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Experimental human malaria infections are generally accepted to be a powerful tool for evaluation of potential malaria vaccine and drug efficacies. Until now, experimental infections have been performed exclusively using infectious mosquitoes. Recently, Sanaria has been able to overcome the technical issues associated with the production of aseptic, purified, cryopreserved Plasmodium falciparum (Pf) sporozoites (PfSPZ). Performing experimental human malaria infections with aseptic, purified, cryopreserved sporozoites clearly provides advantages over infectious mosquitoes, in terms of dose determination and standardisation and overcoming batch differences when performing sequential clinical trials. This trial is designed to find the dose of aseptic, purified, cryopreserved sporozoites (PfSPZ Challenge) that should be used for experimental human malaria infections.
Experimental human malaria is generally accepted to be a powerful tool for evaluation of potential malaria vaccine and drug efficacies. Until now, experimental infections have been exclusively performed using infectious mosquitoes or infected donor blood. The use of Pf-infected mosquitoes harbors disadvantages, primarily because of the great variability in the number of sporozoites that are injected with each mosquito bite (Beier, J.C. et al. Am J Trop Med Hyg. 1991 44(5): 564-70, Frischknecht, F. et al. Cell Microbiol. 2004 6(7): 687-94). Furthermore, the use of mosquitoes makes comparison difficult between trials performed with different mosquito batches. Moreover, the use of mosquitoes gives rise to unwanted local side-effects. Until now a challenge with injected aseptic sporozoites was thought to be impossible because it was not considered conceivable to manufacture, vial, and preserve Pf sporozoites that met regulatory standards, including sterility, purity, and potency.
Sanaria Inc. was founded in 2003 to produce a live, attenuated Pf sporozoite (SPZ) vaccine (Luke, T.C. and Hoffman S.L. J Exp Biol. 2003 206(pt 21):3803-8). To do so, Sanaria has had to manufacture attenuated PfSPZ that are aseptic, pure, and potent. This has been done successfully, an Investigational New Drug application (IND) was submitted to the U.S. Food and Drug Administration in February 2009, and a Phase 1 clinical trial with experimental challenge of volunteers was initiated in April 2009 (Hoffman, S.L. et al. Hum Vaccin. 2010 6(1):21). The same manufacturing procedures and processes and quality control release assays that were used to manufacture the PfSPZ Vaccine have been used to manufacture PfSPZ Challenge. This has resulted in the production of aseptic, pure, potent PfSPZ that have been vialed and cryopreserved to produce PfSPZ Challenge. This trial is designed to perform experimental human malaria infections with PfSPZ Challenge.
Previous experience with experimental human malaria infections in the Radboud University Nijmegen Medical Centre has shown that the bites of 5 infectious mosquitoes are required to obtain a 100% infection rate. Entomologists have generally noted that each mosquito injects only 5-10 sporozoites per bite (Beier, J.C. et al. Am. J. Trop. Med. Hyg. 1991 44(5): 564-70). However recent publications by Vanderberg, Frischknecht and colleagues indicate that the number of sporozoites injected by each mosquito is more likely within the range of 100-300 sporozoites per bite (Jin, Y. et al. Inf. Immun. 2007 Nov 75(11): 5532-9, Frischknecht, F. et al., Cell Microbiol. 2004 6(7): 687-94). Based on these numbers, 5 infectious bites would be equivalent to 25 to 1500 sporozoites. Because we do not know how cryopreservation and intradermal delivery will affect the viability and infectivity of PfSPZ Challenge, our study design calls for administration of three different doses of PfSPZ Challenge: a dose of 2,500 PfSPZ Challenge (Group 1); a dose of 10,000 PfSPZ Challenge (Group 2) if not all volunteers become thick smear positive (TS+) in Group 1; and a dose of 25,000 PfSPZ Challenge (Group 3) if there is not 100% TS+ in Group 2. If all volunteers in Group 1 (2,500 PfSPZ Challenge) become thick smear positive, then Group 2a will receive 1,000 PfSPZ Challenge. If all volunteers in Group 2a become TS+, the volunteers in Group 3a will receive 500 PfSPZ Challenge. If all volunteers in Group 2 (10,000 PfSPZ Challenge) become TS+, Group 3b will receive 5,000 PfSPZ. If less than 100% of volunteers in Group 2a (1,000 PfSPZ Challenge) become TS+ then Group 3c will receive 1,750 PfSPZ Challenge.
Allocation: Non-Randomized, Control: Dose Comparison, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label
PfSPZ (Pf sporozoites)
Radboud University Nijmegen Medical Center
Not yet recruiting
Published on BioPortfolio: 2014-08-27T03:15:12-0400
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