Development of an experimental human blood-stage model for studying Plasmodium knowlesi.

Abstract

The zoonotic parasite Plasmodium knowlesi is an increasing cause of human malaria in Southeast Asia. We aimed to develop a P. knowlesi induced blood-stage malaria (IBSM) model to facilitate study of parasite biology, host responses to infection, and activity of antimalarial treatments. We manufactured and characterised a P. knowlesi parasite bank using the P. knowlesi YH1 strain adapted to grow in human serum. This P. knowlesi bank was evaluated in an IBSM study involving four adults intravenously inoculated with P. knowlesi-infected erythrocytes using a dose escalation strategy (10-fold increases from ∼2,800 parasites). Parasitaemia was monitored by qPCR. All participants received curative treatment with artemether-lumefantrine. Endpoints included safety and infectivity of the P. knowlesi bank. Two of the four participants developed detectable parasitaemia. Participant two (administered ∼28,000 parasites) had detectable parasites (∼6 parasites/mL) immediately prior to protocol-defined treatment on day 21. Participant three (administered ∼280,000 parasites) developed detectable parasites on day 17, peaking at 202 parasites/mL just after protocol-defined treatment on day 24; the parasite multiplication rate over 32 hours (PMR32) was 2.33 (95% CI 1.66-3.25). Participant four (also administered ∼280,000 parasites) did not become infected. Adverse events were mostly mild and unrelated to the challenge agent. A GMP-grade P. knowlesi YH1-HS parasite bank was successfully manufactured and shown to establish patent infection in humans. The finding that only one of two participants became infected at the highest inoculum dose highlights the potential for this IBSM model to evaluate factors influencing inter-individual variability in susceptibility to infection.