Identifying new transmission-blocking agents

Identifying new transmission-blocking agents

The lifecycle of the parasite in man and mosquito perpetuates transmission and disease. One way to break the transmission cycle is to have medicines that kill the gametocytes or sexual stages, and so prevent patients from re-infecting mosquitoes.

Demonstrating transmission-blocking potential 

Several of the molecules progressing through clinical development and translational research have demonstrated that they can kill the sexual stages or the gametocytes in vitro. Using a Standard Membrane Feeding Assay (SMFA) in collaboration with scientists at TropIQ in the Netherlands and GSK in Spain we have shown that many of these molecules also have the potential to block the transmission of malaria in the laboratory.

Testing the compounds on mosquitoes

The assay works by allowing mosquitoes to feed on malaria-infected blood cultured in vitro, combined with a compound and then dissecting the mosquitoes to see if the parasite was able to develop. This assay has enabled us to rank compounds in terms of activity.

To verify this activity clinically, we have two approaches. First, with the Ifakara Health Institute in Tanzania, MMV has established an insectary and proof-of-concept transmission-blocking model using the SMFA, but where mosquitoes feed on blood from study participants treated with a test drug, under very carefully controlled conditions. We are currently validating this model with the standard treatment regimens of artemisinin combination therapy and a single low dose of primaquine.

Second, we are working with the QIMR Berghofer Medical Research Institute in Queensland Australia to adapt the Volunteer Infection Studies model to assess transmission-blocking capabilities. 

Continuing the hunt for transmission-blocking chemical scaffolds

In collaboration with the Bill & Melinda Gates Foundation, the hunt continues for new transmission-blocking chemical scaffolds. We can carry out high-throughput screens against the gametocytes themselves and find compounds capable of killing both these and the normal blood stages. However, what would be really useful is to have a complete transmission-blocking assay for P. falciparum. The biggest challenge is that the current assay (SMFA) is very labour intensive and therefore time consuming. Working with TropIQ and with GSK, we have increased the efficiency of the assay and therefore the number of molecules that can be analyzed.