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Abstract Typhoid fever, caused by Salmonella enterica serovar Typhi, results in over 1.2 million cases and 29 thousand deaths annually from sub-Saharan Africa. Combating this disease requires various intervention approaches, such as typhoid conjugate vaccines and improving water, sanitation, and hygiene. Enhancing the effectiveness of these strategies necessitates a deeper understanding of the variation of the typhoid fever across the target region. Although the magnitude and variation of typhoid fever at the country level have been studied globally, sub-national variation remains underexplored. To address this gap, we collected data from 229 published reports on typhoid fever occurrences in sub-Saharan Africa between January 2000 and December 2020. The dataset includes information on the year and geographical location of observation, diagnostic tests used, and the type of studies in which typhoid fever was reported. By analyzing this dataset, we can gain insights into the sub-national heterogeneity of typhoid fever’s burden in the region. This knowledge will be instrumental in designing more effective intervention strategies to combat the disease.

Background India has a high typhoid fever burden. In 2022, the National Technical Advisory Group on Immunisation recommended introducing typhoid conjugate vaccine (TCV) into the Universal Immunisation Programme. Our study aims to identify research priorities to support ongoing TCV decision-making in India.Methods We identified 45 evidence factors for TCV decision-making in India by adapting WHO’s Evidence-to-Recommendation framework. We assigned an evidence gap score for each evidence factor from 0 (low) to 4 (high) based on the availability and sufficiency, quality, breadth and applicability of evidence identified in a literature review (end date 30 November 2023). We assigned each evidence factor an importance score based on the results of an online survey conducted among national immunisation stakeholders (n=22, 1 July 2023–31 October 2023), where they ranked the importance of seven WHO’s Evidence-to-Recommendation criteria and several evidence factors within them. We rescaled mean stakeholder rankings into importance scores from 0 (low) to 4 (high). Finally, we added the evidence gap score to the importance score and used the overall scores to identify research priorities to support ongoing TCV decision-making in India.Results We estimated the highest evidence priority scores for public perception of typhoid fever, vaccination budget impact, vaccine availability, socioeconomic impact, fiscal space, antimicrobial resistance tracking, typhoid fever mortality, public perception of TCV, immunisation managers’ acceptance and vaccine schedule preferences among caregivers.Conclusion By adapting WHO’s Evidence-to-Recommendation framework to the Indian context, we systematically identified several research priorities to support ongoing decision-making on TCV in India. These priorities will evolve as new research studies and questions emerge about the optimal scheduling, roll-out and implementation of TCV in India.

Abstract The spectrum of diseases caused by Streptococcus pyogenes (Strep A) ranges from superficial to serious life-threatening invasive infections. We conducted a scoping review of published articles between 1980 and 2021 to synthesize evidence of state transitions across the Strep A disease spectrum. We identified 175 articles reporting 262 distinct observations of Strep A disease state transitions. Among the included articles, the transition from an invasive or toxin-mediated disease state to another disease state (i.e., to recurrent ARF, RHD or death) was described 115 times (43.9% of all included transition pairs) while the transition to and from locally invasive category was the lowest (n = 7; 0.02%). Transitions from well to any other state was most frequently reported (49%) whereas a relatively higher number of studies (n = 71) reported transition from invasive disease to death. Transitions from any disease state to locally invasive, Strep A pharyngitis to invasive disease, and chronic kidney disease to death were lacking. Transitions related to severe invasive diseases were more frequently reported than superficial ones. Most evidence originated from high-income countries and there is a critical need for new studies in low- and middle-income countries to infer the state transitions across the Strep A disease spectrum in these high-burden settings.

Abstract Group A Streptococcus causes a wide range of diseases from relatively mild infections including pharyngitis to more severe illnesses such as invasive diseases and rheumatic heart disease (RHD). Our aim is to estimate the cost-effectiveness of a hypothetical Strep A vaccine on multiple disease manifestations at the global-level. Cost-effectiveness analyses were carried out by building on the potential epidemiological impact of vaccines that align with the WHO’s Preferred Product Characteristics for Strep A vaccines. Maximum vaccination costs for a cost-effective vaccination strategy were estimated at the thresholds of 1XGDP per capita and health opportunity costs. The maximum cost per fully vaccinated person for Strep A vaccination to be cost-effective was $385–$489 in high-income countries, $213–$312 in upper-income-income countries, $74–$132 in lower-middle-income countries, and $37–$69 in low-income countries for routine vaccination at birth and 5 years of age respectively. While the threshold costs are sensitive to vaccine characteristics such as efficacy, and waning immunity, a cost-effective Strep A vaccine will lower morbidity and mortality burden in all income settings.

BackgroundWith more than 1.2 million illnesses and 29,000 deaths in sub-Saharan Africa in 2017, typhoid fever continues to be a major public health problem. Effective control of the disease would benefit from an understanding of the subnational geospatial distribution of the disease incidence.MethodWe collated records of the incidence rate of typhoid fever confirmed by culture of blood in Africa from 2000 to 2022. We estimated the typhoid incidence rate for sub-Saharan Africa on 20 km × 20 km grids by exploring the association with geospatial covariates representing access to improved water and sanitation, health conditions of the population, and environmental conditions.ResultsWe identified six published articles and one pre-print representing incidence rate estimates in 22 sites in 2000-2022. Estimated incidence rates showed geospatial variation at sub-national, national, and regional levels. The incidence rate was high in Western and Eastern African subregions followed by Southern and Middle African subregions. By age, the incidence rate was highest among 5-14 yo followed by 2-4 yo, > 14 yo, and 0-1 yo. When aggregated across all age classes and grids that comprise each country, predicted incidence rates ranged from 43.7 (95% confidence interval: 0.6 to 591.2) in Zimbabwe to 2,957.8 (95% CI: 20.8 to 4,245.2) in South Sudan per 100,000 person-years. Sub-national heterogeneity was evident with the coefficient of variation at the 20 km × 20 km grid-level ranging from 0.7 to 3.3 and was generally lower in high-incidence countries and widely varying in low-incidence countries.ConclusionOur study provides estimates of 20 km × 20 km incidence rate of typhoid fever across sub-Saharan Africa based on data collected from 2000 through 2020. Increased understanding of the subnational geospatial variation of typhoid fever in Africa may inform more effective intervention programs by better targeting resources to heterogeneously disturbed disease risk.

