malaria trial

Malaria remains a major threat to human health, as strains resistant to current therapeutics are discovered. Efforts in finding new drug targets are hampered by the lack of sufficiently specific tools to provide target validation prior to initiating expensive drug discovery projects. Thus, new approaches that can rapidly enable drug target validation are of significant interest. In this manuscript we present the crystal structure of malate dehydrogenase from Plasmodium falciparum (PfMDH) at 2.4 Å resolution and structure-based mutagenic experiments interfering with the inter-oligomeric interactions of the enzyme...

BACKGROUND: Plasmodium knowlesi is the most common cause of human malaria in Malaysia. Acute kidney injury (AKI) is a frequent complication. AKI of any cause can have long-term consequences, including increased risk of chronic kidney disease, adverse cardiovascular events and increased mortality. Additional management strategies are therefore needed to reduce the frequency and severity of AKI in malaria. In falciparum malaria, cell-free haemoglobin (CFHb)-mediated oxidative damage contributes to AKI...

BACKGROUND: Methylene blue (MB) was the first synthetic antimalarial to be discovered and was used during the late 19th and early 20th centuries against all types of malaria. MB has been shown to be effective in inhibiting Plasmodium falciparum in culture, in the mouse model and in rhesus monkeys. MB was also shown to have a potent ex vivo activity against drug-resistant isolates of P. falciparum and P. vivax. In preclinical studies, MB acted synergistically with artemisinin derivates and demonstrated a strong effect on gametocyte reduction in P...

OBJECTIVES: To investigate if high-dosed folate supplements might diminish the efficacy of malaria intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) in a cohort of pregnant women in Benin, where malaria is holoendemic. METHODS: We followed 318 women during the entire pregnancy and analyzed hematological and P.falciparum indicators in the context of an intermittent preventive treatment trial in Benin. During the follow-up women received two-dose IPTp (1500/75 mg of SP per dose) at the maternity clinic, and 600 mg of albendazole, 200 mg ferrous sulfate and 5 mg folic acid per day for home treatment...

Immune responses to poorly immunogenic antigens, such as polysaccharides, can be enhanced by conjugation to carriers. Our previous studies indicate that conjugation to Vi polysaccharide of Salmonella Typhi may also enhance immunogenicity of some protein carriers. We therefore explored the possibility of generating a bivalent vaccine against Plasmodium falciparum malaria and typhoid fever, which are co-endemic in many parts of the world, by conjugating Vi polysaccharide, an approved antigen in typhoid vaccine, to Pfs25, a malaria transmission blocking vaccine antigen in clinical trials...

BACKGROUND: The World Health Organization's integrated community case management (iCCM) guidelines recommend that all children presenting with uncomplicated fever and no danger signs return for follow-up on day 3 following the initial consultation on day 1. Such fevers often resolve rapidly, however, and previous studies suggest that expectant home care for uncomplicated fever can be safely recommended. We aimed to determine if a conditional follow-up visit was non-inferior to a universal follow-up visit for these children...

BACKGROUND: With declining malaria prevalence and improved use of malaria diagnostic tests, an increasing proportion of children seen by community health workers (CHWs) have unclassified fever. Current community management guidelines by WHO advise that children seen with non-severe unclassified fever (on day 1) should return to CHWs on day 3 for reassessment. We compared the safety of conditional follow-up reassessment only in cases where symptoms do not resolve with universal follow-up on day 3...

BACKGROUND: Intermittent preventive treatment (IPT) is a well established malaria control intervention. Evidence that delivering IPT to schoolchildren could provide community-level benefits is limited. We did a cluster-randomised controlled trial to assess the effect of IPT of primary schoolchildren with dihydroartemisinin-piperaquine (DP) on indicators of malaria transmission in the community, in Jinja, Uganda. METHODS: We included 84 clusters, each comprising one primary school and the 100 closest available households...

BACKGROUND: Understanding population genetic structure in the malaria vector Anopheles gambiae (s.s.) is crucial to inform genetic control and manage insecticide resistance. Unfortunately, species characteristics such as high nucleotide diversity, large effective population size, recent range expansion, and high dispersal ability complicate the inference of genetic structure across its range in sub-Saharan Africa. The ocean, along with the Great Rift Valley, is one of the few recognized barriers to gene flow in this species, but the effect of inland lakes, which could be useful sites for initial testing of genetic control strategies, is relatively understudied...

Background: Although consensus exists that malaria in pregnancy (MiP) increases the risk of malaria in infancy, and eventually nonmalarial fevers (NMFs), there is a lack of conclusive evidence of benefits of MiP preventive strategies in infants. Methods: In Burkina Faso, a birth cohort study was nested to a clinical trial assessing the effectiveness of a community-based scheduled screening and treatment of malaria in combination with intermittent preventive treatment with sulfadoxine-pyrimethamine (CSST/IPTp-SP) to prevent placental malaria...

