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

Abstract

Background 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 enable further study of parasite biology, host responses to infection, and activity of antimalarial treatments. Methods 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 healthy adults intravenously inoculated with P. knowlesi-infected erythrocytes using a dose escalation strategy (10-fold increases from ~2,800 viable parasites). Parasitemia was monitored by qPCR. All participants received curative treatment with artemether-lumefantrine. Endpoints included safety and infectivity of the P. knowlesi parasite bank. Findings Four participants were inoculated. Two participants became infected. Participant two (administered ~28,000 viable parasites) had detectable parasites (~6 parasites/mL) immediately prior to protocol-defined treatment on day 21. Participant three (administered ~280,000 viable 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). Adverse events were mostly mild and unrelated to the challenge agent. Interpretation A P. knowlesi YH1-HS parasite bank suitable for use in human volunteers was successfully manufactured; however, infectivity was suboptimal. Further optimisation of the P. knowlesi parasite bank and/or study design will be required to improve infectivity. Funding National Health and Medical Research Council of Australia and the Royal Brisbane and Women’s Hospital Foundation.