Target For Malaria Control Research Articles

Spatial distribution and determinants of intermittent preventive treatment for malaria during pregnancy: a secondary data analysis of the 2019 Ghana malaria indicators survey

BackgroundMalaria during pregnancy is associated with poor maternal, foetal, and neonatal outcomes. To prevent malaria infection during pregnancy, the World Health Organization recommended the use of intermittent preventive therapy with sulfadoxine-pyrimethamine (IPTp-SP) in addition to vector control strategies. Although Ghana’s target is to ensure that all pregnant women receive at least three (optimal) doses of SP, the uptake of SP has remained low; between 2020 and 2022, only 60% of pregnant women received optimal SP during their most recent pregnancy. This study sought to map the geospatial distribution and identify factors associated with SP uptake during pregnancy in Ghana.MethodsSecondary data analysis was conducted using the 2019 Ghana Malaria Indicator Survey dataset. The data analysed were restricted to women aged 15–49 years who reported having a live birth within the two years preceding the survey. A modified Poisson regression model was used to determine factors associated with SP uptake during pregnancy. Geospatial analysis was employed to map the spatial distribution of optimal SP uptake across the ten regions of Ghana using R software.ResultsThe likelihood that pregnant women received optimal SP correlated with early initiation of first antenatal care (ANC), number of ANC contacts, woman’s age, region of residence, and family size. Overall, the greater the number of ANC contacts, the more likely for pregnant women to receive optimal SP. Women with four or more ANC contacts were 2 times (aPR: 2.16; 95% CI: [1.34–3.25]) more likely to receive optimal SP than pregnant women with fewer than four ANC contacts. In addition, early initiation and a high number of ANC contacts were associated with a high number of times a pregnant woman received SP. Regarding spatial distribution, a high uptake of optimal SP was significantly observed in the Upper East and Upper West Regions, whereas the lowest was observed in the Eastern Region of Ghana.ConclusionsIn Ghana, there were regional disparities in the uptake of SP during pregnancy, with the uptake mainly correlated with the provision of ANC services. To achieve the country’s target for malaria control during pregnancy, there is a need to strengthen intermittent preventive treatment for malaria during pregnancy by prioritizing comprehensive ANC services.

Is Brazil reaching malaria elimination? A time series analysis of malaria cases from 2011 to 2023.

In Brazil, 99% of malaria cases occur in the Amazon region, mainly caused by Plasmodium vivax (~83%) and Plasmodium falciparum (Pf) species. Aligned with the Sustainable Development Goals, Brazil aims to eliminate autochthonous malaria by 2035. This study aims to analyse epidemiological patterns of malaria in Brazil to discuss if Brazil is on track to meet malaria control targets. A time-series study was conducted analysing autochthonous malaria new infections notifications in the Brazilian Amazon region from 2011 until June 2023. Descriptive analyses were conducted, along with joinpoint regression and forecast models to verify trend and future behaviour. A total of 2,067,030 malaria cases were reported in the period. Trend analysis indicated a decreasing trend in all malaria infections since late 2017 (monthly reduction = 0.81%, p-value <0.05), while Pf infections have increased progressively since 2015 (monthly increase = 0.46%, p-value <0.05). Forecast models predict over 124,000 malaria cases in 2023 and over 96,000 cases in 2024. Predictions for Pf infections are around 23,900 cases in 2023 and 22,300 in 2024. Cases in indigenous population villages are predicted to reach 48,000 cases in 2023 and over 51,000 in 2024. In gold mining areas it is expected over 21,000 cases in 2023 and over 20.000 in 2024. Malaria elimination in Brazil has advanced over the last decade, but its speed has slowed. The country exhibits noteworthy advancements in the reduction of overall malaria cases. It is imperative, however, to proactively target specific issues such as the incidence raise among indigenous populations and in gold mining areas. Pf infections remain a persistent challenge to control in the country and may require novel measures for containment. Current government supporting actions towards combating illegal goldmining activities and protecting indigenous populations may help malaria control indicators for the following years.

