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Plasmodium falciparum clearance rates in response to artesunate in Malian children with malaria: effect of acquired immunity.

ABSTRACT: Artemisinin resistance, a long parasite clearance half-life in response to artemisinin, has been described in patients with Plasmodium falciparum malaria in southeast Asia. Few baseline half-lives have been reported from Africa, where artemisinins were recently introduced.We treated P. falciparum malaria in 215 Malian children aged 0.5-15 years with artesunate (0, 24, 48 hours) and amodiaquine (72, 96, 120 hours). We estimated half-life by measuring parasite density every 6 hours until undetectable and evaluated the effects of age, sex, ethnicity, and red blood cell (RBC) polymorphisms on half-life. We quantified the proportion of parasitized RBCs recognized by autologous immunoglobulin G (IgG).The geometric mean half-life was 1.9 hours (95% confidence interval, 1.8-2.0) and did not correlate with parasite ex vivo susceptibility to artemisinins. In a linear model accounting for host factors, half-life decreased by 4.1 minutes for every 1-year increase in age. The proportion of parasitized RBCs recognized by IgG correlated inversely with half-life (r = -0.475; P = .0006).Parasite clearance in response to artesunate is faster in Mali than in southeast Asia. IgG responses to parasitized RBCs shorten half-life and may influence this parameter in areas where age is not an adequate surrogate of immunity and correlates of parasite-clearing immunity have not been identified.NCT00669084.

SUBMITTER: Lopera-Mesa TM

PROVIDER: S-EPMC3636783 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Plasmodium falciparum clearance rates in response to artesunate in Malian children with malaria: effect of acquired immunity.

Lopera-Mesa Tatiana M TM Doumbia Saibou S Chiang Serena S Zeituni Amir E AE Konate Drissa S DS Doumbouya Mory M Keita Abdoul S AS Stepniewska Kasia K Traore Karim K Diakite Seidina A S SA Ndiaye Daouda D Sa Juliana M JM Anderson Jennifer M JM Fay Michael P MP Long Carole A CA Diakite Mahamadou M Fairhurst Rick M RM

The Journal of infectious diseases 20130228 11

<h4>Background</h4>Artemisinin resistance, a long parasite clearance half-life in response to artemisinin, has been described in patients with Plasmodium falciparum malaria in southeast Asia. Few baseline half-lives have been reported from Africa, where artemisinins were recently introduced.<h4>Methods</h4>We treated P. falciparum malaria in 215 Malian children aged 0.5-15 years with artesunate (0, 24, 48 hours) and amodiaquine (72, 96, 120 hours). We estimated half-life by measuring parasite de ...[more]

PMID: 23448727

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Project description:The blood-stage malaria vaccine FMP2.1/AS02A, comprised of recombinant Plasmodium falciparum apical membrane antigen 1 (AMA1) and the adjuvant system AS02A, had strain-specific efficacy against clinical malaria caused by P. falciparum with the vaccine strain 3D7 AMA1 sequence. To evaluate a potential correlate of protection, we measured the ability of participant sera to inhibit growth of 3D7 and FVO strains in vitro using high-throughput growth inhibition assay (GIA) testing. Sera from 400 children randomized to receive either malaria vaccine or a control rabies vaccine were assessed at baseline and over two annual malaria transmission seasons after immunization. Baseline GIA against vaccine strain 3D7 and FVO strain was similar in both groups, but more children in the malaria vaccine group than in the control group had 3D7 and FVO GIA activity ≥15% 30 days after the last vaccination (day 90) (49% vs. 16%, p<0.0001; and 71.8% vs. 60.4%, p = 0.02). From baseline to day 90, 3D7 GIA in the vaccine group was 7.4 times the mean increase in the control group (p<0.0001). In AMA1 vaccinees, 3D7 GIA activity subsequently returned to baseline one year after vaccination (day 364) and did not correlate with efficacy in the extended efficacy time period to day 730. In Cox proportional hazards regression models with time-varying covariates, there was a slight suggestion of an association between 3D7 GIA activity and increased risk of clinical malaria between day 90 and day 240. We conclude that vaccination with this AMA1-based malaria vaccine increased inhibition of parasite growth, but this increase was not associated with allele-specific efficacy in the first malaria season. These results provide a framework for testing functional immune correlates of protection against clinical malaria in field trials, and will help to guide similar analyses for next-generation malaria vaccines. Clinical trials registry: This clinical trial was registered on clinicaltrials.gov, registry number NCT00460525.

Project description:BackgroundPlasmodium falciparum elicits host inflammatory responses that cause the symptoms and severe manifestations of malaria. One proposed mechanism involves formation of immunostimulatory uric acid (UA) precipitates, which are released from sequestered schizonts into microvessels. Another involves hypoxanthine and xanthine, which accumulate in parasitized red blood cells (RBCs) and may be converted by plasma xanthine oxidase to UA at schizont rupture. These two forms of 'parasite-derived' UA stimulate immune cells to produce inflammatory cytokines in vitro.Methods and findingsWe measured plasma levels of soluble UA and inflammatory cytokines and chemokines (IL-6, IL-10, sTNFRII, MCP-1, IL-8, TNF?, IP-10, IFN?, GM-CSF, IL-1?) in 470 Malian children presenting with uncomplicated malaria (UM), non-cerebral severe malaria (NCSM) or cerebral malaria (CM). UA levels were elevated in children with NCSM (median 5.74 mg/dl, 1.21-fold increase, 95% CI 1.09-1.35, n = 23, p = 0.0007) and CM (median 5.69 mg/dl, 1.19-fold increase, 95% CI 0.97-1.41, n = 9, p = 0.0890) compared to those with UM (median 4.60 mg/dl, n = 438). In children with UM, parasite density and plasma creatinine levels correlated with UA levels. These UA levels correlated with the levels of seven cytokines [IL-6 (r = 0.259, p<0.00001), IL-10 (r = 0.242, p<0.00001), sTNFRII (r = 0.221, p<0.00001), MCP-1 (r = 0.220, p<0.00001), IL-8 (r = 0.147, p = 0.002), TNF? (r = 0.132, p = 0.006) and IP-10 (r = 0.120, p = 0.012)]. In 39 children, UA levels were 1.49-fold (95% CI 1.34-1.65; p<0.0001) higher during their malaria episode [geometric mean titer (GMT) 4.67 mg/dl] than when they were previously healthy and aparasitemic (GMT 3.14 mg/dl).ConclusionsElevated UA levels may contribute to the pathogenesis of P. falciparum malaria by activating immune cells to produce inflammatory cytokines. While this study cannot identify the cause of elevated UA levels, their association with parasite density and creatinine levels suggest that parasite-derived UA and renal function may be involved. Defining pathogenic roles for parasite-derived UA precipitates, which we have not directly studied here, requires further investigation.Trial registrationClinicalTrials.gov NCT00669084.

Dataset Information

Plasmodium falciparum clearance rates in response to artesunate in Malian children with malaria: effect of acquired immunity.

Publications

Plasmodium falciparum clearance rates in response to artesunate in Malian children with malaria: effect of acquired immunity.

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