Stephen D Woolley1,2,3, Melissa Fernandez1, Maria Rebelo1, Stacey A Llewellyn1, Louise Marquart1, Fiona H Amante1, Helen E Jennings1, Rebecca Webster1, Katharine Trenholme1,4, Stephan Chalon5, Joerg J Moehrle5, James S McCarthy1, Bridget E Barber6. 1. QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. 2. Centre for Defence Pathology, Royal Centre for Defence Medicine, Joint Hospital Group, ICT Building, Birmingham Research Park, Vincent Drive, Birmingham, UK. 3. Clinical Sciences Department, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, UK. 4. School of Medicine, University of Queensland, Herston, QLD, Australia. 5. Medicines for Malaria Venture, 20 Route de Pre-Bois, PO Box 1826, 1215, Geneva 15, Switzerland. 6. QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. bridget.barber@qimrberghofer.edu.au.
Abstract
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.
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 falciparummalaria 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.
Entities:
Keywords:
CHMI; Induced blood-stage malaria; Malaria; Plasmodium falciparum; VIS
Authors: John Woodford; Katharine A Collins; Anand Odedra; Claire Wang; Ihn Kyung Jang; Gonzalo J Domingo; Rebecca Watts; Louise Marquart; Matthew Berriman; Thomas D Otto; James S McCarthy Journal: J Infect Dis Date: 2020-03-02 Impact factor: 5.226
Authors: Leesa F Wockner; Isabell Hoffmann; Lachlan Webb; Benjamin Mordmüller; Sean C Murphy; James G Kublin; Peter O'Rourke; James S McCarthy; Louise Marquart Journal: J Infect Dis Date: 2020-03-02 Impact factor: 5.226
Authors: Rebecca Webster; Silvana Sekuloski; Anand Odedra; Stephen Woolley; Helen Jennings; Fiona Amante; Katharine R Trenholme; Julie Healer; Alan F Cowman; Emily M Eriksson; Priyanka Sathe; Jocelyn Penington; Adam J Blanch; Matthew W A Dixon; Leann Tilley; Michael F Duffy; Alister Craig; Janet Storm; Jo-Anne Chan; Krystal Evans; Anthony T Papenfuss; Louis Schofield; Paul Griffin; Bridget E Barber; Dean Andrew; Michelle J Boyle; Fabian de Labastida Rivera; Christian Engwerda; James S McCarthy Journal: BMC Med Date: 2021-11-22 Impact factor: 8.775
Authors: John Woodford; Ashley Gillman; Peter Jenvey; Jennie Roberts; Stephen Woolley; Bridget E Barber; Melissa Fernandez; Stephen Rose; Paul Thomas; Nicholas M Anstey; James S McCarthy Journal: Sci Rep Date: 2022-04-05 Impact factor: 4.996