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Mansonella perstans, a filarial nematode, infects large populations in Africa and Latin America. Recently, a potential new species, Mansonella sp “DEUX,” was reported. Carriage of endosymbiotic Wolbachia opens treatment options for Mansonella infections. Within a cross-sectional study, we assessed the prevalence of filarial infections in 834 Gabonese individuals and the presence of the endosymbiont Wolbachia. Almost half of the participants (400/834 [48%]) were infected with filarial nematodes, with Mansonella sp “DEUX” being the most frequent (295/400 [74%]), followed by Loa loa (273/400 [68%]) and Mansonella perstans (82/400 [21%]). Being adult/elderly, male, and living in rural areas was associated with a higher risk of infection. Wolbachia carriage was confirmed in M. perstans and Mansonella sp “DEUX.” In silico analysis revealed that Mansonella sp “DEUX” is not detected with currently published M. perstans–specific assays. Mansonella infections are highly prevalent in Gabon and might have been underreported, likely also beyond Gabon.

Fosmidomycin–piperaquine is being developed as nonartemisinin-based combination therapy to meet the challenge of emerging artemisinin resistance. The combination appeared to have high efficacy and be safe and well tolerated despite observed transient changes in electrocardiogram with prolongation of the QT interval., Background Fosmidomycin–piperaquine is being developed as nonartemisinin-based combination therapy to meet the challenge of emerging artemisinin resistance. Methods The study was a phase 2, single-arm, proof-of-concept study of the efficacy, tolerability, and safety of fosmidomycin–piperaquine for the treatment of uncomplicated Plasmodium falciparum monoinfection in Gabon. Adults and children of both sexes with initial parasite counts between 1000 and 150000/µL received oral treatment with fosmidomycin (twice daily doses of 30 mg/kg) and piperaquine (once daily dose of 16 mg/kg) for 3 days and followed-up for 63 days. The primary efficacy endpoint was the per-protocol polymerase chain reaction (PCR)–corrected day 28 adequate clinical and parasitological response (ACPR). Results One hundred patients were enrolled. The PCR-corrected day 28 ACPR rate was 83/83, or 100% (95% confidence interval, 96–100). Fourteen patients had asexual parasitaemia between day 28 and day 63; all were typed by PCR as new infections. Fosmidomycin–piperaquine therapy led to rapid parasite clearance (median, 36 hours; interquartile range [IQR], 6–60) and fever clearance time (median, 12 hours; IQR, 6–48). The electrocardiogram assessments showed 2 patients with prolonged QT interval >500 msec following study drug administration. The majority of adverse events affected the gastrointestinal and respiratory tracts and were transient and mild to moderate in severity. Conclusions This is the first report of the use of the combination fosmidomycin–piperaquine. The combination appeared to have high efficacy and be safe and well tolerated despite observed transient changes in electrocardiogram with prolongation of the QT interval. Clinical Trials Registration. NCT02198807.

Background The RTS,S/AS01E malaria vaccine has moderate efficacy, lower in infants than children. Current efforts to enhance RTS,S/AS01E efficacy would benefit from learning about the vaccine-induced immunity and identifying correlates of malaria protection, which could, for instance, inform the choice of adjuvants. Here, we sought cellular immunity-based correlates of malaria protection and risk associated with RTS,S/AS01E vaccination. Methods We performed a matched case-control study nested within the multicenter African RTS,S/AS01E phase 3 trial. Children and infant samples from 57 clinical malaria cases (32 RTS,S/25 comparator vaccinees) and 152 controls without malaria (106 RTS,S/46 comparator vaccinees) were analyzed. We measured 30 markers by Luminex following RTS,S/AS01E antigen stimulation of cells 1 month postimmunization. Crude concentrations and ratios of antigen to background control were analyzed. Results Interleukin (IL) 2 and IL-5 ratios were associated with RTS,S/AS01E vaccination (adjusted P ≤ .01). IL-5 circumsporozoite protein (CSP) ratios, a helper T cell type 2 cytokine, correlated with higher odds of malaria in RTS,S/AS01E vaccinees (odds ratio, 1.17 per 10% increases of CSP ratios; P value adjusted for multiple testing = .03). In multimarker analysis, the helper T cell type 1 (TH1)–related markers interferon-γ, IL-15, and granulocyte-macrophage colony-stimulating factor protected from subsequent malaria, in contrast to IL-5 and RANTES, which increased the odds of malaria. Conclusions RTS,S/AS01E-induced IL-5 may be a surrogate of lack of protection, whereas TH1-related responses may be involved in protective mechanisms. Efforts to develop second-generation vaccine candidates may concentrate on adjuvants that modulate the immune system to support enhanced TH1 responses and decreased IL-5 responses.

