Identifying Liver Stage Antimalarials that Drive Protective Immunity

Kirsten Hanson from the Instituto de Medicina Molecular in Portugal has developed a screening strategy to identify compounds that specifically block the final maturation stage of the malaria-causing Plasmodium parasite that occurs in human liver. These compounds could prevent the symptoms and establishment of malaria in humans (i.e. act as prophylactics), and block transmission back to the mosquitoes. In addition, high antigen levels will result from drug-killed late liver-stage parasites in humans that could act like a vaccine and provide immune protection against subsequent infected mosquito bites. In Phase I, they developed an assay suitable for high-throughput screens to quantify late Plasmodium liver-stage development in vitro using Plasmodium berghei infection of HepG2 hepatoma cells, and screened the 400 compounds in the Malaria Box, identifying nine hits (compounds that specifically disrupt late liver-stage development according to their assay). In Phase II, they are modifying their criteria for defining a compound as a hit in order to identify those most likely to act as a chemoprophylactic and provide protective immunity in humans, and will perform high-throughput screens using additional compound libraries with candidate hits being tested first in a rodent malaria model.