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Malar J. 2015 Mar 18;14:117. doi: 10.1186/s12936-015-0628-0.

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

Author information

1
Institut für Tropenmedizin, Eberhard Karls Universität Tübingen and German Center for Infection Research, 72074, Tübingen, Germany. benjamin.mordmueller@uni-tuebingen.de.
2
Institut für Tropenmedizin, Eberhard Karls Universität Tübingen and German Center for Infection Research, 72074, Tübingen, Germany. christian.supan@medizin.uni-tuebingen.de.
3
Sanaria Inc, Rockville, MD, 20850, USA. ksim@protpot.com.
4
Barcelona Center for International Health Research (CRESIB), Hospital Clínic, University of Barcelona, E-08036, Barcelona, Spain. patricia.gomez@cresib.cat.
5
Institut für Tropenmedizin, Eberhard Karls Universität Tübingen and German Center for Infection Research, 72074, Tübingen, Germany. carmenlucelly@hotmail.com.
6
Institut für Tropenmedizin, Eberhard Karls Universität Tübingen and German Center for Infection Research, 72074, Tübingen, Germany. janaheld@hotmail.de.
7
Institut für Tropenmedizin, Eberhard Karls Universität Tübingen and German Center for Infection Research, 72074, Tübingen, Germany. stefanie.bolte@web.de.
8
Institut für Tropenmedizin, Eberhard Karls Universität Tübingen and German Center for Infection Research, 72074, Tübingen, Germany. meral.esen@uni-tuebingen.de.
9
Institut für Tropenmedizin, Eberhard Karls Universität Tübingen and German Center for Infection Research, 72074, Tübingen, Germany. serena.tschan@gmail.com.
10
Institut für Tropenmedizin, Eberhard Karls Universität Tübingen and German Center for Infection Research, 72074, Tübingen, Germany. fanny.joanny@gmail.com.
11
Institut für Tropenmedizin, Eberhard Karls Universität Tübingen and German Center for Infection Research, 72074, Tübingen, Germany. carlos.lamsfus@gmail.com.
12
Institut für Tropenmedizin, Eberhard Karls Universität Tübingen and German Center for Infection Research, 72074, Tübingen, Germany. sascha-zori-loehr@web.de.
13
Institut für Tropenmedizin, Eberhard Karls Universität Tübingen and German Center for Infection Research, 72074, Tübingen, Germany. albrt.04@gmail.com.
14
Sanaria Inc, Rockville, MD, 20850, USA. agunasekera@sanaria.com.
15
Sanaria Inc, Rockville, MD, 20850, USA. ejames@sanaria.com.
16
Sanaria Inc, Rockville, MD, 20850, USA. pbillingsley@sanaria.com.
17
Sanaria Inc, Rockville, MD, 20850, USA. arichman@sanaria.com.
18
Sanaria Inc, Rockville, MD, 20850, USA. schakravarty@sanaria.com.
19
Barcelona Center for International Health Research (CRESIB), Hospital Clínic, University of Barcelona, E-08036, Barcelona, Spain. almudena.legarda@gmail.com.
20
Barcelona Center for International Health Research (CRESIB), Hospital Clínic, University of Barcelona, E-08036, Barcelona, Spain. jmunozg@clinic.ub.es.
21
Drug Research Center (CIM), Institute of Biomedical Research (IIB), Research Institute of Santa Creu and Sant Pau Hospital, Barcelona, Spain. rantonijoana@santpau.cat.
22
Department of Pharmacology and Therapeutics, Autonomous University of Barcelona (UAB), Santa Creu and Sant Pau Hospital, E-08026, Barcelona, Spain. rantonijoana@santpau.cat.
23
Drug Research Center (CIM), Institute of Biomedical Research (IIB), Research Institute of Santa Creu and Sant Pau Hospital, Barcelona, Spain. mballesterv@santpau.cat.
24
Department of Pharmacology and Therapeutics, Autonomous University of Barcelona (UAB), Santa Creu and Sant Pau Hospital, E-08026, Barcelona, Spain. mballesterv@santpau.cat.
25
Sanaria Inc, Rockville, MD, 20850, USA. slhoffman@sanaria.com.
26
Barcelona Center for International Health Research (CRESIB), Hospital Clínic, University of Barcelona, E-08036, Barcelona, Spain. pedro.alonso@isglobal.org.
27
Institut für Tropenmedizin, Eberhard Karls Universität Tübingen and German Center for Infection Research, 72074, Tübingen, Germany. peter.kremsner@uni-tuebingen.de.

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-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.

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 .

PMID:
25889522
PMCID:
PMC4371633
DOI:
10.1186/s12936-015-0628-0
[Indexed for MEDLINE]
Free PMC Article

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