Starving the Beast: Limiting Coenzyme A Biosynthesis to Prevent Disease and Transmission in Malaria.

Malaria parasites must acquire all necessary nutrients from the vertebrate and mosquito hosts to successfully complete their life cycle. Failure to acquire these nutrients can limit or even block parasite development and presents a novel target for malaria control. One such essential nutrient is pantothenate, also known as vitamin B5, which the parasite cannot synthesize de novo and is required for the synthesis of coenzyme A (CoA) in the parasite. This review examines pantothenate and the CoA biosynthesis pathway in the human-mosquito-malaria parasite triad and explores possible approaches to leverage the CoA biosynthesis pathway to limit malaria parasite development in both human and mosquito hosts. This includes a discussion of sources for pantothenate for the mosquito, human, and parasite, examining the diverse strategies used by the parasite to acquire substrates for CoA synthesis across life stages and host resource pools and a discussion of drugs and alternative approaches being studied to disrupt CoA biosynthesis in the parasite. The latter includes antimalarial pantothenate analogs, known as pantothenamides, that have been developed to target this pathway during the human erythrocytic stages. In addition to these parasite-targeted drugs, we review studies of mosquito-targeted allosteric enzymatic regulators known as pantazines as an approach to limit pantothenate availability in the mosquito and subsequently deprive the parasite of this essential nutrient.

Novel systems to study vector-pathogen interactions in malaria.

Some parasitic diseases, such as malaria, require two hosts to complete their lifecycle: a human and an insect vector. Although most malaria research has focused on parasite development in the human host, the life cycle within the vector is critical for the propagation of the disease. The mosquito stage of the Plasmodium lifecycle represents a major demographic bottleneck, crucial for transmission blocking strategies. Furthermore, it is in the vector, where sexual recombination occurs generating "de novo" genetic diversity, which can favor the spread of drug resistance and hinder effective vaccine development. However, understanding of vector-parasite interactions is hampered by the lack of experimental systems that mimic the natural environment while allowing to control and standardize the complexity of the interactions. The breakthrough in stem cell technologies has provided new insights into human-pathogen interactions, but these advances have not been translated into insect models. Here, we review in vivo and in vitro systems that have been used so far to study malaria in the mosquito. We also highlight the relevance of single-cell technologies to progress understanding of these interactions with higher resolution and depth. Finally, we emphasize the necessity to develop robust and accessible ex vivo systems (tissues and organs) to enable investigation of the molecular mechanisms of parasite-vector interactions providing new targets for malaria control.

PCR–RFLP assays for the identification of Anopheles (Diptera: Culicidae) species circulating in Honduras

BackgroundVector populations are a key target for malaria control and elimination. In Honduras, there are at least 12 reported anopheline species, however, the definitive number of species remains uncertain. Due to the inherent limitations of morphological identification of Anopheles species, molecular approaches have been developed to provide accurate identification and robust surveillance of local malaria vectors. The aim of this study was to design and assess three PCR–RFLP assays to identify anopheline species known to presently occur in Honduras.MethodsMosquitoes captured between 2018 and 2022 in seven malaria-endemic and non-endemic departments in Honduras were analysed. The ITS2 ribosomal region and three restriction enzyme-based assays were evaluated in silico and experimentally.ResultsA total of 132 sequences from 12 anopheline species were analysed. The ITS2 marker showed length polymorphisms that generated products between 388 and 592 bp and no relevant intraspecies polymorphisms were found. Furthermore, the three PCR–RFLP assays were able to differentiate 11 species with sufficient precision and resolution.ConclusionThe ITS2 region was shown to be a useful molecular marker for identifying local Anopheles species. In addition, the PCR–RFLP assays evaluated here proved to be capable of discriminating most of the anopheline species present in Honduras. These methods provide alternatives to improve entomological surveillance of Anopheles in Honduras and other Mesoamerican countries.

