospital by standard method. The study hospitals were selected based on accessibility to data and cooperation. Eighty-three Widal-positive and/or culture-confirmed patients with typhoid fever during November 2003-April 2006 were included in the study. Most (93%) patients were children. Eighty-one percent was treated at the outpatient department. The average duration of hospitalization for child and adult patients was 8.4 and 4.2 days respectively. The average cost of treating children, adults, and all patients was US$ 16.72, 72.71, and 20.77 respectively (in 2004 prices). Recalculation based on 80% occupancy rate in inpatient wards (following the recommendation of the World Health Organization) found that the cost of treating children, adults, and all patients was US$ 14.53, 36.44, and 16.11 respectively.

Evaluating investments in typhoid vaccines in two slums in Kolkata, India.

New-generation vaccines against typhoid fever have the potential to reduce the burden of disease in areas where the disease is endemic. The case for public expenditure on typhoid Vi polysaccharide vaccines for two low-income, high-incidence slums (Narkeldanga and Tiljala) in Kolkata, India, was examined. Three measures of the economic benefits of the vaccines were used: private and public cost-of-illness (COI) avoided; avoided COI plus mortality risk-reduction benefits; and willingness-to-pay (WTP) derived from stated preference (contingent valuation) studies conducted in Tiljala in 2004. Benefits and costs were examined from a social perspective. The study represents a unique opportunity to evaluate typhoid-vaccine programmes using a wealth of new site-specific epidemiological and economic data. Three typhoid-vaccination strategies (targeting only enrolled school children, targeting all children, and targeting adults and children) would most likely pass a social cost-benefit test, unless benefits are restricted to include only avoided COI. All three strategies would be considered 'very cost-effective' using the standard comparisons of cost per disability-adjusted life-year avoided with per-capita gross domestic product. However, at an average total cost per immunized person of approximately US$ 1.1, a typhoid-vaccination programme would absorb a sixth of existing public-sector spending on health (on a per-capita basis) in India. Because there appears to be significant private economic demand for typhoid vaccines, the Government could design a financially-sustainable programme with user-fees. The results show that a programme where adults pay a higher fee to subsidize vaccines for children (who have higher incidence) would avoid more cases than a uniform user-fee and still achieve revenue-neutrality.

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.

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.

A review of the disease burden, impact and prevention of typhoid fever in Nigeria.

BACKGROUND: Typhoid fever is still a common infection in many parts of the world, especially in developing countries where sanitation and water supply are a common problem. A recent study placed the disease burden at 21650 974 illnesses and 216510 deaths during 2000. The infection is a major cause of morbidity and mortality in Nigeria. OBJECTIVE: This review set out to present in one concise volume a review of the major findings from published articles on the burden and impact of typhoid fever in Nigeria to aid easy reference for researchers. It highlights the disease burden, the different diagnostic methods and their sensitivities, complications, treatment methods as well as the various preventive measures including the use of typhoid vaccine in the control of the disease. METHODS: Several published articles covering a period of 40 years were accessed different journals and reviewed, and their major findings presented in this review. RESULTS: The disease burden from typhoid fever in Nigeria is still high with associated serious complications, which in most cases have been managed effectively with the use of potent antibiotics and surgical intervention. However, the typhoid problem has been compounded by the emergence and circulation of multi-drug resistant strains of the organism being sensitive only to the newer generation antibiotics. CONCLUSION: Typhoid fever remains a major public health problem in Nigeria. The infection however can be prevented by good sanitation, improving good water supply, the provision of proper sewage disposal system, as well as the effective use of the available typhoid vaccines. The government and people of Nigeria should rise up to the challenge of stamping out this ugly trend.

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.

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.