Nicolas Maire

Towards a comprehensive simulation model of malaria epidemiology and control

Planning of the control of Plasmodium falciparum malaria leads to a need for models of malaria epidemiology that provide realistic quantitative prediction of likely epidemiological outcomes of a wide range of control strategies. Predictions of the effects of control often ignore medium- and long-term dynamics. The complexities of the Plasmodium life-cycle, and of within-host dynamics, limit the applicability of conventional deterministic malaria models. We use individual-based stochastic simulations of malaria epidemiology to predict the impacts of interventions on infection, morbidity, mortality, health services use and costs. Individual infections are simulated by stochastic series of parasite densities, and naturally acquired immunity acts by reducing densities. Morbidity and mortality risks, and infectiousness to vectors, depend on parasite densities. The simulated infections are nested within simulations of individuals in human populations, and linked to models of interventions and health systems. We use numerous field datasets to optimise parameter estimates. By using a volunteer computing system we obtain the enormous computational power required for model fitting, sensitivity analysis, and exploration of many different intervention strategies. The project thus provides a general platform for comparing, fitting, and evaluating different model structures, and for quantitative prediction of effects of different interventions and integrated control programmes.

Ensemble Modeling of the Likely Public Health Impact of a Pre-Erythrocytic Malaria Vaccine

Using an ensemble modeling approach, Thomas Smith and colleagues find that targeted mass vaccination with a pre-erythrocytic malaria vaccine RTS,S in low-transmission settings might have better health effects than vaccination through national EPI programs.

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.

Rapid microarray-based method for monitoring of all currently known single-nucleotide polymorphisms associated with parasite resistance to antimalaria drugs

ABSTRACT Parasite drug resistance is partly conferred by single-nucleotide polymorphisms (SNPs), and monitoring them has been proposed as an alternative to monitoring drug resistance. Therefore, techniques are required to facilitate analyses of multiple SNPs on an epidemiological scale. We report a rapid and affordable microarray technique for application in epidemiological studies of malaria drug resistance. We have designed a multiwell microarray that is used in conjunction with PCR-amplified target genes implicated in the drug resistance of malaria with subsequent one-tube minisequencing using two fluorochromes. The drug-resistance-associated genes pfdhfr, pfdhps, pfcrt, pfmdr1, and pfATPase were amplified and analyzed for cultured Plasmodium falciparum strains and from field samples. We obtained a specificity of 94%, and comparison of field sample results to those of restriction fragment length polymorphism (RFLP) typing resulted in an overall consistency of >90%, except for pfdhfr51, for which most discrepancies were due to false determinations by RFLP of mixed infections. The system is sufficiently sensitive to assay parasites in clinical malaria cases and in most asymptomatic cases, and it allows high throughput with minimal hands-on time. The cost for the assay has been calculated as 0.27 euros/SNP (US

The SolarMal Project: innovative mosquito trapping technology for malaria control

0.33), which is below the cost incurred with other systems. Due to the simplicity of the approach, newly identified SNPs can be incorporated rapidly. Such a monitoring system also makes it possible to identify the reemergence of drug-susceptible parasites once a drug has been withdrawn.

The distribution of Plasmodium falciparum infection durations.

The use of insecticides against mosquitoes, and drugs to treat infection, continue to form the mainstays of malaria control programmes, but the long term success and sustainability of these approaches is threatened by the development of insecticide and drug resistance. New complementary approaches to control must be explored. The development by Okumu and others [1] of a blend of synthetic chemical attractants which was capable of attracting more Anopheles gambiae s.s. than a human, provided the key breakthrough towards creation of a mass trapping system which could be used for malaria control. By luring Anopheles mosquitoes to traps in numbers that are high enough to suppress population size and reduce biting intensity, a decline in malaria transmission could be realized. Here we describe our plans for the development and testing of odour-baited traps for malaria control in Western Kenya. The SolarMal project aims to demonstrate proof of principle for the elimination of malaria from Rusinga Island, Western Kenya, using the nationwide adopted strategy of LLINs and case management, augmented by mass trapping of mosquito vectors. The use of novel technology and scientific development underpins all areas of the project; from the optimisation of chemical baits to attract mosquitoes, to the design of a new mosquito trap and the installation of solar panel systems to provide power to run the traps. Electronic tablets are used to record health and demographic surveillance data. The mosquito traps operate according to a counterflow mechanism previously shown to be highly effective in collecting anopheline mosquitoes [2] and are designed to collect mosquitoes outdoors prior to house entry. Odour baits placed within the traps mimic human odourants [3]. In a unique variation on the stepped wedge intervention strategy, which we refer to as the hierarchical design, intervention implementation begins at one randomly selected household and expands radially until a cluster of houses with the intervention is created. The intervention implementation then commences in a second geographically distinct location, then a third, fourth, fifth etc, continuing until the whole island is covered. Outcome measures of malaria parasite prevalence and incidence, as well as estimates of malaria transmission intensity, will be used to assess the impact of the intervention. We expect the results to demonstrate that the use of odour baited traps is an effective, novel means of integrated malaria control.