Plasmodium DDI1 is a potential therapeutic target and important chromatin-associated protein

DNA damage inducible 1 protein (DDI1) is involved in a variety of cellular processes including proteasomal degradation of specific proteins. All DDI1 proteins contain a ubiquitin-like (UBL) domain and a retroviral protease (RVP) domain. Some DDI1 proteins also contain a ubiquitin-associated (UBA) domain. The three domains confer distinct activities to DDI1 proteins. The presence of a RVP domain makes DDI1 a potential target of HIV protease inhibitors, which also block the development of malaria parasites. Hence, we investigated the DDI1 of malaria parasites to identify its roles during parasite development and potential as a therapeutic target. DDI1 proteins of Plasmodium and other apicomplexan parasites share the UBL-RVP domain architecture, and some also contain the UBA domain. Plasmodium DDI1 is expressed across all the major life cycle stages and is important for parasite survival, as conditional depletion of DDI1 protein in the mouse malaria parasite Plasmodium berghei and the human malaria parasite Plasmodium falciparum compromised parasite development. Infection of mice with DDI1 knock-down P. berghei was self-limiting and protected the recovered mice from subsequent infection with homologous as well as heterologous parasites, indicating the potential of DDI1 knock-down parasites as a whole organism vaccine. Plasmodium falciparum DDI1 (PfDDI1) is associated with chromatin and DNA-protein crosslinks. PfDDI1-depleted parasites accumulated DNA-protein crosslinks and showed enhanced susceptibility to DNA-damaging chemicals, indicating a role of PfDDI1 in removal of DNA-protein crosslinks. Knock-down of PfDDI1 increased susceptibility to the retroviral protease inhibitor lopinavir and antimalarial artemisinin, which suggests that simultaneous inhibition of DDI1 could potentiate antimalarial activity of these drugs. As DDI1 knock-down parasites confer protective immunity and it could be a target of HIV protease inhibitors, Plasmodium DDI1 is a potential therapeutic target for malaria control.

Socioeconomic determinants of malaria prevalence among under five children in Uganda: Evidence from 2018-19 Uganda Malaria Indicator Survey.

Malaria remains a significant public health problem in sub-Saharan Africa, affecting mainly children and pregnant women. In Uganda, little is known about the underlying socioeconomic correlates of malaria prevalence in children under five years of age. This study investigated the link between malaria infection among children under five and the socio-economic factors in Uganda. We estimated the prevalence of malaria among under-five children using secondary data from the 2019 Uganda Malaria Indicator Survey. Malaria infection status was ascertained using rapid diagnostic tests (RDTs). Multivariable logistic regression was employed to explore the socioeconomic correlates of malaria prevalence. Svyset command in STATA 16.0 was used to control for survey design. Overall, 6503 children were enrolled in the study. Of these, 1516 children tested positive for malaria, leading to an observed malaria prevalence of 23.3%. Older children (OR 1.01, 95%CI 1.01-1.01), and those from rural areas (OR 1.8, 95%CI 1.09-2.84) had higher odds of malaria infection. Children belonging to the highest wealth quintile had lower odds of malaria (OR 0.2, 95%CI 0.08-0.44). Indoor residual spray (OR 0.2, 95%CI 0.10-0.51) and use of treated bed nets (OR 0.8, 95%CI 0.69-0.99) were associated with reduced odds of malaria in children Interpretation & conclusion: Despite the significant increase in malaria preventive interventions in the last two decades, malaria remains highly prevalent in Ugandan under-five children. Indoor residual spraying and treated bed nets need to be promoted countrywide to reach malaria control targets. It is also imperative that appropriate education on proper and consistent use of mosquito bed-nets should be emphasized alongside embracing living habits that reduce the chances of mosquito bites like staying indoors.

Rethinking integrated service delivery for malaria.

