A Plasmodium LARC GAP provides preerythrocytic, stage and species transcending protection in mice

Malonyl-CoA-acyl carrier protein transacylase (MCAT) catalyzes the transfer of a malonyl moiety from malonyl-CoA to acyl carrier protein during the initiation step of type II fatty acid synthesis (FASII). The Plasmodium FASII pathway was found to be essential for late liver-stage development in rodent malaria parasites. Here, we generated a novel genetically attenuated parasite (GAP) by disrupting Plasmodium MCAT. Deleting MCAT in rodent malaria parasites did not affect asexual blood-stage propagation and mosquito-stage development. MCAT KO sporozoites failed to initiate blood-stage infection in mice. Hepatic MCAT KO parasites showed impaired nuclear division and apicoplast biogenesis. This led to a defect in hepatic merozoite formation and attenuation of parasites during late liver stages. Vaccination of mice with MCAT KO sporozoites exhibited sterilizing immunity against homologous and heterologous species challenge. Further, MCAT KO-immunized mice were able to clear blood stage infection after iRBCs challenge. These findings highlight that late-liver arresting MCAT KO sporozoite is a promising GAP vaccine candidate for inducing pre-erythrocytic, stage, and species-transcending protection in mice.