title: Demonstration of the Blood-Stage Plasmodium falciparum Controlled Human Malaria Infection Model to Assess Efficacy of the P. falciparum Apical Membrane Antigen 1 Vaccine, FMP2.1/AS01.
abstract: BACKGROUND
  Models of controlled human malaria infection (CHMI) initiated by mosquito bite have been widely used to assess efficacy of preerythrocytic vaccine candidates in small proof-of-concept phase 2a clinical trials. Efficacy testing of blood-stage malaria parasite vaccines, however, has generally relied on larger-scale phase 2b field trials in malaria-endemic populations. We report the use of a blood-stage P. falciparum CHMI model to assess blood-stage vaccine candidates, using their impact on the parasite multiplication rate (PMR) as the primary efficacy end point.
  
  
  METHODS
  Fifteen healthy United Kingdom adult volunteers were vaccinated with FMP2.1, a protein vaccine that is based on the 3D7 clone sequence of apical membrane antigen 1 (AMA1) and formulated in Adjuvant System 01 (AS01). Twelve vaccinees and 15 infectivity controls subsequently underwent blood-stage CHMI. Parasitemia was monitored by quantitative real-time polymerase chain reaction (PCR) analysis, and PMR was modeled from these data.
  
  
  RESULTS
  FMP2.1/AS01 elicited anti-AMA1 T-cell and serum antibody responses. Analysis of purified immunoglobulin G showed functional growth inhibitory activity against P. falciparum in vitro. There were no vaccine- or CHMI-related safety concerns. All volunteers developed blood-stage parasitemia, with no impact of the vaccine on PMR.
  
  
  CONCLUSIONS
  FMP2.1/AS01 demonstrated no efficacy after blood-stage CHMI. However, the model induced highly reproducible infection in all volunteers and will accelerate proof-of-concept testing of future blood-stage vaccine candidates.
  
