Abstract
BackgroundNew anti-malarial therapeutics are required to counter the threat of increasing drug resistance. Malaria volunteer infection studies (VIS), particularly the induced blood stage malaria (IBSM) model, play a key role in accelerating anti-malarial drug development. Supply of the reference 3D7-V2 Plasmodium falciparum malaria cell bank (MCB) is limited. This study aimed to develop a new MCB, and compare the safety and infectivity of this MCB with the existing 3D7-V2 MCB, in a VIS. A second bank (3D7-V1) developed in 1995 was also evaluated.MethodsThe 3D7-V2 MCB was expanded in vitro using a bioreactor to produce a new MCB designated 3D7-MBE-008. This bank and 3D7-V1 were then evaluated using the IBSM model, where healthy participants were intravenously inoculated with blood-stage parasites. Participants were treated with artemether-lumefantrine when parasitaemia or clinical thresholds were reached. Safety, infectivity and parasite growth and clearance were evaluated.ResultsThe in vitro expansion of 3D7-V2 produced 200 vials of the 3D7-MBE-008 MCB, with a parasitaemia of 4.3%. This compares to 0.1% in the existing 3D7-V2 MCB, and < 0.01% in the 3D7-V1 MCB. All four participants (two per MCB) developed detectable P. falciparum infection after inoculation with approximately 2800 parasites. For the 3D7-MBE-008 MCB, the parasite multiplication rate of 48 h (PMR48) using non-linear mixed effects modelling was 34.6 (95% CI 18.5–64.6), similar to the parental 3D7-V2 line; parasitaemia in both participants exceeded 10,000/mL by day 8. Growth of the 3D7-V1 was slower (PMR48 of 11.5 [95% CI 8.5–15.6]), with parasitaemia exceeding 10,000 parasites/mL on days 10 and 8.5. Rapid parasite clearance followed artemether-lumefantrine treatment in all four participants, with clearance half-lives of 4.01 and 4.06 (weighted mean 4.04 [95% CI 3.61–4.57]) hours for 3D7-MBE-008 and 4.11 and 4.52 (weighted mean 4.31 [95% CI 4.16–4.47]) hours for 3D7-V1. A total of 59 adverse events occurred; most were of mild severity with three being severe in the 3D7-MBE-008 study.ConclusionThe safety, growth and clearance profiles of the expanded 3D7-MBE-008 MCB closely resemble that of its parent, indicating its suitability for future studies. Trial Registration: Australian New Zealand Clinical Trials registry numbers: P3487 (3D7-V1): ACTRN12619001085167. P3491 (3D7-MBE-008): ACTRN12619001079134
Highlights
New anti-malarial therapeutics are required to counter the threat of increasing drug resistance
Two malaria cell bank (MCB) were produced (3D7-V1 and 3D7-V2), the higher parasitaemia in the 3D7-V2 bank (0.1% compared to < 0.01% of erythrocytes parasitized, respectively) has led to this bank being utilized in subsequent malaria volunteer infection studies (VIS)
The analysis of the three genetic markers (Pf msp-1, Plasmodium falciparum (Pf) msp-2 and Pf glurp) showed that no changes had taken place between the starting 3D7-V2 MCB and resulting 3D7-MBE-008 MCB, ruling out high level genetic change during the biomanufacturing process
Summary
New anti-malarial therapeutics are required to counter the threat of increasing drug resistance. Malaria volunteer infection studies (VIS), the induced blood stage malaria (IBSM) model, play a key role in accelerating anti-malarial drug development. The current anti-malarial drug pipeline has been accelerated by the use of human volunteer infection studies (VIS) [4,5,6,7,8], the induced blood-stage malaria model (IBSM) [5, 6]. In these studies, healthy, malaria-naïve participants are inoculated with Plasmodium-infected erythrocytes, enabling the assessment of the blood stage schizont activity of antimalarial drug candidates [5, 6, 9,10,11]. The 3D7-V1 has been utilized only once, for re-inoculation into the original donor [19]
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