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Genetically attenuated malaria parasites (GAP) that arrest during liver stage development are powerful immunogens and afford complete and durable protection against sporozoite infection. Late liver stage-arresting GAP provide superior protection against sporozoite challenge in mice compared to early live stage-arresting attenuated parasites. However, very few late liver stage-arresting GAP have been generated to date. Therefore, identification of additional loci that are critical for late liver stage development and can be used to generate novel late liver stage-arresting GAPs is of importance. We further explored genetic attenuation inPlasmodium yoelii by combining two gene deletions,PlasMei2 andliver-specific protein 2 (LISP2 ), that each cause late liver stage arrest with various degrees of infrequent breakthrough to blood stage infection. The dual gene deletion resulted in a synthetic lethal phenotype that caused complete attenuation in a highly susceptible mouse strain.P. yoelii plasmei2 − lisp2 − arrested late in liver stage development and did not persist in livers beyond 3 days after infection. Immunization with this GAP elicited robust protective antibody responses in outbred and inbred mice against sporozoites, liver stages, and blood stages as well as eliciting protective liver-resident T cells. The immunization afforded protection against both sporozoite challenge and blood stage challenge. These findings provide evidence that completely attenuated late liver stage-arresting GAP are achievable via the synthetic lethal approach and might enable a path forward for the creation of a completely attenuated late liver stage-arrestingP. falciparum GAP.

A Plasmodium Parasite with Complete Late Liver Stage Arrest Protects against Preerythrocytic and Erythrocytic Stage Infection in Mice