Malaria elimination campaigns in the Lake Kariba region of Zambia: a spatial dynamical model

Background As more regions approach malaria elimination, understanding how different interventions interact to reduce transmission becomes critical. The Lake Kariba area of Southern Province, Zambia, is part of a multi-country elimination effort and presents a particular challenge as it is an interconnected region of variable transmission intensities. Methods In 2012-13, six rounds of mass-screen-and-treat drug campaigns were carried out in the Lake Kariba region. A spatial dynamical model of malaria transmission in the Lake Kariba area, with transmission and climate modeled at the village scale, was calibrated to the 2012-13 prevalence survey data, with case management rates, insecticide-treated net usage, and drug campaign coverage informed by surveillance. The model was used to simulate the effect of various interventions implemented in 2014-22 on reducing regional transmission, achieving elimination by 2022, and maintaining elimination through 2028. Findings The model captured the spatio-temporal trends of decline and rebound in malaria prevalence in 2012-13 at the village scale. Simulations predicted that elimination required repeated mass drug administrations coupled with simultaneous increase in net usage. Drug campaigns targeted only at high-burden areas were as successful as campaigns covering the entire region. Interpretation Elimination in the Lake Kariba region is possible through coordinating mass drug campaigns with high-coverage vector control. Targeting regional hotspots is a viable alternative to global campaigns when human migration within an interconnected area is responsible for maintaining transmission in low-burden areas

Optimal population-level infection detection strategies for malaria control and elimination in a spatial model of malaria transmission

Mass campaigns with antimalarial drugs are potentially a powerful tool for local elimination of malaria, yet current diagnostic technologies are insufficiently sensitive to identify all individuals who harbor infections. At the same time, overtreatment of uninfected individuals increases the risk of accelerating emergence of drug resistance and losing community acceptance. Local heterogeneity in transmission intensity may allow campaign strategies that respond to index cases to successfully target subpatent infections while simultaneously limiting overtreatment. While selective targeting of hotspots of transmission has been proposed as a strategy for malaria control, such targeting has not been tested in the context of malaria elimination. Using household locations, demographics, and prevalence data from a survey of four health facility catchment areas in southern Zambia and an agent-based model of malaria transmission and immunity acquisition, a transmission intensity was fit to each household based on neighborhood age-dependent malaria prevalence. A set of individual infection trajectories was constructed for every household in each catchment area, accounting for heterogeneous exposure and immunity. Various campaign strategies (mass drug administration, mass screen and treat, focal mass drug administration, snowball reactive case detection, pooled sampling, and a hypothetical serological diagnostic) were simulated and evaluated for performance at finding infections, minimizing overtreatment, reducing clinical case counts, and interrupting transmission. For malaria control, presumptive treatment leads to substantial overtreatment without additional morbidity reduction under all but the highest transmission conditions. Selective targeting of hotspots with drug campaigns is an ineffective tool for elimination due to limited sensitivity of available field diagnostics

Mass campaigns with antimalarial drugs: a modelling comparison of artemether-lumefantrine and DHA-piperaquine with and without primaquine as tools for malaria control and elimination

Antimalarial drugs are a powerful tool for malaria control and elimination. Artemisinin-based combination therapies (ACTs) can reduce transmission when widely distributed in a campaign setting. Modelling mass antimalarial campaigns can elucidate how to most effectively deploy drug-based interventions and quantitatively compare the effects of cure, prophylaxis, and transmission-blocking in suppressing parasite prevalence. A previously established agent-based model that includes innate and adaptive immunity was used to simulate malaria infections and transmission. Pharmacokinetics of artemether, lumefantrine, dihydroartemisinin, piperaquine, and primaquine were modelled with a double-exponential distribution-elimination model including weight-dependent parameters and age-dependent dosing. Drug killing of asexual parasites and gametocytes was calibrated to clinical data. Mass distribution of ACTs and primaquine was simulated with seasonal mosquito dynamics at a range of transmission intensities. A single mass campaign with antimalarial drugs is insufficient to permanently reduce malaria prevalence when transmission is high. Current diagnostics are insufficiently sensitive to accurately identify asymptomatic infections, and mass-screen-and-treat campaigns are much less efficacious than mass drug administrations. Improving campaign coverage leads to decreased prevalence one month after the end of the campaign, while increasing compliance lengthens the duration of protection against reinfection. Use of a long-lasting prophylactic as part of a mass drug administration regimen confers the most benefit under conditions of high transmission and moderately high coverage. Addition of primaquine can reduce prevalence but exerts its largest effect when coupled with a long-lasting prophylactic.Comment: 14 pages, 5 figure

