Modelling the relative cost-effectiveness of the RTS,S/AS01 malaria vaccine compared to investment in vector control or chemoprophylaxis.

BACKGROUND: The World Health Organization has recommended a 4-dose schedule of the RTS,S/AS01 (RTS,S) vaccine for children in regions of moderate to high P. falciparum transmission. Faced with limited supply and finite resources, global funders and domestic malaria control programs will need to examine the relative cost-effectiveness of RTS,S and identify target areas for vaccine implementation relative to scale-up of existing interventions. METHODS: Using an individual-based mathematical model of P. falciparum, we modelled the cost-effectiveness of RTS,S across a range of settings in sub-Saharan Africa, incorporating various rainfall patterns, insecticide-treated net (ITN) use, treatment coverage, and parasite prevalence bands. We compare age-based and seasonal RTS,S administration to increasing ITN usage, switching to next generation ITNs in settings experiencing insecticide-resistance, and introduction of seasonal malaria chemoprevention (SMC) in areas of seasonal transmission. RESULTS: For RTS,S to be the most cost-effective intervention option considered, the maximum cost per dose was less than $9.30 USD in 90.9% of scenarios. Nearly all (89.8%) values at or above $9.30 USD per dose were in settings with 60% established bed net use and / or with established SMC, and 76.3% were in the highest PfPR2-10 band modelled (40%). Addition of RTS,S to strategies involving 60% ITN use, increased ITN usage or a switch to PBO nets, and SMC, if eligible, still led to significant marginal case reductions, with a median of 2,653 (IQR: 1,741 to 3,966) cases averted per 100,000 people annually, and 82,270 (IQR: 54,034 to 123,105) cases averted per 100,000 fully vaccinated children (receiving at least three doses). CONCLUSIONS: Use of RTS,S results in reductions in malaria cases and deaths even when layered upon existing interventions. When comparing relative cost-effectiveness, scale up of ITNs, introduction of SMC, and switching to new technology nets should be prioritized in eligible settings.

Projected health impact of post-discharge malaria chemoprevention among children with severe malarial anaemia in Africa.

Children recovering from severe malarial anaemia (SMA) remain at high risk of readmission and death after discharge from hospital. However, a recent trial found that post-discharge malaria chemoprevention (PDMC) with dihydroartemisinin-piperaquine reduces this risk. We developed a mathematical model describing the daily incidence of uncomplicated and severe malaria requiring readmission among 0-5-year old children after hospitalised SMA. We fitted the model to a multicentre clinical PDMC trial using Bayesian methods and modelled the potential impact of PDMC across malaria-endemic African countries. In the 20 highest-burden countries, we estimate that only 2-5 children need to be given PDMC to prevent one hospitalised malaria episode, and less than 100 to prevent one death. If all hospitalised SMA cases access PDMC in moderate-to-high transmission areas, 38,600 (range 16,900-88,400) malaria-associated readmissions could be prevented annually, depending on access to hospital care. We estimate that recurrent SMA post-discharge constitutes 19% of all SMA episodes in moderate-to-high transmission settings.

Seasonal use case for the RTS,S/AS01 malaria vaccine: a mathematical modelling study.

