A double-blind, placebo-controlled phase 1/2a trial of the genetically attenuated malaria vaccine PfSPZ-GA1

Abstract

Immunization with attenuated Plasmodium sporozoites can induce protection against malaria infection, as shown byPlasmodium falciparum (Pf) sporozoites attenuated by radiation in multiple clinical trials. As alternative attenuationstrategy with a more homogeneous population of Pf sporozoites (PfSPZ), genetically engineered Plasmodium bergheisporozoites (SPZ) lacking the genes b9 and slarp induced sterile protection against malaria in mice. Consequently,PfSPZ-GA1 Vaccine, a Pf identical double knockout (Pf∆b9∆slarp), was generated as a genetically attenuated malariaparasite vaccine and tested for safety, immunogenicity, and preliminary efficacy in malaria-naïve Dutch volunteers.Dose-escalation immunizations up to 9.0 × 105 PfSPZ of PfSPZ-GA1 Vaccine were well tolerated without break-through blood-stage infection. Subsequently, groups of volunteers were immunized three times by direct venousinoculation with cryopreserved PfSPZ-GA1 Vaccine (9.0 × 105 or 4.5 × 105 PfSPZ, N = 13 each), PfSPZ Vaccine(radiation-attenuated PfSPZ, 4.5 × 105 PfSPZ, N = 13), or normal saline placebo at 8-week intervals, followed byexposure to mosquito bite controlled human malaria infection (CHMI). After CHMI, 3 of 25 volunteers from bothPfSPZ-GA1 groups were sterilely protected, and the remaining 17 of 22 showed a patency ≥9 days (median patencyin controls, 7 days; range, 7 to 9). All volunteers in the PfSPZ Vaccine control group developed parasitemia (medianpatency, 9 days; range, 7 to 12). Immunized groups exhibited a significant, dose-related increase in anti-Pf circum-sporozoite protein (CSP) antibodies and Pf-specific interferon- (IFN-)–producing T cells. Although no definiteconclusion can be drawn on the potential strength of protective efficacy of PfSPZ-GA1 Vaccine, the favorable safetyprofile and induced immune responses by PfSPZ-GA1 Vaccine warrant further clinical evaluation.