title: Controlled human malaria infection by intramuscular and direct venous inoculation of cryopreserved Plasmodium falciparum sporozoites in malaria-naïve volunteers: effect of injection volume and dose on infectivity rates.
abstract: BACKGROUND
  Controlled 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.
  
  
  METHODS
  An 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).
  
  
  RESULTS
  Four/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.
  
  
  CONCLUSIONS
  IM 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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01771848.
authors.affiliation: ISGlobal, Barcelona Ctr Int Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain. patricia.gomez@isglobal.org.|Department of Infectious Diseases, Centre of Tropical Medicine and Travel Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, PO Box 22660, 1100 DD, Amsterdam, The Netherlands. patricia.gomez@isglobal.org.
authors.forename: Gloria P
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authors.affiliation: ISGlobal, Barcelona Ctr Int Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain. almudena.legarda@gmail.com.
authors.forename: Almudena
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authors.affiliation: ISGlobal, Barcelona Ctr Int Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain. jose.munoz@isglobal.org.
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authors.affiliation: Drug Research Centre (CIM), Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. mballesterv@santpau.cat.|Department of Pharmacology and Therapeutics, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain. mballesterv@santpau.cat.
authors.forename: María Rosa
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authors.lastname: Ballester
authors.affiliation: ISGlobal, Barcelona Ctr Int Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain. cdobano@clinic.ub.es.
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authors.affiliation: ISGlobal, Barcelona Ctr Int Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain. pau.cistero@isglobal.org.
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authors.affiliation: ISGlobal, Barcelona Ctr Int Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain. alfons.jimenez@isglobal.org.
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authors.affiliation: ISGlobal, Barcelona Ctr Int Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain. diana.barrios@isglobal.org.
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authors.lastname: Nhamuave
authors.affiliation: ISGlobal, Barcelona Ctr Int Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain. alberto.garcia-basteiro@isglobal.org.|Centro de Investigação em Saúde de Manhiça, Maputo, Mozambique. alberto.garcia-basteiro@isglobal.org.
authors.forename: Alberto L
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authors.affiliation: ISGlobal, Barcelona Ctr Int Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain. MALDEA@clinic.ub.es.|Centro de Investigação em Saúde de Manhiça, Maputo, Mozambique. MALDEA@clinic.ub.es.
authors.forename: Marta
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authors.affiliation: Sanaria Inc, Rockville, MD, USA. amanoj@sanaria.com.
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authors.forename: John J
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authors.affiliation: Sanaria Inc, Rockville, MD, USA. ejames@sanaria.com.
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authors.affiliation: Drug Research Centre (CIM), Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. rantonijoana@santpau.cat.|Department of Pharmacology and Therapeutics, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain. rantonijoana@santpau.cat.
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mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007273:Injections, Intramuscular; D016778:Malaria, Falciparum / Q000276:immunology* / Q000469:parasitology; D008297:Male; D008875:Middle Aged; D018512:Parasitemia / Q000276:immunology* / Q000469:parasitology; D010963:Plasmodium falciparum / Q000276:immunology*; D013030:Spain; D034101:Sporozoites / Q000276:immunology*; D014838:Volunteers; D055815:Young Adult