BACKGROUND: A 2021 clinical trial of seasonal RTS,S/AS01E (RTS,S) vaccination showed that vaccination was non-inferior to seasonal malaria chemoprevention (SMC) in preventing clinical malaria. The combination of these two interventions provided significant additional protection against clinical and severe malaria outcomes. Projections of the effect of this novel approach to RTS,S vaccination in seasonal transmission settings for extended timeframes and across a range of epidemiological settings are needed to inform policy recommendations. METHODS: We used a mathematical, individual-based model of malaria transmission that was fitted to data on the relationship between entomological inoculation rate and parasite prevalence, clinical disease, severe disease, and deaths from multiple sites across Africa. The model was validated with results from a phase 3b trial assessing the effect of SV-RTS,S in Mali and Burkina Faso. We developed three intervention efficacy models with varying degrees and durations of protection for our population-level modelling analysis to assess the potential effect of an RTS,S vaccination schedule based on age (doses were delivered to children aged 6 months, 7·5 months, and 9 months for the first three doses, and at 27 months of age for the fourth dose) or season (children aged 5-17 months at the time of first vaccination received the first three doses in the 3 months preceding the transmission season, with any subsequent doses up to five doses delivered annually) in seasonal transmission settings both in the absence and presence of SMC with sulfadoxine-pyrimethamine plus amodiaquine. This is modelled as a full therapeutic course delivered every month for four or five months of the peak in transmission season. Estimates of cases and deaths averted in a population of 100 000 children aged 0-5 years were calculated over a 15-year time period for a range of levels of malaria transmission intensity (Plasmodium falciparum parasite prevalence in children aged 2-10 years between 10% and 65%) and over two west Africa seasonality archetypes. FINDINGS: Seasonally targeting RTS,S resulted in greater absolute reductions in malaria cases and deaths compared with an age-based strategy, averting an additional 14 000-47 000 cases per 100 000 children aged 5 years and younger over 15 years, dependent on seasonality and transmission intensity. We predicted that adding seasonally targeted RTS,S to SMC would reduce clinical incidence by up to an additional 42 000-67 000 cases per 100 000 children aged 5 years and younger over 15 years compared with SMC alone. Transmission season duration was a key determinant of intervention effect, with the advantage of adding RTS,S to SMC predicted to be smaller with shorter transmission seasons. INTERPRETATION: RTS,S vaccination in seasonal settings could be a valuable additional tool to existing interventions, with seasonal delivery maximising the effect relative to an age-based approach. Decisions surrounding deployment strategies of RTS,S in such settings will need to consider the local and regional variations in seasonality, current rates of other interventions, and potential achievable RTS,S coverage. FUNDING: UK Medical Research Council, UK Foreign Commonwealth & Development Office, The Wellcome Trust, and The Royal society.

Global variation in force-of-infection trends for human Taenia solium taeniasis/cysticercosis.

Infection by Taenia solium poses a major burden across endemic countries. The World Health Organization (WHO) 2021-2030 Neglected Tropical Diseases roadmap has proposed that 30% of endemic countries achieve intensified T. solium control in hyperendemic areas by 2030. Understanding geographical variation in age-prevalence profiles and force-of-infection (FoI) estimates will inform intervention designs across settings. Human taeniasis (HTT) and human cysticercosis (HCC) age-prevalence data from 16 studies in Latin America, Africa, and Asia were extracted through a systematic review. Catalytic models, incorporating diagnostic performance uncertainty, were fitted to the data using Bayesian methods, to estimate rates of antibody (Ab)-seroconversion, infection acquisition and Ab-seroreversion or infection loss. HCC FoI and Ab-seroreversion rates were also estimated across 23 departments in Colombia from 28,100 individuals. Across settings, there was extensive variation in all-ages seroprevalence. Evidence for Ab-seroreversion or infection loss was found in most settings for both HTT and HCC and for HCC Ab-seroreversion in Colombia. The average duration until humans became Ab-seropositive/infected decreased as all-age (sero)prevalence increased. There was no clear relationship between the average duration humans remain Ab-seropositive and all-age seroprevalence. Marked geographical heterogeneity in T. solium transmission rates indicate the need for setting-specific intervention strategies to achieve the WHO goals.

Taenia solium taeniasis/cysticercosis: From parasite biology and immunology to diagnosis and control.

