TY - JOUR
T1 - 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
AU - Chughlay, M. Farouk
AU - Chalon, Stephan
AU - El Gaaloul, Myriam
AU - Gobeau, Nathalie
AU - Moehrle, Joerg J.
AU - Berghmans, Pieter-Jan
AU - Van Leuven, Katrin
AU - Marx, Michael W.
AU - Rosanas-Urgell, Anna
AU - Flynn, Julia
AU - Escoffier, Emilie
AU - Izquierdo-Juncas, Daniel
AU - Jansen, Bastiaan
AU - Mitov, Venelin
AU - Kuemmel, Anne
AU - Van Geertruyden, Jean-Pierre
AU - Barnes, Karen
N1 - FTX; (CC BY 4.0)
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - Adult
KW - Animals
KW - Antimalarials/adverse effects
KW - Artemether, Lumefantrine Drug Combination/adverse effects
KW - Artemether/therapeutic use
KW - Humans
KW - Malaria/drug therapy
KW - Parasitemia/drug therapy
KW - Parasites
KW - Plasmodium falciparum
KW - Sporozoites
U2 - 10.4269/ajtmh.21-1297
DO - 10.4269/ajtmh.21-1297
M3 - A1: Web of Science-article
C2 - 36037868
SN - 0002-9637
VL - 107
SP - 804
EP - 814
JO - American Journal of Tropical Medicine and Hygiene
JF - American Journal of Tropical Medicine and Hygiene
IS - 4
ER -