Direct venous inoculation of Plasmodium falciparum sporozoites for controlled human malaria infection: a dose-finding trial in two centres
Por:
Mordmuller, B, Supan, C, Sim, KL, Gomez-Perez, GP, Salazar, CLO, Held, J, Bolte, S, Esen, M, Tschan, S, Joanny, F, Calle, CL, Lohr, SJZ, Lalremruata, A, Gunasekera, A, James, ER, Billingsley, PF, Richman, A, Chakravarty, S, Legarda, A, Munoz, J, Antonijoan, RM, Ballester, MR, Hoffman, SL, Alonso, PL, Kremsner, PG
Publicada:
18 mar 2015
Resumen:
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.
Filiaciones:
Mordmuller, B:
Univ Tubingen, Inst Tropenmed, D-72074 Tubingen, Germany
German Ctr Infect Res, D-72074 Tubingen, Germany
Supan, C:
Univ Tubingen, Inst Tropenmed, D-72074 Tubingen, Germany
German Ctr Infect Res, D-72074 Tubingen, Germany
Sim, KL:
Sanaria Inc, Rockville, MD 20850 USA
Gomez-Perez, GP:
Univ Barcelona, Hosp Clin, Barcelona Ctr Int Hlth Res CRESIB, E-08036 Barcelona, Spain
Salazar, CLO:
Univ Tubingen, Inst Tropenmed, D-72074 Tubingen, Germany
German Ctr Infect Res, D-72074 Tubingen, Germany
Held, J:
Univ Tubingen, Inst Tropenmed, D-72074 Tubingen, Germany
German Ctr Infect Res, D-72074 Tubingen, Germany
Bolte, S:
Univ Tubingen, Inst Tropenmed, D-72074 Tubingen, Germany
German Ctr Infect Res, D-72074 Tubingen, Germany
Esen, M:
Univ Tubingen, Inst Tropenmed, D-72074 Tubingen, Germany
German Ctr Infect Res, D-72074 Tubingen, Germany
Tschan, S:
Univ Tubingen, Inst Tropenmed, D-72074 Tubingen, Germany
German Ctr Infect Res, D-72074 Tubingen, Germany
Joanny, F:
Univ Tubingen, Inst Tropenmed, D-72074 Tubingen, Germany
German Ctr Infect Res, D-72074 Tubingen, Germany
Calle, CL:
Univ Tubingen, Inst Tropenmed, D-72074 Tubingen, Germany
German Ctr Infect Res, D-72074 Tubingen, Germany
Lohr, SJZ:
Univ Tubingen, Inst Tropenmed, D-72074 Tubingen, Germany
German Ctr Infect Res, D-72074 Tubingen, Germany
Lalremruata, A:
Univ Tubingen, Inst Tropenmed, D-72074 Tubingen, Germany
German Ctr Infect Res, D-72074 Tubingen, Germany
Gunasekera, A:
Sanaria Inc, Rockville, MD 20850 USA
James, ER:
Sanaria Inc, Rockville, MD 20850 USA
Billingsley, PF:
Sanaria Inc, Rockville, MD 20850 USA
Richman, A:
Sanaria Inc, Rockville, MD 20850 USA
Chakravarty, S:
Sanaria Inc, Rockville, MD 20850 USA
Legarda, A:
Univ Barcelona, Hosp Clin, Barcelona Ctr Int Hlth Res CRESIB, E-08036 Barcelona, Spain
Munoz, J:
Univ Barcelona, Hosp Clin, Barcelona Ctr Int Hlth Res CRESIB, E-08036 Barcelona, Spain
Antonijoan, RM:
Res Inst Santa Creu, Inst Biomed Res IIB, Drug Res Ctr CIM, Barcelona, Spain
Sant Pau Hosp, Barcelona, Spain
Autonomous Univ Barcelona UAB, Santa Creu & Sant Pau Hosp, Dept Pharmacol & Therapeut, E-08026 Barcelona, Spain
Ballester, MR:
Res Inst Santa Creu, Inst Biomed Res IIB, Drug Res Ctr CIM, Barcelona, Spain
Sant Pau Hosp, Barcelona, Spain
Autonomous Univ Barcelona UAB, Santa Creu & Sant Pau Hosp, Dept Pharmacol & Therapeut, E-08026 Barcelona, Spain
Hoffman, SL:
Sanaria Inc, Rockville, MD 20850 USA
Alonso, PL:
Univ Barcelona, Hosp Clin, Barcelona Ctr Int Hlth Res CRESIB, E-08036 Barcelona, Spain
Kremsner, PG:
Univ Tubingen, Inst Tropenmed, D-72074 Tubingen, Germany
German Ctr Infect Res, D-72074 Tubingen, Germany
Green Published, gold
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