Infection with the pork tapeworm (Taenia solium) is responsible for a substantial global burden of disease, not only restricted to its impact on human health, but also resulting in a considerable economic burden to smallholder pig farmers due to pig cysticercosis infection. The life-cycle, parasitology and immunology of T. solium are complex, involving pigs (the intermediate host, harbouring the larval metacestode stage), humans (the definitive host, harbouring the adult tapeworm, in addition to acting as accidental intermediate hosts) and the environment (the source of infection with eggs/proglottids). We review the parasitology, immunology, and epidemiology of the infection associated with each of the T. solium life-cycle stages, including the pre-adult/adult tapeworm responsible for human taeniasis; post-oncosphere and cysticercus associated with porcine and human cysticercosis, and the biological characteristics of eggs in the environment. We discuss the burden associated, in endemic settings, with neurocysticercosis (NCC) in humans, and the broader cross-sectoral economic impact associated both with NCC and porcine cysticercosis, the latter impacting food-value chains. Existing tools for diagnostics and control interventions that target different stages of the T. solium transmission cycle are reviewed and their limitations discussed. Currently, no national T. solium control programmes have been established in endemic areas, with further work required to identify optimal strategies according to epidemiological setting. There is increasing evidence suggesting that cross-sectoral interventions which target the parasite in both the human and pig host provide the most effective approaches for achieving control and ultimately elimination. We discuss future avenues for research on T. solium to support the attainment of the goals proposed in the revised World Health Organisation neglected tropical diseases roadmap for 2021-2030 adopted at the 73rd World Health Assembly in November 2020.

Seasonal malaria chemoprevention in the Sahel subregion of Africa: a cost-effectiveness and cost-savings analysis.

BACKGROUND: The intermittent administration of seasonal malaria chemoprevention (SMC) is recommended to prevent malaria among children aged 3-59 months in areas of the Sahel subregion in Africa. However, the cost-effectiveness and cost savings of SMC have not previously been evaluated in large-scale studies. METHODS: We did a cost-effectiveness and cost-savings analysis of a large-scale, multi-country SMC campaign with sulfadoxine-pyrimethamine plus amodiaquine for children younger than 5 years in seven countries in the Sahel subregion (Burkina Faso, Chad, Guinea, Mali, Niger, Nigeria, and The Gambia) in 2016. The financial and economic costs were analysed from the programmatic perspective and are reported in 2016 US$ for each country. The estimated numbers of averted malaria cases, deaths, and disability-adjusted life-years (DALYs) were based on numbers of SMC treatments administered and modelled malaria transmission. Cost savings were calculated from a programmatic perspective corresponding to the diagnostic and treatment costs for malaria cases averted. FINDINGS: The total cost of SMC for all seven countries was $22·8 million, and the weighted average economic cost of administering four monthly SMC cycles was $3·63 per child (ranging from $2·71 in Niger to $8·20 in The Gambia). Based on 80% modelled effectiveness of SMC, the incremental economic cost per malaria case averted ranged from $2·91 in Niger to $30·73 in The Gambia; the cost per severe case averted ranged from $119·63 in Niger to $506·00 in The Gambia; the cost per death averted ranged from $533·56 in Niger to $2256·92 in The Gambia; and the cost per DALY averted (discounted by 3%) ranged from $18·66 in Niger to $78·91 in The Gambia. The estimated total economic cost savings to the health systems in all seven countries were US$66·0 million and the total net economic cost savings were US$43·2 million. INTERPRETATION: SMC is a low-cost and highly cost-effective intervention that contributes to substantial cost savings by reducing malaria diagnostic and treatment costs among children. FUNDING: Unitaid.

Force-of-infection of Taenia solium porcine cysticercosis: a modelling analysis to assess global incidence and prevalence trends.

The World Health Organization (WHO) called, in 2012, for a validated strategy towards Taenia solium taeniasis/cysticercosis control and elimination. Estimating pig force-of-infection (FoI, the average rate at which susceptible pigs become infected) across geographical settings will help understand local epidemiology and inform effective intervention design. Porcine cysticercosis (PCC) age-prevalence data (from 15 studies in Latin America, Africa and Asia) were identified through systematic review. Catalytic models were fitted to the data using Bayesian methods, incorporating uncertainty in diagnostic performance, to estimate rates of antibody seroconversion, viable metacestode acquisition, and seroreversion/infection loss. There was evidence of antibody seroreversion across 5 studies, and of infection loss in 6 studies measured by antigen or necropsy, indicating transient serological responses and natural resolution of infection. Concerted efforts should be made to collect robust data using improved diagnostics to better understand geographical heterogeneities in T. solium transmission to support post-2020 WHO targets.

