The cost and cost-effectiveness of novel tuberculosis vaccines in low- and middle-income countries: A modeling study.

BACKGROUND: Tuberculosis (TB) is preventable and curable but eliminating it has proven challenging. Safe and effective TB vaccines that can rapidly reduce disease burden are essential for achieving TB elimination. We assessed future costs, cost-savings, and cost-effectiveness of introducing novel TB vaccines in low- and middle-income countries (LMICs) for a range of product characteristics and delivery strategies. METHODS AND FINDINGS: We developed a system of epidemiological and economic models, calibrated to demographic, epidemiological, and health service data in 105 LMICs. For each country, we assessed the likely future course of TB-related outcomes under several vaccine introduction scenarios, compared to a "no-new-vaccine" counterfactual. Vaccine scenarios considered 2 vaccine product profiles (1 targeted at infants, 1 at adolescents/adults), both assumed to prevent progression to active TB. Key economic inputs were derived from the Global Health Cost Consortium, World Health Organization (WHO) patient cost surveys, and the published literature. We estimated the incremental impact of vaccine introduction for a range of health and economic outcomes. In the base-case, we assumed a vaccine price of $4.60 and used a 1× per-capita gross domestic product (GDP) cost-effectiveness threshold (both varied in sensitivity analyses). Vaccine introduction was estimated to require substantial near-term resources, offset by future cost-savings from averted TB burden. From a health system perspective, adolescent/adult vaccination was cost-effective in 64 of 105 LMICs. From a societal perspective (including productivity gains and averted patient costs), adolescent/adult vaccination was projected to be cost-effective in 73 of 105 LMICs and cost-saving in 58 of 105 LMICs, including 96% of countries with higher TB burden. When considering the monetized value of health gains, we estimated that introduction of an adolescent/adult vaccine could produce $283 to 474 billion in economic benefits by 2050. Limited data availability required assumptions and extrapolations that may omit important country-level heterogeneity in epidemiology and costs. CONCLUSIONS: TB vaccination would be highly impactful and cost-effective in most LMICs. Further efforts are needed for future development, adoption, and implementation of novel TB vaccines.

Direct estimates of absolute ventilation and estimated Mycobacterium tuberculosis transmission risk in clinics in South Africa.

Healthcare facilities are important sites for the transmission of pathogens spread via bioaerosols, such as Mycobacterium tuberculosis. Natural ventilation can play an important role in reducing this transmission. We aimed to measure rates of natural ventilation in clinics in KwaZulu-Natal and Western Cape provinces, South Africa, then use these measurements to estimate Mycobacterium tuberculosis transmission risk. We measured ventilation in clinic spaces using a tracer-gas release method. In spaces where this was not possible, we estimated ventilation using data on indoor and outdoor carbon dioxide levels. Ventilation was measured i) under usual conditions and ii) with all windows and doors fully open. Under various assumptions about infectiousness and duration of exposure, measured absolute ventilation rates were related to risk of Mycobacterium tuberculosis transmission using the Wells-Riley Equation. In 2019, we obtained ventilation measurements in 33 clinical spaces in 10 clinics: 13 consultation rooms, 16 waiting areas and 4 other clinical spaces. Under usual conditions, the absolute ventilation rate was much higher in waiting rooms (median 1769 m3/hr, range 338-4815 m3/hr) than in consultation rooms (median 197 m3/hr, range 0-1451 m3/hr). When compared with usual conditions, fully opening existing doors and windows resulted in a median two-fold increase in ventilation. Using standard assumptions about infectiousness, we estimated that a health worker would have a 24.8% annual risk of becoming infected with Mycobacterium tuberculosis, and that a patient would have an 0.1% risk of becoming infected per visit. Opening existing doors and windows and rearranging patient pathways to preferentially use better ventilated clinic spaces result in important reductions in Mycobacterium tuberculosis transmission risk. However, unless combined with other tuberculosis infection prevention and control interventions, these changes are insufficient to reduce risk to health workers, and other highly exposed individuals, to acceptable levels.

Modelling the effect of infection prevention and control measures on rate of Mycobacterium tuberculosis transmission to clinic attendees in primary health clinics in South Africa.