Abstract Considering the lack of existing evidence on economic burden for diseases caused by group A Streptococcus, we estimated the economic burden per episode for selected diseases. Each cost component of direct medical costs (DMCs), direct non-medical costs (DNMCs), and indirect costs (ICs) was separately extrapolated and aggregated to estimate the economic burden per episode by income group as classified by the World Bank. Adjustment factors for DMC and DNMC were generated to overcome related data insufficiencies. To address uncertainty surrounding input parameters, a probabilistic multivariate sensitivity was carried out. The average economic burden per episode ranged from $22 to $392 for pharyngitis, $25 to $2,903 for impetigo, $47 to $2,725 for cellulitis, $662 to $34,330 for invasive and toxin-mediated infections, $231 to $6,332 for acute rheumatic fever (ARF), $449 to $11,717 for rheumatic heart disease (RHD), and $949 to $39,560 for severe RHD across income groups. The economic burden for multiple Group A Streptococcus diseases underscores an urgent need to develop effective prevention strategies including vaccines.

Abstract Background Differences in definitions and methodological approaches have hindered comparison and synthesis of economic evaluation results across multiple health domains, including immunization. At the request of the World Health Organization’s (WHO) Immunization and Vaccines-related Implementation Research Advisory Committee (IVIR-AC), WHO convened an ad hoc Vaccine Delivery Costing Working Group, comprising experts from eight organizations working in immunization costing, to address a lack of standardization and gaps in definitions and methodological guidance. The aim of the Working Group was to develop a consensus statement harmonizing terminology and principles and to formulate recommendations for vaccine delivery costing for decision making. This paper discusses the process, findings of the review, and recommendations in the Consensus Statement. Methods The Working Group conducted several interviews, teleconferences, and one in-person meeting to identify groups working in vaccine delivery costing as well as existing guidance documents and costing tools, focusing on those for low- and middle-income country settings. They then reviewed the costing aims, perspectives, terms, methods, and principles in these documents. Consensus statement principles were drafted to align with the Global Health Cost Consortium costing guide as an agreed normative reference, and consensus definitions were drafted to reflect the predominant view across the documents reviewed. Results The Working Group identified four major workstreams on vaccine delivery costing as well as nine guidance documents and eleven costing tools for immunization costing. They found that some terms and principles were commonly defined while others were specific to individual workstreams. Based on these findings and extensive consultation, recommendations to harmonize differences in terminology and principles were made. Conclusions Use of standardized principles and definitions outlined in the Consensus Statement within the immunization delivery costing community of practice can facilitate interpretation of economic evidence by global, regional, and national decision makers. Improving methodological alignment and clarity in program costing of health services such as immunization is important to support evidence-based policies and optimal resource allocation. On the other hand, this review and Consensus Statement development process revealed the limitations of our ability to harmonize given that study designs will vary depending upon the policy question that is being addressed and the country context.

A Measles-Rubella (MR) vaccination campaign was launched in India in a phased manner in February 2017 to cover children aged 9 months to 15 years. As evidence on campaign vaccine delivery costs is limited, the delivery cost for MR campaign from a government provider perspective was estimated in four Indian states, namely, Assam, Gujarat, Himachal Pradesh, and Uttar Pradesh. Costs were calculated in top-down and bottom-up approaches using data collected from 84 sites at different administrative levels and immunization partners in the study states from August 2019 to March 2020. All costs were presented in 2019 US$ and Indian Rupee (INR). The financial cost per dose of the MR campaign including all partner support ranged from US$0.16 (INR 10.95) in Uttar Pradesh to US$0.34 (INR 24.13) in Gujarat. In Uttar Pradesh, the full economic cost per dose was US$0.87 (INR 61.39). The key financial cost drivers were incentives related to service delivery and supervision, the printing of reporting formats for record-keeping, social mobilization, and advocacy. The financial delivery cost per dose estimated was higher than the government pre-fixed budget per child for the MR campaign, probably indicating an insufficient budget. However, the study found underutilization of MR budget in two states and use of other sources of funding for the campaign indicating the need for proper utilization of the campaign budgets by the states. Unit cost information generated from this study will be useful for planning, cost projections, and economic analysis of future vaccination campaigns in India.