Despite worldwide efforts and much progress toward malaria control, declines in malaria morbidity and mortality have hit a plateau. While many nations achieved significant malaria suppression or even elimination, success has been uneven, and other nations have made little headway-or even lost ground in this battle. These alarming trends threaten to derail the attainment of global targets for malaria control. Among the challenges impeding success in malaria reduction, many strategies center malaria as a set of technical problems in commodity development and delivery. Yet, this narrow perspective overlooks the importance of strong health systems and robust healthcare delivery. This paper argues that strategies that move the needle on health services and behaviors offer a significant opportunity to achieve malaria control through a comprehensive approach that integrates malaria with broader health services efforts. Indeed, malaria may serve as the thread that weaves integrated service delivery into a path forward for universal health coverage. Using key themes identified by the "Rethinking Malaria in the Context of COVID-19" effort through engagement with key stakeholders, we provide recommendations for pursuing integrated service delivery that can advance malaria control via strengthening health systems, increasing visibility and use of high-quality data at all levels, centering issues of equity, promoting research and innovation for new tools, expanding knowledge on effective implementation strategies for interventions, making the case for investing in malaria among stakeholders, and engaging impacted communities and nations.

CRISPR/Cas9 mediates efficient site-specific mutagenesis of the odorant receptor co-receptor (Orco) in the malaria vector Anopheles sinensis.

Anopheles sinensis is the most widely distributed mosquito species and is the main transmitter of Plasmodium vivax malaria in China. Most previous research has focused on the mechanistic understanding of biological processes in An. sinensis and novel ways of interrupting malaria transmission. However, the development of functional genomics and genetics-based vector control strategies against An. sinensis remain limited because of insufficient site-specific genome editing tools. We report the first successful application of the CRISPR/Cas9 mediated knock-in for highly efficient, site-specific mutagenesis in An. sinensis. The EGFP marker gene driven by the 3 × P3 promoter was precisely integrated into the odorant receptor co-receptor (Orco) by direct injections of Cas9 protein, double-stranded DNA donor, and Orco-gRNA. We achieved a mutation rate of 3.77%, similar to rates in other mosquito species. Precise knock-in at the intended locus was confirmed by polymerase chain reaction (PCR) amplification and sequencing. The Orco mutation severely impaired mosquito sensitivity to some odors and their ability to locate and discriminate a human host. Orco was confirmed as a key mediator of multiple olfactory-driven behaviors in the An. sinensis life cycle, highlighting the importance of Orco as a key molecular target for malaria control. The results also demonstrated that CRISPR/Cas9 was a simple and highly efficient genome editing technique for An. sinensis and could be used to develop genetic control tools for this vector. © 2022 Society of Chemical Industry.

Discovery of metabolic alterations in the serum of patients infected with Plasmodium spp. by high-resolution metabolomics.

Despite the advances in diagnosis and treatment, malaria has still not been eradicated. Metabolic interactions between the host and Plasmodium may present novel targets for malaria control, but such interactions are yet to be deciphered. An exploration of metabolic interactions between humans and two Plasmodium species by high-resolution metabolomics may provide fundamental insights that can aid the development of a new strategy for the control of malaria. This study aimed at exploring the metabolic changes in the sera of patients infected with Plasmodium falciparum and Plasmodium vivax. Uni- and multivariate metabolomic analyses were performed on the sera of four groups of patients, namely normal control (N, n = 100), P. falciparum-infected patients (PF, n = 21), P. vivax-infected patients (PV, n = 74), and non-malarial pyretic patients (Pyr, n = 25). Univariate and multivariate analyses of N, PF, and PV groups showed differential metabolic phenotypes and subsequent comparisons in pairs revealed significant features. Pathway enrichment test with significant features showed the affected pathways, namely glycolysis/gluconeogenesis for PF and retinol metabolism for PV. The metabolites belonging to the affected pathways included significantly low 2,3-diphosphoglycerate and glyceraldehyde-3-phosphate in the sera of PF. The sera of PV had significantly low levels of retinol but high levels of retinoic acid. Our study reveals metabolic alterations induced by Plasmodium spp. in human serum and would serve as a milestone in the development of novel anti-malarial strategies.

