A Plasmodium vivax experimental human infection model for evaluating efficacy of interventions

Abstract

BACKGROUND. Interventions that interrupt Plasmodium vivax transmission or eliminate dormant P. vivax liver-stage parasites will be essential for malaria elimination. Development of these interventions has been hindered by the lack of P. vivax in vitro culture and could be accelerated by a safe and reproducible clinical model in malaria-naive individuals. METHODS. Healthy, malaria-naive adults were enrolled in 2 studies to assess the safety, infectivity, and transmissibility of a new P. vivax isolate. Participants (Study 1, n = 2; Study 2, n = 24) were inoculated with P. vivax-infected red blood cells to initiate infection, and were treated with artemether-lumefantrine (Study 1) or chloroquine (Study 2). Primary endpoints were safety and infectivity of the new isolate. In Study 2, transmission to mosquitoes was also evaluated using mosquito feeding assays, and sporozoite viability was assessed using in vitro cultured hepatocytes. RESULTS. Parasitemia and gametocytemia developed in all participants and was cleared by antimalarial treatment. Adverse events were mostly mild or moderate and none were serious. Sixty-nine percent of participants (11/16) were infectious to Anopheles mosquitoes at peak gametocytemia. Mosquito infection rates reached 97% following membrane feeding with gametocyte-enriched blood, and sporozoites developed into liver-stage schizonts in culture. CONCLUSION. We have demonstrated the safe, reproducible, and efficient transmission of P. vivax gametocytes from humans to mosquitoes, and have established an experimental model that will accelerate the development of interventions targeting multiple stages of the P. vivax life cycle. TRIAL REGISTRATION. ACTRN12614000930684 and ACTRN12616000174482.

Liver Function Test Abnormalities in Experimental and Clinical Plasmodium vivax Infection

“…All eight subjects enrolled in the artefenomel study were male compared with a more even gender ratio in the chloroquine study where 13/24 (54%) of subjects were males. There was no difference in the age of subjects recruited in the artefenomel and chloroquine studies (median [IQR] 23.5 [22-25.8] years and 24.5 [20][21][22][23][24][25][26][27][28][29][30] years, respectively).…”

“…Although chloroquine was administered over 3 days, the initial parasite PCt 1/2 was assumed to represent a continuous pharmacodynamic effect. 29 A variable was calculated to capture the biomass of parasites cleared in the first 24 hours after treatment. This variable, termed as the parasite clearance burden (PCB peak-24 ) was calculated by subtracting the parasitemia at 24 hours posttreatment initiation from the peak parasitemia on the log 10 scale and is reported as a log-fold change.…”

Population Pharmacokinetics and Pharmacodynamics of Chloroquine in a Plasmodium vivax Volunteer Infection Study

“…All subjects from the previously reported clinical trial (three cohorts, n = 8 per cohort) were included in the analysis. 15 Table 1 shows the demographic characteristics of the subjects, chloroquine dose, and treatment day. The majority of the subjects (91.7%) received 1,000 mg chloroquine phosphate initially, followed by 500 mg or 375 mg at 6, 24, and 48 hours after the first dose administration.…”

“…Study design, procedure, and main results were described in detail elsewhere. 15 Briefly, the study was a phase Ib, single-center, open-label trial (ACTRN12616000174482) in three cohorts of eight subjects each. The 24 healthy subjects were inoculated with ~ 564 viable P. vivax-infected erythrocytes administered intravenously on day 0.…”

“…In this study, we investigated the PK/PD relationship of chloroquine and desethylchloroquine by analyzing data from a volunteer infection study (VIS) using the P. vivax induced blood-stage malaria model. 15 We used nonlinear mixed effects modeling to characterize the PK and PD properties of chloroquine and desethylchloroquine. The results from our modeling will help optimizing chloroquine dosing regimens in P. vivax malaria field studies.…”