  
  BACKGROUND
  NCT02044198.
authors.affiliation: Jenner Institute Laboratories Centre for Clinical Vaccinology and Tropical Medicine.
authors.forename: Ruth O
authors.initials: RO
authors.lastname: Payne
authors.affiliation: Jenner Institute Laboratories.
authors.forename: Kathryn H
authors.initials: KH
authors.lastname: Milne
authors.affiliation: Jenner Institute Laboratories.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Elias
authors.affiliation: Jenner Institute Laboratories.
authors.forename: Nick J
authors.initials: NJ
authors.lastname: Edwards
authors.affiliation: Jenner Institute Laboratories.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Douglas
authors.affiliation: Jenner Institute Laboratories.
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Brown
authors.affiliation: Jenner Institute Laboratories.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Silk
authors.affiliation: Jenner Institute Laboratories.
authors.forename: Sumi
authors.initials: S
authors.lastname: Biswas
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda.
authors.forename: Kazutoyo
authors.initials: K
authors.lastname: Miura
authors.affiliation: Centre for Clinical Vaccinology and Tropical Medicine.
authors.forename: Rachel
authors.initials: R
authors.lastname: Roberts
authors.affiliation: Jenner Institute Laboratories Centre for Clinical Vaccinology and Tropical Medicine.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Rampling
authors.affiliation: Jenner Institute Laboratories Centre for Clinical Vaccinology and Tropical Medicine.
authors.forename: Navin
authors.initials: N
authors.lastname: Venkatraman
authors.affiliation: Jenner Institute Laboratories Centre for Clinical Vaccinology and Tropical Medicine.
authors.forename: Susanne H
authors.initials: SH
authors.lastname: Hodgson
authors.affiliation: Jenner Institute Laboratories.
authors.forename: Geneviève M
authors.initials: GM
authors.lastname: Labbé
authors.affiliation: Jenner Institute Laboratories.
authors.forename: Fenella D
authors.initials: FD
authors.lastname: Halstead
authors.affiliation: Centre for Clinical Vaccinology and Tropical Medicine.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Poulton
authors.affiliation: Jenner Institute Laboratories.
authors.forename: Fay L
authors.initials: FL
authors.lastname: Nugent
authors.affiliation: National Institute for Health Research (NIHR) Wellcome Trust Clinical Research Facility, University Hospital Southampton National Health Service (NHS) Foundation Trust Faculty of Medicine, University of Southampton.
authors.forename: Hans
authors.initials: H
authors.lastname: de Graaf
authors.affiliation: National Institute for Health Research (NIHR) Wellcome Trust Clinical Research Facility, University Hospital Southampton National Health Service (NHS) Foundation Trust Faculty of Medicine, University of Southampton.
authors.forename: Priya
authors.initials: P
authors.lastname: Sukhtankar
authors.affiliation: Centre for Statistics in Medicine Botnar Research Centre, University of Oxford.
authors.forename: Nicola C
authors.initials: NC
authors.lastname: Williams
authors.affiliation: Military Malaria Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland PATH Malaria Vaccine Initiative.
authors.forename: Christian F
authors.initials: CF
authors.lastname: Ockenhouse
authors.affiliation: Military Malaria Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland.
authors.forename: April K
authors.initials: AK
authors.lastname: Kathcart
authors.affiliation: Military Malaria Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland.
authors.forename: Aziz N
authors.initials: AN
authors.lastname: Qabar
authors.affiliation: Military Malaria Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland.
authors.forename: Norman C
authors.initials: NC
authors.lastname: Waters
authors.affiliation: US Agency for International Development, Washington D.C.
authors.forename: Lorraine A
authors.initials: LA
authors.lastname: Soisson
authors.affiliation: PATH Malaria Vaccine Initiative.
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Birkett
authors.affiliation: NIHR Wellcome Trust Clinical Research Facility, Imperial College Healthcare NHS Trust, London, United Kingdom.
authors.forename: Graham S
authors.initials: GS
authors.lastname: Cooke
authors.affiliation: National Institute for Health Research (NIHR) Wellcome Trust Clinical Research Facility, University Hospital Southampton National Health Service (NHS) Foundation Trust Faculty of Medicine, University of Southampton.
authors.forename: Saul N
authors.initials: SN
authors.lastname: Faust
authors.affiliation: PATH Malaria Vaccine Initiative.
authors.forename: Colleen
authors.initials: C
authors.lastname: Woods
authors.affiliation: PATH Malaria Vaccine Initiative.
authors.forename: Karen
authors.initials: K
authors.lastname: Ivinson
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, Australia.
authors.forename: James S
authors.initials: JS
authors.lastname: McCarthy
authors.affiliation: US Agency for International Development, Washington D.C.
authors.forename: Carter L
authors.initials: CL
authors.lastname: Diggs
authors.affiliation: GlaxoSmithKline Vaccines, Rixensart, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Vekemans
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda.
authors.forename: Carole A
authors.initials: CA
authors.lastname: Long
authors.affiliation: Jenner Institute Laboratories.
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
authors.affiliation: Centre for Clinical Vaccinology and Tropical Medicine.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Lawrie
authors.affiliation: Military Malaria Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland.
authors.forename: Sheetij
authors.initials: S
authors.lastname: Dutta
authors.affiliation: Jenner Institute Laboratories.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Draper
mesh_terms: D000328:Adult; D000953:Antigens, Protozoan / Q000276:immunology*; D058501:Enzyme-Linked Immunospot Assay; D004912:Erythrocytes / Q000469:parasitology; D005260:Female; D006801:Humans; D000071497:Immunogenicity, Vaccine; D008018:Life Cycle Stages; D017780:Malaria Vaccines / Q000276:immunology*; D016778:Malaria, Falciparum / Q000469:parasitology / Q000517:prevention & control*; D008297:Male; D008565:Membrane Proteins / Q000276:immunology*; D008875:Middle Aged; D008954:Models, Biological; D010963:Plasmodium falciparum / Q000276:immunology* / Q000502:physiology; D015800:Protozoan Proteins / Q000276:immunology*; D055815:Young Adult
chemical_list: D000953:Antigens, Protozoan; D017780:Malaria Vaccines; D008565:Membrane Proteins; D015800:Protozoan Proteins; C090077:apical membrane antigen I, Plasmodium
keywords: AMA1; CHMI; blood stage; malaria; vaccine