Adaptation of blood-stage Controlled Human Malaria Infection for evaluation of transmission blocking malaria interventions in endemic countries

Controlled Human Malaria Infection (CHMI) has revolutionized the development of malaria vaccines. The procedure involves administration of known numbers of sporozoites or infected erythrocytes to healthy human volunteers under controlled environment. Use of highly sensitive molecular malaria diagnostic methods informs treatment decisions before symptoms develop, and allow characterization of parasite growth dynamics. Sporozoite CHMI has safely been used in six countries in Africa providing a platform to assess the efficacy of malaria vaccine candidates, and study the natural immunity to malaria.

Blood stage CHMI involves administration of known number of chloroquine 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 gametocytemia, 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.

Therefore, 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 candidate malaria vaccine and drugs before larger, more complex and expensive field efficacy studies are conducted.

The project intends to use an ideal dose of chloroquine-sensitive infected erythrocytes to establish an in vivo transmission model for studying TBI. Specifically, the project is designed to achieve the following:
1. Assess the efficiency of two antimalarial drugs regimens (Sulfadoxinepyrimethamine and doxycycline) to induce high levels of    gametocytemia and mosquito infection rates in healthy African adults.
2. 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.
3. Establish a PhD studentship in malaria immunoepidemiology to undertake the studies described in this project.

Finally, additional funding will be sought to test the utility of this model for evaluating the in vivo gametocytocidal activity of a candidate transmission blocking vaccine as a proof of concept in a small phase Ib trial in healthy African adults.

This project is part of the European and Developing Countries Clinical Trial Partnership (EDCTP2) program supported by the European Union (EU).