Development of virulence-attenuated Plasmodium berghei parasites

Blood stage rodent malaria parasites causing a mild and self limited infection in susceptible mice had been obtained with either radiation or chemical mutagenesis showing the possibility of developing an attenuated malaria vaccine. Targeted disruption of blood stage genes including plasmepsin 4 (pm4) and the merozoite surface protein 7 (msp7) also induces a virulence-attenuated phenotype that manifests itself with absence of experimental cerebral malaria (ECM), delayed increase of parasitemia and reduced mortality rate. The decrease in virulence in parasites lacking either pm4 or msp7 is however incomplete and dependent on the parasite species and mouse strain combination. The disruption of both parasite genes induced a remarkable virulence-attenuated phenotype characterized by a self-resolving infection with low levels of parasitemia and no ECM. Furthermore, convalescent mice were completely protected against subsequent challenge with the lethal P. berghei or P. yoelii parasites for several months. This work demonstrates that the sequential disruption of parasite genes can generate progressively induced virulence-attenuated blood-stage parasites that are capable of stimulate a long lasting protective immunity. These observations provide a proof-of-concept step for the development of human malaria vaccines based on genetically attenuated blood-stage parasites.