Navi Mumbai Municipal Corporation (NMMC), a local government in Mumbai, India, implemented the first public sector TCV campaign in 2018. This study estimated the delivery costs of this TCV campaign using a Microsoft Excel-based tool based on a micro-costing approach from the government (NMMC) perspective. The campaign's financial (direct expenditures) and economic costs (financial costs plus the monetized value of additional donated or existing items) incremental to the existing immunization program were collected. The data collection methods involved consultations with NMMC staff, reviews of financial and programmatic records of NMMC and the World Health Organization (WHO), and interviews with the health staff of sampled urban health posts (UHPs). Three UHPs were purposively sampled, representing the three dominant residence types in the catchment area: high-rise, slum, and mixed (high-rise and slum) areas. The high-rise area UHP had lower vaccination coverage (47%) compared with the mixed area (71%) and slum area UHPs (76%). The financial cost of vaccine and vaccination supplies (syringes, safety boxes) was $1.87 per dose, and the economic cost was $2.96 per dose in 2018 US dollars. Excluding the vaccine and vaccination supplies cost, the financial delivery cost across the 3 UHPs ranged from $0.37 to $0.53 per dose, and the economic delivery cost ranged from $1.37 to $3.98 per dose, with the highest delivery costs per dose in the high-rise areas. Across all 11 UHPs included in the campaign, the weighted average financial delivery cost was $0.38 per dose, and the economic delivery cost was $1.49 per dose. WHO has recommended the programmatic use of TCV in typhoid-endemic countries, and Gavi has included TCV in its vaccine portfolio. This first costing study of large-scale TCV introduction within a public sector immunization program provides empirical evidence for policymakers, stakeholders, and future vaccine campaign planning.

Introduction Mozambique suffers from regular floods along its principal river basins and periodic cyclones that resulted in several cholera epidemics during the last decades. Cholera outbreaks in the recent 5 years affected particularly the northern provinces of the country including Nampula and Niassa provinces. A pre-emptive oral cholera vaccine (OCV) mass vaccination campaign was conducted in Cuamba District, Niassa Province, and the feasibility, costs, and vaccination coverage assessed.Methods WHO prequalified OCV (Euvichol-Plus), a killed whole-cell bivalent vaccine containing Vibrio cholerae O1 (classical and El Tor) and O139, was administered in two doses with a 15-day interval during 7–31 August 2018, targeting around 180 000 people aged above 1 year in Cuamba District. Microplanning, community sensitisation, and training of local public health professionals and field enumerators were conducted. Feasibility and costs of vaccination were assessed using CholTool. Vaccination coverage and barriers were assessed through community surveys.Results The administrative coverage of the first and second rounds of the campaign were 98.9% (194 581) and 98.8% (194 325), respectively, based on the available population data that estimated total 196 652 inhabitants in the target area. The vaccination coverage survey exhibited 75.9% (±2.2%) and 68.5% (±3.3%) coverage for the first and second rounds, respectively. Overall, 60.4% (±3.4%) of the target population received full two doses of OCV. Barriers to vaccination included incompatibility between working hours and campaign time. No severe adverse events were notified. The total financial cost per dose delivered was US$0.60 without vaccine cost and US$1.98 including vaccine costs.Conclusion The pre-emptive OCV mass vaccination campaign in remote setting in Mozambique was feasible with reasonable full-dose vaccination coverage to confer sufficient herd immunity for at least the next 3 to 5 years. The delivery cost estimate indicates that the OCV campaign is affordable as it is comparable with Gavi’s operational support for vaccination campaigns.

Abstract Background Invasive non-typhoidal Salmonella (iNTS) is a growing health-concern in many parts of sub-Saharan Africa. iNTS is associated with fatal diseases such as HIV and malaria. Despite high case fatality rates, the disease has not been given much attention. The limited number of population-based surveillance studies hampers accurate estimation of global disease burden. Given the lack of available evidence on the disease, it is critical to identify high risk areas for future surveillance and to improve our understanding of iNTS endemicity. Methods Considering that population-based surveillance data were sparse, a composite index called the iNTS risk factor (iNRF) index was constructed based on risk factors that commonly exist across countries. Four risk factors associated with the prevalence of iNTS were considered: malaria, HIV, malnutrition, and safe water. The iNRF index was first generated based on the four risk factors which were collected within a 50 km radius of existing surveillance sites. Pearson product-moment correlation was used to test statistical associations between the iNRF index and the prevalence of iNTS observed in the surveillance sites. The index was then further estimated at the subnational boundary level across selected countries and used to identify high risk areas for iNTS. Results While the iNRF index in some countries was generally low (i.e. Rwanda) or high (i.e. Cote d’Ivoire), the risk-level of iNTS was variable not only by country but also within a country. At the provincial-level, the highest risk area was identified in Maniema, the Democratic Republic of Congo, whereas Dakar in Senegal was at the lowest risk. Conclusions The iNRF index can be a useful tool to understand the geographically varying risk-level of iNTS. Given that conducting a population-based surveillance study requires extensive human and financial resources, identifying high risk areas for iNTS prior to a study implementation can facilitate an appropriate site-selection process in the future.

Abstract The World Health Organization (WHO) has articulated a priority pathogens list (PPL) to provide strategic direction to research and develop new antimicrobials. Antimicrobial resistance (AMR) patterns of WHO PPL in a tertiary health care facility in Southern India were explored to understand the local priority pathogens. Culture reports of laboratory specimens collected between 1st January 2014 and 31st October 2019 from paediatric patients were extracted. The antimicrobial susceptibility patterns for selected antimicrobials on the WHO PPL were analysed and reported. Of 12,256 culture specimens screened, 2335 (19%) showed culture positivity, of which 1556 (66.6%) were organisms from the WHO-PPL. E. coli was the most common organism isolated (37%), followed by Staphylococcus aureus (16%). Total of 72% of E. coli were extended-spectrum beta-lactamases (ESBL) producers, 55% of Enterobacteriaceae were resistant to 3rd generation cephalosporins due to ESBL, and 53% of Staph. aureus were Methicillin-resistant. The analysis showed AMR trends and prevalence patterns in the study setting and the WHO-PPL document are not fully comparable. This kind of local priority difference needs to be recognised in local policies and practices.