Modelling for Taenia solium control strategies beyond 2020.

The cestode Taenia solium is responsible for a considerable cross-sectoral health and economic burden due to human neurocysticercosis and porcine cysticercosis. The 2012 World Health Organization (WHO) roadmap for neglected tropical diseases called for the development of a validated strategy for control of T. solium; however, such a strategy is not yet available. In 2019, WHO launched a global consultation aimed at refining the post-2020 targets for control of T. solium for a new roadmap for neglected tropical diseases. In response, two groups working on taeniasis and cysticercosis mathematical models (cystiSim and EPICYST models), together with a range of other stakeholders organized a workshop to provide technical input to the WHO consultation and develop a research plan to support efforts to achieve the post-2020 targets. The workshop led to the formation of a collaboration, CystiTeam, which aims to tackle the population biology, transmission dynamics, epidemiology and control of T. solium through mathematical modelling approaches. In this paper, we outline developments in T. solium control and in particular the use of modelling to help achieve post-2020 targets for control of T. solium. We discuss the steps involved in improving confidence in the predictive capacities of existing mathematical and computational models on T. solium transmission, including model comparison, refinement, calibration and validation. Expanding the CystiTeam partnership to other research groups and stakeholders, particularly those operating in different geographical and endemic areas, will enhance the prospects of improving the applicability of T. solium transmission models to inform taeniasis and cysticercosis control strategies.

Taenia solium est un cestode qui entraîne une charge intersectorielle économique et sanitaire considérable en provoquant une neurocysticercose humaine et une cysticercose porcine. La feuille de route sur les maladies tropicales négligées, publiée en 2012 par l'Organisation mondiale de la Santé (OMS), appelait à développer une stratégie de contrôle validée pour T. solium ; cependant, cette stratégie n'est pas encore disponible à l'heure actuelle. En 2019, l'OMS a lancé une procédure de consultation mondiale visant à préciser les objectifs de contrôle de T. solium après 2020, afin de rédiger une nouvelle feuille de route sur les maladies tropicales négligées. Deux groupes qui travaillent sur des modèles mathématiques de taeniasis et cysticercose (modèles cystiSim et EPICYST) ainsi qu'une série d'autres intervenants ont donc organisé un atelier pour fournir une contribution technique à cette consultation et développer un programme de recherche destiné à soutenir les efforts de réalisation des objectifs ultérieurs à 2020. L'atelier a donné naissance à une collaboration, CystiTeam, qui s'intéresse à la biologie des populations, à la dynamique de transmission, à l'épidémiologie et au contrôle de T. solium en employant des méthodes de modélisation mathématique. Le présent document retrace l'évolution du contrôle de T. solium, en particulier l'usage de la modélisation pour contribuer à atteindre les objectifs d'après 2020 en la matière. Nous abordons les diverses étapes de renforcement de la confiance accordée aux capacités prédictives des modèles mathématiques et informatiques existants sur la transmission de T. solium, notamment la comparaison, l'optimisation, le calibrage et la validation des modèles. Élargir le partenariat CystiTeam en intégrant d'autres groupes de recherche et intervenants, surtout ceux opérant dans différentes zones géographiques et endémiques, accroîtra les chances d'amélioration de l'applicabilité pour les modèles de transmission de T. solium, et permettra ainsi d'établir des stratégies de lutte contre la taeniasis et la cysticercose.

