{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T06:33:47Z","timestamp":1767854027640,"version":"3.49.0"},"reference-count":59,"publisher":"American Society of Tropical Medicine and Hygiene","issue":"4","license":[{"start":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T00:00:00Z","timestamp":1665532800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,10,12]]},"abstract":"<jats:title>ABSTRACT.<\/jats:title>\n<jats:p><jats:italic>Plasmodium falciparum<\/jats:italic> sporozoite (PfSPZ) direct venous inoculation (DVI) using cryopreserved, infectious PfSPZ (PfSPZ Challenge [Sanaria, Rockville, Maryland]) is an established controlled human malaria infection model. However, to evaluate new chemical entities with potential blood-stage activity, more detailed data are needed on safety, tolerability, and parasite clearance kinetics for DVI of PfSPZ Challenge with established schizonticidal antimalarial drugs. This open-label, phase Ib study enrolled 16 malaria-na\u00efve healthy adults in two cohorts (eight per cohort). Following DVI of 3,200 PfSPZ (NF54 strain), parasitemia was assessed by quantitative polymerase chain reaction (qPCR) from day 7. The approved antimalarial artemether-lumefantrine was administered at a qPCR-defined target parasitemia of \u2265 5,000 parasites\/mL of blood. The intervention was generally well tolerated, with two grade 3 adverse events of neutropenia, and no serious adverse events. All 16 participants developed parasitemia after a mean of 9.7 days (95% CI 9.1\u201310.4) and a mean parasitemia level of 511 parasites\/mL (95% CI 369\u2013709). The median time to reach \u2265 5,000 parasites\/mL was 11.5 days (95% CI 10.4\u201312.4; Kaplan\u2013Meier), at that point the geometric mean (GM) parasitemia was 15,530 parasites\/mL (95% CI 10,268\u201323,488). Artemether-lumefantrine was initiated at a GM of 12.1 days (95% CI 11.5\u201312.7), and a GM parasitemia of 6,101 parasites\/mL (1,587\u201323,450). Mean parasite clearance time was 1.3 days (95% CI 0.9\u20132.1) and the mean log<jats:sub>10<\/jats:sub> parasite reduction ratio over 48 hours was 3.6 (95% CI 3.4\u20133.7). This study supports the safety, tolerability, and feasibility of PfSPZ Challenge by DVI for evaluating the blood-stage activity of candidate antimalarial drugs.<\/jats:p>","DOI":"10.4269\/ajtmh.21-1297","type":"journal-article","created":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T13:26:34Z","timestamp":1661779594000},"page":"804-814","source":"Crossref","is-referenced-by-count":5,"title":["Safety, Tolerability, and Parasite Clearance Kinetics in Controlled Human Malaria Infection after Direct Venous Inoculation of Plasmodium falciparum Sporozoites: A Model for Evaluating New Blood-Stage Antimalarial Drugs"],"prefix":"10.4269","volume":"107","author":[{"given":"M. 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spread","volume":"41","author":"Woodrow","year":"2017"},{"key":"b3","series-title":"Vaccine","first-page":"7065","article-title":"The frontline of controlled human malaria infections: a report from the controlled human infection models Workshop in Leiden University Medical Centre 5 May 2016","volume":"35","author":"Roestenberg","year":"2017"},{"key":"b4","series-title":"BMC Infect Dis","first-page":"1274","article-title":"Reproducibility of malaria sporozoite challenge model in humans for evaluating efficacy of vaccines and drugs: a systematic review","volume":"21","author":"Shibeshi","year":"2021"},{"key":"b5","series-title":"Infect Immun","first-page":"e00479","article-title":"Controlled human malaria infection: applications, advances, and challenges","volume":"86","author":"Stanisic","year":"2018"},{"key":"b6","series-title":"Nat Rev Immunol","first-page":"57","article-title":"Experimental human challenge infections can accelerate clinical malaria vaccine development","volume":"11","author":"Sauerwein","year":"2011"},{"key":"b7","series-title":"J Infect Dis","first-page":"319","article-title":"Efficacy of preerythrocytic and blood-stage malaria vaccines can be assessed in small sporozoite challenge trials in human volunteers","volume":"206","author":"Roestenberg","year":"2012"},{"key":"b8","series-title":"J Antimicrob Chemother","first-page":"2620","article-title":"Efficacy of OZ439 (artefenomel) against early Plasmodium falciparum blood-stage malaria infection in