Cholera is both an endemic and epidemic disease in many low and middle-income countries (LMICs). Strategies for cholera control include improving water, sanitation, and hygiene; providing early and effective treatment; and deploying oral cholera vaccine (OCV). This last strategy is relatively new, and countries considering its introduction are interested in knowing the potential cost not only of the vaccine, but also the cost of introduction. This paper describes the costing of OCV introduction in LMICs using a publicly available Excel-based tool known as the CholTool. It includes estimates of delivery cost categories which cover not only the service delivery costs (e.g. vaccine procurement, handling, storage, and transport; vaccination administration, monitoring supervision, and field support), but also the programmatic costs associated with introducing a new vaccine (i.e. microplanning, communication and training materials development, sensitization/social mobilization, and personnel training) to ensure that a comprehensive estimate is provided with health payer perspective. CholTool takes the user through a structured sequence of interlinked modules containing input parameter cells (assumptions), decision cells (variable selections), and formulas (calculations) to produce customized cost estimates based on standardized methods. The tool provides both financial and economic cost estimates, to ensure that both costs are available for consideration. Four examples of applications of CholTool are presented in three countries- one in Ethiopia, two in Malawi and one in Nepal. The estimates of economic delivery cost per dose (including service delivery and programmatic costs) were (in USD 2016): $2.89 in Ethiopia, $3.04 in Malawi1, $3.35 in Malawi2 and $3.06 in Nepal. A cost projection conducted before the campaign using the tool and a retrospective costing using the tool in Nepal resulted in no significant difference between economic delivery costs per dose.

Cholera remains a public health threat among the least privileged populations and regions affected by conflicts and natural disasters. Together with Water, Sanitation and Hygiene practices, use of oral cholera vaccines (OCVs) is a key tool to prevent cholera. Bivalent whole-cell killed OCVs have been extensively used worldwide and found effective in protecting populations against cholera in endemic and outbreak settings. No cholera vaccine had been available for United States (US) travelers at risk for decades until 2016 when CVD 103-HgR (Vaxchora™), an oral live attenuated vaccine, was licensed by the US FDA. A single dose of Vaxchora™ protected US volunteers against experimental challenge 10 days and 3 months after vaccination. However, use of Vaxchora™ poses several challenges in resource poor settings as it requires reconstitution, is age-restricted to 18 to 64 years, has no data in populations endemic for cholera, and faces challenges related to cold chain and cost.

Objectives To estimate the economic burden of cholera in Africa.Settings Cholera affected 44 countries in Africa.Participants The analysis used data from public sources in Africa published until September 2019.Methods Based on existing data from field-based cost-of-illness studies, estimated cholera incidence rates, and reported cholera cases to WHO, this research estimates the economic burden of cholera in Africa from a societal perspective with 2015 as the base year. The estimate included out-of-pocket costs, public health system costs, productivity loss related to illness and an optional productivity loss related to premature deaths valued by the human capital approach. As various input data such as cholera incidence, hospitalisation rates and the number of workdays lost were not well defined, a series of scenario analyses and uncertainty analyses, accounting for unknowns and data variability, was conducted. Similarly, the value of time lost due to illness and deaths using the human capital approach was explored through scenario analyses.Results In 2015, an estimated 1 008 642 cases in 44 African countries resulted in an economic burden of US$130 million from cholera-related illness and its treatment. When the estimated 38 104 cholera deaths were included in the analysis, the economic burden increased to US$1 billion or international $2.4 billion for the same year. At the same time, when only the 71 126 cases and 937 deaths reported to the WHO are considered, the economic burden was only US$68 million for the year 2015. The estimates of economic burden are thus heavily dependent on the cholera incidence rate, how time lost due to illness and deaths are calculated, hospitalisation rates and hospitalisation costs.Conclusion The findings can be used as an economic justification for cholera control in Africa and for generating value-for-money evidence to underpin Ending Cholera—A Global Roadmap to 2030 with considerations to study limitations.

Background: Understanding the public health value of a vaccine at an early stage of development helps in valuing and prioritizing the investment needed. Here we present the potential cost-effectiveness of an upcoming 12 valent pneumococcal conjugate vaccine (PCV 12) in the case study country, Thailand. Methods: The cost-effectiveness analysis included a hypothetical scenario of three doses (2 + 1 regimen) PCV12 introduction in the national immunization program of Thailand compared to no PCV, PCV10, and PCV13 among

Shanchol™, a WHO-prequalified oral cholera vaccine (OCV), has been used to control endemic cholera in Asia, as well as in emergencies and outbreaks elsewhere. The vaccine has not been used by public health systems in cholera-endemic settings of Africa although several outbreak response campaigns have been conducted. Here we present experiences from a mass vaccination campaign in a cholera-endemic setting of Ethiopia in which Shanchol™ was introduced through the public health system. The vaccination site was selected based on cholera cases reported in previous years. Social mobilization involved sensitization of community leaders, household visits, and mass distribution of banners, posters and leaflets. The vaccination was implemented after careful microplanning of logistics and cold chain, manpower, transportation, vaccine supply and supervision and monitoring of adverse events. Vaccine administration was recorded on individual vaccination cards. Vaccine delivery costs were collected and analyzed after vaccination. As there was no experience with Shanchol™ in Ethiopia, a bridging trial was conducted to demonstrate safety and immunogenicity of the vaccine in the local population prior to the mass vaccination. Oral cholera vaccination was conducted in two rounds of four days each in February 2015 and March 2015 in 10 selected villages of Shashemenae rural district of Ethiopia. A total of 62,161 people targeted. 47,137 people (76%) received the first dose, and 40,707 (65%) received two doses. The financial cost of the vaccination campaign was estimated at US $2·60 per dose or US $5·64 per fully immunized person. The cost of vaccine delivery excluding vaccine procurement was $0·68 per dose or $1·48 per fully immunized person. The study demonstrates that mass cholera vaccination administered through the public health system in Ethiopia is feasible, can be implemented through the existing health system at an affordable cost, and the vaccine is acceptable to the community. The lessons from this study are useful for deploying OCV in other African endemic settings through the public health system and may guide future immunization policy decisions.

