Insights from modelling malaria vaccines for policy decisions: the focus on RTS,S.

Mathematical models are increasingly used to inform decisions throughout product development pathways from pre-clinical studies to country implementation of novel health interventions. This review illustrates the utility of simulation approaches by reviewing the literature on malaria vaccine modelling, with a focus on its link to the development of policy guidance for the first licensed product, RTS,S/AS01. The main contributions of modelling studies have been in inferring the mechanism of action and efficacy profile of RTS,S; to predicting the public health impact; and economic modelling mainly comprising cost-effectiveness analysis. The value of both product-specific and generic modelling of vaccines is highlighted.

Mechanistic within-host models of the asexual Plasmodium falciparum infection: a review and analytical assessment.

BACKGROUND: Malaria blood-stage infection length and intensity are important drivers of disease and transmission; however, the underlying mechanisms of parasite growth and the host's immune response during infection remain largely unknown. Over the last 30 years, several mechanistic mathematical models of malaria parasite within-host dynamics have been published and used in malaria transmission models. METHODS: Mechanistic within-host models of parasite dynamics were identified through a review of published literature. For a subset of these, model code was reproduced and descriptive statistics compared between the models using fitted data. Through simulation and model analysis, key features of the models were compared, including assumptions on growth, immune response components, variant switching mechanisms, and inter-individual variability. RESULTS: The assessed within-host malaria models generally replicate infection dynamics in malaria-naïve individuals. However, there are substantial differences between the model dynamics after disease onset, and models do not always reproduce late infection parasitaemia data used for calibration of the within host infections. Models have attempted to capture the considerable variability in parasite dynamics between individuals by including stochastic parasite multiplication rates; variant switching dynamics leading to immune escape; variable effects of the host immune responses; or via probabilistic events. For models that capture realistic length of infections, model representations of innate immunity explain early peaks in infection density that cause clinical symptoms, and model representations of antibody immune responses control the length of infection. Models differed in their assumptions concerning variant switching dynamics, reflecting uncertainty in the underlying mechanisms of variant switching revealed by recent clinical data during early infection. Overall, given the scarce availability of the biological evidence there is limited support for complex models. CONCLUSIONS: This study suggests that much of the inter-individual variability observed in clinical malaria infections has traditionally been attributed in models to random variability, rather than mechanistic disease dynamics. Thus, it is proposed that newly developed models should assume simple immune dynamics that minimally capture mechanistic understandings and avoid over-parameterization and large stochasticity which inaccurately represent unknown disease mechanisms.

Costing malaria interventions from pilots to elimination programmes.

BACKGROUND: Malaria programmes in countries with low transmission levels require evidence to optimize deployment of current and new tools to reach elimination with limited resources. Recent pilots of elimination strategies in Ethiopia, Senegal, and Zambia produced evidence of their epidemiological impacts and costs. There is a need to generalize these findings to different epidemiological and health systems contexts. METHODS: Drawing on experience of implementing partners, operational documents and costing studies from these pilots, reference scenarios were defined for rapid reporting (RR), reactive case detection (RACD), mass drug administration (MDA), and in-door residual spraying (IRS). These generalized interventions from their trial implementation to one typical of programmatic delivery. In doing so, resource use due to interventions was isolated from research activities and was related to the pilot setting. Costing models developed around this reference implementation, standardized the scope of resources costed, the valuation of resource use, and the setting in which interventions were evaluated. Sensitivity analyses were used to inform generalizability of the estimates and model assumptions. RESULTS: Populated with local prices and resource use from the pilots, the models yielded an average annual economic cost per capita of $0.18 for RR, $0.75 for RACD, $4.28 for MDA (two rounds), and $1.79 for IRS (one round, 50% households). Intervention design and resource use at service delivery were key drivers of variation in costs of RR, MDA, and RACD. Scale was the most important parameter for IRS. Overall price level was a minor contributor, except for MDA where drugs accounted for 70% of the cost. The analyses showed that at implementation scales comparable to health facility catchment area, systematic correlations between model inputs characterizing implementation and setting produce large gradients in costs. CONCLUSIONS: Prospective costing models are powerful tools to explore resource and cost implications of policy alternatives. By formalizing translation of operational data into an estimate of intervention cost, these models provide the methodological infrastructure to strengthen capacity gap for economic evaluation in endemic countries. The value of this approach for decision-making is enhanced when primary cost data collection is designed to enable analysis of the efficiency of operational inputs in relation to features of the trial or the setting, thus facilitating transferability.

