Liver injury in uncomplicated malaria: an overlooked phenomenon

et al. 2021

Malar J

Background New 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. Methods The 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. Results The 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. Conclusion The 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

Section: Discussionsupporting

confidence: 86%

Development and evaluation of a new Plasmodium falciparum 3D7 blood stage malaria cell bank for use in malaria volunteer infection studies

et al. 2021

Malar J

“…The adverse events reported for both studies are in keeping with previous IBSM studies [9][10][11]26,27]. The raised asymptomatic raised liver enzymes, with no associated signi cant rise in bilirubin, have been reported in previous IBSM studies [28,29], sporozoite VIS [30] and in naturally occurring malaria [28,31]. Similarly, the reduction in white cell counts, especially lymphopenia and neutropenia have previously been reported in IBSM VIS, sporozoite VIS and clinical malaria [12,16,[32][33][34].…”

Section: Discussionsupporting

confidence: 85%

Development and Evaluation of a New P. Falciparum 3D7 Blood Stage Malaria Cell Bank for Use in Malaria Volunteer Infection Studies

et al. 2020

Preprint

BackgroundNew antimalarial 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 antimalarial drug development. Supply of the reference 3D7-V2 Plasmodium falciparum malaria cell bank (MCB) is limited. We 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.MethodsWe expanded the 3D7-V2 MCB 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 Plasmodium falciparum infection after inoculation with approximately 2800 parasites. The parasite multiplication rates of 48 hours (PMR48) for the two participants inoculated with 3D7-MBE-008 MCB were 26 and 61, similar to the parental (3D7-V-2) line, with both parasitaemia in both participants exceeding 10,000/mL by day 8. Growth of the 3D7-V1 was slower (PMR48 of 8 and 18), with parasitaemia exceeded 10,000 parasites/mL on days 10 and 8.5 respectively. Rapid parasite clearance followed artemether-lumefantrine treatment in all four participants (clearance half-lives of 4.01 and 4.06 hours for 3D7-MBE-008 and 4.11 and 4.52 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 RegistrationAustralian New Zealand Clinical Trials registry numbers:P3487 (3D7-V1): ACTRN12619001085167P3491 (3D7-MBE-008): ACTRN12619001079134

“…The adverse events reported for both studies are in keeping with previous IBSM studies [9][10][11]28,29]. The asymptomatic raised liver enzymes, with no associated signi cant rise in bilirubin, have been reported in previous IBSM studies [30,31], sporozoite VIS [32] and in naturally occurring malaria [30,33]. Similarly, the reduction in white cell counts, especially lymphopenia and neutropenia have previously been reported in IBSM VIS, sporozoite VIS and clinical malaria [12,16,[34][35][36].…”

Section: Discussionsupporting

confidence: 85%

Development and evaluation of a new P. falciparum 3D7 blood stage malaria cell bank for use in malaria volunteer infection studies

et al. 2021

Preprint

Background New antimalarial 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 antimalarial drug development. Supply of the reference 3D7-V2 Plasmodium falciparum malaria cell bank (MCB) is limited. We 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.Methods We expanded the 3D7-V2 MCB 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. Results The 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 Plasmodium falciparum infection after inoculation with approximately 2800 parasites. For the 3D7-MBE-008 MCB, the parasite multiplication rate of 48 hours (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. Conclusion The 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): ACTRN12619001085167P3491 (3D7-MBE-008): ACTRN12619001079134