In 2010, MMV and Prof. James McCarthy from QIMR Berghofer Medical Research Institute, Australia, assessed the safety and feasibility of using the controlled human malaria infection (CHMI) model to test for blood-stage activity. In a tightly controlled environment, the level of parasitaemia is closely monitored in volunteers inoculated with a low number of drug-sensitive parasites who, around 7 days later, receive the drug candidate. In this way the model allows us to understand quickly whether a compound will be efficaciousand guides dose selection for subsequent clinical studies.

In 2015, we began looking at how molecules work in combination, initially exploring how artefenomel and DSM265 act together. This type of study informs the selection of optimum partner drugs, the potential interactions between them and their dosages. More recently, the model was adapted to explore compound activity against the sexual (gametocyte) stages of the malaria parasite to assess transmission-blocking activity. After completion of a pilot study with artefenomel in 2016, the model is being used to assess the transmission-blocking activity of new molecules coming through the pipeline from drug discovery.

Dr Katharine Collins explains how volunteer safety is assured and how the model has been adapted to explore transmission-blocking activity.

1. How do you ensure that volunteers are not at risk?

During all the studies, when volunteers are inoculated with parasites they are monitored very frequently via visits to the clinic or telephone follow-up and, if needed, treatment is promptly initiated. When the test drug is administered, the volunteers remain in the clinic for 72 hours so we can readily detect if the drug is not working and deliver a rescue therapy, if needed.

The only difference for evaluating transmission-blocking activity is that a small cup of mosquitoes feed on volunteers’ arms once or twice during the study. At the end of all our studies the participants receive an antimalarial to clear any remaining parasites and ensure they are completely free of malaria. The model has been shown to be very safe.

2. How was the original blood-stage model adapted to look at the transmission-blocking potential of new molecules?

A transmission-blocking drug could either kill or sterilize the mature gametocytes (which are the form of the malaria parasite that are transmitted to mosquitoes), thereby preventing transmission; or it could kill the early forms of the gametocyte and prevent them from maturing and becoming transmissible.

The simplest way to assess transmission-blocking activity is to evaluate if a drug can kill the early-stage developing gametocytes at the same time as it clears the asexual parasites. In these studies, volunteers are inoculated with a low number of drug-sensitive parasites and when a certain threshold of parasitaemia is reached, they are treated with the experimental drug. We then closely monitor the clearance of the asexual parasites and the development of gametocytes, to determine if the drug can kill the earlystage gametocytes.

A second more complex method is currently under development to evaluate a drug’s action against the mature gametocytes. In this model, volunteers are inoculated with blood-stage parasites as before, but are then treated with a drug known to clear asexual parasites while allowing early-stage gametocytes to continue developing. When mature gametocytes are detected we administer the experimental drug and evaluate their clearance. We also feed mosquitoes with the test subject’s blood containing the gametocytes to see if the drug can prevent transmission.

3. What are the advantages of the CHMI model compared with other tools to assess transmission-blocking activity, such as laboratory assays?

These models will enable us to learn what actually happens in humans and help us determine an effective dose to assess in the field. The ability to tightly control the infection process and frequently monitor subjects also means that accurate determinations can be made from a relatively limited number of test subjects. The laboratory assays are extremely valuable for looking at the drug’s ability to kill or sterilize the gametocytes, or block transmission, and to select the most promising drug candidates. But we don’t know how well they predict what will actually occur in humans. 4. What has it been like to work with MMV on this project? It’s been an extremely challenging project but MMV has understood this and has been incredibly supportive and enthusiastic in helping us succeed. I would say it’s MMV’s supportive approach that has actually made the project possible.