healthy volunteers","volume":"71","author":"McCarthy","year":"2016"},{"key":"b9","series-title":"Lancet Infect Dis","first-page":"626","article-title":"Safety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265: a two-part first-in-human phase 1a\/1b randomised study","volume":"17","author":"McCarthy","year":"2017"},{"key":"b10","series-title":"Lancet Infect Dis","first-page":"964","article-title":"Safety, tolerability, pharmacokinetics, and antimalarial efficacy of a novel Plasmodium falciparum ATP4 inhibitor SJ733: a first-in-human and induced blood-stage malaria phase 1a\/b trial","volume":"20","author":"Gaur","year":"2020"},{"key":"b11","series-title":"Trends Parasitol","first-page":"515","article-title":"Experimentally induced blood stage malaria infection as a tool for clinical research","volume":"28","author":"Engwerda","year":"2012"},{"key":"b12","series-title":"N Engl J Med","first-page":"468","article-title":"Protection against a malaria challenge by sporozoite inoculation","volume":"361","author":"Roestenberg","year":"2009"},{"key":"b13","series-title":"JCI Insight","first-page":"e89154","article-title":"Protection against Plasmodium falciparum malaria by PfSPZ vaccine","volume":"2","author":"Epstein","year":"2017"},{"key":"b14","series-title":"Proc Natl Acad Sci USA","first-page":"2711","article-title":"Attenuated PfSPZ vaccine induces strain-transcending T cells and durable protection against heterologous controlled human malaria infection","volume":"114","author":"Lyke","year":"2017"},{"key":"b15","series-title":"Am J Trop Med Hyg","first-page":"528","article-title":"Phase I\/II evaluation of the prophylactic antimalarial activity of pafuramidine in healthy volunteers challenged with Plasmodium falciparum sporozoites","volume":"80","author":"Nyunt","year":"2009"},{"key":"b16","series-title":"J Infect Dis","first-page":"693","article-title":"A randomized trial evaluating the prophylactic activity of DSM265 against preerythrocytic Plasmodium falciparum infection during controlled human malarial infection by mosquito bites and direct venous inoculation","volume":"217","author":"Murphy","year":"2018"},{"key":"b17","series-title":"Am J Trop Med Hyg","first-page":"556","article-title":"The controlled human malaria infection experience at the University of Maryland","volume":"100","author":"Friedman-Klabanoff","year":"2019"},{"key":"b18","series-title":"Clin Infect Dis","first-page":"1377","article-title":"Controlled human malaria infection of healthy adults with lifelong malaria exposure to assess safety, immunogenicity, and efficacy of the asexual blood stage malaria vaccine candidate GMZ2","volume":"69","author":"Dejon-Agobe","year":"2019"},{"key":"b19","series-title":"Trop Med Int Health","first-page":"380","article-title":"Ivermectin for causal malaria prophylaxis: a randomised controlled human infection trial","volume":"25","author":"Metzger","year":"2020"},{"key":"b20","series-title":"Lancet Infect Dis","first-page":"636","article-title":"DSM265 for Plasmodium falciparum chemoprophylaxis: a randomised, double blinded, phase 1 trial with controlled human malaria infection","volume":"17","author":"Sulyok","year":"2017"},{"key":"b21","series-title":"PLoS Pathog","first-page":"e1009594","article-title":"PfSPZ-CVac efficacy against malaria increases from 0% to 75% when administered in the absence of erythrocyte stage parasitemia: a randomized, placebo-controlled trial with controlled human malaria infection","volume":"17","author":"Murphy","year":"2021"},{"key":"b22","series-title":"Am J Trop Med Hyg","first-page":"338","article-title":"Safety, immunogenicity, and protective efficacy against controlled human malaria infection of Plasmodium falciparum sporozoite vaccine in Tanzanian adults","volume":"99","author":"Jongo","year":"2018"},{"key":"b23","series-title":"Vaccine","first-page":"4263","article-title":"Effect of immune regulatory pathways after immunization with GMZ2 malaria vaccine candidate in healthy lifelong malaria-exposed adults","volume":"38","author":"Nouatin","year":"2020"},{"key":"b24","series-title":"Nature","first-page":"445","article-title":"Sterile protection against human malaria by chemoattenuated PfSPZ vaccine","volume":"542","author":"Mordm\u00fcller","year":"2017"},{"key":"b25","series-title":"eLife","first-page":"e53080","article-title":"Proteome-wide