The role of research in viral disease eradication and elimination programs: Lessons for malaria eradication

By examining the role research has played in eradication or regional elimination initiatives for three viral diseases-smallpox, poliomyelitis, and measles-we derive nine cross-cutting lessons applicable to malaria eradication. In these initiatives, some types of research commenced as the programs began and proceeded in parallel. Basic laboratory, clinical, and field research all contributed notably to progress made in the viral programs. For each program, vaccine was the lynchpin intervention, but as the programs progressed, research was required to improve vaccine formulations, delivery methods, and immunization schedules. Surveillance was fundamental to all three programs, whilst polio eradication also required improved diagnostic methods to identify asymptomatic infections. Molecular characterization of pathogen isolates strengthened surveillance and allowed insights into the geographic source of infections and their spread. Anthropologic, sociologic, and behavioural research were needed to address cultural and religious beliefs to expand community acceptance. The last phases of elimination and eradication became increasingly difficult, as a nil incidence was approached. Any eradication initiative for malaria must incorporate flexible research agendas that can adapt to changing epidemiologic contingencies and allow planning for posteradication scenarios. © 2011 Breman et al

High Effective Coverage of Vector Control Interventions in Children After Achieving Low Malaria Transmission in Zanzibar, Tanzania.

\ud \ud Formerly a high malaria transmission area, Zanzibar is now targeting malaria elimination. A major challenge is to avoid resurgence of malaria, the success of which includes maintaining high effective coverage of vector control interventions such as bed nets and indoor residual spraying (IRS). In this study, caretakers' continued use of preventive measures for their children is evaluated, following a sharp reduction in malaria transmission. A cross-sectional community-based survey was conducted in June 2009 in North A and Micheweni districts in Zanzibar. Households were randomly selected using two-stage cluster sampling. Interviews were conducted with 560 caretakers of under-five-year old children, who were asked about perceptions on the malaria situation, vector control, household assets, and intention for continued use of vector control as malaria burden further decreases. Effective coverage of vector control interventions for under-five children remains high, although most caretakers (65%; 363/560) did not perceive malaria as presently being a major health issue. Seventy percent (447/643) of the under-five children slept under a long-lasting insecticidal net (LLIN) and 94% (607/643) were living in houses targeted with IRS. In total, 98% (628/643) of the children were covered by at least one of the vector control interventions. Seasonal bed-net use for children was reported by 25% (125/508) of caretakers of children who used bed nets. A high proportion of caretakers (95%; 500/524) stated that they intended to continue using preventive measures for their under-five children as malaria burden further reduces. Malaria risk perceptions and different perceptions of vector control were not found to be significantly associated with LLIN effective coverage While the majority of caretakers felt that malaria had been reduced in Zanzibar, effective coverage of vector control interventions remained high. Caretakers appreciated the interventions and recognized the value of sustaining their use. Thus, sustaining high effective coverage of vector control interventions, which is crucial for reaching malaria elimination in Zanzibar, can be achieved by maintaining effective delivery of these interventions

