A systems serology approach to identifying key antibody correlates of protection from cerebral malaria in Malawian children.

Background: Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) proteins are expressed on the surface of infected erythrocytes, mediating parasite sequestration in the vasculature. PfEMP1 is a major target of protective antibodies, but the features of the antibody response are poorly defined.

Methods: In Malawian children with cerebral or uncomplicated malaria, we characterized the antibody response to 39 recombinant PfEMP1 Duffy binding like (DBL) domains or cysteine-rich interdomain regions (CIDRs) in detail, including measures of antibody classes, subclasses, and engagement with Fcγ receptors and complement.

Evaluation of a Bayesian hierarchical pharmacokinetic-pharmacodynamic model for predicting parasitological outcomes in Phase 2 studies of new antimalarial drugs.

The rise of multidrug-resistant malaria requires accelerated development of novel antimalarial drugs. Pharmacokinetic-pharmacodynamic (PK-PD) models relate blood antimalarial drug concentrations with the parasite-time profile to inform dosing regimens. We performed a simulation study to assess the utility of a Bayesian hierarchical mechanistic PK-PD model for predicting parasite-time profiles for a Phase 2 study of a new antimalarial drug, cipargamin.

Effect of adherence to primaquine on the risk of Plasmodium vivax recurrence: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis.

Background: Imperfect adherence is a major barrier to effective primaquine radical cure of Plasmodium vivax. This study investigated the effect of reduced adherence on the risk of P. vivax recurrence.

Evidence Based Optimal Dosing of Intravenous Artesunate in Children with Severe Falciparum Malaria.

The majority of deaths from malaria are in young African children. Parenteral artesunate (ARS) is the first-line treatment for severe falciparum malaria. Since 2015, the World Health Organization has recommended individual doses of 3 mg/kg for children weighing < 20 kg.

Quantification of parasite clearance in Plasmodium knowlesi infections.

Background: The incidence of zoonotic Plasmodium knowlesi infections in humans is rising in Southeast Asia, leading to clinical studies to monitor the efficacy of anti-malarial treatments for knowlesi malaria. One of the key outcomes of anti-malarial drug efficacy is parasite clearance. For Plasmodium falciparum, parasite clearance is typically estimated using a two-stage method, that involves estimating parasite clearance for individual patients followed by pooling of individual estimates to derive population estimates.

Quantification of the dynamics of antibody response to malaria to inform sero-surveillance in pregnant women.

Background: Malaria remains a major public health threat and tools sensitive to detect infections in low malaria transmission areas are needed to progress elimination efforts. Pregnant women are particularly vulnerable to malaria infections. Throughout pregnancy they access routine antenatal care, presenting a unique sentinel population to apply novel sero-surveillance tools to measure malaria transmission.

Developing a multivariate prediction model of antibody features associated with protection of malaria-infected pregnant women from placental malaria.

Background: causes placental malaria, which results in adverse outcomes for mother and child. -infected erythrocytes that express the parasite protein VAR2CSA on their surface can bind to placental chondroitin sulfate A. It has been hypothesized that naturally acquired antibodies towards VAR2CSA protect against placental infection, but it has proven difficult to identify robust antibody correlates of protection from disease.

Seeking an optimal dosing regimen for OZ439/DSM265 combination therapy for treating uncomplicated falciparum malaria.

Background: The efficacy of artemisinin-based combination therapies (ACTs), the first-line treatments for uncomplicated falciparum malaria, has been declining in malaria-endemic countries due to the emergence of malaria parasites resistant to these compounds. Novel alternative therapies are needed urgently to prevent the likely surge in morbidity and mortality due to failing ACTs.

Objectives: This study investigates the efficacy of the combination of two novel drugs, OZ439 and DSM265, using a biologically informed within-host mathematical model.

Development and Validation of an Decision Tool To Guide Optimization of Intravenous Artesunate Dosing Regimens for Severe Falciparum Malaria Patients.

Most deaths from severe falciparum malaria occur within 24 h of presentation to a hospital. Intravenous (i.v.

Parasite-Host Dynamics throughout Antimalarial Drug Development Stages Complicate the Translation of Parasite Clearance.

Ensuring continued success against malaria depends on a pipeline of new antimalarials. Antimalarial drug development utilizes preclinical murine and experimental human malaria infection studies to evaluate drug efficacy. A sequential approach is typically adapted, with results from each stage informing the design of the next stage of development.

The risk of morbidity and mortality following recurrent malaria in Papua, Indonesia: a retrospective cohort study.

Background: An acute episode of malaria can be followed by multiple recurrent episodes either due to re-infection, recrudescence of a partially treated parasite or, in the case of Plasmodium vivax or P. ovale, relapse from the dormant liver stage of the parasite. The aim of this study was to quantify the impact of recurrent malaria episodes on morbidity and mortality in Papua, Indonesia.

Early and late mortality after malaria in young children in Papua, Indonesia.

Background: In southern Papua, Indonesia, malaria is highly prevalent in young children and is a significant cause of morbidity and early mortality. The association between malaria and delayed mortality is unknown.

Methods: Routinely-collected hospital surveillance data from southern Papua, Indonesia, were used to assess the risk of recurrent malaria and mortality within 12 months of an initial presentation with malaria in all children younger than 5 years old attending the local hospital.

Investigation of the Decline in Clinical Efficacy of Artemisinin Combination Therapies Due to Increasing Artemisinin and Partner Drug Resistance.

Antimalarial treatment currently relies on an artemisinin derivative and a longer-acting partner drug. With the emergence of resistance to the artemisinin derivatives and the potential pressure this exerts on the partner drugs, the impact of resistance to each drug on efficacy needs to be investigated. An exploration of dihydroartemisinin-piperaquine and mefloquine-artesunate, two artemisinin-based combination therapies that are commonly used in Southeast Asia, was performed.

Investigating the Efficacy of Triple Artemisinin-Based Combination Therapies for Treating Plasmodium falciparum Malaria Patients Using Mathematical Modeling.

The first line treatment for uncomplicated falciparum malaria is artemisinin-based combination therapy (ACT), which consists of an artemisinin derivative coadministered with a longer-acting partner drug. However, the spread of resistant to both artemisinin and its partner drugs poses a major global threat to malaria control activities. Novel strategies are needed to retard and reverse the spread of these resistant parasites.