Simulation of the cost-effectiveness of malaria vaccines

OBJECTIVES The duration of untreated Plasmodium falciparum infections in naturally exposed human populations is of interest for rational planning of malaria control interventions as it is related to the duration of infectivity. The extent of variability in duration is relevant where transmission is seasonal, and for the planning of elimination efforts. Methods for measuring these quantities from genotyping data have been restricted to exponential models of infection survival, as implied by constant clearance rates. Such models have greatly improved the understanding of infection dynamics on a population level but likely misrepresent the within-host dynamics of many pathogens. Conversely, the statistical properties of the distribution of infection durations, and how these are affected by exposure, should contain information on within-host dynamics. METHODS AND RESULTS We extended existing methods for the analysis of longitudinal genotyping data on P. falciparum infections. Our method simultaneously estimates force of infection, detectability, and the distribution of infection durations. Infection durations are modeled using parametric survival distributions. The method is validated using simulated data, and applied to data from a cohort study in Navrongo, Northern Ghana. Distribution estimates from exponential, Weibull, lognormal, and gamma models are compared with the distribution of durations in malariatherapy data. CONCLUSIONS The Weibull model fitted the data best. It estimated a shorter mean duration than the exponential model, which gave the worst fit. The distribution estimates appeared positively skewed when compared with the distribution of durations in malariatherapy data, suggesting that a significant proportion of infections is cleared shortly after inoculation. We conclude that malariatherapy data, the most important source of information on P. falciparum within-host dynamics, may not be representative of the actual processes in natural populations, and should be used with care. Further, conclusions from transmission models assuming exponential infection survival may be biased.

Modelling the cost-effectiveness of mass screening and treatment for reducing Plasmodium falciparum malaria burden

BackgroundA wide range of possible malaria vaccines is being considered and there is a need to identify which vaccines should be prioritized for clinical development. An important element of the information needed for this prioritization is a prediction of the cost-effectiveness of potential vaccines in the transmission settings in which they are likely to be deployed. This analysis needs to consider a range of delivery modalities to ensure that clinical development plans can be aligned with the most appropriate deployment strategies.MethodsThe simulations are based on a previously published individual-based stochastic model for the natural history and epidemiology of Plasmodium falciparum malaria. Three different vaccine types: pre-erythrocytic vaccines (PEV), blood stage vaccines (BSV), mosquito-stage transmission-blocking vaccines (MSTBV), and combinations of these, are considered each delivered via a range of delivery modalities (Expanded Programme of Immunization – EPI-, EPI with booster, and mass vaccination combined with EPI). The cost-effectiveness ratios presented are calculated for four health outcomes, for assumed vaccine prices of US

Modelling the epidemiological impact of intermittent preventive treatment against malaria in infants.

2 or US

The effect of mass mosquito trapping on malaria transmission and disease burden (SolarMal): a stepped-wedge cluster-randomised trial

10 per dose, projected over a 10-year period.ResultsThe simulations suggest that PEV will be more cost-effective in low transmission settings, while BSV at higher transmission settings. Combinations of BSV and PEV are more efficient than PEV, especially in moderate to high transmission settings, while compared to BSV they are more cost-effective in moderate to low transmission settings. Combinations of MSTBV and PEV or PEV and BSV improve the effectiveness and the cost-effectiveness compared to PEV and BSV alone only when applied with EPI and mass vaccinations. Adding booster doses to the EPI is unlikely to be a cost-effective alternative to delivering vaccines via the EPI for any vaccine, while mass vaccination improves effectiveness, especially in low transmission settings, and is often a more efficient alternative to the EPI. However, the costs of increasing the coverage of mass vaccination over 50% often exceed the benefits.ConclusionThe simulations indicate malaria vaccines might be efficient malaria control interventions, and that both transmission setting and vaccine delivery modality are important to their cost-effectiveness. Alternative vaccine delivery modalities to the EPI may be more efficient than the EPI. Mass vaccination is predicted to provide substantial health benefits at low additional costs, although achieving high coverage rates can lead to substantial incremental costs.