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

M. Farouk Chughlay, Stephan Chalon, Myriam El Gaaloul, Nathalie Gobeau, Joerg J. Moehrle, Pieter-Jan Berghmans, Katrin Van Leuven, Michael W. Marx, Anna Rosanas-Urgell, Julia Flynn, Emilie Escoffier, Daniel Izquierdo-Juncas, Bastiaan Jansen, Venelin Mitov, Anne Kuemmel, Jean-Pierre Van Geertruyden, Karen Barnes

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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.

Original languageEnglish
JournalAmerican Journal of Tropical Medicine and Hygiene
Volume107
Issue number4
Pages (from-to)804-814
Number of pages11
ISSN0002-9637
DOIs
Publication statusPublished - 2022

Keywords

  • Adult
  • Animals
  • Antimalarials/adverse effects
  • Artemether, Lumefantrine Drug Combination/adverse effects
  • Artemether/therapeutic use
  • Humans
  • Malaria/drug therapy
  • Parasitemia/drug therapy
  • Parasites
  • Plasmodium falciparum
  • Sporozoites

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