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Evaluating the effectiveness of malaria control interventions on the basis of their impact on transmission is increasingly important as countries move from malaria control to pre-elimination programs. Mathematical modeling can examine relationships between malaria indicators, allowing translation of easily measured data into measures of transmission, and addressing key concerns with traditional methods for quantifying transmission. Simulations show these indicators are statistically correlated, allowing direct comparisons of malaria transmission using data collected using different methods across a range of transmission intensities and seasonal patterns. Results from such models can provide public health officials with accurate estimates of transmission, by seasonal pattern, that are necessary for assessing and tailoring malaria control and elimination programs to specific settings., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: The RTS,S malaria vaccine may soon be licensed. Models of impact of such vaccines have mainly considered deployment via the World Health Organization's Expanded Programme on Immunization (EPI) in areas of stable endemic transmission of Plasmodium falciparum, and have been calibrated for such settings. Their applicability to low transmission settings is unclear. Evaluations of the efficiency of different deployment strategies in diverse settings should consider uncertainties in model structure., Methods and Findings: An ensemble of 14 individual-based stochastic simulation models of P. falciparum dynamics, with differing assumptions about immune decay, transmission heterogeneity, and treatment access, was constructed. After fitting to an extensive library of field data, each model was used to predict the likely health benefits of RTS,S deployment, via EPI (with or without catch-up vaccinations), supplementary vaccination of school-age children, or mass vaccination every 5 y. Settings with seasonally varying transmission, with overall pre-intervention entomological inoculation rates (EIRs) of two, 11, and 20 infectious bites per person per annum, were considered. Predicted benefits of EPI vaccination programs over the simulated 14-y time horizon were dependent on duration of protection. Nevertheless, EPI strategies (with an initial catch-up phase) averted the most deaths per dose at the higher EIRs, although model uncertainty increased with EIR. At two infectious bites per person per annum, mass vaccination strategies substantially reduced transmission, leading to much greater health effects per dose, even at modest coverage., Conclusions: In higher transmission settings, EPI strategies will be most efficient, but vaccination additional to the EPI in targeted low transmission settings, even at modest coverage, might be more efficient than national-level vaccination of infants. The feasibility and economics of mass vaccination, and the circumstances under which vaccination will avert epidemics, remain unclear. The approach of using an ensemble of models provides more secure conclusions than a single-model approach, and suggests greater confidence in predictions of health effects for lower transmission settings than for higher ones.

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., (Copyright © 2011 Elsevier B.V. All rights reserved.)

A quantitative framework is used to explore the potential applications and probable effects of sexual stage or mosquito stage transmission blocking vaccines (TBVs) against malaria. The combination of TBVs with biocides or other malaria vaccines will increase chances of interrupting transmission, whereas the value of TBVs for morbidity control will be limited. Vaccine combination will also protect against selection of insensitive parasites. Simulations indicate that TBVs will reduce risks of reestablishment of transmission when vector control is withdrawn. Simple mathematical analysis shows that efficacy and coverage are equally important, implying that a vaccine that requires a small number of doses (ideally one) is preferable to one that is difficult to deliver, even if this entails accepting a lower efficacy., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

BACKGROUND: Global interest in malaria elimination has prompted research on active test and treat (TaT) strategies. METHODS: A systematic review and meta-analysis were conducted to assess the effectiveness of TaT strategies to reduce malaria transmission. RESULTS: A total of 72 empirical research and 24 modelling studies were identified, mainly focused on proactive mass TaT (MTaT) and reactive case detection (RACD) in higher and lower transmission settings, respectively. Ten intervention studies compared MTaT to no MTaT and the evidence for impact on malaria incidence was weak. No intervention studies compared RACD to no RACD. Compared to passive case detection (PCD) alone, PCD + RACD using standard diagnostics increased infection detection 52.7% and 11.3% in low and very low transmission settings, respectively. Using molecular methods increased this detection of infections by 1.4- and 1.1-fold, respectively. CONCLUSION: Results suggest MTaT is not effective for reducing transmission. By increasing case detection, surveillance data provided by RACD may indirectly reduce transmission by informing coordinated responses of intervention targeting.

