Controlled Human Malaria Infection Clinical Trial
Official title:
Adaptation of Blood-stage Controlled Human Malaria Infection for Evaluation of Transmission Blocking Malaria Interventions in Malaria Endemic Countries
Controlled human malaria infection (CHMI) has revolutionized the development of malaria vaccines. It involves the administration of either known numbers of sporozoites or infected erythrocytes to healthy human volunteers under a controlled environment. The use of highly sensitive molecular malaria diagnostic methods informs treatment decisions before symptom development and allows the characterization of parasite growth dynamics. Sporozoite CHMI has safely been used in six countries in Africa providing a platform to assess the efficacy of candidate malaria vaccines and study the natural immunity to malaria. Blood stage CHMI involves administration of known number of Artemether Lumefantrine sensitive infected erythrocytes in healthy volunteers, and it is a more sensitive model for modelling parasite growths and study the efficacy of blood-stage malaria vaccines. It has been safely used in Australia and Europe but not in Africa. Adaptation of this model by administration of combination of suboptimal and optimal antimalarial drugs lead to increased gametocytaemia, and infection rates in mosquitoes following standard membrane feeding assay. Such adaptation allows the model to be used to study parasite transmission from human to mosquitoes and evaluate transmission blocking malaria interventions. There is an urgent need to establish an in vivo model for early-stage clinical evaluation of transmission blocking interventions (TBI) in volunteers living in malaria endemic countries. This would allow rapid and cost-effective way to down-select transmission blocking candidate malaria vaccine and gametocidal antimalarial drugs before larger, more complex, and expensive field efficacy studies are conducted. A study done in naïve individual showed 100% success in establishing a malaria infection using 2800 P. falciparum infected RBCs, while a recent study (manuscript in development) has demonstrated success in establishing infection in Tanzanian semi-immune individuals with low malaria exposure using 1000 P. falciparum infected RBCs. We will use 1000 ALU-sensitive 3D7 P. falciparum infected RBCs to establish an in vivo transmission model for studying Transmission blocking interventions and assess the efficiency of two antimalarial drugs regimens (Piperaquine and doxycycline) to induce high levels of gametocytaemia and mosquito infection rates in healthy African adults. We will also investigate the determinants of successful transmission to mosquitoes including underlying immune responses to both asexual and sexual malaria antigens, asexual parasite dynamics and gametocyte burden, sex ratio of male and female gametocytes, and the relationship between gametocyte density and mosquito infection rate
Adaptation of blood-stage Controlled Human Malaria Infection for evaluation of transmission blocking malaria interventions in malaria endemic countries. This will be Phase I Randomized open label trial. It will recruit Healthy male adults aged 18-45 years from low malaria endemic area (Bagamoy0) for three months. BACKGROUND AND RATIONALE Plasmodium falciparum (Pf) malaria remains a disease of public health significance affecting millions across the globe (1). Scaling up of malaria interventions has reduced the malaria burden in several parts of Africa (2-5), but this has not been consistent everywhere, with some areas reporting sustained or even an increase in the burden of malaria (6, 7). Vaccination is one of the most cost-effective public health interventions (8, 9) and would play a critical role in the elimination efforts. There is a significant development in research to identify promising transmission-blocking malaria vaccines, with several candidate vaccines in the pipeline. To down-select the most promising candidates, antibody tests and functional assays that prevent infection of mosquitoes are normally used (10). It is however unclear how well these assays represent the in vivo transmission-blocking efficacy making it difficult to choose which candidate to develop further (11). Before a transmission blocking vaccine (TBV) can be approved, a randomized trial to evaluate the effect on gametocyte carriage and transmission to mosquitoes or Phase 3 trial to demonstrate vaccine impact on the incidence of infection in the target population are required. Both study designs are large and expensive (11). Alternatively, accelerated approval could be sought through surrogate markers of efficacy that would require either analytical or biological, but not clinical validation. However currently there is no known surrogate markers. Therefore, in vivo transmission blocking model for early-stage clinical evaluation of TBV is needed to rapidly down-select promising candidate vaccines before large field trials are conducted. Although such model has been studied in malaria naïve population, it is important to establish this model in target populations to provide relevant results that considers the genetic background and underlying natural immunity. ;
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
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Controlled Human Malaria Infection Model for Evaluation of Transmission-blocking Interventions - Study 2
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| Terminated |
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