Up to 25% of hepatitis E virus (HEV)-infected pregnant women in their third trimester die. Despite HEV being an important cause of viral hepatitis, no robust surveillance exists in India. We reviewed jaundice outbreaks records and hospital records from jaundiced individuals seeking treatment and linked those records to laboratory results (HEV immunoglobulin M enzyme-linked immunosorbent assay) for January 2012 to September 2013 in Odisha state. A total of 14 HEV confirmed outbreaks were identified, of which 33% of 139 jaundiced cases were HEV positive. There were two deaths. An additional 495 jaundiced cases were identified through hospital records, of which 18% were HEV positive. Among HEV-positive women (n = 35), 34% were of childbearing age. While one may not be able to generalize our results, this finding suggests HE is widespread in Odisha and may represent hidden disease burden in this region. The policymakers should monitor HEV infections in similar geographical areas, especially among population of childbearing age women to initiate evidence-based control measures.

A Typhoid Conjugate Vaccine (TCV) is expected to acquire WHO prequalification soon, which will pave the way for its use in many low- and middle-income countries where typhoid fever is endemic. Thus it is critical to forecast future vaccine demand to ensure supply meets demand, and to facilitate vaccine policy and introduction planning. We forecasted introduction dates for countries based on specific criteria and estimated vaccine demand by year for defined vaccination strategies in 2 scenarios: rapid vaccine introduction and slow vaccine introduction. In the rapid introduction scenario, we forecasted 17 countries and India introducing TCV in the first 5 y of the vaccine's availability while in the slow introduction scenario we forecasted 4 countries and India introducing TCV in the same time period. If the vaccine is targeting infants in high-risk populations as a routine single dose, the vaccine demand peaks around 40 million doses per year under the rapid introduction scenario. Similarly, if the vaccine is targeting infants in the general population as a routine single dose, the vaccine demand increases to 160 million doses per year under the rapid introduction scenario. The demand forecast projected here is an upper bound estimate of vaccine demand, where actual demand depends on various factors such as country priorities, actual vaccine introduction, vaccination strategies, Gavi financing, costs, and overall product profile. Considering the potential role of TCV in typhoid control globally; manufacturers, policymakers, donors and financing bodies should work together to ensure vaccine access through sufficient production capacity, early WHO prequalification of the vaccine, continued Gavi financing and supportive policy.

Typhoid fever remains a significant health problem in sub-Saharan Africa, with incidence rates of >100 cases per 100,000 person-years of observation. Despite the prequalification of safe and effective typhoid conjugate vaccines (TCV), some uncertainties remain around future demand. Real-life effectiveness data, which inform public health programs on the impact of TCVs in reducing typhoid-related mortality and morbidity, from an African setting may help encourage the introduction of TCVs in high-burden settings. Here, we describe a cluster-randomized trial to investigate population-level protection of TYPBAR-TCV®, a Vi-polysaccharide conjugated to a tetanus-toxoid protein carrier (Vi-TT) against blood-culture-confirmed typhoid fever, and the synthesis of health economic evidence to inform policy decisions. A total of 80 geographically distinct clusters are delineated within the Agogo district of the Asante Akim region in Ghana. Clusters are randomized to the intervention arm receiving Vi-TT or a control arm receiving the meningococcal A conjugate vaccine. The primary study endpoint is the total protection of Vi-TT against blood-culture-confirmed typhoid fever. Total, direct, and indirect protection are measured as secondary outcomes. Blood-culture-based enhanced surveillance enables the estimation of incidence rates in the intervention and control clusters. Evaluation of the real-world impact of TCVs and evidence synthesis improve the uptake of prequalified/licensed safe and effective typhoid vaccines in public health programs of high burden settings. This trial is registered at the Pan African Clinical Trial Registry, accessible at Pan African Clinical Trials Registry (ID: PACTR202011804563392).

BACKGROUND:Dengue fever is a rapidly growing public health problem in many parts of the tropics and sub-tropics in the world. While there are existing studies on the economic burden of dengue fever in some of dengue-endemic countries, cost components are often not standardized, making cross-country comparisons challenging. Furthermore, no such studies have been available in Africa. METHODS/PRINCIPAL FINDINGS:A patient-specific survey questionnaire was developed and applied in Burkina Faso, Kenya, and Cambodia in a standardized format. Multiple interviews were carried out in order to capture the entire cost incurred during the period of dengue illness. Both private (patient's out-of-pocket) and public (non-private) expenditure were accessed to understand how the economic burden of dengue is distributed between private and non-private payers. A substantial number of dengue-confirmed patients were identified in all three countries: 414 in Burkina Faso, 149 in Kenya, and 254 in Cambodia. The average cost of illness for dengue fever was $26 (95% CI $23-$29) and $134 (95% CI $119-$152) per inpatient in Burkina Faso and Cambodia, respectively. In the case of outpatients, the average economic burden per episode was $13 (95% CI $23-$29) in Burkina Faso and $23 (95% CI $19-$28) in Kenya. Compared to Cambodia, public contributions were trivial in Burkina Faso and Kenya, reflecting that a majority of medical costs had to be directly borne by patients in the two countries. CONCLUSIONS/SIGNIFICANCE:The cost of illness for dengue fever is significant in the three countries. In particular, the current study sheds light on the potential economic burden of the disease in Burkina Faso and Kenya where existing evidence is sparse in the context of dengue fever, and underscores the need to achieve Universal Health Coverage. Given the availability of the current (CYD-TDV) and second-generation dengue vaccines in the near future, our study outcomes can be used to guide decision makers in setting health policy priorities.