BACKGROUND: Progress in malaria control is under threat by wide-scale insecticide resistance in malaria vectors. Two recent vector control products have been developed: a long-lasting insecticidal net that incorporates a synergist piperonyl butoxide (PBO) and a long-lasting indoor residual spraying formulation of the insecticide pirimiphos-methyl. We evaluated the effectiveness of PBO long-lasting insecticidal nets versus standard long-lasting insecticidal nets as single interventions and in combination with the indoor residual spraying of pirimiphos-methyl...

BACKGROUND: Under the World Health Organization's integrated community case management strategy, febrile children seen by community health workers (on day 1) without a diagnosable illness and without danger signs are advised to return on day 3, regardless of symptom resolution. This advice might be unnecessary and place additional time and cost burdens on caregivers and community health workers. However, the safety of not following up with respect to children with unclassified fever is unknown...

Ivermectin has demonstrated many successes in the treatment of a range of nematode infections. Considering the increase in malaria resistance attention has turned towards ivermectin as a candidate for repurposing for malaria. This study developed and validated an ivermectin physiologically-based pharmacokinetic model in healthy adults (20-50 years) and paediatric (3-5 years/15-25 kg) subjects and in a representative adult malaria population group (Thailand). Dosing optimisation demonstrated a twice daily for 3- or 5-day regimens would provide a time above the LC50 of more than 7 days for adult and paediatric...

BACKGROUND: The production of recombinant proteins with proper conformation, appropriate post-translational modifications in an easily scalable and cost-effective system is challenging. Lactococcus lactis has recently been identified as an efficient Gram positive cell factory for the production of recombinant protein. We and others have used this expression host for the production of selected malaria vaccine candidates. The safety of this production system has been confirmed in multiple clinical trials...

BACKGROUND: Artemether-lumefantrine and artesunate-amodiaquine are used as first-line artemisinin-based combination therapies (ACTs) in west Africa. Pyronaridine-artesunate and dihydroartemisinin-piperaquine are potentially useful for diversification of ACTs in this region, but further safety and efficacy data are required on malaria retreatment. METHODS: We did a randomised, multicentre, open-label, longitudinal, controlled phase 3b/4 clinical trial at seven tertiary centres in Burkina Faso, Guinea, and Mali...

BACKGROUND: Adoption of prevention and therapeutic innovations to ensure that National Malaria Control Programmes meet their incidence reduction targets is highly dependent on the conduct of rigorous clinical trials. In Liberia, malaria control virtually halted during the recent Ebola epidemic, and could enormously benefit from innovations to protect its most vulnerable populations, including pregnant women, against malaria. Health policy-planners could feel more inclined to adopt novel interventions with demonstrated safety and efficacy when trialled among their women population...

BACKGROUND: Ivermectin is being considered for mass drug administration for malaria due to its ability to kill mosquitoes feeding on recently treated individuals. However, standard, single doses of 150-200 μg/kg used for onchocerciasis and lymphatic filariasis have a short-lived mosquitocidal effect (<7 days). Because ivermectin is well tolerated up to 2000 μg/kg, we aimed to establish the safety, tolerability, and mosquitocidal efficacy of 3 day courses of high-dose ivermectin, co-administered with a standard malaria treatment...

BACKGROUND: Since 2011, cohorts of schoolchildren in regions bordering Lake Victoria in Kenya and Tanzania have been investigated for morbidity caused by Schistosoma mansoni infection. Despite being neighbouring countries with similar lifestyles and ecological environments, Tanzanian schoolchildren had lower S. mansoni prevalence and intensity and they were taller and heavier, fewer were wasted and anaemic, and more were physical fit compared to their Kenyan peers. The aim of the present study was to evaluate whether diet and school-related markers of socioeconomic status (SES) could explain differences in morbidity beyond the effect of infection levels...

Background: Overcoming antigenic diversity is a key challenge in the development of effective P. falciparum malaria vaccines. Strategies that promote the generation of antibodies targeting conserved epitopes of vaccine antigens may provide protection against diverse parasites strains. Understanding differences between vaccine-induced and naturally-acquired immunity is important to achieving this goal. Methods: We analysed antibodies generated in a phase 1 human vaccine trial, MSP2-C1, which included two allelic forms MSP2, an abundant vaccine antigen on the merozoites surface...

Background: Mass screening and treatment (MST) aims to reduce malaria risk in communities by identifying and treating infected without regard to illness. Methods: A cluster-randomized trial evaluated malaria incidence with and without MST. Clusters were randomized to three, two, or no MST interventions: MST3=6 clusters (156 households/670 individuals); MST2=5 clusters (89 households/423 individuals); and MST0=5 clusters (174 households/777 individuals). All clusters completed the study with 15 residents withdrawing...