Background: Efforts to improve the impact of long-lasting insecticidal nets (LLINs) should be informed by understanding of the causes of decay in effect. Holes in LLINs have been estimated to account for 7–11% of loss in effect on vectorial capacity for Plasmodium falciparum malaria in an analysis of repeated cross-sectional surveys of LLINs in Kenya. This does not account for the effect of holes as a cause of net attrition or non-use, which cannot be measured using only cross-sectional data. There is a need for estimates of how much these indirect effects of physical damage on use and attrition contribute to decay in effectiveness of LLINs. Methods: Use, physical integrity, and survival were assessed in a cohort of 4514 LLINs followed for up to 4 years in Kenya. Flow diagrams were used to illustrate how the status of nets, in terms of categories of use, physical integrity, and attrition, changed between surveys carried out at 6-month intervals. A compartment model defined in terms of ordinary differential equations (ODEs) was used to estimate the transition rates between the categories. Effects of physical damage to LLINs on use and attrition were quantified by simulating counterfactuals in which there was no damage. Results: Allowing for the direct effect of holes, the effect on use, and the effect on attrition, 18% of the impact on vectorial capacity was estimated to be lost because of damage. The estimated median lifetime of the LLINs was 2.9 years, but this was extended to 5.7 years in the counterfactual without physical damage. Nets that were in use were more likely to be in a damaged state than unused nets but use made little direct difference to LLIN lifetimes. Damage was reported as the reason for attrition for almost half of attrited nets, but the model estimated that almost all attrited nets had suffered some damage before attrition. Conclusions: Full quantification of the effects of damage will require measurement of the supply of new nets and of household stocks of unused nets, and also of their impacts on both net use and retention. The timing of mass distribution campaigns is less important than ensuring sufficient supply. In the Kenyan setting, nets acquired damage rapidly once use began and the damage led to rapid attrition. Increasing the robustness of nets could substantially increase their lifetime and impact but the impact of LLIN programmes on malaria transmission is ultimately limited by levels of use. Longitudinal analyses of net integrity data from different settings are needed to determine the importance of physical damage to nets as a driver of attrition and non-use, and the importance of frequent use as a cause of physical damage in different contexts. [ABSTRACT FROM AUTHOR]

Background: Increasing coverage of malaria vector control interventions globally has led to significant reductions in disease burden. However due to its high recurrent cost, there is a need to determine if and when vector control can be safely scaled back after transmission has been reduced. Methods and findings: A mathematical model of Plasmodium falciparum malaria epidemiology was simulated to determine the impact of scaling back vector control on transmission and disease. A regression analysis of simulation results was conducted to derive predicted probabilities of resurgence, severity of resurgence and time to resurgence under various settings. Results indicate that, in the absence of secular changes in transmission, there are few scenarios where vector control can be removed without high expectation of resurgence. These, potentially safe, scenarios are characterized by low historic entomological inoculation rates, successful vector control programmes that achieve elimination or near elimination, and effective surveillance systems with high coverage and effective treatment of malaria cases. Conclusions: Programmes and funding agencies considering scaling back or withdrawing vector control from previously malaria endemic areas need to first carefully consider current receptivity and other available interventions in a risk assessment. Surveillance for resurgence needs to be continuously conducted over a long period of time in order to ensure a rapid response should vector control be withdrawn. [ABSTRACT FROM AUTHOR]

Background: Malaria elimination requires reducing both the potential of mosquitoes to transmit parasites to humans and humans to transmit parasites to mosquitoes. To achieve this goal in Southern province, Zambia a mass test and treat (MTAT) campaign was conducted from 2011-2013 to complement high coverage of long-lasting insecticide-treated nets (LLIN). To identify factors likely to increase campaign effectiveness, a modelling approach was applied to investigate the simulated effect of alternative operational strategies for parasite clearance in southern province. Methods: OpenMalaria, a discrete-time, individual-based stochastic model of malaria, was parameterized for the study area to simulate anti-malarial drug administration for interruption of transmission. Simulations were run for scenarios with a range of artemisinin-combination therapies, proportion of the population reached by the campaign, targeted age groups, time between campaign rounds, Plasmodium falciparum test protocols, and the addition of drugs aimed at preventing onward transmission. A sensitivity analysis was conducted to assess uncertainty of simulation results. Scenarios were evaluated based on the reduction in all-age parasite prevalence during the peak transmission month one year following the campaign, compared to the currently-implemented strategy of MTAT 19 % population coverage at pilot and 40 % coverage during the first year of implementation in the presence of 56 % LLIN use and 18 % indoor residual spray coverage. Results: Simulation results suggest the most important determinant of success in reducing prevalence is the population coverage achieved in the campaign, which would require more than 1 year of campaign implementation for elimination. The inclusion of single low-dose primaquine, which acts as a gametocytocide, or ivermectin, which acts as an endectocide, to the drug regimen did not further reduce parasite prevalence one year following the campaign compared to the currently-implemented strategy. Simulation results indicate a high proportion of low-density infections were missed by rapid diagnostic tests that would be treated and cleared with mass drug administration (MDA). Conclusions: The optimal implementation strategy for MTAT or MDA will vary by background level of prevalence, by rate of infections imported to the area, and by ability to operationally achieve high population coverage. Overall success with new parasite clearance strategies depends on continued coverage of vector control interventions to ensure sustained gains in reduction of disease burden. [ABSTRACT FROM AUTHOR]