BACKGROUND: Elevated rates of tuberculosis in healthcare workers demonstrate the high rate of Mycobacterium tuberculosis (Mtb) transmission in health facilities in high-burden settings. In the context of a project taking a whole systems approach to tuberculosis infection prevention and control (IPC), we aimed to evaluate the potential impact of conventional and novel IPC measures on Mtb transmission to patients and other clinic attendees. METHODS: An individual-based model of patient movements through clinics, ventilation in waiting areas, and Mtb transmission was developed, and parameterised using empirical data from eight clinics in two provinces in South Africa. Seven interventions-codeveloped with health professionals and policy-makers-were simulated: (1) queue management systems with outdoor waiting areas, (2) ultraviolet germicidal irradiation (UVGI) systems, (3) appointment systems, (4) opening windows and doors, (5) surgical mask wearing by clinic attendees, (6) simple clinic retrofits and (7) increased coverage of long antiretroviral therapy prescriptions and community medicine collection points through the Central Chronic Medicine Dispensing and Distribution (CCMDD) service. RESULTS: In the model, (1) outdoor waiting areas reduced the transmission to clinic attendees by 83% (IQR 76%-88%), (2) UVGI by 77% (IQR 64%-85%), (3) appointment systems by 62% (IQR 45%-75%), (4) opening windows and doors by 55% (IQR 25%-72%), (5) masks by 47% (IQR 42%-50%), (6) clinic retrofits by 45% (IQR 16%-64%) and (7) increasing the coverage of CCMDD by 22% (IQR 12%-32%). CONCLUSIONS: The majority of the interventions achieved median reductions in the rate of transmission to clinic attendees of at least 45%, meaning that a range of highly effective intervention options are available, that can be tailored to the local context. Measures that are not traditionally considered to be IPC interventions, such as appointment systems, may be as effective as more traditional IPC measures, such as mask wearing.

Estimating ventilation rates in rooms with varying occupancy levels: Relevance for reducing transmission risk of airborne pathogens.

BACKGROUND: In light of the role that airborne transmission plays in the spread of SARS-CoV-2, as well as the ongoing high global mortality from well-known airborne diseases such as tuberculosis and measles, there is an urgent need for practical ways of identifying congregate spaces where low ventilation levels contribute to high transmission risk. Poorly ventilated clinic spaces in particular may be high risk, due to the presence of both infectious and susceptible people. While relatively simple approaches to estimating ventilation rates exist, the approaches most frequently used in epidemiology cannot be used where occupancy varies, and so cannot be reliably applied in many of the types of spaces where they are most needed. METHODS: The aim of this study was to demonstrate the use of a non-steady state method to estimate the absolute ventilation rate, which can be applied in rooms where occupancy levels vary. We used data from a room in a primary healthcare clinic in a high TB and HIV prevalence setting, comprising indoor and outdoor carbon dioxide measurements and head counts (by age), taken over time. Two approaches were compared: approach 1 using a simple linear regression model and approach 2 using an ordinary differential equation model. RESULTS: The absolute ventilation rate, Q, using approach 1 was 2407 l/s [95% CI: 1632-3181] and Q from approach 2 was 2743 l/s [95% CI: 2139-4429]. CONCLUSIONS: We demonstrate two methods that can be used to estimate ventilation rate in busy congregate settings, such as clinic waiting rooms. Both approaches produced comparable results, however the simple linear regression method has the advantage of not requiring room volume measurements. These methods can be used to identify poorly-ventilated spaces, allowing measures to be taken to reduce the airborne transmission of pathogens such as Mycobacterium tuberculosis, measles, and SARS-CoV-2.

Associations between infection intensity categories and morbidity prevalence in school-age children are much stronger for Schistosoma haematobium than for S. mansoni.

BACKGROUND: World Health Organization (WHO) guidelines for measuring global progress in schistosomiasis control classify individuals with Schistosoma spp. infections based on the concentration of excreted eggs. We assessed the associations between WHO infection intensity categories and morbidity prevalence for selected S. haematobium and S. mansoni morbidities in school-age children. METHODOLOGY: A total of 22,488 children aged 6-15 years from monitoring and evaluation cohorts in Burkina Faso, Mali, Niger, Uganda, Tanzania, and Zambia from 2003-2008 were analyzed using Bayesian logistic regression. Models were utilized to evaluate associations between intensity categories and the prevalence of any urinary bladder lesion, any upper urinary tract lesion, microhematuria, and pain while urinating (for S. haematobium) and irregular hepatic ultrasound image pattern (C-F), enlarged portal vein, laboratory-confirmed diarrhea, and self-reported diarrhea (for S. mansoni) across participants with infection and morbidity data. PRINCIPAL FINDINGS: S. haematobium infection intensity categories possessed consistent morbidity prevalence across surveys for multiple morbidities and participants with light infections had elevated morbidity levels, compared to negative participants. Conversely, S. mansoni infection intensity categories lacked association with prevalence of the morbidity measures assessed. CONCLUSIONS/SIGNIFICANCE: Current status infection intensity categories for S. haematobium were associated with morbidity levels in school-age children, suggesting urogenital schistosomiasis morbidity can be predicted by an individual's intensity category. Conversely, S. mansoni infection intensity categories were not consistently indicative of childhood morbidity at baseline or during the first two years of a preventive chemotherapy control program.

