scholarly journals Author response: A randomized feasibility trial comparing four antimalarial drug regimens to induce Plasmodium falciparum gametocytemia in the controlled human malaria infection model

2017 ◽  
Author(s):  
Isaie J Reuling ◽  
Lisanne A van de Schans ◽  
Luc E Coffeng ◽  
Kjerstin Lanke ◽  
Lisette Meerstein-Kessel ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Drug ◽  
Malaria Infection ◽  
Author Response ◽  
Feasibility Trial ◽  
Infection Model ◽  
Human Malaria ◽  
Controlled Human Malaria Infection ◽  
Drug Regimens

scholarly journals A randomized feasibility trial comparing four antimalarial drug regimens to induce Plasmodium falciparum gametocytemia in the controlled human malaria infection model

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Isaie J Reuling ◽  
Lisanne A van de Schans ◽  
Luc E Coffeng ◽  
Kjerstin Lanke ◽  
Lisette Meerstein-Kessel ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Plasmodium Falciparum ◽  
Adverse Events ◽  
Antimalarial Drug ◽  
Malaria Infection ◽  
Infection Model ◽  
Transmission Blocking ◽  
Human Malaria ◽  
Controlled Human Malaria Infection ◽  
Drug Regimens

Background:Malaria elimination strategies require a thorough understanding of parasite transmission from human to mosquito. A clinical model to induce gametocytes to understand their dynamics and evaluate transmission-blocking interventions (TBI) is currently unavailable. Here, we explore the use of the well-established Controlled Human Malaria Infection model (CHMI) to induce gametocyte carriage with different antimalarial drug regimens.Methods:In a single centre, open-label randomised trial, healthy malaria-naive participants (aged 18–35 years) were infected with Plasmodium falciparum by bites of infected Anopheles mosquitoes. Participants were randomly allocated to four different treatment arms (n = 4 per arm) comprising low-dose (LD) piperaquine (PIP) or sulfadoxine-pyrimethamine (SP), followed by a curative regimen upon recrudescence. Male and female gametocyte densities were determined by molecular assays.Results:Mature gametocytes were observed in all participants (16/16, 100%). Gametocytes appeared 8.5–12 days after the first detection of asexual parasites. Peak gametocyte densities and gametocyte burden was highest in the LD-PIP/SP arm, and associated with the preceding asexual parasite biomass (p=0.026). Male gametocytes had a mean estimated circulation time of 2.7 days (95% CI 1.5–3.9) compared to 5.1 days (95% CI 4.1–6.1) for female gametocytes. Exploratory mosquito feeding assays showed successful sporadic mosquito infections. There were no serious adverse events or significant differences in the occurrence and severity of adverse events between study arms (p=0.49 and p=0.28).Conclusions:The early appearance of gametocytes indicates gametocyte commitment during the first wave of asexual parasites emerging from the liver. Treatment by LD-PIP followed by a curative SP regimen, results in the highest gametocyte densities and the largest number of gametocyte-positive days. This model can be used to evaluate the effect of drugs and vaccines on gametocyte dynamics, and lays the foundation for fulfilling the critical unmet need to evaluate transmission-blocking interventions against falciparum malaria for downstream selection and clinical development.Funding:Funded by PATH Malaria Vaccine Initiative (MVI).Clinical trial number:NCT02836002.

scholarly journals Multidose Priming and Delayed Boosting Improve PfSPZ Vaccine Efficacy against Heterologous P. falciparum Controlled Human Malaria Infection

2020 ◽  
Author(s):  
Kirsten E Lyke ◽  
Alexandra Singer ◽  
Andrea A Berry ◽  
Sharina Reyes ◽  
Sumana Chakravarty ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Vaccine Efficacy ◽  
Malaria Infection ◽  
Human Malaria ◽  
Group 4 ◽  
Controlled Human Malaria Infection ◽  
Group 3 ◽  
Group 2 ◽  
The Impact ◽  
Group 1

Abstract Background A live-attenuated Plasmodium falciparum (Pf) sporozoite (SPZ) vaccine (PfSPZ Vaccine) has shown up to 100% protection against controlled human malaria infection (CHMI) using homologous parasites (same Pf strain as in the vaccine). Using a more stringent CHMI, with heterologous parasites (different Pf strain), we assessed the impact of higher PfSPZ doses, a novel multi-dose prime regimen, and a delayed vaccine boost upon vaccine efficacy. Methods Four groups of 15 healthy, malaria-naïve adults were immunized. Group (Grp) 1 received five doses of 4.5x10 5 PfSPZ (days 1, 3, 5, 7; week 16). Grps 2, 3 and 4 received three doses (weeks 0, 8, 16) with Gp 2 receiving 9.0×10 5/dose, Grp 3 receiving 18.0×10 5/dose, and Grp 4 receiving 27.0×10 5 for dose 1 and 9.0×10 5 for doses 2 and 3. VE was assessed by heterologous CHMI after 12 or 24 weeks. Volunteers not protected at 12 weeks were boosted prior to repeat CHMI at 24 weeks. Results At 12-week CHMI, 6/15 (40%) Group 1 (P=0.04), 3/15 (20%) Group 2 vs. 0/8 controls remained aparasitemic. At 24-week CHMI, 3/13 (23%) Group 3, 3/14 (21%) Group 4 vs. 0/8 controls remained aparasitemic (Groups 2-4, VE not significant). Post-boost, 9/14 (64%) vs. 0/8 controls remained aparasitemic (3/6 Group 1, P=0.025; 6/8 Group 2, P=0.002). Conclusions Four stacked, priming injections (multi-dose priming) showed 40% VE against heterologous CHMI, while dose escalation of PfSPZ using single dose priming was not significantly protective. Boosting unprotected subjects improved VE at 24 weeks to 64%.

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