title: Safety and comparability of controlled human Plasmodium falciparum infection by mosquito bite in malaria-naïve subjects at a new facility for sporozoite challenge.
abstract: BACKGROUND
  Controlled human malaria infection (CHMI) studies which recapitulate mosquito-borne infection are a critical tool to identify protective vaccine and drug candidates for advancement to field trials. In partnership with the Walter Reed Army Institute of Research, the CHMI model was established at the Seattle Biomedical Research Institute's Malaria Clinical Trials Center (MCTC). Activities and reagents at both centers were aligned to ensure comparability and continued safety of the model. To demonstrate successful implementation, CHMI was performed in six healthy malaria-naïve volunteers.
  
  
  METHODS
  All volunteers received NF54 strain Plasmodium falciparum by the bite of five infected Anopheles stephensi mosquitoes under controlled conditions and were monitored for signs and symptoms of malaria and for parasitemia by peripheral blood smear. Subjects were treated upon diagnosis with chloroquine by directly observed therapy. Immunological (T cell and antibody) and molecular diagnostic (real-time quantitative reverse transcriptase polymerase chain reaction [qRT-PCR]) assessments were also performed.
  
  
  RESULTS
  All six volunteers developed patent parasitemia and clinical malaria. No serious adverse events occurred during the study period or for six months post-infection. The mean prepatent period was 11.2 days (range 9-14 days), and geometric mean parasitemia upon diagnosis was 10.8 parasites/µL (range 2-69) by microscopy. qRT-PCR detected parasites an average of 3.7 days (range 2-4 days) earlier than blood smears. All volunteers developed antibodies to the blood-stage antigen merozoite surface protein 1 (MSP-1), which persisted up to six months. Humoral and cellular responses to pre-erythrocytic antigens circumsporozoite protein (CSP) and liver-stage antigen 1 (LSA-1) were limited.
  
  
  CONCLUSIONS
  The CHMI model was safe, well tolerated and characterized by consistent prepatent periods, pre-symptomatic diagnosis in 3/6 subjects and adverse event profiles as reported at established centers. The MCTC can now evaluate candidates in the increasingly diverse vaccine and drug pipeline using the CHMI model.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01058226.
authors.affiliation: Malaria Clinical Trials Center, Seattle Biomedical Research Institute, Seattle, Washington, United States of America.
authors.forename: Angela K
authors.initials: AK
authors.lastname: Talley
authors.affiliation: Laboratory for Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Sara A
authors.initials: SA
authors.lastname: Healy
authors.affiliation: Malaria Clinical Trials Center, Seattle Biomedical Research Institute, Seattle, Washington, United States of America.
authors.forename: Olivia C
authors.initials: OC
authors.lastname: Finney
authors.affiliation: Department of Laboratory Medicine, University of Washington Medical Center, Seattle, Washington, United States of America.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Murphy
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Kublin
authors.affiliation: United States Naval Medical Research Unit Number 6, Lima, Peru.
authors.forename: Carola J
authors.initials: CJ
authors.lastname: Salas
authors.affiliation: Malaria Clinical Trials Center, Seattle Biomedical Research Institute, Seattle, Washington, United States of America.
authors.forename: Susan
authors.initials: S
authors.lastname: Lundebjerg
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Gilbert
authors.affiliation: Department of Medicine, University of Washington Medical Center, Seattle, Washington, United States of America.
authors.forename: Wesley C
authors.initials: WC
authors.lastname: Van Voorhis
authors.affiliation: Malaria Clinical Trials Center, Seattle Biomedical Research Institute, Seattle, Washington, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Whisler
authors.affiliation: Malaria Clinical Trials Center, Seattle Biomedical Research Institute, Seattle, Washington, United States of America.
authors.forename: Ruobing
authors.initials: R
authors.lastname: Wang
authors.affiliation: United States Military Malaria Vaccine Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: Chris F
authors.initials: CF
authors.lastname: Ockenhouse
authors.affiliation: United States Military Malaria Vaccine Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: D Gray
authors.initials: DG
authors.lastname: Heppner
authors.affiliation: Malaria Clinical Trials Center, Seattle Biomedical Research Institute, Seattle, Washington, United States of America.
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Kappe
authors.affiliation: Laboratory for Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Patrick E
authors.initials: PE
authors.lastname: Duffy
mesh_terms: D000328:Adult; D000818:Animals; D000852:Anopheles / Q000469:parasitology / Q000502:physiology; D001733:Bites and Stings / Q000469:parasitology; D005260:Female; D006805:Human Experimentation; D006801:Humans; D016778:Malaria, Falciparum / Q000150:complications / Q000175:diagnosis* / Q000209:etiology / Q000276:immunology; D008297:Male; D010963:Plasmodium falciparum / Q000472:pathogenicity* / Q000502:physiology; D034101:Sporozoites