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.
Highlights
Controlled human malaria infection (CHMI) accelerates development of anti-malarial interventions
Injection of 50, 200 and 800 PfSPZ IV led to asexual erythrocytic stage parasitaemia in 1/3, 1/3 and 7/9 volunteers, respectively
Injection of 3,200 PfSPZ led to asexual erythrocytic stage parasitaemia in 9/9 (100%) volunteers (Table 3)
Summary
Controlled human malaria infection (CHMI) accelerates development of anti-malarial interventions. Controlled human malaria infection (CHMI) with Plasmodium falciparum is among the best studied challenge models and has paved the way for many current malaria vaccine candidates [3] and some drugs for treatment and chemoprophylaxis [4]. Perhaps the main advantage of CHMI over studies under natural exposure is that it provides consistent and predictable infections, which translates to the ability to conduct simple, well-controlled trials in a small number of healthy subjects, who do not belong to a vulnerable group. This results in early, well-founded decisions on further clinical development
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