Dengue fever is a major public health concern in many parts of the tropics and subtropics. The first dengue vaccine has already been licensed in six countries. Given the growing interests in the effective use of the vaccine, it is critical to understand the economic burden of dengue fever to guide decision-makers in setting health policy priorities.A standardized cost-of-illness study was conducted in three dengue endemic countries: Vietnam, Thailand, and Colombia. In order to capture all costs during the entire period of illness, patients were tested with rapid diagnostic tests on the first day of their clinical visits, and multiple interviews were scheduled until the patients recovered from the current illness. Various cost items were collected such as direct medical and non-medical costs, indirect costs, and non-out-of-pocket costs. In addition, socio-economic factors affecting disease severity were also identified by adopting a logit model. We found that total cost per episode ranges from $141 to $385 for inpatient and from $40 to $158 outpatient, with Colombia having the highest and Thailand having the lowest. The percentage of the private economic burden of dengue fever was highest in the low-income group and lowest in the high-income group. The logit analyses showed that early treatment, higher education, and better knowledge of dengue disease would reduce the probability of developing more severe illness.The cost of dengue fever is substantial in the three dengue endemic countries. Our study findings can be used to consider accelerated introduction of vaccines into the public and private sector programs and prioritize alternative health interventions among competing health problems. In addition, a community would be better off by propagating the socio-economic factors identified in this study, which may prevent its members from developing severe illness in the long run.

Abstract Objectives: To compare cost‐effectiveness of an asthma clinic that would provide education, promotion of self‐monitoring of symptoms, regular review of treatment by a medical practitioner and a written asthma action plan to current practice in Australia. Methods: A decision tree model was used to compare treatment and improved management using asthma clinics under three scenarios: 1) intervention reduces only emergency department visits; 2) in addition, it leads to a reduction in days out of role; and 3) it also reduces unplanned general practitioner visits and hospitalisations. Evidence from existing published studies was used for asthma incidence, duration, treatment practices and health seeking behaviours. Costs for one year were estimated based on an asthma clinic trial in Australia. Results: The estimated $274 million annual cost of asthma clinics is much greater than the potential cost savings of $11 million resulting from reduced emergency department visits, and an overall potential cost saving of $85 million resulting from decreased GP visits and hospitalisations. The incremental cost‐effective ratio (ICER) is $24,000 if a reduction in days out of role is quantified as a health benefit in estimating disability‐adjusted life years (DALY). If a potential $85 million in cost‐savings from decreased emergency department visits, GP visits and hospitalisation is taken into account, the ICER drops to $17,000 per DALY averted. Conclusions: An asthma clinic as an intervention for improving self‐management may be cost‐effective in Australia if multiple benefits can be achieved. Implications: A large‐scale asthma clinic trial and long‐term evaluation of benefits are necessary to obtain stronger evidence on the benefit of asthma clinic approach in Australia.

Cholera remains an important public health problem in many low- and middle-income countries. Vaccination has been recommended as a possible intervention for the prevention and control of cholera. Evidence, especially data on disease burden, cost-of-illness, delivery costs and cost-effectiveness to support a wider use of vaccine is still weak. This study aims at estimating the cost-of-illness of cholera to households and health facilities in Machinga and Zomba Districts, Malawi. A cross-sectional study using retrospectively collected cost data was undertaken in this investigation. One hundred patients were purposefully selected for the assessment of the household cost-of-illness and four cholera treatment centres and one health facility were selected for the assessment conducted in health facilities. Data collected for the assessment in households included direct and indirect costs borne by cholera patients and their families while only direct costs were considered for the assessment conducted in health facilities. Whenever possible, descriptive and regression analysis were used to assess difference in mean costs between groups of patients. The average costs to patients' households and health facilities for treating an episode of cholera amounted to US$65.6 and US$59.7 in 2016 for households and health facilities, respectively equivalent to international dollars (I$) 249.9 and 227.5 the same year. Costs incurred in treating a cholera episode were proportional to duration of hospital stay. Moreover, 52% of households used coping strategies to compensate for direct and indirect costs imposed by the disease. Both households and health facilities could avert significant treatment expenditures through a broader use of pre-emptive cholera vaccination. These findings have direct policy implications regarding priority investments for the prevention and control of cholera.

