Abstract
Background
The whole Plasmodium falciparum sporozoite (PfSPZ) vaccine is being evaluated for malaria prevention. The vaccine is administered intravenously for maximal efficacy. Direct venous ...inoculation (DVI) with PfSPZ vaccine has been safe, tolerable, and feasible in adults, but safety data for children and infants are limited.
Methods
We conducted an age de-escalation, dose-escalation randomized controlled trial in Siaya County, western Kenya. Children and infants (aged 5–9 years, 13–59 months, and 5–12 months) were enrolled into 13 age-dose cohorts of 12 participants and randomized 2:1 to vaccine or normal saline placebo in escalating doses: 1.35 × 105, 2.7 × 105, 4.5 × 105, 9.0 × 105, and 1.8 × 106 PfSPZ, with the 2 highest doses given twice, 8 weeks apart. Solicited adverse events (AEs) were monitored for 8 days after vaccination, unsolicited AEs for 29 days, and serious AEs throughout the study. Blood taken prevaccination and 1 week postvaccination was tested for immunoglobulin G antibodies to P. falciparum circumsporozoite protein (PfCSP) using enzyme-linked immunosorbent assay.
Results
Rates of AEs were similar in vaccinees and controls for solicited (35.7% vs 41.5%) and unsolicited (83.9% vs 92.5%) AEs, respectively. No related grade 3 AEs, serious AEs, or grade 3 laboratory abnormalities occurred. Most (79.0%) vaccinations were administered by a single DVI. Among those in the 9.0 × 105 and 1.8 × 106 PfSPZ groups, 36 of 45 (80.0%) vaccinees and 4 of 21 (19.0%) placebo controls developed antibodies to PfCSP (P < .001).
Conclusions
PfSPZ vaccine in doses as high as 1.8 × 106 can be administered to infants and children by DVI, and was safe, well tolerated, and immunogenic.
Clinical Trials Registration
NCT02687373.
In a double-blind, placebo-controlled dose-escalation, age de-escalation trial of Plasmodium falciparum sporozoite (PfSPZ) vaccine, doses as high as 1.8 × 106 PfSPZ were found to be safe and immunogenic in infants and children aged 5 months to 9 years.
Keywords. xxx; xxx; xxx.
In 2012, the World Health Organization (WHO) recommended single low-dose (SLD, 0.25 mg/kg) primaquine to be added as a Plasmodium (P.) falciparum gametocytocide to artemisinin-based combination ...therapy (ACT) without glucose-6-phosphate dehydrogenase (G6PD) testing, to accelerate malaria elimination efforts and avoid the spread of artemisinin resistance. Uptake of this recommendation has been relatively slow primarily due to safety concerns.
A systematic review and individual patient data (IPD) meta-analysis of single-dose (SD) primaquine studies for P. falciparum malaria were performed. Absolute and fractional changes in haemoglobin concentration within a week and adverse effects within 28 days of treatment initiation were characterised and compared between primaquine and no primaquine arms using random intercept models.
Data comprised 20 studies that enrolled 6406 participants, of whom 5129 (80.1%) had received a single target dose of primaquine ranging between 0.0625 and 0.75 mg/kg. There was no effect of primaquine in G6PD-normal participants on haemoglobin concentrations. However, among 194 G6PD-deficient African participants, a 0.25 mg/kg primaquine target dose resulted in an additional 0.53 g/dL (95% CI 0.17-0.89) reduction in haemoglobin concentration by day 7, with a 0.27 (95% CI 0.19-0.34) g/dL haemoglobin drop estimated for every 0.1 mg/kg increase in primaquine dose. Baseline haemoglobin, young age, and hyperparasitaemia were the main determinants of becoming anaemic (Hb < 10 g/dL), with the nadir observed on ACT day 2 or 3, regardless of G6PD status and exposure to primaquine. Time to recovery from anaemia took longer in young children and those with baseline anaemia or hyperparasitaemia. Serious adverse haematological events after primaquine were few (9/3, 113, 0.3%) and transitory. One blood transfusion was reported in the primaquine arms, and there were no primaquine-related deaths. In controlled studies, the proportions with either haematological or any serious adverse event were similar between primaquine and no primaquine arms.
