Genetic Diversity and Protective Efficacy of the RTS,S/AS01 Malaria Vaccine.

BACKGROUND: The RTS,S/AS01 vaccine targets the circumsporozoite protein of Plasmodium falciparum and has partial protective efficacy against clinical and severe malaria disease in infants and children. We investigated whether the vaccine efficacy was specific to certain parasite genotypes at the circumsporozoite protein locus. METHODS: We used polymerase chain reaction-based next-generation sequencing of DNA extracted from samples from 4985 participants to survey circumsporozoite protein polymorphisms. We evaluated the effect that polymorphic positions and haplotypic regions within the circumsporozoite protein had on vaccine efficacy against first episodes of clinical malaria within 1 year after vaccination. RESULTS: In the per-protocol group of 4577 RTS,S/AS01-vaccinated participants and 2335 control-vaccinated participants who were 5 to 17 months of age, the 1-year cumulative vaccine efficacy was 50.3% (95% confidence interval [CI], 34.6 to 62.3) against clinical malaria in which parasites matched the vaccine in the entire circumsporozoite protein C-terminal (139 infections), as compared with 33.4% (95% CI, 29.3 to 37.2) against mismatched malaria (1951 infections) (P=0.04 for differential vaccine efficacy). The vaccine efficacy based on the hazard ratio was 62.7% (95% CI, 51.6 to 71.3) against matched infections versus 54.2% (95% CI, 49.9 to 58.1) against mismatched infections (P=0.06). In the group of infants 6 to 12 weeks of age, there was no evidence of differential allele-specific vaccine efficacy. CONCLUSIONS: These results suggest that among children 5 to 17 months of age, the RTS,S vaccine has greater activity against malaria parasites with the matched circumsporozoite protein allele than against mismatched malaria. The overall vaccine efficacy in this age category will depend on the proportion of matched alleles in the local parasite population; in this trial, less than 10% of parasites had matched alleles. (Funded by the National Institutes of Health and others.).

The incidence of malaria and the comparison of hematological and biochemical indices of Plasmodium falciparum-parasitemic and aparasitemic sickle cell disease (SCD) patients.

Hemolytic anemia is common in sickle cell disease (SCD), but the course and extent differ, depending on genetic, epigenetic, and environmental factors. In the malaria-endemic tropical environment, some vulnerable subjects would be infected and the impact of infection would vary. Therefore, this study was to find malaria incidence and the associated changes in some laboratory indices in 330 SCD subjects. Following blood smear preparation for falciparum detection, hematological and biochemical indices were measured for a comparison of parasitemic and age-matched, genotype-matched, and sex-matched nonparasitemics. For sixty-nine parasitemics, constituting about 21% of all subjects studied, and sixty-six matched nonparasitemics, hematological indices (hemoglobin, white-cell count, red-cell count, mean cellular volume, reticulocyte count, and HbF) as well as biochemical indices (LDH, total bilirubin, AST, and ALT) were determined. For all quantities, except the reticulocyte count (12.3% ± 12.4% for parasitemics and 23.6% ± 17.7% for nonparasitemics), no statistically significant differences were observed. Classification of both cohorts according to their genotypes showed some intergenotypic differences for hemoglobin and WBC counts. Mathematical modeling of the reticulocyte counts shows the distribution in the parasitemics followed an exponential pattern, while the nonparasitemic showed a polynomial distribution, with each model characterized by an equation of best fit. The study has shown about 21% incidence of parasitemia. All differences in the indices can be seen as normal variations, unattributable to the malaria infection. However, the lower reticulocyte count in the parasitemic is a reflection of lowered erythropoietic activity because of the infection.

Population pharmacokinetics of intramuscular quinine in children with severe malaria.

We present the first population pharmacokinetic analysis of quinine in patients with Plasmodium falciparum malaria. Ghanaian children (n = 120; aged 12 months to 10 years) with severe malaria received an intramuscular loading dose of quinine dihydrochloride (20 mg/kg of body weight). A two-compartment model with first-order absorption and elimination gave post hoc estimates for pharmacokinetic parameters that were consistent with those derived from non-population pharmacokinetic studies (clearance [CL] = 0.05 liter/h/kg of body weight; volume of distribution in the central compartment [V(1)] = 0.65 liter/kg; volume of distribution at steady state = 1.41 liter/kg; half-life at beta phase = 19.9 h). There were no covariates (including age, gender, acidemia, anemia, coma, parasitemia, or anticonvulsant use) that explained interpatient variability in weight-normalized CL and V(1). Intramuscular quinine was associated with minor, local toxicity in some patients (13 of 108; 12%), and 11 patients (10%) experienced one or more episodes of postadmission hypoglycemia. A loading dose of intramuscular quinine results in predictable population pharmacokinetic profiles in children with severe malaria and may be preferred to the intravenous route of administration in some circumstances.