Use of the oral cholera vaccine (OCV) is a vital short-term strategy to control cholera in endemic areas with poor water and sanitation infrastructure. Identifying, estimating, and categorizing the delivery costs of OCV campaigns are useful in analyzing cost-effectiveness, understanding vaccine affordability, and in planning and decision making by program managers and policy makers.To review and re-estimate oral cholera vaccination program costs and propose a new standardized categorization that can help in collation, analysis, and comparison of delivery costs across countries.Peer reviewed publications listed in PubMed database, Google Scholar and World Health Organization (WHO) websites and unpublished data from organizations involved in oral cholera vaccination.The publications and reports containing oral cholera vaccination delivery costs, conducted in low- and middle-income countries based on World Bank Classification. Limits are humans and publication date before December 31st, 2014.No participants are involved, only costs are collected.Oral cholera vaccination and cost estimation.A systematic review was conducted using pre-defined inclusion and exclusion criteria. Cost items were categorized into four main cost groups: vaccination program preparation, vaccine administration, adverse events following immunization and vaccine procurement; the first three groups constituting the vaccine delivery costs. The costs were re-estimated in 2014 US dollars (US$) and in international dollar (I$).Ten studies were identified and included in the analysis. The vaccine delivery costs ranged from US$0.36 to US$ 6.32 (in US$2014) which was equivalent to I$ 0.99 to I$ 16.81 (in I$2014). The vaccine procurement costs ranged from US$ 0.29 to US$ 29.70 (in US$2014), which was equivalent to I$ 0.72 to I$ 78.96 (in I$2014). The delivery costs in routine immunization systems were lowest from US$ 0.36 (in US$2014) equivalent to I$ 0.99 (in I$2014).The reported cost categories are not standardized at collection point and may lead to misclassification. Costs for some OCV campaigns are not available and analysis does not include direct and indirect costs to vaccine recipients.Vaccine delivery cost estimation is needed for budgeting and economic analysis of vaccination programs. The cost categorization methodology presented in this study is helpful in collecting OCV delivery costs in a standardized manner, comparing delivery costs, planning vaccination campaigns and informing decision-making.

BACKGROUND:This review aimed to synthesize and analyze the diagnostic accuracy and the likelihood of providing correct treatment of the syndromic approach Vaginal Discharge Flowchart in managing cervical infections caused by Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT), and vaginal infections caused by Trichomonas vaginalis (TV) and Bacterial vaginosis (BV) and Candida albicans. This review will inform updating the WHO 2003 guidelines on Vaginal Discharge syndromic case management. METHODS:A systematic review was conducted on published studies from 01-01-2000 to 30-03-2015 in multiple databases. Studies evaluating the diagnostic accuracy and validation of the WHO Vaginal Discharge Flowchart were included. Validation parameters including sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) and the 95% confidence intervals for the different types of the flowchart were taken as outcomes, re-calculated, and analysed using a fixed model meta-analysis for data pooling. The level of agreement between the index and reference test were determined by the Cohen's Kappa co-efficiency test. Each individual study was assessed on quality using the QUADAS-2 tool. FINDINGS:The search yielded 2,845 studies of which 16 met the eligibility criteria for final analysis. The diagnostic performance to identify cervical infections was low and resulted in a high proportion of over and missed treatment. The four flowcharts had a sensitivity between 27.37% in history and risk assessment and 90.13% with microscopy, with the inverse in specificity rates. The treatment performances between the flowcharts were inconsistent. The same applies to the use of vaginal discharge flowchart for treating vaginal infections. For vaginal infections the vaginal discharge flowchart had a good performance in flowchart 3 with 91.68% of sensitivity; 99.97% specificity; 99.93% PPV and 0.02% who missed their treatment and 8.32% of women who were over treated by the vaginal discharge flowchart. CONCLUSION:The vaginal discharge flowchart should focus on management of vaginal infection. It could be used as an intermediate approach for cervical infections for sex workers until a point of care test is available in resource poor settings.

BACKGROUND:The rise in dengue fever cases and the absence of dengue vaccines will likely cause governments to consider various types of effective means for controlling the disease. Given strong public interests in potential dengue vaccines, it is essential to understand the private economic benefits of dengue vaccines for accelerated introduction of vaccines into the public sector program and private markets of high-risk countries. METHODOLOGY/PRINCIPAL FINDINGS:A contingent valuation study for a hypothetical dengue vaccine was administered to 400 households in a multi-country setting: Vietnam, Thailand, and Colombia. All respondents received a description of the hypothetical dengue vaccine scenarios of 70% or 95% effectiveness for 10 or 30 years with a three dose series. Five price points were determined after pilot tests in order to reflect different local situations such as household income levels and general perceptions towards dengue fever. We adopted either Poisson or negative binomial regression models to calculate average willingness-to-pay (WTP), as well as median WTP. We found that there is a significant demand for dengue vaccines. The parametric median WTP is $26.4 ($8.8 per dose) in Vietnam, $70.3 ($23.4 per dose) in Thailand, and $23 ($7.7 per dose) in Colombia. Our study also suggests that respondents place more value on vaccinating young children than school age children and adults. CONCLUSIONS/SIGNIFICANCE:Knowing that dengue vaccines are not yet available, our study provides critical information to both public and private sectors. The study results can be used to ensure broad coverage with an affordable price and incorporated into cost benefit analyses, which can inform prioritization of alternative health interventions at the national level.

BACKGROUND:Service provider costs for vaccine delivery have been well documented; however, vaccine recipients' costs have drawn less attention. This research explores the private household out-of-pocket and opportunity costs incurred to receive free oral cholera vaccine during a mass vaccination campaign in rural Odisha, India. METHODS:Following a government-driven oral cholera mass vaccination campaign targeting population over one year of age, a questionnaire-based cross-sectional survey was conducted to estimate private household costs among vaccine recipients. The questionnaire captured travel costs as well as time and wage loss for self and accompanying persons. The productivity loss was estimated using three methods: self-reported, government defined minimum daily wages and gross domestic product per capita in Odisha. FINDINGS:On average, families were located 282.7 (SD = 254.5) meters from the nearest vaccination booths. Most family members either walked or bicycled to the vaccination sites and spent on average 26.5 minutes on travel and 15.7 minutes on waiting. Depending upon the methodology, the estimated productivity loss due to potential foregone income ranged from $0.15 to $0.29 per dose of cholera vaccine received. The private household cost of receiving oral cholera vaccine constituted 24.6% to 38.0% of overall vaccine delivery costs. INTERPRETATION:The private household costs resulting from productivity loss for receiving a free oral cholera vaccine is a substantial proportion of overall vaccine delivery cost and may influence vaccine uptake. Policy makers and program managers need to recognize the importance of private costs and consider how to balance programmatic delivery costs with private household costs to receive vaccines.

