A genetically engineered Plasmodium falciparum parasite vaccine provides protection from controlled human malaria infection

Abstract

Genetically engineered live Plasmodium falciparum sporozoites constitute a potential platform for creating consistently attenuated, genetically defined, whole-parasite vaccines against malaria through targeted gene deletions. Such genetically attenuated parasites (GAPs) do not require attenuation by irradiation or concomitant drug treatment. We previously developed a P. falciparum (Pf) GAP with deletions in P52 , P36 , and SAP1 genes (PfGAP3KO) and demonstrated its safety and immunogenicity in humans. Here, we further assessed safety, tolerability, and immunogenicity of the PfGAP3KO vaccine and tested its efficacy against controlled human malaria infection (CHMI) in malaria-naïve subjects. The vaccine was delivered by three ( n = 6) or five ( n = 8) immunizations with ~200 PfGAP3KO-infected mosquito bites per immunization. PfGAP3KO was safe and well tolerated with no breakthrough P. falciparum blood stage infections. Vaccine-related adverse events were predominately localized urticaria related to the numerous mosquito bites administered per vaccination. CHMI via bites with mosquitoes carrying fully infectious Pf NF54 parasites was carried out 1 month after the last immunization. Half of the study participants who received either three or five PfGAP3KO immunizations remained P. falciparum blood stage negative, as shown by a lack of detection of Plasmodium 18 S rRNA in the blood for 28 days after CHMI. Six protected study participants received a second CHMI 6 months later, and one remained completely protected. Thus, the PfGAP3KO vaccine was safe and immunogenic and was capable of inducing protection against sporozoite infection. These results warrant further evaluation of PfGAP3KO vaccine efficacy in dose-range finding trials with an injectable formulation.

Abstract

The genetically attenuated P. falciparum PfGAP3KO vaccine was safe and immunogenic and protected half of subjects against CHMI.

Malaria vaccine advance

Genetically attenuated malaria parasite vaccines are currently being developed as candidates for protection against Plasmodium falciparum infection. Murphy et al. used a genetically attenuated P. falciparum sporozoite vaccine they had previously developed that has deletions in parasite genes P52 , P36, and SAP1 (PfGAP3KO) to evaluate protection against controlled human malaria infection (CHMI). Vaccine was administered three or five times by ~200 PfGAP3KO-infected mosquito bites per immunization and did not cause any breakthrough infections. CHMI challenge was carried out 1 month after final immunization via P. falciparum –infected mosquito bites. Half of the individuals in each vaccine group did not develop detectable P. falciparum infection, and a subset of these individuals was subjected to a second CHMI 6 months later and remained partially protected. These results support further development of genetically attenuated sporozoites as potential malaria vaccines.