The effects of insecticides on two splice variants of the glutamate-gated chloride channel receptor of the major malaria vector, Anopheles gambiae.

Between half to 1 million people die annually from malaria. Anopheles gambiae mosquitoes are major malaria vectors. Unfortunately, resistance has emerged to the agents currently used to control A.gambiae, creating a demand for novel control measures. The pentameric glutamate-gated chloride channel (GluCl) expressed in the muscle and nerve cells of these organisms are a potentially important biological target for malaria control. The pharmacological properties of Anophiline GluCl receptors are, however, largely unknown. Accordingly, we compared the efficacy of four insecticides (lindane, fipronil, picrotoxin, and ivermectin) on two A.gambiae GluCl receptor splice variants with the aim of providing a molecular basis for designing novel anti-malaria treatments. The A.gambiae GluCl receptor b1 and c splice variants were expressed homomerically in Xenopus laevis oocytes and studied with electrophysiological techniques, using two-electrode voltage-clamp. The b1 and c GluCl receptors were activated with similar potencies by glutamate and ivermectin. Fipronil was more potent than picrotoxin and lindane at inhibiting glutamate- and ivermectin-gated currents. Importantly, b1 GluCl receptors exhibited reduced sensitivity to picrotoxin and lindane. They also recovered from these effects to a greater extent than c GluCl receptors CONCLUSIONS AND IMPLICATIONS: The two splice variant subunits exhibited differential sensitivities to multiple, structurally divergent insecticides, without accompanying changes in the sensitivity to the endogenous neurotransmitter, glutamate, implying that drug resistance may be caused by alterations in relative subunit expression levels, without affecting physiological function. Our results strongly suggest that it should be feasible to develop novel subunit-specific pharmacological agents.

Low Levels of Human Antibodies to Gametocyte-Infected Erythrocytes Contrasts the PfEMP1-Dominant Response to Asexual Stages in P. falciparum Malaria.

Vaccines that target Plasmodium falciparum gametocytes have the potential to reduce malaria transmission and are thus attractive targets for malaria control. However, very little is known about human immune responses to gametocytes present in human hosts. We evaluated naturally-acquired antibodies to gametocyte-infected erythrocytes (gametocyte-IEs) of different developmental stages compared to other asexual parasite stages among naturally-exposed Kenyan residents. We found that acquired antibodies strongly recognized the surface of mature asexual-IEs, but there was limited reactivity to the surface of gametocyte-IEs of different stages. We used genetically-modified P. falciparum with suppressed expression of PfEMP1, the major surface antigen of asexual-stage IEs, to demonstrate that PfEMP1 is a dominant target of antibodies to asexual-IEs, in contrast to gametocyte-IEs. Antibody reactivity to gametocyte-IEs was similar to asexual-IEs lacking PfEMP1. Significant antibody reactivity to the surface of gametocytes was observed when outside of the host erythrocyte, including recognition of the major gametocyte antigen, Pfs230. This indicates that there is a deficiency of acquired antibodies to gametocyte-IEs despite the acquisition of antibodies to gametocyte antigens and asexual IEs. Our findings suggest that the acquisition of substantial immunity to the surface of gametocyte-IEs is limited, which may facilitate immune evasion to enable malaria transmission even in the face of substantial host immunity to malaria. Further studies are needed to understand the basis for the limited acquisition of antibodies to gametocytes and whether vaccine strategies can generate substantial immunity.

Highly Efficient Site-Specific Mutagenesis in Malaria Mosquitoes Using CRISPR.

Anopheles mosquitoes transmit at least 200 million annual malaria infections worldwide. Despite considerable genomic resources, mechanistic understanding of biological processes in Anopheles has been hampered by a lack of tools for reverse genetics. Here, we report successful application of the CRISPR/Cas9 system for highly efficient, site-specific mutagenesis in the diverse malaria vectors Anopheles albimanus, A. coluzzii, and A. funestus. When guide RNAs (gRNAs) and Cas9 protein are injected at high concentration, germline mutations are common and usually biallelic, allowing for the rapid creation of stable mutant lines for reverse genetic analysis. Our protocol should enable researchers to dissect the molecular and cellular basis of anopheline traits critical to successful disease transmission, potentially exposing new targets for malaria control.