Schistosomiasis - Assessing Progress toward the 2020 and 2025 Global Goals.

BACKGROUND: With the vision of "a world free of schistosomiasis," the World Health Organization (WHO) set ambitious goals of control of this debilitating disease and its elimination as a public health problem by 2020 and 2025, respectively. As these milestones become imminent, and if programs are to succeed, it is important to evaluate the WHO programmatic guidelines empirically. METHODS: We collated and analyzed multiyear cross-sectional data from nine national schistosomiasis control programs (in eight countries in sub-Saharan Africa and in Yemen). Data were analyzed according to schistosome species (Schistosoma mansoni or S. haematobium), number of treatment rounds, overall prevalence, and prevalence of heavy-intensity infection. Disease control was defined as a prevalence of heavy-intensity infection of less than 5% aggregated across sentinel sites, and the elimination target was defined as a prevalence of heavy-intensity infection of less than 1% in all sentinel sites. Heavy-intensity infection was defined as at least 400 eggs per gram of feces for S. mansoni infection or as more than 50 eggs per 10 ml of urine for S. haematobium infection. RESULTS: All but one country program (Niger) reached the disease-control target by two treatment rounds or less, which is earlier than projected by current WHO guidelines (5 to 10 years). Programs in areas with low endemicity levels at baseline were more likely to reach both the control and elimination targets than were programs in areas with moderate and high endemicity levels at baseline, although the elimination target was reached only for S. mansoni infection (in Burkina Faso, Burundi, and Rwanda within three treatment rounds). Intracountry variation was evident in the relationships between overall prevalence and heavy-intensity infection (stratified according to treatment rounds), a finding that highlights the challenges of using one metric to define control or elimination across all epidemiologic settings. CONCLUSIONS: These data suggest the need to reevaluate progress and treatment strategies in national schistosomiasis control programs more frequently, with local epidemiologic data taken into consideration, in order to determine the treatment effect and appropriate resource allocations and move closer to achieving the global goals. (Funded by the Children's Investment Fund Foundation and others.).

Evaluating the variation in the projected benefit of community-wide mass treatment for schistosomiasis: Implications for future economic evaluations.

BACKGROUND: The majority of schistosomiasis control programmes focus on targeting school-aged children. Expanding the use of community-wide mass treatment to reach more adults is under consideration. However, it should be noted that this would require a further increase in programmatic resources, international aid, and commitment for the provision of praziquantel. Consequently, it is important to understand (i) where a change of strategy would have the greatest benefit, and (ii) how generalisable the conclusions of field trials and analytical studies based on mathematical models investigating the impact of community-wide mass treatment, are to a broad range of settings. METHODS: In this paper, we employ a previously described deterministic fully age-structured schistosomiasis transmission model and evaluate the benefit of community-wide mass treatment both in terms of controlling morbidity and eliminating transmission for Schistosoma mansoni, across a wide range of epidemiological settings and programmatic scenarios. This included variation in the baseline relative worm pre-control burden in adults, the overall level of transmission in defined settings, choice of effectiveness metric (basing morbidity calculations on prevalence or intensity), the level of school enrolment and treatment compliance. RESULTS: Community-wide mass treatment was found to be more effective for controlling the transmission of schistosome parasites than using a school-based programme only targeting school-aged children. However, in the context of morbidity control, the potential benefit of switching to community-wide mass treatment was highly variable across the different scenarios analysed. In contrast, for areas where the goal is to eliminate transmission, the projected benefit of community-wide mass treatment was more consistent. CONCLUSION: Whether community-wide mass treatment is appropriate will depend on the local epidemiological setting (i.e. the relative pre-control burden in adults and transmission intensity), and whether the goal is morbidity control or eliminating transmission. This has important implications regarding the generalisability of cost-effectiveness analyses of schistosomiasis interventions. Our results indicate that areas with poor school-enrolment/coverage could benefit more from community-wide treatment of praziquantel and should potentially be prioritised for any change in strategy. This work highlights the importance of not over-generalising conclusions and policy in this area, but of basing decisions on high quality epidemiological data and quantitative analyses of the impact of interventions in a range of settings.