Mathematical analysis to prioritise strategies for malaria elimination.

Malaria and some other tropical diseases are currently targeted for elimination and eventually eradication. Since resources are limited, prioritisation of countries or areas for elimination is often necessary. However, this prioritisation is frequently conducted in an ad hoc manner. Lower transmission areas are usually targeted for elimination first, but for some areas this necessitates long and potentially expensive surveillance programs while transmission is eliminated from neighbouring higher transmission areas. We use a mathematical model to compare the implications of prioritisation choices in reducing overall burden and costs. We show that when the duration of the elimination program is independent of the transmission potential, burden is always reduced most by targeting high transmission areas first, but to reduce costs the optimal ordering depends on the actual transmission levels. In general, when overall transmission potential is low and the surveillance cost per secondary case compared to the cost per imported case is low, targeting the higher transmission area for elimination first is favoured.

State of inequality in malaria intervention coverage in sub-Saharan African countries.

BACKGROUND: Scale-up of malaria interventions over the last decade have yielded a significant reduction in malaria transmission and disease burden in sub-Saharan Africa. We estimated economic gradients in the distribution of these efforts and of their impacts within and across endemic countries. METHODS: Using Demographic and Health Surveys we computed equity metrics to characterize the distribution of malaria interventions in 30 endemic countries proxying economic position with an asset-wealth index. Gradients were summarized in a concentration index, tabulated against level of coverage, and compared among interventions, across countries, and against respective trends over the period 2005-2015. RESULTS: There remain broad differences in coverage of malaria interventions and their distribution by wealth within and across countries. In most, economic gradients are lacking or favor the poorest for vector control; malaria services delivered through the formal healthcare sector are much less equitable. Scale-up of interventions in many countries improved access across the wealth continuum; in some, these efforts consistently prioritized the poorest. Expansions in control programs generally narrowed coverage gaps between economic strata; gradients persist in countries where growth was slower in the poorest quintile or where baseline inequality was large. Despite progress, malaria is consistently concentrated in the poorest, with the degree of inequality in burden far surpassing that expected given gradients in the distribution of interventions. CONCLUSIONS: Economic gradients in the distribution of interventions persist over time, limiting progress toward equity in malaria control. We found that, in countries with large baseline inequality in the distribution of interventions, even a small bias in expansion favoring the least poor yielded large gradients in intervention coverage while pro-poor growth failed to close the gap between the poorest and least poor. We demonstrated that dimensions of disadvantage compound for the poor; a lack of economic gradients in the distribution of malaria services does not translate to equity in coverage nor can it be interpreted to imply equity in distribution of risk or disease burden. Our analysis testifies to the progress made by countries in narrowing economic gradients in malaria interventions and highlights the scope for continued monitoring of programs with respect to equity.

Country specific predictions of the cost-effectiveness of malaria vaccine RTS,S/AS01 in endemic Africa.

BACKGROUND: RTS,S/AS01 is a safe and moderately efficacious vaccine considered for implementation in endemic Africa. Model predictions of impact and cost-effectiveness of this new intervention could aid in country adoption decisions. METHODS: The impact of RTS,S was assessed in 43 countries using an ensemble of models of Plasmodium falciparum epidemiology. Informed by the 32months follow-up data from the phase 3 trial, vaccine effectiveness was evaluated at country levels of malaria parasite prevalence, coverage of control interventions and immunization. Benefits and costs of the program incremental to routine malaria control were evaluated for a four dose schedule: first dose administered at six months, second and third - before 9months, and fourth dose at 27months of age. Sensitivity analyses around vaccine properties, transmission, and economic inputs were conducted. RESULTS: If implemented in all 43 countries the vaccine has the potential to avert 123 (117;129) million malaria episodes over the first 10years. Burden averted averages 18,413 (range of country median estimates 156-40,054) DALYs per 100,000 fully vaccinated children with much variation across settings primarily driven by differences in transmission intensity. At a price of $5 per dose program costs average $39.8 per fully vaccinated child with a median cost-effectiveness ratio of $188 (range $78-$22,448) per DALY averted; the ratio is lower by one third - $136 (range $116-$220) - in settings where parasite prevalence in children aged 2-10years is at or above 10%. CONCLUSION: RTS,S/AS01has the potential to substantially reduce malaria burden in children across Africa. Conditional on assumptions on price, coverage, and vaccine properties, adding RTS,S to routine malaria control interventions would be highly cost-effective. Implementation decisions will need to further consider feasibility of scaling up existing control programs, and operational constraints in reaching children at risk with the schedule.