Eliminating malaria from highly endemic settings will require unprecedented levels of vector control. To suppress mosquito populations, vector control products targeting their blood hosts must attain high biological coverage of all available sources, rather than merely high demographic coverage of a targeted resource subset, such as humans while asleep indoors. Beyond defining biological coverage in a measurable way, the proportion of blood meals obtained from humans and the proportion of bites upon unprotected humans occurring indoors also suggest optimal target product profiles for delivering insecticides to humans or livestock. For vectors that feed only occasionally upon humans, preferred animal hosts may be optimal targets for mosquito-toxic insecticides, and vapour-phase insecticides optimized to maximize repellency, rather than toxicity, may be ideal for directly protecting people against indoor and outdoor exposure. However, for vectors that primarily feed upon people, repellent vapour-phase insecticides may be inferior to toxic ones and may undermine the impact of contact insecticides applied to human sleeping spaces, houses or clothing if combined in the same time and place. These concepts are also applicable to other mosquito-borne anthroponoses so that diverse target species could be simultaneously controlled with integrated vector management programmes. Measurements of these two crucial mosquito behavioural parameters should now be integrated into programmatically funded, longitudinal, national-scale entomological monitoring systems to inform selection of available technologies and investment in developing new ones. [ABSTRACT FROM AUTHOR]

Background: The effectiveness of long-lasting, insecticidal nets (LLINs) in preventing malaria is threatened by the changing biting behaviour of mosquitoes, from nocturnal and endophagic to crepuscular and exophagic, and by their increasing resistance to insecticides. Methods: Using epidemiological stochastic simulation models, we studied the impact of a mass LLIN distribution on Plasmodium falciparum malaria. Specifically, we looked at impact in terms of episodes prevented during the effective life of the batch and in terms of net health benefits (NHB) expressed in disability adjusted life years (DALYs) averted, depending on biting behaviour, resistance (as measured in experimental hut studies), and on pre-intervention transmission levels. Results: Results were very sensitive to assumptions about the probabilistic nature of host searching behaviour. With a shift towards crepuscular biting, under the assumption that individual mosquitoes repeat their behaviour each gonotrophic cycle, LLIN effectiveness was far less than when individual mosquitoes were assumed to vary their behaviour between gonotrophic cycles. LLIN effectiveness was equally sensitive to variations in host-searching behaviour (if repeated) and to variations in resistance. LLIN effectiveness was most sensitive to pre-intervention transmission level, with LLINs being least effective at both very low and very high transmission levels, and most effective at around four infectious bites per adult per year. A single LLIN distribution round remained cost effective, except in transmission settings with a pre-intervention inoculation rate of over 128 bites per year and with resistant mosquitoes that displayed a high proportion (over 40%) of determined crepuscular host searching, where some model variants showed negative NHB. Conclusions: Shifts towards crepuscular host searching behaviour can be as important in reducing LLIN effectiveness and cost effectiveness as resistance to pyrethroids. As resistance to insecticides is likely to slow down the development of behavioural resistance and vice versa, the two types of resistance are unlikely to occur within the same mosquito population. LLINs are likely cost effective interventions against malaria, even in areas with strong resistance to pyrethroids or where a large proportion of host-mosquito contact occurs during times when LLIN users are not under their nets. [ABSTRACT FROM AUTHOR]

Background: Past experience and modelling suggest that, in most cases, mass treatment strategies are not likely to succeed in interrupting Plasmodium falciparum malaria transmission. However, this does not preclude their use to reduce disease burden. Mass screening and treatment (MSAT) is preferred to mass drug administration (MDA), as the latter involves massive over-use of drugs. This paper reports simulations of the incremental cost-effectiveness of well-conducted MSAT campaigns as a strategy for P. falciparum malaria disease-burden reduction in settings with varying receptivity (ability of the combined vector population in a setting to transmit disease) and access to case management. Methods: MSAT incremental cost-effectiveness ratios (ICERs) were estimated in different sub-Saharan African settings using simulation models of the dynamics of malaria and a literature-based MSAT cost estimate. Imported infections were simulated at a rate of two per 1,000 population per annum. These estimates were compared to the ICERs of scaling up case management or insecticide-treated net (ITN) coverage in each baseline health system, in the absence of MSAT. Results: MSAT averted most episodes, and resulted in the lowest ICERs, in settings with a moderate level of disease burden. At a low preintervention entomological inoculation rate (EIR) of two infectious bites per adult per annum (IBPAPA) MSAT was never more cost-effective than scaling up ITNs or case management coverage. However, at pre-intervention entomological inoculation rates (EIRs) of 20 and 50 IBPAPA and ITN coverage levels of 40 or 60%, respectively, the ICER of MSAT was similar to that of scaling up ITN coverage further. Conclusions: In all the transmission settings considered, achieving a minimal level of ITN coverage is a "best buy". At low transmission, MSAT probably is not worth considering. Instead, MSAT may be suitable at medium to high levels of transmission and at moderate ITN coverage. If undertaken as a burden-reducing intervention, MSAT should be continued indefinitely and should complement, not replace, case management and vector control interventions. [ABSTRACT FROM AUTHOR]

