2 research outputs found
Direct venous inoculation of Plasmodium falciparum sporozoites for controlled human malaria infection: a dose-finding trial in two centres
BACKGROUND: Controlled 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. METHODS: An
open-labelled, randomized, dose-finding study in 18-45 year old,
healthy, malaria-naive 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. RESULTS: IV 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.
CONCLUSIONS: IV 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 REGISTRATION: ClinicalTrials.gov NCT01624961 and
NCT01771848