Adaptation of Plasmodium falciparum to its transmission environment.

Success in eliminating malaria will depend on whether parasite evolution outpaces control efforts. Here, we show that Plasmodium falciparum parasites (the deadliest of the species causing human malaria) found in low-transmission-intensity areas have evolved to invest more in transmission to new hosts (reproduction) and less in within-host replication (growth) than parasites found in high-transmission areas. At the cellular level, this adaptation manifests as increased production of reproductive forms (gametocytes) early in the infection at the expense of processes associated with multiplication inside red blood cells, especially membrane transport and protein trafficking. At the molecular level, this manifests as changes in the expression levels of genes encoding epigenetic and translational machinery. Specifically, expression levels of the gene encoding AP2-G-the transcription factor that initiates reproduction-increase as transmission intensity decreases. This is accompanied by downregulation and upregulation of genes encoding HDAC1 and HDA1-two histone deacetylases that epigenetically regulate the parasite's replicative and reproductive life-stage programmes, respectively. Parasites in reproductive mode show increased reliance on the prokaryotic translation machinery found inside the plastid-derived organelles. Thus, our dissection of the parasite's adaptive regulatory architecture has identified new potential molecular targets for malaria control.

Investigating unlicensed retail drug vendors’ preparedness and knowledge about malaria: An exploratory study in rural Uganda

BackgroundDespite major efforts to increase the uptake of preventive measures and timely use of the first line antimalarial treatment artemisinin-based combination therapies (ACT), Uganda continues to fall short of meeting its national malaria control targets. One of the challenges has been scaling up effective measures in rural and remote areas where the unlicensed private retail sector remains the first point of contact and a common source of treatment. The current paper discusses unlicensed vendors’ (1) training related to malaria case management for children aged five and under, and (2) knowledge related to the cause of malaria, preventive measures, common signs, and symptoms, diagnostic procedures, and best treatment options. MethodsA qualitative study using semi-structured interviews was conducted in the rural district of Butaleja, Uganda in 2011. All 88 unlicensed drug outlets enumerated in the study area were visited by six locally recruited research assistants, with one vendor from each outlet invited to participate. The transcripts were analyzed using acceptable qualitative research protocols. ResultsAbout half of the 75 vendors interviewed had received some sort of formal training on malaria at a post-secondary institution, although only 6.7% had qualifications which met licensure requirements. The study found widespread misconceptions relating to the cause, as well as prevention and treatment of malaria. A large majority of the vendors relied primarily on non-specific symptoms and limited physical exams for diagnoses, with less than one-tenth of the vendors recognizing that rapid or microscopic blood testing was necessary to confirm a clinical diagnosis of malaria. While most recognized mosquitoes as the primary vector for malaria, over two-fifths of the vendors held misconceptions about the factors that could increase the risk of malaria, and nearly a third believed that malaria could not be prevented. With respect to acute case management, three-quarters viewed as the best option a medicine other than the government’s first-line antimalarial, artemisinin-based combination therapies (ACT). Almost three-fifths specified quinine as their preferred option, with about one-fifth recommending quinine injection. ConclusionFindings from this study confirm significant gaps in unlicensed vendors’ knowledge related to malaria. With increased utilization of unlicensed drug outlets in rural and remote settings such as Butaleja, findings from this study strongly supports the need to implement strategies to improve the quality of care delivered at these outlet.

Global investment targets for malaria control and elimination between 2016 and 2030

BackgroundAccess to malaria control interventions falls short of universal health coverage. The Global Technical Strategy for malaria targets at least 90% reduction in case incidence and mortality rates, and elimination...

Plasmodium falciparum parasitaemia and malaria among pregnant women at first clinic visit in the mount Cameroon Area.