El cestodo Taenia solium es responsable de una importante carga sanitaria y económica transversal debido a la neurocisticercosis humana y la cisticercosis porcina. En la hoja de ruta de la Organización Mundial de la Salud (OMS) de 2012 sobre las enfermedades tropicales desatendidas se solicitaba la elaboración de una estrategia validada para el control de T. solium; sin embargo, dicha estrategia aún no está disponible. En 2019, la OMS inició una consulta mundial destinada a perfeccionar los objetivos de control de T. solium aplicables a partir de 2020 con miras a elaborar una hoja de ruta nueva sobre las enfermedades tropicales desatendidas. Consecuentemente, dos grupos que trabajan en modelos matemáticos de teniasis y cisticercosis (modelos cystiSim y EPICYST), junto con un grupo de otros interesados, organizaron un seminario para contribuir técnicamente a la consulta de la OMS y elaborar un plan de investigación a fin de apoyar los esfuerzos para lograr los objetivos a partir de 2020. El seminario impulsó la formación de un equipo de colaboración, CystiTeam, para abordar la biología de la población, la dinámica de la transmisión, la epidemiología y el control de T. solium mediante enfoques de modelos matemáticos. En el presente documento se describen las novedades en el control de T. solium y, en particular, la aplicación de modelos para ayudar a lograr los objetivos a partir de 2020 sobre el control de T. solium. Se analizan las etapas necesarias para mejorar la confianza en las capacidades de predicción de los modelos matemáticos y computacionales existentes sobre la transmisión de T. solium, incluyendo la comparación, el perfeccionamiento, el ajuste y la validación de los modelos. La ampliación de la asociación CystiTeam a otros grupos de investigación e interesados, en particular los que operan en diferentes zonas geográficas y endémicas, reforzará las perspectivas de mejorar la aplicabilidad de los modelos sobre las transmisión de T. solium para fundamentar las estrategias de control de la teniasis y la cisticercosis.

Strategies for tackling Taenia solium taeniosis/cysticercosis: A systematic review and comparison of transmission models, including an assessment of the wider Taeniidae family transmission models.

BACKGROUND: The cestode Taenia solium causes the neglected (zoonotic) tropical disease cysticercosis, a leading cause of preventable epilepsy in endemic low and middle-income countries. Transmission models can inform current scaling-up of control efforts by helping to identify, validate and optimise control and elimination strategies as proposed by the World Health Organization (WHO). METHODOLOGY/PRINCIPAL FINDINGS: A systematic literature search was conducted using the PRISMA approach to identify and compare existing T. solium transmission models, and related Taeniidae infection transmission models. In total, 28 modelling papers were identified, of which four modelled T. solium exclusively. Different modelling approaches for T. solium included deterministic, Reed-Frost, individual-based, decision-tree, and conceptual frameworks. Simulated interventions across models agreed on the importance of coverage for impactful effectiveness to be achieved. Other Taeniidae infection transmission models comprised force-of-infection (FoI), population-based (mainly Echinococcus granulosus) and individual-based (mainly E. multilocularis) modelling approaches. Spatial structure has also been incorporated (E. multilocularis and Taenia ovis) in recognition of spatial aggregation of parasite eggs in the environment and movement of wild animal host populations. CONCLUSIONS/SIGNIFICANCE: Gaps identified from examining the wider Taeniidae family models highlighted the potential role of FoI modelling to inform model parameterisation, as well as the need for spatial modelling and suitable structuring of interventions as key areas for future T. solium model development. We conclude that working with field partners to address data gaps and conducting cross-model validation with baseline and longitudinal data will be critical to building consensus-led and epidemiological setting-appropriate intervention strategies to help fulfil the WHO targets.

Prioritizing the scale-up of interventions for malaria control and elimination.

BACKGROUND: A core set of intervention and treatment options are recommended by the World Health Organization for use against falciparum malaria. These are treatment, long-lasting insecticide-treated bed nets, indoor residual spraying, and chemoprevention options. Both domestic and foreign aid funding for these tools is limited. When faced with budget restrictions, the introduction and scale-up of intervention and treatment options must be prioritized. METHODS: Estimates of the cost and impact of different interventions were combined with a mathematical model of malaria transmission to estimate the most cost-effective prioritization of interventions. The incremental cost effectiveness ratio was used to select between scaling coverage of current interventions or the introduction of an additional intervention tool. RESULTS: Prevention, in the form of vector control, is highly cost effective and scale-up is prioritized in all scenarios. Prevention reduces malaria burden and therefore allows treatment to be implemented in a more cost-effective manner by reducing the strain on the health system. The chemoprevention measures (seasonal malaria chemoprevention and intermittent preventive treatment in infants) are additional tools that, provided sufficient funding, are implemented alongside treatment scale-up. Future tools, such as RTS,S vaccine, have impact in areas of higher transmission but were introduced later than core interventions. CONCLUSIONS: In a programme that is budget restricted, it is essential that investment in available tools be effectively prioritized to maximize impact for a given investment. The cornerstones of malaria control: vector control and treatment, remain vital, but questions of when to scale and when to introduce other interventions must be rigorously assessed. This quantitative analysis considers the scale-up or core interventions to inform decision making in this area.

