A genetically attenuated malaria vaccine candidate based on P. falciparum b9/slarp gene-deficient sporozoites

A highly efficacious pre-erythrocytic stage vaccine would be an important tool for the control and elimination of malaria but is currently unavailable. High-level protection in humans can be achieved by experimental immunization with Plasmodium falciparum sporozoites attenuated by radiation or under anti-malarial drug coverage. Immunization with genetically attenuated parasites (GAP) would be an attractive alternative approach. Here we present data on safety and protective efficacy using sporozoites with deletions of two genes i.e. the newly identified b9 and slarp, which govern independent and critical processes for successful liver-stage development. In the rodent malaria model, Pb Delta b9 Delta slarpGAP was completely attenuated showing no breakthrough infections while efficiently inducing high level protection. The human Pf Delta b9 Delta slarpGAP generated without drug-resistance markers were infective to human hepatocytes in vitro and to humanized mice engrafted with human hepatocytes in vivo but completely aborted development after infection. These findings support the clinical development of a Pf Delta b9 Delta slarpSPZ vaccine.