Safety and Reproducibility of a Clinical Trial System Using Induced Blood Stage Plasmodium vivax Infection and Its Potential as a Model to Evaluate Malaria Transmission

Abstract

BackgroundInterventions to interrupt transmission of malaria from humans to mosquitoes represent an appealing approach to assist malaria elimination. A limitation has been the lack of systems to test the efficacy of such interventions before proceeding to efficacy trials in the field. We have previously demonstrated the feasibility of induced blood stage malaria (IBSM) infection with Plasmodium vivax. In this study, we report further validation of the IBSM model, and its evaluation for assessment of transmission of P. vivax to Anopheles stephensi mosquitoes.MethodsSix healthy subjects (three cohorts, n = 2 per cohort) were infected with P. vivax by inoculation with parasitized erythrocytes. Parasite growth was monitored by quantitative PCR, and gametocytemia by quantitative reverse transcriptase PCR (qRT-PCR) for the mRNA pvs25. Parasite multiplication rate (PMR) and size of inoculum were calculated by linear regression. Mosquito transmission studies were undertaken by direct and membrane feeding assays over 3 days prior to commencement of antimalarial treatment, and midguts of blood fed mosquitoes dissected and checked for presence of oocysts after 7–9 days.ResultsThe clinical course and parasitemia were consistent across cohorts, with all subjects developing mild to moderate symptoms of malaria. No serious adverse events were reported. Asymptomatic elevated liver function tests were detected in four of six subjects; these resolved without treatment. Direct feeding of mosquitoes was well tolerated. The estimated PMR was 9.9 fold per cycle. Low prevalence of mosquito infection was observed (1.8%; n = 32/1801) from both direct (4.5%; n = 20/411) and membrane (0.9%; n = 12/1360) feeds.ConclusionThe P. vivax IBSM model proved safe and reliable. The clinical course and PMR were reproducible when compared with the previous study using this model. The IBSM model presented in this report shows promise as a system to test transmission-blocking interventions. Further work is required to validate transmission and increase its prevalence.Trial RegistrationAnzctr.org.au ACTRN12613001008718

Early Immune Regulatory Changes in a Primary Controlled Human Plasmodium vivax Infection: CD1c + Myeloid Dendritic Cell Maturation Arrest, Induction of the Kynurenine Pathway, and Regulatory T Cell Activation

“…On day 14, at a median peak parasitemia of 31,395 parasites/ml, individuals were treated with artemether-lumefantrine ( Table 1). All the subjects cleared parasitemia 48 h after commencement of antimalarial therapy (27). Automated whole-blood white cell counts revealed a significant decline in the number of circulating lymphocytes and platelets at peak parasitemia (Table 1) (P ϭ 0.03).…”

“…Following infection, all the subjects experienced some symptoms of malaria (with a mean onset on day 12), including fever of Ն39°C (n ϭ 5) (27). Parasites were detectable by PCR in all the subjects from day 8 after inoculation of the P. vivax-infected erythrocytes (pRBC), as previously reported (27,28). On day 14, at a median peak parasitemia of 31,395 parasites/ml, individuals were treated with artemether-lumefantrine ( Table 1).…”

“…This study was nested in a clinical trial conducted to confirm the safety and reproducibility of the human P. vivax-induced blood-stage malaria model. The conduct of the clinical study (trial registration ACTRN12613001008718) and the PCR method used to quantify parasitemia were described in detail elsewhere (27,28). Six healthy adults (3 males and 3 females), 22 to 32 years (median, 26 years [IQR, 24 to 31 years]) of age, received ϳ100 pRBC via intravenous injection in saline (27).…”

“…The conduct of the clinical study (trial registration ACTRN12613001008718) and the PCR method used to quantify parasitemia were described in detail elsewhere (27,28). Six healthy adults (3 males and 3 females), 22 to 32 years (median, 26 years [IQR, 24 to 31 years]) of age, received ϳ100 pRBC via intravenous injection in saline (27). Antimalarial drug treatment was administered on day 14 using artemether-lumefantrine (27).…”

“…Six healthy adults (3 males and 3 females), 22 to 32 years (median, 26 years [IQR, 24 to 31 years]) of age, received ϳ100 pRBC via intravenous injection in saline (27). Antimalarial drug treatment was administered on day 14 using artemether-lumefantrine (27). Blood parasitemia.…”