Background Growth rate of malaria parasites in the blood of infected subjects is an important measure of efficacy of drugs and vaccines. Methods We used log-linear and sine-wave models to estimate the parasite growth rate of the 3D7 strain of Plasmodium falciparum using data from 177 subjects from 14 induced blood stage malaria (IBSM) studies conducted at QIMR Berghofer. We estimated parasite multiplication rate per 48 hour (PMR48), PMR per life-cycle (PMRLC), and parasite life-cycle duration. We compared these parameters to those from studies conducted elsewhere with infections induced by IBSM (n=66), sporozoites via mosquito bite (n=336) or injection (n=51). Results The parasite growth rate of 3D7 in QIMR Berghofer studies was 0.75/day (95% CI: 0.73–0.77/day), PMR48 was 31.9 (95% CI: 28.7–35.4), PMRLC was 16.4 (95% CI: 15.1–17.8) and parasite life-cycle was 38.8 hour (95% CI: 38.3–39.2 hour). These parameters were similar to estimates from IBSM studies elsewhere (0.71/day, 95% CI: 0.67–0.75/day; PMR48 26.6, 95% CI: 22.2–31.8), but significantly higher (P < 0.001) than in sporozoite studies (0.47/day, 95% CI: 0.43–0.50/day; PMR48 8.6, 95% CI: 7.3–10.1). Conclusion Parasite growth rates were similar across different IBSM studies and higher than infections induced by sporozoite.

Background. Antigenic variation in Plasmodium falciparum is mediated by the multicopy var gene family. Each parasite possesses about 60 var genes, and switching between active var loci results in antigenic variation. In the current study, the effect of mosquito and host passage on in vitro var gene transcription was investigated. Methods. Thirty malaria-naive individuals were inoculated by intradermal or intravenous injection with cryopreserved, isogenic NF54 P. falciparum sporozoites (PfSPZ) generated from 1 premosquito culture. Microscopic parasitemia developed in 22 individuals, and 21 in vitro cultures were established. The var gene transcript levels were determined in early and late postpatient cultures and in the premosquito culture. Results. At the early time point, all cultures preferentially transcribed 8 subtelomeric var genes. Intradermal infections had higher var gene transcript levels than intravenous infections and a significantly longer intrahost replication time (P =.03). At the late time point, 9 subtelomeric and 8 central var genes were transcribed at the same levels in almost all cultures. Premosquito and late postpatient cultures transcribed the same subtelomeric and central var genes, except for var2csa. Conclusions. The duration of intrahost replication influences in vitro var gene transcript patterns. Differences between premosquito and postpatient cultures decrease with prolonged in vitro growth.

BACKGROUND Parenteral artesunate is recommended as first-line therapy for severe malaria. While its efficacy is firmly established, data on safety are still incomplete. Delayed hemolysis has been described in hyperparasitemic nonimmune travelers, but it is unknown if African children are equally at risk. METHODS Children aged 6 to 120 months with severe malaria were followed up after treatment with parenteral artesunate in Lambarene, Gabon, and Kumasi, Ghana. The primary outcome was incidence of delayed hemolysis on day 14. RESULTS In total, 72 children contributed complete data sets necessary for primary outcome assessment. Delayed hemolysis was detected in 5 children (7%), with 1 child reaching a nadir in hemoglobin of 2.8 g/dL. Patients with delayed hemolysis had higher parasite counts on admission (geometric mean parasite densities (GMPD) 306 968/µL vs 92 642/µL, P = .028) and were younger (median age: 24 months vs 43 months, P = .046) than the rest of the cohort. No correlation with sickle cell trait or glucose-6-phosphate-dehydrogenase deficiency was observed. CONCLUSIONS Delayed hemolysis is a frequent and relevant complication in hyperparasitemic African children treated with parenteral artesunate for severe malaria. Physicians should be aware of this complication and consider prolonged follow-up. CLINICAL TRIALS REGISTRATION Pan-African Clinical Trials Registry: PACTR201102000277177 (www.pactr.org).