BackgroundPregnant women in malaria endemic areas are at high risk of P. falciparum infection and its complications. This study investigated the prevalence and risk factors for P. falciparum infection and malaria among pregnant women reporting for first antenatal care (ANC) clinic visit in the mount Cameroon area.MethodsVenous blood samples from consented pregnant women were screened for malaria parasitaemia by light microscopy. Haemoglobin levels, white blood cell (WBC) counts, lymphocyte counts and percentage were determined using an automated haematology analyser. Socio-demographic/economic data, environmental factors and use of malaria control measures were documented. Univariate and multivariate statistical analyses were used.ResultsSixty-eight (22.4 %; N = 303) of the women enrolled were positive for P. falciparum parasitaemia. Malaria parasitaemia was significantly (P < 0.001) associated with febrile illness. The overall prevalence of malaria and asymptomatic infection was 16.0 % (95 % CI = 11-20 %) and 10.5 % (95 % CI = 7.3-15 %) respectively. A greater proportion of the malaria cases (61 %) reported at the clinic during unscheduled days meanwhile women with asymptomatic parasitaemia mostly (92.8 %) seek for ANC during scheduled clinic days. Lower lymphocyte percentage was significantly associated with increase parasite density (r = − 0.34; P = 0.011) and febrile status (MU = 2.46; P = 0.014). While age and gravidity were significant factors associated with P. falciparum infection and/or malaria, the presence of bush and/or standing water around human residence was an independent risk factor of P. falciparum parasitaemia (OR = 3.3: 95 % CI = 1.6 – 7.0; P = 0.002) and malaria ( OR = 5.2: 95 % CI = 2.0 – 14; P = 0.001). Being unmarried was significantly associated with increase risk (OR = 2.6:95 % CI = 1.1 – 6.0; P = 0.032) of P. falciparum parasitaemia. Similarly, single women (938) had a significantly higher (t = 2.70; P = 0.009) geometric mean parasite density (GMPD) compared with married women (338).ConclusionMarital status and human residence in areas with bushes and/or standing water modify risk of P. falciparum infection and malaria. Education on early ANC attendance and environmental sanitation are important public health targets for malaria control in pregnancy in this setting.

Phenotypic Dissection of a Plasmodium-Refractory Strain of Malaria Vector Anopheles stephensi: The Reduced Susceptibility to P. berghei and P. yoelii

Anopheline mosquitoes are the major vectors of human malaria. Parasite-mosquito interactions are a critical aspect of disease transmission and a potential target for malaria control. Current investigations into parasite-mosquito interactions frequently assume that genetically resistant and susceptible mosquitoes exist in nature. Therefore, comparisons between the Plasmodium susceptibility profiles of different mosquito species may contribute to a better understanding of vectorial capacity. Anopheles stephensi is an important malaria vector in central and southern Asia and is widely used as a laboratory model of parasite transmission due to its high susceptibility to Plasmodium infection. In the present study, we identified a rodent malaria-refractory strain of A. stephensi mysorensis (Ehime) by comparative study of infection susceptibility. A very low number of oocysts develop in Ehime mosquitoes infected with P. berghei and P. yoelii, as determined by evaluation of developed oocysts on the basal lamina. A stage-specific study revealed that this reduced susceptibility was due to the impaired formation of ookinetes of both Plasmodium species in the midgut lumen and incomplete crossing of the midgut epithelium. There were no apparent abnormalities in the exflagellation of male parasites in the ingested blood or the maturation of oocysts after the rounding up of the ookinetes. Overall, these results suggest that invasive-stage parasites are eliminated in both the midgut lumen and epithelium in Ehime mosquitoes by strain-specific factors that remain unknown. The refractory strain newly identified in this report would be an excellent study system for investigations into novel parasite-mosquito interactions in the mosquito midgut.