Shrinking the Malaria Map: A Prospectus on Malaria Elimination

\ud Thirty-nine countries across the world are making progress toward malaria elimination. Some are committed to nationwide elimination, while others are pursuing spatially progressive elimination within their borders. Influential donor and multilateral organizations are supporting their goals of achieving malaria-free status. With elimination back on the global agenda, countries face a myriad of questions. Should they change their programs to eliminate rather than control malaria? What tools are available? What policies need to be put into place? How will they benefit from elimination? Unfortunately, answers to these questions, and resources for agencies and country program managers considering or pursuing elimination, are scarce. The 39 eliminating countries are all positioned along the endemic margins of the disease, yet they naturally experience a variety of country characteristics and epidemiologies that make their malaria situations different from one another. The Malaria Elimination Group (MEG) and this Prospectus recognize\ud that there is no single solution, strategy, or time line that will be appropriate for every country, and each is encouraged to initiate a comprehensive evaluation of its readiness and strategy for elimination. The Prospectus is designed to guide countries in conducting these assessments. The Prospectus provides detailed and informed discussion on the practical means of achieving and sustaining zero transmission. It is designed as a road map, providing direction and options from which to choose an appropriate path. As on all maps, the destination is clearly marked, but the possible routes to reach it are numerous. The Prospectus is divided into two sections: Section 1 Eliminating Malaria comprises four chapters covering the strategic components important to the periods before, during, and after an elimination program. Section 2 Tools for the Job, comprises six chapters that outline basic information about how interventions in an elimination program will be different from those in a control setting. Chapter 1, Making the Decision, evaluates the issues that a country should consider when deciding whether or not to eliminate malaria. The chapter begins with a discussion about the quantitative and qualitative benefits that a country could expect from eliminating malaria and then recommends a thorough feasibility assessment. The feasibility assessment is based on three major components: operational, technical, and financial feasibility. Cross-border and regional collaboration is a key subject in this chapter. Chapter 2, Getting to Zero, describes changes that programs must consider when moving from sustained control to an elimination goal. The key strategic issues that must be addressed are considered, including supply chains, surveillance systems, intersectoral collaboration, political will, and legislative framework. Cross-border collaboration is again a key component in Getting to Zero. Chapter 3, Holding the Line, provides recommendations on how to conduct an assessment of two key factors that will affect preventing the reemergence of malaria once transmission is interrupted: outbreak risk and importation risk. The chapter emphasizes the need for a strong surveillance system in order to prevent and, if necessary, respond to imported cases. Chapter 4, Financing Elimination, reviews the cost-effectiveness of elimination as compared with sustained control and then presents the costs of selected elimination programs as examples. It evaluates four innovative financing mechanisms that must support elimination, emphasizing the need for predictable and stable financing. Case studies from Swaziland and two provinces in China are provided. Chapter 5, Understanding Malaria, considers malaria from the point of view of elimination and provides a concise overview of the current burden of the disease, malaria transmission, and the available interventions that can be used in an elimination program. Chapter 6, Learning from History, extracts important lessons from the Global Malaria Eradication Program and analyzes some elimination efforts that were successful and some that were unsuccessful. The chapter also reviews how the malaria map has been shrinking since 1900. xiv A Prosp ectus on Mala ria Elimi natio n\ud Chapter 7, Measuring Malaria for Elimination, provides a precise language for discussing malaria and gives the elimination discussion a quantitative structure. The chapter also describes the role of epidemiological theory and mathematical modeling in defining and updating an elimination agenda for malaria. Chapter 8, Killing the Parasite, outlines the importance of case detection and management in an elimination setting. Options for diagnosis, the hidden challenge of Plasmodium vivax in an elimination setting, and the impact of immunity are all discussed. Chapter 9, Suppressing the Vector, explores vector control, a necessary element of any malaria program. It considers optimal methods available to interrupt transmission and discusses potential changes, such as insecticide resistance, that may affect elimination efforts. Chapter 10, Identifying the Gaps — What We Need to Know, reviews the gaps in our understanding of what is required for elimination. The chapter outlines a short-term research agenda with a focus on the operational needs that countries are facing today. The Prospectus reviews the operational, technical, and financial feasibility for those working on the front lines and considers whether, when, and how to eliminate malaria. A companion document, A Guide on Malaria Elimination for Policy Makers, is provided for those countries or agencies whose responsibility is primarily to make the policy decisions on whether to pursue or support a malaria elimination strategy. The Guide is available at www.malaria eliminationgroup.org

Epidemiology of Subpatent Plasmodium Falciparum Infection: Implications for Detection of Hotspots with Imperfect Diagnostics.