Modelling the cost-effectiveness of introducing the RTS,S malaria vaccine relative to scaling up other malaria interventions in sub-Saharan Africa.

OBJECTIVES: To evaluate the relative cost-effectiveness of introducing the RTS,S malaria vaccine in sub-Saharan Africa compared with further scale-up of existing interventions. DESIGN: A mathematical modelling and cost-effectiveness study. SETTING: Sub-Saharan Africa. PARTICIPANTS: People of all ages. INTERVENTIONS: The analysis considers the introduction and scale-up of the RTS,S malaria vaccine and the scale-up of long-lasting insecticide-treated bed nets (LLINs), indoor residual spraying (IRS) and seasonal malaria chemoprevention (SMC). MAIN OUTCOME MEASURE: The number of Plasmodium falciparum cases averted in all age groups over a 10-year period. RESULTS: Assuming access to treatment remains constant, increasing coverage of LLINs was consistently the most cost-effective intervention across a range of transmission settings and was found to occur early in the cost-effectiveness scale-up pathway. IRS, RTS,S and SMC entered the cost-effective pathway once LLIN coverage had been maximised. If non-linear production functions are included to capture the cost of reaching very high coverage, the resulting pathways become more complex and result in selection of multiple interventions. CONCLUSIONS: RTS,S was consistently implemented later in the cost-effectiveness pathway than the LLINs, IRS and SMC but was still of value as a fourth intervention in many settings to reduce burden to the levels set out in the international goals.

Assessing the impact of intervention strategies against Taenia solium cysticercosis using the EPICYST transmission model.

BACKGROUND: The pork tapeworm, Taenia solium, and associated human infections, taeniasis, cysticercosis and neurocysticercosis, are serious public health problems, especially in developing countries. The World Health Organization (WHO) has set goals for having a validated strategy for control and elimination of T. solium taeniasis/cysticercosis by 2015 and interventions scaled-up in selected countries by 2020. Timely achievement of these internationally-endorsed targets requires that the relative benefits and effectiveness of potential interventions be explored rigorously within a quantitative framework. METHODS: A deterministic, compartmental transmission model (EPICYST) was developed to capture the dynamics of the taeniasis/cysticercosis disease system in the human and pig hosts. Cysticercosis prevalence in humans, an outcome of high epidemiological and clinical importance, was explicitly modelled. A next generation matrix approach was used to derive an expression for the basic reproduction number, R 0. A full sensitivity analysis was performed using a methodology based on Latin-hypercube sampling partial rank correlation coefficient index. RESULTS: EPICYST outputs indicate that chemotherapeutic intervention targeted at humans or pigs would be highly effective at reducing taeniasis and cysticercosis prevalence when applied singly, with annual chemotherapy of humans and pigs resulting, respectively, in 94 and 74% of human cysticercosis cases averted. Improved sanitation, meat inspection and animal husbandry are less effective but are still able to reduce prevalence singly or in combination. The value of R 0 for taeniasis was estimated at 1.4 (95% Credible Interval: 0.5-3.6). CONCLUSIONS: Human- and pig-targeted drug-focussed interventions appear to be the most efficacious approach from the options currently available. The model presented is a forward step towards developing an informed control and elimination strategy for cysticercosis. Together with its validation against field data, EPICYST will be a valuable tool to help reach the WHO goals and to conduct economic evaluations of interventions in varying epidemiological settings.