Public health impact and cost-effectiveness of the RTS,S/AS01 malaria vaccine: a systematic comparison of predictions from four mathematical models.

BACKGROUND: The phase 3 trial of the RTS,S/AS01 malaria vaccine candidate showed modest efficacy of the vaccine against Plasmodium falciparum malaria, but was not powered to assess mortality endpoints. Impact projections and cost-effectiveness estimates for longer timeframes than the trial follow-up and across a range of settings are needed to inform policy recommendations. We aimed to assess the public health impact and cost-effectiveness of routine use of the RTS,S/AS01 vaccine in African settings. METHODS: We compared four malaria transmission models and their predictions to assess vaccine cost-effectiveness and impact. We used trial data for follow-up of 32 months or longer to parameterise vaccine protection in the group aged 5-17 months. Estimates of cases, deaths, and disability-adjusted life-years (DALYs) averted were calculated over a 15 year time horizon for a range of levels of Plasmodium falciparum parasite prevalence in 2-10 year olds (PfPR2-10; range 3-65%). We considered two vaccine schedules: three doses at ages 6, 7·5, and 9 months (three-dose schedule, 90% coverage) and including a fourth dose at age 27 months (four-dose schedule, 72% coverage). We estimated cost-effectiveness in the presence of existing malaria interventions for vaccine prices of US$2-10 per dose. FINDINGS: In regions with a PfPR2-10 of 10-65%, RTS,S/AS01 is predicted to avert a median of 93,940 (range 20,490-126,540) clinical cases and 394 (127-708) deaths for the three-dose schedule, or 116,480 (31,450-160,410) clinical cases and 484 (189-859) deaths for the four-dose schedule, per 100,000 fully vaccinated children. A positive impact is also predicted at a PfPR2-10 of 5-10%, but there is little impact at a prevalence of lower than 3%. At $5 per dose and a PfPR2-10 of 10-65%, we estimated a median incremental cost-effectiveness ratio compared with current interventions of $30 (range 18-211) per clinical case averted and $80 (44-279) per DALY averted for the three-dose schedule, and of $25 (16-222) and $87 (48-244), respectively, for the four-dose schedule. Higher ICERs were estimated at low PfPR2-10 levels. INTERPRETATION: We predict a significant public health impact and high cost-effectiveness of the RTS,S/AS01 vaccine across a wide range of settings. Decisions about implementation will need to consider levels of malaria burden, the cost-effectiveness and coverage of other malaria interventions, health priorities, financing, and the capacity of the health system to deliver the vaccine. FUNDING: PATH Malaria Vaccine Initiative; Bill & Melinda Gates Foundation; Global Good Fund; Medical Research Council; UK Department for International Development; GAVI, the Vaccine Alliance; WHO.

Defining the relationship between infection prevalence and clinical incidence of Plasmodium falciparum malaria.

In many countries health system data remain too weak to accurately enumerate Plasmodium falciparum malaria cases. In response, cartographic approaches have been developed that link maps of infection prevalence with mathematical relationships to predict the incidence rate of clinical malaria. Microsimulation (or 'agent-based') models represent a powerful new paradigm for defining such relationships; however, differences in model structure and calibration data mean that no consensus yet exists on the optimal form for use in disease-burden estimation. Here we develop a Bayesian statistical procedure combining functional regression-based model emulation with Markov Chain Monte Carlo sampling to calibrate three selected microsimulation models against a purpose-built data set of age-structured prevalence and incidence counts. This allows the generation of ensemble forecasts of the prevalence-incidence relationship stratified by age, transmission seasonality, treatment level and exposure history, from which we predict accelerating returns on investments in large-scale intervention campaigns as transmission and prevalence are progressively reduced.

Effects of pyrethroid resistance on the cost effectiveness of a mass distribution of long-lasting insecticidal nets: a modelling study.