analysis of a malaria vaccine study reveals personalized humoral immune profiles in Tanzanian adults","volume":"9","author":"Camponovo","year":"2020"},{"key":"b26","series-title":"Am J Trop Med Hyg","first-page":"508","article-title":"Impact of sickle cell trait and naturally acquired immunity on uncomplicated malaria after controlled human malaria infection in adults in Gabon","volume":"98","author":"Lell","year":"2018"},{"key":"b27","series-title":"PLoS Negl Trop Dis","first-page":"e0009361","article-title":"Exploratory analysis of the effect of helminth infection on the immunogenicity and efficacy of the asexual blood-stage malaria vaccine candidate GMZ2","volume":"15","author":"Nouatin","year":"2021"},{"key":"b28","series-title":"Clin Infect Dis","first-page":"2544","article-title":"Serologic markers of previous malaria exposure and functional antibodies inhibiting parasite growth are associated with parasite kinetics following a Plasmodium falciparum controlled human infection","volume":"70","author":"Achan","year":"2020"},{"key":"b29","series-title":"JCI Insight","first-page":"e146443","article-title":"Safety and PCR monitoring in 161 semi-immune Kenyan adults following controlled human malaria infection","volume":"6","author":"Kapulu","year":"2021"},{"key":"b30","series-title":"J Clin Invest","first-page":"515","article-title":"Serum cytokine profiles in experimental human malaria. Relationship to protection and disease course after challenge","volume":"90","author":"Harpaz","year":"1992"},{"key":"b31","series-title":"Cell Rep","first-page":"399","article-title":"Type I interferons regulate immune responses in humans with blood-stage Plasmodium falciparum infection","volume":"17","author":"Montes de Oca","year":"2016"},{"key":"b32","series-title":"PLoS One","first-page":"e21914","article-title":"A pilot randomised trial of induced blood-stage Plasmodium falciparum infections in healthy volunteers for testing efficacy of new antimalarial drugs","volume":"6","author":"McCarthy","year":"2011"},{"key":"b33","series-title":"J Infect Dis","first-page":"963","article-title":"Growth rate of Plasmodium falciparum: analysis of parasite growth data from malaria volunteer infection studies","volume":"221","author":"Wockner","year":"2020"},{"key":"b34","series-title":"J Infect Dis","first-page":"1257","article-title":"A randomized clinical trial to compare P. falciparum gametocytaemia and infectivity following blood-stage or mosquito bite induced controlled malaria infection","volume":"224","author":"Alkema","year":"2020"},{"key":"b35","series-title":"J Infect Dis","first-page":"145","article-title":"Safety and clinical outcome of experimental challenge of human volunteers with Plasmodium falciparum-infected mosquitoes: an update","volume":"196","author":"Epstein","year":"2007"},{"key":"b36","series-title":"Neth J Med","first-page":"52","article-title":"Clinical outcome of experimental human malaria induced by Plasmodium falciparum-infected mosquitoes","volume":"63","author":"Verhage","year":"2005"},{"key":"b37","series-title":"J Infect Dis","first-page":"915","article-title":"Clinical manifestations of Plasmodium falciparum malaria experimentally induced by mosquito challenge","volume":"175","author":"Church","year":"1997"},{"key":"b38","series-title":"eLife","first-page":"e31549","article-title":"A randomized feasibility trial comparing four antimalarial drug regimens to induce Plasmodium falciparum gametocytemia in the controlled human malaria infection model","volume":"7","author":"Reuling","year":"2018"},{"key":"b39","series-title":"PLoS One","first-page":"e38434","article-title":"Comparison of clinical and parasitological data from controlled human malaria infection trials","volume":"7","author":"Roestenberg","year":"2012"},{"key":"b40","series-title":"Am J Trop Med Hyg","first-page":"66","article-title":"Malaria transmitted to humans by mosquitoes infected from cultured Plasmodium falciparum.","volume":"35","author":"Chulay","year":"1986"},{"key":"b41","series-title":"Am J Trop Med Hyg","first-page":"663","article-title":"Safety, immunogenicity, and protective efficacy of intradermal immunization with aseptic, purified, cryopreserved Plasmodium falciparum sporozoites in volunteers under chloroquine prophylaxis: a randomized controlled trial","volume":"94","author":"Bastiaens","year":"2016"},{"key":"b42","series-title":"Am