Antibody to Plasmodium falciparum Variant Surface Antigens, var Gene Transcription, and ABO Blood Group in Children With Severe or Uncomplicated Malaria.

BACKGROUND: Antibodies to variant surface antigens (VSAs) such as Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) may vary with malaria severity. The influence of ABO blood group on antibody development is not understood. METHODS: Immunoglobulin G antibodies to VSAs in Papua New Guinean children with severe (n = 41) or uncomplicated (n = 30) malaria were measured by flow cytometry using homologous P falciparum isolates. Isolates were incubated with ABO-matched homologous and heterologous acute and convalescent plasma. RNA was used to assess var gene transcription. RESULTS: Antibodies to homologous, but not heterologous, isolates were boosted in convalescence. The relationship between antibody and severity varied by blood group. Antibodies to VSAs were similar in severe and uncomplicated malaria at presentation, higher in severe than uncomplicated malaria in convalescence, and higher in children with blood group O than other children. Six var gene transcripts best distinguished severe from uncomplicated malaria, including UpsA and 2 CIDRα1 domains. CONCLUSIONS: ABO blood group may influence antibody acquisition to VSAs and susceptibility to severe malaria. Children in Papua New Guinea showed little evidence of acquisition of cross-reactive antibodies following malaria. Var gene transcripts in Papua New Guinean children with severe malaria were similar to those reported from Africa.

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. An alternative approach is Bayesian hierarchical modelling which simultaneously analyses all parasite-time patient profiles to determine parasite clearance. This study compared these methods for estimating parasite clearance in P. knowlesi treatment efficacy studies, with typically fewer parasite measurements per patient due to high susceptibility to anti-malarials. METHODS: Using parasite clearance data from 714 patients with knowlesi malaria and enrolled in three trials, the Worldwide Antimalarial Resistance Network (WWARN) Parasite Clearance Estimator (PCE) standard two-stage approach and Bayesian hierarchical modelling were compared. Both methods estimate the parasite clearance rate from a model that incorporates a lag phase, slope, and tail phase for the parasitaemia profiles. RESULTS: The standard two-stage approach successfully estimated the parasite clearance rate for 678 patients, with 36 (5%) patients excluded due to an insufficient number of available parasitaemia measurements. The Bayesian hierarchical estimation method was applied to the parasitaemia data of all 714 patients. Overall, the Bayesian method estimated a faster population mean parasite clearance (0.36/h, 95% credible interval [0.18, 0.65]) compared to the standard two-stage method (0.26/h, 95% confidence interval [0.11, 0.46]), with better model fits (compared visually). Artemisinin-based combination therapy (ACT) is more effective in treating P. knowlesi than chloroquine, as confirmed by both methods, with a mean estimated parasite clearance half-life of 2.5 and 3.6 h, respectively using the standard two-stage method, and 1.8 and 2.9 h using the Bayesian method. CONCLUSION: For clinical studies of P. knowlesi with frequent parasite measurements, the standard two-stage approach (WWARN's PCE) is recommended as this method is straightforward to implement. For studies with fewer parasite measurements per patient, the Bayesian approach should be considered. Regardless of method used, ACT is more efficacious than chloroquine, confirming the findings of the original trials.

Antibody mechanisms of protection against malaria in RTS,S-vaccinated children: a post-hoc serological analysis of phase 2 trial.

BACKGROUND: The RTS,S malaria vaccine is currently recommended for children aged 5-6 months in regions with moderate-to-high Plasmodium falciparum transmission. However, vaccination only confers 55% efficacy over 12 months and wanes within 18 months. The immunological mechanisms of RTS,S-mediated immunity are poorly understood; therefore, we aimed to identify antibody response types associated with protection against malaria in children vaccinated with RTS,S. METHODS: In this post-hoc analysis, we evaluated antibody responses in 737 children aged 1-4 years vaccinated with RTS,S in a phase 2b clinical trial conducted in Mozambique in 2003. We evaluated all available samples collected from children 30 days after the three-dose vaccination schedule at study month 3 (M3; n=737 available of 803 children allocated to receive RTS,S). For comparison, we tested a subset of samples collected before vaccination at study month 0 (M0; n=50) and from children in the control vaccine group (M0 n=25; M3 n=99). We quantified the induction of antibodies to different regions of the vaccine antigen that function by fixing serum complement proteins and binding to Fcγ receptors (FcγRs; FcγRI, FcγRIIa, and FcγRIII) expressed on immune cells as potential mechanisms of immunity. FINDINGS: Functional antibody responses to the C-terminal region of the vaccine antigen, circumsporozoite protein (CSP), were associated with a reduced risk of malaria (C1q p=0·0060, FcγRIIa p=0·014, and FcγRIII p=0·019). These associations remained significant in male participants when the analyses were stratified by sex (C1q p=0·012, FcγRI p=0·023, FcγRIIa p=0·0070, and FcγRIII p=0·0080). IgA to the central repeat (p=0·0010) and C-terminal (p=0·0040) regions of CSP were also associated with protection. We show that IgA can bind FcαRI and mediate opsonic phagocytosis using a serum pool and monoclonal antibodies. Multiparameter analysis using machine-learning methods suggest that IgA, complement fixation, and FcγRI binding were most predictive of protection against malaria (hazard ratio <1) and suggested that associations differed between male and female participants. INTERPRETATION: We provide evidence that functional antibody responses mediated by IgG and IgA are associated with protection against malaria in young children vaccinated with RTS,S, and suggest potential differences in the correlates of immunity between males and females. These findings reveal new avenues that could be used to achieve malaria vaccines with higher efficacy. FUNDING: National Health and Medical Research Council, Australia, and Thrasher Research Fund.

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. Recently, the US Food and Drug Administration (FDA) has challenged this recommendation, based on a simulated pediatric population, and argued for a lower dose in younger children (2.4 mg/kg). In this study, we performed population pharmacokinetic (PK) modeling of plasma concentration data from 80 children with severe falciparum malaria in the Democratic Republic of Congo who were given 2.4 mg/kg of ARS intravenously. Bayesian hierarchical modeling and a two-compartment parent drug-metabolite PK model for ARS were used to describe the population PKs of ARS and its main biologically active metabolite dihydroartemisinin. We then generated a virtual population representative of the target population in which the drug is used and simulated the total first-dose exposures. Our study shows that the majority of younger children given the lower 2.4 mg/kg dose of intravenous ARS do not reach the same drug exposures as older children above 20 kg. This finding supports withdrawal of the FDA's recent lower ARS dose recommendation as parenteral ARS is an extremely safe and well-tolerated drug and there is potential for harm from underdosing in this rapidly lethal infection.

Mathematical modeling of velocity and number density profiles of particles across the flame propagation through a micro-iron dust cloud.

In this study, an attempt has been made to analytically investigate the concentration and velocity profiles of particles across flame propagation through a micro-iron dust cloud. In the first step, Lagrangian particle equation of motion during upward flame propagation in a vertical duct is employed and then forces acting upon the particle, such as thermophoretic force (resulted from the temperature gradient), gravitation and buoyancy are introduced; and consequently, the velocity profile as a function of the distance from the leading edge of the combustion zone is extracted. In the resumption, a control volume above the leading edge of the combustion zone is considered and the change in the particle number density in this control volume is obtained via the balance of particle mass fluxes passing through it. This study explains that the particle concentration at the leading edge of the combustion zone is more than the particle agglomeration in a distance far from the flame front. This increase in the particle aggregation above the combustion zone has a remarkable effect on the lower flammability limits of combustible particle cloud. It is worth noticing that the velocity and particle concentration profiles show a reasonable compatibility with the experimental data.