Genetic engineering of attenuated malaria parasites for vaccination

Vaccination with live-attenuated Plasmodium sporozoites that arrest in the liver can completely protect against a malaria infection both in animal models and in humans; this has provided the conceptual basis for the most promising, but also challenging, approach to develop an efficacious malaria vaccine. Advances in genetic manipulation of Plasmodium in conjunction with improved genomic and biological information has enabled new approaches to design genetically attenuated parasites (GAPs). In this review we discuss the principles in discovery and development of GAPs in preclinical models that are important in selecting GAP parasites for first-in-human clinical studies. Finally, we highlight the challenges in manufacture, formulation and delivery of a live-attenuated whole parasite malaria vaccine, as well as the further refinements that may be implemented in the next generation GAP vaccines.

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► Genetically attenuated parasites (GAPs) as potential vaccines against malaria.
► Attenuated Plasmodium sporozoites confer sustained sterile immunity against malaria.
► Rodent malaria models are an important in vivo platform to delineate GAP safety and potency.
► Late liver-arresting GAPs elicit superior protective immunity than early arresting parasites.
► P. falciparum GAP vaccine candidates need ultimately to be validated in clinical studies.