Safety, Tolerability, and Parasite Clearance Kinetics in Controlled Human Malaria Infection after Direct Venous Inoculation of Plasmodium falciparum Sporozoites: A Model for Evaluating New Blood-Stage Antimalarial Drugs

Abstract

Plasmodium falciparum sporozoite (PfSPZ) direct venous inoculation (DVI) using cryopreserved, infectious PfSPZ (PfSPZ Challenge [Sanaria, Rockville, Maryland]) is an established controlled human malaria infection model. However, to evaluate new chemical entities with potential blood-stage activity, more detailed data are needed on safety, tolerability, and parasite clearance kinetics for DVI of PfSPZ Challenge with established schizonticidal antimalarial drugs. This open-label, phase Ib study enrolled 16 malaria-naïve healthy adults in two cohorts (eight per cohort). Following DVI of 3,200 PfSPZ (NF54 strain), parasitemia was assessed by quantitative polymerase chain reaction (qPCR) from day 7. The approved antimalarial artemether-lumefantrine was administered at a qPCR-defined target parasitemia of ≥ 5,000 parasites/mL of blood. The intervention was generally well tolerated, with two grade 3 adverse events of neutropenia, and no serious adverse events. All 16 participants developed parasitemia after a mean of 9.7 days (95% CI 9.1–10.4) and a mean parasitemia level of 511 parasites/mL (95% CI 369–709). The median time to reach ≥ 5,000 parasites/mL was 11.5 days (95% CI 10.4–12.4; Kaplan–Meier), at that point the geometric mean (GM) parasitemia was 15,530 parasites/mL (95% CI 10,268–23,488). Artemether-lumefantrine was initiated at a GM of 12.1 days (95% CI 11.5–12.7), and a GM parasitemia of 6,101 parasites/mL (1,587–23,450). Mean parasite clearance time was 1.3 days (95% CI 0.9–2.1) and the mean log10 parasite reduction ratio over 48 hours was 3.6 (95% CI 3.4–3.7). This study supports the safety, tolerability, and feasibility of PfSPZ Challenge by DVI for evaluating the blood-stage activity of candidate antimalarial drugs.

Accelerated prime-and-trap vaccine regimen in mice using repRNA-based CSP malaria vaccine

“…However notable progress in in vitro culture of Pf SPZ under current Good Manufacturing Practices has been made by Sanaria ® . It is hoped that their cGMP mosquito-dissected spz, known as Pf SPZ vaccine (irradiated PfSPZ) or PfSPZ-CVac (PfSPZ used with chemoprophylaxis vaccination), will soon be available for human clinical trials 3 , 22 , 62 , 63 . Current clinical trials involving injection of several doses of cryopreserved Sanaria PfSPZ have proven that large-scale implementation in endemic areas using liquid-nitrogen storage conditions is achievable 29 , 30 , 64 , 65 .…”

Perceptions and acceptability of the Controlled Human Malaria Infection (CHMI) model in The Gambia: a qualitative study

“…with malaria parasites, either by mosquito bites or direct injection of sporozoites or parasitized erythrocytes. These well-controlled proof of concept studies allow to both understand the development of the immune response against malaria infection, and to rapidly screen for potential vaccine and drug candidates [8][9][10][11][12]. They are substantially smaller (only tens of participants), shorter (can be completed in a few weeks), and less expensive than large clinical trials, and allow for the selection of candidate vaccines and drug products worthy of further investigation in larger eld trials [5,13].…”

Perceptions and acceptability of the controlled human malaria infection (CHMI) model in The Gambia: a qualitative study

“…Controlled human malaria infection (CHMI) studies consist of deliberate infection of healthy volunteers with malaria parasites, either by mosquito bites or direct injection of sporozoites or parasitized erythrocytes. These well-controlled proof of concept studies allow to both understand the development of the immune response against malaria infection, and to rapidly screen for potential vaccine and drug candidates 8 – 12 . They are substantially smaller (only tens of participants), shorter (can be completed in a few weeks), and less expensive than large clinical trials, and allow for the selection of candidate vaccines and drug products worthy of further investigation in larger field trials 5 , 13 .…”