Progress towards malaria control targets in relation to national malaria programme funding

BackgroundMalaria control has been dramatically scaled up the past decade, mainly thanks to increasing international donor financing since 2003. This study assessed progress up to 2010 towards global malaria impact targets, in relation to Global Fund, other donor and domestic malaria programme financing over 2003 to 2009.MethodsAssessments used domestic malaria financing reported by national programmes, and Global Fund/OECD data on donor financing for 90 endemic low- and middle-income countries, WHO estimates of households owning one or more insecticide-treated mosquito net (ITN) for countries in sub-Saharan Africa, and WHO-estimated malaria case incidence and deaths in countries outside sub-Saharan Africa.ResultsGlobal Fund and other donor funding is concentrated in a subset of the highest endemic African countries. Outside Africa, donor funding is concentrated in those countries with highest malaria mortality and case incidence rates over the years 2000 to 2003. ITN coverage in 2010 in Africa, and declines in case and death rates per person at risk over 2004 to 2010 outside Africa, were greatest in countries with highest donor funding per person at risk, and smallest in countries with lowest donor malaria funding per person at risk. Outside Africa, all-source malaria programme funding over 2003 to 2009 per case averted ($56-5,749) or per death averted ($58,000-3,900,000) over 2004 to 2010 tended to be lower (more favourable) in countries with higher donor malaria funding per person at risk.ConclusionsIncreases in malaria programme funding are associated with accelerated progress towards malaria control targets. Associations between programme funding per person at risk and ITN coverage increases and declines in case and death rates suggest opportunities to maximize the impact of donor funding, by strategic re-allocation to countries with highest continued need.

PRM161 A Paradigm Shift in Health Economic Evaluations for Developing Countries - Optimization Modelling for Assessing Which Mix of Malaria Prevention Strategies Achieves a Defined Public Health Target at the Lowest Budget

PRM161 A PARADIGM SHIFT IN HEALTH ECONOMIC EVALUATIONS FOR DEVELOPING COUNTRIES OPTIMIZATION MODELLING FOR ASSESSING WHICH MIX OF MALARIA PREVENTION STRATEGIES ACHIEVES A DEFINED PUBLIC HEALTH TARGET AT THE LOWEST BUDGET Van Vlaenderen I1, Sauboin C2, Van Bellinghen LA1, Standaert B2 1CHESS, Ternat, Belgium, 2GlaxoSmithKline Vaccines, Wavre, Belgium Malaria remains one of the leading causes of ill health with the majority of cases and deaths occurring in young children in Sub-Saharan Africa. Key interventions currently recommended for preventing childhood malaria include Insecticide Treated Nets, Indoor Residual Spraying, Intermittent Preventive Treatment in infancy, and Seasonal Malaria Chemoprevention. One-to-one comparisons applied in cost-effectiveness and budget impact analyses fail to examine the health and economic impact of multiple interventions implemented simultaneously, and are therefore unable to evaluate the optimal integration of available malaria preventive interventions and partially efficacious vaccines currently in development. Moreover, an incremental cost-effectiveness ratio with recommended willingnessto-pay threshold provides limited guidance in developing countries. OBJECTIVE: Defining an approach to identify the optimal sequence of introducing different preventive interventions, achieving progressively increasing public health targets for malaria control in children 5years old at the lowest budget. METHODS: Our suggested optimization approach integrates two distinguished models to assess combinations of interventions. A vector model simulates the impact of varying coverages of vector control interventions on vector infectiousness capacity and associated reduction in Entomological Inoculation Rate (EIR) for children. A human host model applies this reduced EIR to simulate disease incidence at varying coverages of interventions directly acting within humans. These connected models provide all potential intervention combinations achieving a pre-defined public health target (e.g. reducing childhood mortality with 50%). Considering malaria policy evolutions at increasing public health targets, a lower bound is set on intervention coverages at each optimization step. The remaining options are ranked according to their budget impact considering cost of interventions and disease management in a health system perspective. CONCLUSIONS: Using the optimization process with progressively increasing public health targets provides an indication on the optimal sequence of introducing interventions at the lowest budget. Therefore, this approach can support decision-making in prioritization of malaria preventive interventions.