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Optimizing Intradermal Administration of Cryopreserved Plasmodium falciparum Sporozoites in Controlled Human Malaria Infection.

ABSTRACT: Controlled human malaria infection (CHMI) is a powerful tool to evaluate malaria vaccine and prophylactic drug efficacy. Until recently CHMI was only carried out by the bite of infected mosquitoes. A parenteral method of CHMI would standardize Plasmodium falciparum sporozoite (PfSPZ) administration, eliminate the need for expensive challenge facility infrastructure, and allow for use of many P. falciparum strains. Recently, intradermal (ID) injection of aseptic, purified, cryopreserved PfSPZ was shown to induce P. falciparum malaria; however, 100% infection rates were not achieved by ID injection. To optimize ID PfSPZ dosing so as to achieve 100% infection, 30 adults aged 18-45 years were randomized to one of six groups composed of five volunteers each. The parameters of dose (1 × 10(4) versus 5 × 10(4) PfSPZ total dose per volunteer), number of injections (two versus eight), and aliquot volume per ID injection (10 ?L versus 50 ?L) were studied. Three groups attained 100% infection: 1 × 10(4) PfSPZ in 50 ?L/2 doses, 1 × 10(4) PfSPZ in 10 ?L/2 doses, and 5 × 10(4) PfSPZ in 10 ?L/8 doses. The group that received 5 × 10(4) PfSPZ total dose in eight 10 ?L injections had a 100% infection rate and the shortest prepatent period (mean of 12.7 days), approaching the prepatent period for the current CHMI standard of five infected mosquitoes.

SUBMITTER: Lyke KE

PROVIDER: S-EPMC4674246 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Optimizing Intradermal Administration of Cryopreserved Plasmodium falciparum Sporozoites in Controlled Human Malaria Infection.

Lyke Kirsten E KE Laurens Matthew B MB Strauss Kathy K Adams Matthew M Billingsley Peter F PF James Eric E Manoj Anita A Chakravarty Sumana S Plowe Christopher V CV Li Ming Lin ML Ruben Adam A Edelman Robert R Green Michael M Dube Tina J TJ Sim B Kim Lee BKL Hoffman Stephen L SL

The American journal of tropical medicine and hygiene 20150928 6

Controlled human malaria infection (CHMI) is a powerful tool to evaluate malaria vaccine and prophylactic drug efficacy. Until recently CHMI was only carried out by the bite of infected mosquitoes. A parenteral method of CHMI would standardize Plasmodium falciparum sporozoite (PfSPZ) administration, eliminate the need for expensive challenge facility infrastructure, and allow for use of many P. falciparum strains. Recently, intradermal (ID) injection of aseptic, purified, cryopreserved PfSPZ was ...[more]

PMID: 26416102

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Project description:BackgroundControlled human malaria infection (CHMI) by mosquito bite is a powerful tool for evaluation of vaccines and drugs against Plasmodium falciparum malaria. However, only a small number of research centres have the facilities required to perform such studies. CHMI by needle and syringe could help to accelerate the development of anti-malaria interventions by enabling centres worldwide to employ CHMI.MethodsAn open-label CHMI study was performed with aseptic, purified, cryopreserved P. falciparum sporozoites (PfSPZ Challenge) in 36 malaria naïve volunteers. In part A, the effect of the inoculation volume was assessed: 18 participants were injected intramuscularly (IM) with a dose of 2,500 PfSPZ divided into two injections of 10 µL (n = 6), 50 µL (n = 6) or 250 µL (n = 6), respectively. In part B, the injection volume that resulted in highest infectivity rates in part A (10 µL) was used to formulate IM doses of 25,000 PfSPZ (n = 6) and 75,000 PfSPZ (n = 6) divided into two 10-µL injections. Results from a parallel trial led to the decision to add a positive control group (n = 6), each volunteer receiving 3,200 PfSPZ in a single 500-µL injection by direct venous inoculation (DVI).ResultsFour/six participants in the 10-µL group, 1/6 in the 50-µL group and 2/6 in the 250-µL group developed parasitaemia. Geometric mean (GM) pre-patent periods were 13.9, 14.0 and 15.0 days, respectively. Six/six (100%) participants developed parasitaemia in the 25,000 and 75,000 PfSPZ IM and 3,200 PfSPZ DVI groups. GM pre-patent periods were 12.2, 11.4 and 11.4 days, respectively. Injection of PfSPZ Challenge was well tolerated and safe in all groups.ConclusionsIM injection of 75,000 PfSPZ and DVI injection of 3,200 PfSPZ resulted in infection rates and pre-patent periods comparable to the bite of five PfSPZ-infected mosquitoes. Remarkably, it required 23.4-fold more PfSPZ administered IM than DVI to achieve the same parasite kinetics. These results allow for translation of CHMI from research to routine use, and inoculation of PfSPZ by IM and DVI regimens.Trial registrationClinicalTrials.gov NCT01771848.

Project description:BackgroundControlled 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.MethodsAn 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.ResultsIV 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.ConclusionsIV 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 registrationClinicalTrials.gov NCT01624961 and NCT01771848 .

Project description:BackgroundPlasmodium falciparum (Pf) sporozoite (SPZ) vaccines are the only candidate malaria vaccines that induce > 90% vaccine efficacy (VE) against controlled human malaria infection and the only malaria vaccines to have achieved reproducible VE against malaria in adults in Africa. The goal is to increase the impact and reduce the cost of PfSPZ vaccines by optimizing vaccine potency and manufacturing, which will benefit from identification of immunological responses contributing to protection in humans. Currently, there is no authentic animal challenge model for assessing P. falciparum malaria VE. Alternatively, Plasmodium knowlesi (Pk), which infects humans and non-human primates (NHPs) in nature, can be used to experimentally infect rhesus macaques (Macaca mulatta) to assess VE.MethodsSanaria has, therefore, produced purified, vialed, cryopreserved PkSPZ and conducted challenge studies in several naïve NHP cohorts. In the first cohort, groups of three rhesus macaques each received doses of 5 × 102, 2.5 × 103, 1.25 × 104 and 2.5 × 104 PkSPZ administered by direct venous inoculation. The infectivity of 1.5 × 103 PkSPZ cryopreserved with an altered method and of 1.5 × 103 PkSPZ cryopreserved for four years was tested in a second and third cohort of rhesus NHPs. The lastly, three pig-tailed macaques (Macaca nemestrina), a natural P. knowlesi host, were challenged with 2.5 × 103 PkSPZ cryopreserved six years earlier.ResultsIn the first cohort, all 12 animals developed P. knowlesi parasitaemia by thick blood smear, and the time to positivity (prepatent period) followed a non-linear 4-parameter logistic sigmoidal model with a median of 11, 10, 8, and 7 days, respectively (r2 = 1). PkSPZ cryopreserved using a modified rapid-scalable method infected rhesus with a pre-patent period of 10 days, as did PkSPZ cryopreserved four years prior to infection, similar to the control group. Cryopreserved PkSPZ infected pig-tailed macaques with median time to positivity by thin smear, of 11 days.ConclusionThis study establishes the capacity to consistently infect NHPs with purified, vialed, cryopreserved PkSPZ, providing a foundation for future studies to probe protective immunological mechanisms elicited by PfSPZ vaccines that cannot be established in humans.

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Optimizing Intradermal Administration of Cryopreserved Plasmodium falciparum Sporozoites in Controlled Human Malaria Infection.

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Optimizing Intradermal Administration of Cryopreserved Plasmodium falciparum Sporozoites in Controlled Human Malaria Infection.

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