At the local level, malaria transmission clusters in hotspots, which may be a group of households that experience higher than average exposure to infectious mosquitoes. Active case detection often relying on rapid diagnostic tests for mass screen and treat campaigns has been proposed as a method to detect and treat individuals in hotspots. Data from a cross-sectional survey conducted in north-western Tanzania were used to examine the spatial distribution of Plasmodium falciparum and the relationship between household exposure and parasite density. Dried blood spots were collected from consenting individuals from four villages during a survey conducted in 2010. These were analysed by PCR for the presence of P. falciparum, with the parasite density of positive samples being estimated by quantitative PCR. Household exposure was estimated using the distance-weighted PCR prevalence of infection. Parasite density simulations were used to estimate the proportion of infections that would be treated using a screen and treat approach with rapid diagnostic tests (RDT) compared to targeted mass drug administration (tMDA) and Mass Drug Administration (MDA). Polymerase chain reaction PCR analysis revealed that of the 3,057 blood samples analysed, 1,078 were positive. Mean distance-weighted PCR prevalence per household was 34.5%. Parasite density was negatively associated with transmission intensity with the odds of an infection being subpatent increasing with household exposure (OR 1.09 per 1% increase in exposure). Parasite density was also related to age, being highest in children five to ten years old and lowest in those > 40 years. Simulations of different tMDA strategies showed that treating all individuals in households where RDT prevalence was above 20% increased the number of infections that would have been treated from 43 to 55%. However, even with this strategy, 45% of infections remained untreated. The negative relationship between household exposure and parasite density suggests that DNA-based detection of parasites is needed to provide adequate sensitivity in hotspots. Targeting MDA only to households with RDT-positive individuals may allow a larger fraction of infections to be treated. These results suggest that community-wide MDA, instead of screen and treat strategies, may be needed to successfully treat the asymptomatic, subpatent parasite reservoir and reduce transmission in similar settings

Reducing Plasmodium falciparum malaria transmission in Africa: a model-based evaluation of intervention strategies.

BACKGROUND: Over the past decade malaria intervention coverage has been scaled up across Africa. However, it remains unclear what overall reduction in transmission is achievable using currently available tools. METHODS AND FINDINGS: We developed an individual-based simulation model for Plasmodium falciparum transmission in an African context incorporating the three major vector species (Anopheles gambiae s.s., An. arabiensis, and An. funestus) with parameters obtained by fitting to parasite prevalence data from 34 transmission settings across Africa. We incorporated the effect of the switch to artemisinin-combination therapy (ACT) and increasing coverage of long-lasting insecticide treated nets (LLINs) from the year 2000 onwards. We then explored the impact on transmission of continued roll-out of LLINs, additional rounds of indoor residual spraying (IRS), mass screening and treatment (MSAT), and a future RTS,S/AS01 vaccine in six representative settings with varying transmission intensity (as summarized by the annual entomological inoculation rate, EIR: 1 setting with low, 3 with moderate, and 2 with high EIRs), vector-species combinations, and patterns of seasonality. In all settings we considered a realistic target of 80% coverage of interventions. In the low-transmission setting (EIR approximately 3 ibppy [infectious bites per person per year]), LLINs have the potential to reduce malaria transmission to low levels (90%) or novel tools and/or substantial social improvements will be required, although considerable reductions in prevalence can be achieved with existing tools and realistic coverage levels. CONCLUSIONS: Interventions using current tools can result in major reductions in P. falciparum malaria transmission and the associated disease burden in Africa. Reduction to the 1% parasite prevalence threshold is possible in low- to moderate-transmission settings when vectors are primarily endophilic (indoor-resting), provided a comprehensive and sustained intervention program is achieved through roll-out of interventions. In high-transmission settings and those in which vectors are mainly exophilic (outdoor-resting), additional new tools that target exophagic (outdoor-biting), exophilic, and partly zoophagic mosquitoes will be required

Why use of interventions targeting outdoor biting mosquitoes will be necessary to achieve malaria elimination

By definition, elimination of malaria means permanent reduction to zero of locally incidence of infections. Achieving this goal among other reasons, it requires fully understanding on where and when persons are most exposed to malaria vectors as these are fundamental for targeting interventions to achieve maximum impact. While elimination can be possible in some settings with low malaria transmission intensity and dominated with late and indoor biting of vectors using Long Lasting Insecticidal Nets (LLIN) and Indoor Residual Spraying (IRs), it’s difficult and even impossible in areas with high and where majority of human exposure to transmission occurs outside human dwellings. Recently in response to wide spread use of LLIN and IRS, human risk of exposure to transmission is increasingly spread across the entire night so that much of it occurs outdoors and before bed time. This modification of vector populations and behaviour has now been reported from across Africa, Asia and from the Solomon Islands. Historical evidence shows that even in areas with intervention coverage exceeding 90% of human population it was so hard to even push prevalence down below the pre elimination threshold of 1% being compromised mainly with the outdoor residual transmission. Malaria control experts must however continue to deliver interventions that tackle indoor transmission but considerable amount of resources that target mosquitoes outside of houses and outside of sleeping hours will therefore be required to sustain and go beyond existing levels of malaria control and achieve elimination