Our results support the WHO recommendation to use 0.25 mg/kg of primaquine as a P. falciparum gametocytocide, including in G6PD-deficient individuals. Although primaquine is associated with a transient reduction in haemoglobin levels in G6PD-deficient individuals, haemoglobin levels at clinical presentation are the major determinants of anaemia in these patients.
PROSPERO, CRD42019128185.
BACKGROUND: Since the World Health Organization recommended single low-dose (0.25mg/kg) primaquine (PQ) in combination with artemisinin-based combination therapies (ACTs) in areas of low transmission ...or artemisinin-resistant P. falciparum, several single-site studies have been conducted to assess its efficacy.
METHODS: An individual patient meta-analysis to assess the gametocytocidal and transmission-blocking efficacy of PQ used in combination with different ACTs was conducted. Random effects logistic regression was used to quantify PQ effect on (i) gametocyte carriage in the first two weeks post-treatment; (ii) the probability of infecting at least one mosquito or of a mosquito becoming infected.
RESULTS: In 2,574 participants from fourteen studies, PQ reduced PCR-determined gametocyte carriage on days 7 and 14, most apparently in patients presenting with gametocytaemia on day 0 (Odds Ratio (OR)=0.22; 95%CI 0.17-0.28 and OR=0.12; 95%CI 0.08-0.16, respectively). The rate of decline in gametocyte carriage was faster when PQ was combined with artemether-lumefantrine (AL) compared to dihydroartemisinin-piperaquine (DP) (p=0.010 for day 7). Addition of 0.25mg/kg PQ was associated with near complete prevention of transmission to mosquitoes.
CONCLUSION: Primaquine's transmission-blocking effects are achieved with 0.25 mg/kg PQ. Gametocyte persistence and infectivity are lower when PQ is combined with AL compared to DP.
Data on malaria rapid diagnostic test (RDT) performance under routine program conditions are limited. We assessed the attributes of RDTs performed by study and health facility (HF) staffs as part of ...routine malaria case management of patients > or = 5 years of age in Kenya. Expert microscopy was used as our gold standard. A total of 1,827 patients were enrolled; 191 (11.6%) were parasitemic by expert microscopy. Sensitivity and specificity of RDTs performed by study staff were 86.6% (95% confidence interval CI: 79.8-93.5%) and 95.4% (95% CI: 93.9-96.9%), respectively. Among tests performed by HF staff, RDTs were 91.7% (95% CI: 80.8-100.0%) sensitive and 96.7% (95% CI: 92.8-100.0%) specific, whereas microscopy was 52.5% (95% CI: 33.2-71.9%) sensitive and 77.0% (95% CI: 67.9-86.2%) specific. Our findings suggest that RDTs perform better than microscopy under routine conditions. Further efforts are needed to maintain this high RDT performance over time.
Rationalization of the solid-state structural properties of odd members (n = 3, 5, 7) of the series Ph2P(O)(CH2) n P(O)Ph2 leads to insights concerning the structural determinants of this class of ...material, particularly with regard to the formation of preferred arrangements of PO dipoles. The odd members of this series are recalcitrant to the formation of single crystals of suitable size and quality for single-crystal X-ray diffraction, and modern techniques for carrying out crystal structure determination directly from powder X-ray diffraction data were essential for determining the structural properties of these materials. In the present work, nonsolvate crystal phases of the materials with n = 3 and 5 were prepared by appropriate solid-state desolvation processes (starting from hydrate and toluene solvate phases, respectively), yielding microcrystalline powders of the nonsolvate phase in each case. Structure determination was carried out directly from powder X-ray diffraction data, employing the direct-space genetic algorithm technique for structure solution followed by Rietveld refinement.
This paper outlines the development of a new human factors assessment tool for the chemical process industry. The approach considers the whole human factors spectrum as the basis for determining the ...overall quality of human factors in the plant under assessment. The output of the technique is a qualitative report and of quantitative value. From the detailed report, the weak areas in a plant can be detected. The actions to improve these areas can be derived and this not only leads to higher safety but also to higher operation efficiency. The developed computer interface makes the technique especially easy to use, even for non‐human factors experts.
A human factors assessment technique is developed for the chemical process industry. The computer interface guides the user through the assessment and enables analyzing chemical plants in a very short period of time.
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