Direct venous inoculation of Plasmodium falciparum sporozoites for controlled human malaria infection: a dose-finding trial in two centres

Abstract

BackgroundControlled human malaria infection (CHMI) accelerates development of anti-malarial interventions. So far, CHMI is done by exposure of volunteers to bites of five mosquitoes carrying Plasmodium falciparum sporozoites (PfSPZ), a technique available in only a few centres worldwide. Mosquito-mediated CHMI is logistically complex, exact PfSPZ dosage is impossible and live mosquito-based interventions are not suitable for further clinical development.MethodsAn open-labelled, randomized, dose-finding study in 18–45 year old, healthy, malaria-naïve volunteers was performed to assess if intravenous (IV) injection of 50 to 3,200 aseptic, purified, cryopreserved PfSPZ is safe and achieves infection kinetics comparable to published data of mosquito-mediated CHMI. An independent study site verified the fully infectious dose using direct venous inoculation of PfSPZ. Parasite kinetics were assessed by thick blood smear microscopy and quantitative real time PCR.ResultsIV inoculation with 50, 200, 800, or 3,200 PfSPZ led to parasitaemia in 1/3, 1/3, 7/9, and 9/9 volunteers, respectively. The geometric mean pre-patent period (GMPPP) was 11.2 days (range 10.5–12.5) in the 3,200 PfSPZ IV group. Subsequently, six volunteers received 3,200 PfSPZ by direct venous inoculation at an independent investigational site. All six developed parasitaemia (GMPPP: 11.4 days, range: 10.4–12.3). Inoculation of PfSPZ was safe. Infection rate and pre-patent period depended on dose, and injection of 3,200 PfSPZ led to a GMPPP similar to CHMI with five PfSPZ-infected mosquitoes. The infectious dose of PfSPZ predicted dosage of radiation-attenuated PfSPZ required for successful vaccination.ConclusionsIV inoculation of PfSPZ is safe, well tolerated and highly reproducible. It shall further accelerate development of anti-malarial interventions through standardization and facilitation of CHMI. Beyond this, rational dose selection for whole PfSPZ-based immunization and complex study designs are now possible.Trial registrationClinicalTrials.gov NCT01624961 and NCT01771848.

Whole organism blood stage vaccines against malaria

“…This method of delivery is being used successfully for controlled human malaria infection studies to administer sporozoites [46]. Portable vein visualisation devices, e.g.…”

Development of whole sporozoite malaria vaccines

“…In a third trial, the i.v. route gave 100% infectivity using 3,200 PfSPZ in a single 500-μL dose with a prepatent period similar to five-bite CHMI [95]. In other trials, 100% infectivity and prepatent periods comparable to five-bite CHMI were achieved using 3,200 PfSPZ administered i.v., 75,000 PfSPZ administered i.m., or 50,000 PfSPZ administered in eight 10 μL doses [96,97]; therefore the i.m.…”

Workshop report: Malaria vaccine development in Europe–preparing for the future

“…Several P. falciparum strains/clones are available for mosquitomediated CHMI, and recently CHMI using DVI of aseptic, purified, vialed, cryopreserved P. falciparum sporozoites of the NF54 strain, was established and shown to be 100% infective with a pre-patent period similar to the sporozoite-infected mosquitoes' bites model [43]. Efforts to produce and supply additional strains and Plasmodium species are underway.…”

“…Current CHMI protocols to test vaccine efficacy are based on challenge by inoculation of asexual P. falciparum blood-stages [36][37][38], and of sporozoites either by controlled mosquito bites [6] or direct intravenous administration (DVI) [39][40][41][42][43].…”