The substantial morbidity and mortality associated with recent cholera outbreaks in Haiti and Zimbabwe, as well as with cholera endemicity in countries throughout Asia and Africa, make a compelling case for supplementary cholera control measures in addition to existing interventions. Clinical trials conducted in Kolkata, India, have led to World Health Organization (WHO)-prequalification of Shanchol, an oral cholera vaccine (OCV) with a demonstrated 65% efficacy at 5 years post-vaccination. However, before this vaccine is widely used in endemic areas or in areas at risk of outbreaks, as recommended by the WHO, policymakers will require empirical evidence on its implementation and delivery costs in public health programs. The objective of the present report is to describe the organization, vaccine coverage, and delivery costs of mass vaccination with a new, less expensive OCV (Shanchol) using existing public health infrastructure in Odisha, India, as a model.All healthy, non-pregnant residents aged 1 year and above residing in selected villages of the Satyabadi block (Puri district, Odisha, India) were invited to participate in a mass vaccination campaign using two doses of OCV. Prior to the campaign, a de jure census, micro-planning for vaccination and social mobilization activities were implemented. Vaccine coverage for each dose was ascertained as a percentage of the censused population. The direct vaccine delivery costs were estimated by reviewing project expenditure records and by interviewing key personnel.The mass vaccination was conducted during May and June, 2011, in two phases. In each phase, two vaccine doses were given 14 days apart. Sixty-two vaccination booths, staffed by 395 health workers/volunteers, were established in the community. For the censused population, 31,552 persons (61% of the target population) received the first dose and 23,751 (46%) of these completed their second dose, with a drop-out rate of 25% between the two doses. Higher coverage was observed among females and among 6-17 year-olds. Vaccine cost at market price (about US$1.85/dose) was the costliest item. The vaccine delivery cost was $0.49 per dose or $1.13 per fully vaccinated person.This is the first undertaken project to collect empirical evidence on the use of Shanchol within a mass vaccination campaign using existing public health program resources. Our findings suggest that mass vaccination is feasible but requires detailed micro-planning. The vaccine and delivery cost is affordable for resource poor countries. Given that the vaccine is now WHO pre-qualified, evidence from this study should encourage oral cholera vaccine use in countries where cholera remains a public health problem.

Typhoid fever remains a major health problem in the developing world. Intestinal perforation is a lethal complication and continues to occur in impoverished areas despite advances in preventive and therapeutic strategies.To estimate the case fatality rate (CFR) and length of hospital stay among patients with typhoid intestinal perforation in developing countries.Peer-reviewed publications listed in PubMed and Google Scholar.The publications containing data on CFR or length of hospitalization for typhoid fever from low, lower middle and upper middle income countries based on World Bank classification. Limits are English language, human research and publication date from 1st January 1991 to 31st December 2011.Subjects with reported typhoid intestinal perforation.None, standard practice as reported in the publication.Systematic literature review followed by meta-analysis after regional classification on primary data. Descriptive methods were applied on secondary data.From 42 published reports, a total of 4,626 hospitalized typhoid intestinal perforation cases and 706 deaths were recorded (CFR = 15·4%; 95% CI; 13·0%-17·8%) with a significant regional differences. The overall mean length of hospitalization for intestinal perforation from 23 studies was 18.4 days (N = 2,542; 95% CI; 15.6-21.1).Most typhoid intestinal perforation studies featured in this review were from a limited number of countries.The CFR estimated in this review is a substantial reduction from the 39.6% reported from a literature review for years 1960 to 1990. Aggressive resuscitation, appropriate antimicrobial coverage, and prompt surgical intervention may have contributed to decrease mortality.The quantification of intestinal perforation outcomes and its regional disparities as presented here is valuable in prioritizing and targeting typhoid-preventive interventions to the most affected areas.

IntroductionIn 2010, the World Health Organization released a new cholera vaccine position paper, which recommended the use of cholera vaccines in high-risk endemic areas. However, there is a paucity of data on the burden of cholera in endemic countries. This article reviewed available cholera surveillance data from Uganda and assessed the sufficiency of these data to inform country-specific strategies for cholera vaccination.MethodsThe Uganda Ministry of Health conducts cholera surveillance to guide cholera outbreak control activities. This includes reporting the number of cases based on a standardized clinical definition plus systematic laboratory testing of stool samples from suspected cases at the outset and conclusion of outbreaks. This retrospective study analyzes available data by district and by age to estimate incidence rates. Since surveillance activities focus on more severe hospitalized cases and deaths, a sensitivity analysis was conducted to estimate the number of non-severe cases and unrecognized deaths that may not have been captured.ResultsCholera affected all ages, but the geographic distribution of the disease was very heterogeneous in Uganda. We estimated that an average of about 11,000 cholera cases occurred in Uganda each year, which led to approximately 61-182 deaths. The majority of these cases (81%) occurred in a relatively small number of districts comprising just 24% of Uganda's total population. These districts included rural areas bordering the Democratic Republic of Congo, South Sudan, and Kenya as well as the slums of Kampala city. When outbreaks occurred, the average duration was about 15 weeks with a range of 4-44 weeks.DiscussionThere is a clear subdivision between high-risk and low-risk districts in Uganda. Vaccination efforts should be focused on the high-risk population. However, enhanced or sentinel surveillance activities should be undertaken to better quantify the endemic disease burden and high-risk populations prior to introducing the vaccine.