Background: Models of Plasmodium falciparum malaria epidemiology that provide realistic quantitative predictions of likely epidemiological outcomes of existing vector control strategies have the potential to assist in planning for the control and elimination of malaria. This work investigates the applicability of mathematical modelling of malaria transmission dynamics in Rachuonyo South, a district with low, unstable transmission in the highlands of western Kenya. Methods: Individual-based stochastic simulation models of malaria in humans and a deterministic model of malaria in mosquitoes as part of the OpenMalaria platform were parameterized to create a scenario for the study area based on data from ongoing field studies and available literature. The scenario was simulated for a period of two years with a population of 10,000 individuals and validated against malaria survey data from Rachuonyo South. Simulations were repeated with multiple random seeds and an ensemble of 14 model variants to address stochasticity and model uncertainty. A one-dimensional sensitivity analysis was conducted to address parameter uncertainty. Results: The scenario was able to reproduce the seasonal pattern of the entomological inoculation rate (EIR) and patent infections observed in an all-age cohort of individuals sampled monthly for one year. Using an EIR estimated from serology to parameterize the scenario resulted in a closer fit to parasite prevalence than an EIR estimated using entomological methods. The scenario parameterization was most sensitive to changes in the timing and effectiveness of indoor residual spraying (IRS) and the method used to detect P. falciparum in humans. It was less sensitive than expected to changes in vector biting behaviour and climatic patterns. Conclusions: The OpenMalaria model of P. falciparum transmission can be used to simulate the impact of different combinations of current and potential control interventions to help plan malaria control in this low transmission setting. In this setting and for these scenarios, results were highly sensitive to transmission, vector exophagy, exophily and susceptibility to IRS, and the detection method used for surveillance. The level of accuracy of the results will thus depend upon the precision of estimates for each. New methods for analysing and evaluating uncertainty in simulation results will enhance the usefulness of simulations for malaria control decision-making. Improved measurement tools and increased primary data collection will enhance model parameterization and epidemiological monitoring. Further research is needed on the relationship between malaria indices to identify the best way to quantify transmission in low transmission settings. Measuring EIR through mosquito collection may not be the optimal way to estimate transmission intensity in areas with low, unstable transmission. [ABSTRACT FROM AUTHOR]

Background: As areas move closer to malaria elimination, a combination of limited resources and increasing heterogeneity in case distribution and transmission favour a shift to targeted reactive interventions. Reactive case detection (RCD), the following up of additional individuals surrounding an index case, has the potential to target transmission pockets and identify asymptomatic cases in them. Current RCD implementation strategies vary, and it is unclear which are most effective in achieving elimination. Methods: OpenMalaria, an established individual-based stochastic model, was used to simulate RCD in a Zambia-like setting. The capacity to follow up index cases, the search radius, the initial transmission and the case management coverage were varied. Suitable settings were identified and probabilities of elimination and time to elimination estimated. The value of routinely collected prevalence and incidence data for predicting the success of RCD was assessed. Results: The results indicate that RCD with the aim of transmission interruption is only appropriate in settings where initial transmission is very low (annual entomological inoculation rate (EIR) 1–2 or prevalence approx. < 7–19% depending on case management levels). Every index case needs to be followed up, up to a maximum case-incidence threshold which defines the suitability threshold of settings for elimination using RCD. Increasing the search radius around index cases is always beneficial. Conclusions: RCD is highly resource intensive, requiring testing and treating of 400–500 people every week for 5–10 years for a reasonable chance of elimination in a Zambia-like setting. [ABSTRACT FROM AUTHOR]

An abstract of the article "Modeling the cost-effectiveness of mass screening and treatment for reducing Plasmodium falciparum malaria burden," by Valerie Crowell, Olivier J. T. Briëf, Diggory Hardy, Nakul Chitnis, Nicolas Maire, Aurelio Di Pasguale, and Thomas A. Smith is presented.