J Trop Med Hyg","first-page":"5","article-title":"Controlled human malaria infections by intradermal injection of cryopreserved Plasmodium falciparum sporozoites","volume":"88","author":"Roestenberg","year":"2013"},{"key":"b43","series-title":"Am J Trop Med Hyg","first-page":"1274","article-title":"Optimizing intradermal administration of cryopreserved Plasmodium falciparum sporozoites in controlled human malaria infection","volume":"93","author":"Lyke","year":"2015"},{"key":"b44","series-title":"Am J Trop Med Hyg","first-page":"471","article-title":"Controlled human malaria infection of Tanzanians by intradermal injection of aseptic, purified, cryopreserved Plasmodium falciparum sporozoites","volume":"91","author":"Shekalaghe","year":"2014"},{"key":"b45","series-title":"PLoS One","first-page":"e65960","article-title":"Optimising controlled human malaria infection studies using cryopreserved P. falciparum parasites administered by needle and syringe","volume":"8","author":"Sheehy","year":"2013"},{"key":"b46","series-title":"Front Microbiol","first-page":"686","article-title":"Evaluating controlled human malaria infection in Kenyan adults with varying degrees of prior exposure to Plasmodium falciparum using sporozoites administered by intramuscular injection","volume":"5","author":"Hodgson","year":"2014"},{"key":"b47","series-title":"Malar J","first-page":"306","article-title":"Controlled human malaria infection by intramuscular and direct venous inoculation of cryopreserved Plasmodium falciparum sporozoites in malaria-naive volunteers: effect of injection volume and dose on infectivity rates","volume":"14","author":"Gomez-Perez","year":"2015"},{"key":"b48","series-title":"Malar J","first-page":"117","article-title":"Direct venous inoculation of Plasmodium falciparum sporozoites for controlled human malaria infection: a dose-finding trial in two centres","volume":"14","author":"Mordm\u00fcller","year":"2015"},{"key":"b49","series-title":"J Infect Dis","first-page":"1962","article-title":"Dose-dependent infectivity of aseptic, purified, cryopreserved Plasmodium falciparum 7G8 sporozoites in malaria-naive adults","volume":"220","author":"Laurens","year":"2019"},{"key":"b50","series-title":"Am J Trop Med Hyg","first-page":"1348","article-title":"Chemoprotective antimalarial activity of P218 against Plasmodium falciparum: a randomized, placebo-controlled volunteer infection study","volume":"104","author":"Chughlay","year":"2021"},{"key":"b51","author":"Sissoko","year":"2021"},{"key":"b52","series-title":"Genome Med","first-page":"6","article-title":"Strains used in whole organism Plasmodium falciparum vaccine trials differ in genome structure, sequence, and immunogenic potential","volume":"12","author":"Moser","year":"2020"},{"key":"b53","series-title":"PLoS Med","first-page":"e1001788","article-title":"Ultra-sensitive detection of Plasmodium falciparum by amplification of multi-copy subtelomeric targets","volume":"12","author":"Hofmann","year":"2015"},{"key":"b54","series-title":"Malar J","first-page":"277","article-title":"Cardiac complication after experimental human malaria infection: a case report","volume":"8","author":"Nieman","year":"2009"},{"key":"b55","series-title":"Malar J","first-page":"38","article-title":"Idiopathic acute myocarditis during treatment for controlled human malaria infection: a case report","volume":"13","author":"van Meer","year":"2014"},{"key":"b56","series-title":"Trends Immunol","first-page":"318","article-title":"Neutrophil kinetics in health and disease","volume":"31","author":"Summers","year":"2010"},{"key":"b57","series-title":"Blood","first-page":"197","article-title":"Studies of the neutropenia of acute malaria","volume":"41","author":"Dale","year":"1973"},{"key":"b58","series-title":"EBioMedicine","first-page":"131","article-title":"Liver injury in uncomplicated malaria is an overlooked phenomenon: an observational study","volume":"36","author":"Reuling","year":"2018"},{"key":"b59","series-title":"Am J Trop Med Hyg","first-page":"378","article-title":"Liver enzyme elevations in Plasmodium falciparum volunteer infection studies: findings and recommendations","volume":"103","author":"Chughlay","year":"2020"}],"container-title":["The American Journal of Tropical Medicine and 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