Abstract
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. In this study, we present data on safety and protective efficacy using sporozoites with deletions of two genes, that is the newly identified b9 and slarp, which govern independent and critical processes for successful liver-stage development. In the rodent malaria model, PbΔb9ΔslarpGAP was completely attenuated showing no breakthrough infections while efficiently inducing high-level protection. The human PfΔb9ΔslarpGAP 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 PfΔb9ΔslarpSPZ vaccine.
Highlights
A vaccine that induces high-level (>90%) sterile protection by inducing immunity that attacks the nonpathologic, asymptomatic pre-erythrocytic stages of Plasmodium falciparum (Pf) will prevent infection, disease, and transmission and could be a powerful instrument to eliminate Pf malaria from geographically defined areas (Plowe et al, 2009; malERA Consultative Group on Vaccines, 2011)
Characterization of the PbΔb9 phenotype showed that liver-stage development was fully abrogated in BALB/c mice and severely compromised in the more stringent C57BL/6 murine model for P. berghei (Annoura et al, 2014)
The Pf genetically attenuated parasites (GAP) PfΔb9Δslarp containing two gene deletions is proposed as a whole-parasite malaria vaccine candidate
Summary
A vaccine that induces high-level (>90%) sterile protection by inducing immunity that attacks the nonpathologic, asymptomatic pre-erythrocytic stages of Plasmodium falciparum (Pf) will prevent infection, disease, and transmission and could be a powerful instrument to eliminate Pf malaria from geographically defined areas (Plowe et al, 2009; malERA Consultative Group on Vaccines, 2011). Induction of complete sustained protective immunity against a challenge infection has been achieved by previous exposure to the bites of mosquitoes infected with i) live radiation-attenuated Plasmodium sporozoites that invade but completely arrest in the liver van Schaijk et al eLife 2014;3:e03582. Human biology and medicine | Microbiology and infectious disease eLife digest Vaccines commonly contain a weakened or dead version of a disease-causing microorganism, or its toxins, or surface proteins. These prime the immune system to rapidly recognize, respond to, and eliminate the actual infectious pathogen if later encountered
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