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Title: Direct venous inoculation of Plasmodium falciparum sporozoites for controlled human malaria infection: a dose-finding trial in two centres
Author: Mordmuller, Benjamin
Supan, Christian
Sim, B. Kim Lee
Gómez-Pérez, Gloria P.
Ospina Salazar, Carmen Lucelly
Held, Jana
Bolte, Stefanie
Esen, Meral
Tschan, Serena
Joanny, Fanny
Lamsfus Calle, Carlos
Lohr, Sascha JZ.
Lalremruata, Albert
Gunasekera, Anusha
James, Eric R.
Billingsley, Peter F.
Richman, Adam
Chakravarty, Sumana
Legarda, Almudena
Muñoz, José
Antonijoan, Rosa M.
Ballester, María Rosa
Hoffman, Stephen L.
Alonso, Pedro
Kremsner, Peter G.
Keywords: Malària
Plasmodium falciparum
Assaigs clínics
Plasmodium falciparum
Clinical trials
Issue Date: 18-Mar-2015
Publisher: BioMed Central
Abstract: 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: NCT01624961 and NCT01771848 .
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It is part of: Malaria Journal, 2015, vol. 14, num. 117, 11 p.
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ISSN: 1475-2875
Appears in Collections:Articles publicats en revistes (ISGlobal)

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