BACKGROUND: The effectiveness of insecticide-treated nets in preventing malaria is threatened by developing resistance against pyrethroids. Little is known about how strongly this affects the effectiveness of vector control programmes. METHODS: Data from experimental hut studies on the effects of long-lasting, insecticidal nets (LLINs) on nine anopheline mosquito populations, with varying levels of mortality in World Health Organization susceptibility tests, were used to parameterize malaria models. Both simple static models predicting population-level insecticidal effectiveness and protection against blood feeding, and complex dynamic epidemiological models, where LLINs decayed over time, were used. The epidemiological models, implemented in OpenMalaria, were employed to study the impact of a single mass distribution of LLINs on malaria, both in terms of episodes prevented during the effective lifetime of the batch of LLINs, and in terms of net health benefits (NHB) expressed in disability-adjusted life years (DALYs) averted during that period, depending on net type (standard pyrethroid-only LLIN or pyrethroid-piperonyl butoxide combination LLIN), resistance status, coverage and pre-intervention transmission level. RESULTS: There were strong positive correlations between insecticide susceptibility status and predicted population level insecticidal effectiveness of and protection against blood feeding by LLIN intervention programmes. With the most resistant mosquito population, the LLIN mass distribution averted up to about 40% fewer episodes and DALYs during the effective lifetime of the batch than with fully susceptible populations. However, cost effectiveness of LLINs was more sensitive to the pre-intervention transmission level and coverage than to susceptibility status. For four out of the six Anopheles gambiae sensu lato populations where direct comparisons between standard LLINs and combination LLINs were possible, combination nets were more cost effective, despite being more expensive. With one resistant population, both net types were equally effective, and with one of the two susceptible populations, standard LLINs were more cost effective. CONCLUSION: Despite being less effective when compared to areas with susceptible mosquito populations, standard and combination LLINs are likely to (still) be cost effective against malaria even in areas with strong pyrethroid resistance. Combination nets are likely to be more cost effective than standard nets in areas with resistant mosquito populations.

What should vaccine developers ask? Simulation of the effectiveness of malaria vaccines.

BACKGROUND: A number of different malaria vaccine candidates are currently in pre-clinical or clinical development. Even though they vary greatly in their characteristics, it is unlikely that any of them will provide long-lasting sterilizing immunity against the malaria parasite. There is great uncertainty about what the minimal vaccine profile should be before registration is worthwhile; how to allocate resources between different candidates with different profiles; which candidates to consider combining; and what deployment strategies to consider. METHODS AND FINDINGS: We use previously published stochastic simulation models, calibrated against extensive epidemiological data, to make quantitative predictions of the population effects of malaria vaccines on malaria transmission, morbidity and mortality. The models are fitted and simulations obtained via volunteer computing. We consider a range of endemic malaria settings with deployment of vaccines via the Expanded program on immunization (EPI), with and without additional booster doses, and also via 5-yearly mass campaigns for a range of coverages. The simulation scenarios account for the dynamic effects of natural and vaccine induced immunity, for treatment of clinical episodes, and for births, ageing and deaths in the cohort. Simulated pre-erythrocytic vaccines have greatest benefits in low endemic settings (EIR of 84) PEV may lead to increased incidence of severe disease in the long term, if efficacy is moderate to low (<70%). Blood stage vaccines (BSV) are most useful in high transmission settings, and are comparable to PEV for low transmission settings. Combinations of PEV and BSV generally perform little better than the best of the contributing components. A minimum half-life of protection of 2-3 years appears to be a precondition for substantial epidemiological effects. Herd immunity effects can be achieved with even moderately effective (>20%) malaria vaccines (either PEV or BSV) when deployed through mass campaigns targeting all age-groups as well as EPI, and especially if combined with highly efficacious transmission-blocking components. CONCLUSIONS: We present for the first time a stochastic simulation approach to compare likely effects on morbidity, mortality and transmission of a range of malaria vaccines and vaccine combinations in realistic epidemiological and health systems settings. The results raise several issues for vaccine clinical development, in particular appropriateness of vaccine types for different transmission settings; the need to assess transmission to the vector and duration of protection; and the importance of deployment additional to the EPI, which again may make the issue of number of doses required more critical. To test the validity and robustness of our conclusions there is a need for further modeling (and, of course, field research) using alternative formulations for both natural and vaccine induced immunity. Evaluation of alternative deployment strategies outside EPI needs to consider the operational implications of different approaches to mass vaccination.