Background We compared a conventional empirically derived regimen with a simplified regimen for parenteral artesunate in severe malaria. Methods This was a randomized, double-blind, placebo-controlled comparison to assess the noninferiority of a simplified 3-dose regimen (given at 0, 24, and 48 hours) compared with the conventional 5-dose regimen of intravenous artesunate (given at 0, 12, 24, 48, and 72 hours) in African children with Plasmodium falciparum malaria with a prespecified delta of 0.2. The total dose of artesunate in each group was 12 mg/kg. The primary end point was the proportion of children clearing ≥ 99% of their admission parasitemia at 24 hours. Safety data, secondary efficacy end points, and pharmacokinetics were also analyzed. Results In 171 children (per protocol), 78% of the recipients (95% confidence interval [CI], 69%-87%) in the 3-dose group achieved ≥ 99% parasite clearance 24 hours after the start of treatment, compared with 85% (95% CI, 77%-93%) of those receiving the conventional regimen (treatment difference, -7.2%; 95% CI, -18.9% to 4.4%). Dihydroartemisinin was cleared slightly more slowly in those children receiving the higher 3-dose regimen (7.4 vs 8.8 L/h for a 13-kg child; P 5 .008). Conclusions Pharmacodynamic analysis suggests that 3 doses of artesunate were not inferior to 5 doses for the treatment of severe malaria in children. Clinical trials registration NCT00522132.

Background. Women with semi-immunity to malaria who live in regions where the disease is endemic are at increased risk for more frequent and severe episodes of malaria during pregnancy. Recent findings indicate that this increased risk might persist beyond delivery, but the underlying mechanisms for this change in risk are poorly understood. Methods. One hundred fifty women were included in a cohort study in Lambarene, Gabon, and were actively followed up weekly for 10 weeks after delivery, as were nonpregnant control women who had been matched to them by location and age. Parasites in samples of placenta and blood were genotyped by use of polymerase chain reaction amplification of the merozoite surface antigen 2 gene and the subtelomeric variable open reading frame gene of Plasmodium falciparum. Results. Eleven puerperal women had cases of clinical malaria, compared with 1 control woman (rate ratio, 9.8; P = .006). Eighteen puerperal women had P. falciparum parasitemia, compared with 6 control women (rate ratio, 2.7; P = .03). Five of 16 puerperal women (31%) with parasitemia on follow-up had identical parasites in their placentas and blood, and 11 of these cases (69%) were the result of reinfection. Puerperal women remained at equal risk for the development of parasitemia throughout the first 10 weeks after delivery. Use of bed nets, use of chloroquine prophylaxis during pregnancy, presence of malaria episodes during pregnancy, gravidity, and age were not associated with the acquisition of parasitemia during follow-up. Conclusions. Compared with nonpregnant women, puerperal women have a considerably increased risk for the development of malaria and/or parasitemia. This increased risk is caused both by the recurrence of P. falciparum parasitemia and by the increased susceptibility to new infections, although the latter plays a more significant role.

A substantial number of reports of cases and small investigations support blood exchange transfusion as a therapy for hyperparasitemia in cases of Plasmodium falciparum malaria, although a prospective and randomized study has never been undertaken. We report on 113 prospectively enrolled children in Lambaréné, Gabon, who had more than 10% parasitized erythrocytes and were treated with chemotherapy alone. All 86 patients with hyperparasitemia as the sole complication recovered uneventfully. Among the 27 patients who had additional complications, parasitemia levels as high as 81% responded well to chemotherapy alone. Two patients with cerebral malaria, who also had other complications and hence a poor prognosis, died. Hyperparasitemia itself might be important for the development of a fatal event in malaria, but a recommendation to perform a dangerous, expensive, and labor-intensive procedure such as blood exchange transfusion for its treatment should be based on substantial clinical research, especially in areas where malaria is a major health problem.