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BackgroundAsymptomatic Plasmodium spp. infections and anemia are highly prevalent conditions in tropical regions. We studied whether asymptomatic parasitemia induces hepcidin-and/or cytokinemediated iron maldistribution and anemia. Design and MethodsA group of 1197 Indonesian schoolchildren, aged 5-15 years, were screened by microscopy for the presence of parasitemia. Concentrations of hemoglobin, serum hepcidin and parameters of iron status and inflammation were determined at baseline and 4 weeks after antimalarial treatment. ResultsAsymptomatic P. falciparum and P. vivax parasitemia were detected in 73 (6.1%) and 18 (1.5%) children, respectively, of whom 84% and 83% had a C-reactive protein concentration below 5 mg/L. Children with P. falciparum or P. vivax parasitemia had significantly lower hemoglobin concentrations than 17 aparasitemic controls (12.6 and 12.2 g/dL versus 14.4 g/dL; P<0.01), together with significantly higher serum hepcidin concentrations (5.2 and 5.6 nM versus 3.1 nM; P<0.05). The latter was associated with signs of iron maldistribution with higher ferritin concentrations and lower values of serum iron concentration, transferrin saturation and erythrocyte mean cell volume. Concentrations of growth differentiation factor 15 were similar across groups. Antimalarial treatment partly reversed these abnormalities and led to a significant increase in hemoglobin concentration. ConclusionsAsymptomatic malarial parasitemia is associated with increased hepcidin concentrations and anemia, in the absence of a manifest acute phase response. Prolonged iron maldistribution may be an underestimated cause of anemia. Screening for parasitemia should be performed before starting iron supplementation, as iron therapy may be less effective and even hazardous in these circumstances.

Key Points Platelet-derived microparticles inhibit IL-17 and IFN-γ production by Tregs and stimulate Treg stability in an inflammatory environment. Platelet-derived microparticles inhibit Treg plasticity in a P-selectin– and partially CXCR3-dependent manner.

BackgroundA highly efficacious vaccine is needed for malaria control and eradication. Immunization with Plasmodium falciparum NF54 parasites under chemoprophylaxis (chemoprophylaxis and sporozoite (CPS)-immunization) induces the most efficient long-lasting protection against a homologous parasite. However, parasite genetic diversity is a major hurdle for protection against heterologous strains.MethodsWe conducted a double-blind, randomized controlled trial in 39 healthy participants of NF54-CPS immunization by bites of 45 NF54-infected (n = 24 volunteers) or uninfected mosquitoes (placebo; n = 15 volunteers) against a controlled human malaria infection with the homologous NF54 or the genetically distinct NF135.C10 and NF166.C8 clones. Cellular and humoral immune assays were performed as well as genetic characterization of the parasite clones.ResultsNF54-CPS immunization induced complete protection in 5/5 volunteers against NF54 challenge infection at 14 weeks post-immunization, but sterilely protected only 2/10 and 1/9 volunteers against NF135.C10 and NF166.C8 challenge infection, respectively. Post-immunization plasma showed a significantly lower capacity to block heterologous parasite development in primary human hepatocytes compared to NF54. Whole genome sequencing showed that NF135.C10 and NF166.C8 have amino acid changes in multiple antigens targeted by CPS-induced antibodies. Volunteers protected against heterologous challenge were among the stronger immune responders to in vitro parasite stimulation.ConclusionsAlthough highly protective against homologous parasites, NF54-CPS-induced immunity is less effective against heterologous parasite clones both in vivo and in vitro. Our data indicate that whole sporozoite-based vaccine approaches require more potent immune responses for heterologous protection.Trial registrationThis trial is registered in clinicaltrials.gov, under identifier NCT02098590.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-017-0923-4) contains supplementary material, which is available to authorized users.

BackgroundLiver injury is a known feature of severe malaria, but is only incidentally investigated in uncomplicated disease. In such cases, drug-induced hepatotoxicity is often thought to be the primary cause of the observed liver injury, and this can be a major concern in antimalaria drug development. We investigated liver function test (LFT) abnormalities in patients with imported uncomplicated malaria, and in Controlled Human Malaria Infection (CHMI) studies.MethodsClinical and laboratory data from 484 imported malaria cases and 254 CHMI participants were obtained from the Rotterdam Malaria Cohort database, and the Radboud University Medical Center database (between 2001 and 2017), respectively. Routine clinical LFTs, clinical profiles, parasite densities, hematological, and inflammation parameters were assessed in 217 patients with imported falciparum malaria upon admission, and from longitudinal data of 187 CHMI participants.FindingsUpon admission, the proportion of patients with imported uncomplicated malaria and elevated liver enzymes was 128/186 (69%). In CHMI, 97/187 (52%) participants showed LFT abnormalities, including mild (64%, >1.0 ≤ 2.5× upper limit of normal (ULN)), moderate (20%, >2.5 ≤ 5.0xULN) or severe (16%, >5.0xULN). LFT abnormalities were primarily ALT/AST elevations and to a lesser extent γGT and ALP. LFT abnormalities peaked shortly after initiation of treatment, regardless of drug regimen, and returned to normal within three to six weeks. Positive associations were found with parasite burden and inflammatory parameters, including cumulative inflammatory cytokine responses and oxidative stress markers (r = 0·65, p = 0·008, and r = −0·63, p = 0·001, respectively).InterpretationThis study shows that reversible liver injury is a common feature of uncomplicated falciparum malaria, most likely caused by an enduring pro-inflammatory response post treatment. The recognition of this phenomenon is of clinical relevance for individual patient care as well as clinical development of (new) antimalarial drugs.FundPATH Malaria Vaccine Initiative (MVI)