title: Evaluation of the efficacy of ChAd63-MVA vectored vaccines expressing circumsporozoite protein and ME-TRAP against controlled human malaria infection in malaria-naive individuals.
abstract: BACKGROUND
  Circumsporozoite protein (CS) is the antigenic target for RTS,S, the most advanced malaria vaccine to date. Heterologous prime-boost with the viral vectors simian adenovirus 63 (ChAd63)-modified vaccinia virus Ankara (MVA) is the most potent inducer of T-cells in humans, demonstrating significant efficacy when expressing the preerythrocytic antigen insert multiple epitope-thrombospondin-related adhesion protein (ME-TRAP). We hypothesized that ChAd63-MVA containing CS may result in a significant clinical protective efficacy.
  
  
  METHODS
  We conducted an open-label, 2-site, partially randomized Plasmodium falciparum sporozoite controlled human malaria infection (CHMI) study to compare the clinical efficacy of ChAd63-MVA CS with ChAd63-MVA ME-TRAP.
  
  
  RESULTS
  One of 15 vaccinees (7%) receiving ChAd63-MVA CS and 2 of 15 (13%) receiving ChAd63-MVA ME-TRAP achieved sterile protection after CHMI. Three of 15 vaccinees (20%) receiving ChAd63-MVA CS and 5 of 15 (33%) receiving ChAd63-MVA ME-TRAP demonstrated a delay in time to treatment, compared with unvaccinated controls. In quantitative polymerase chain reaction analyses, ChAd63-MVA CS was estimated to reduce the liver parasite burden by 69%-79%, compared with 79%-84% for ChAd63-MVA ME-TRAP.
  
  
  CONCLUSIONS
  ChAd63-MVA CS does reduce the liver parasite burden, but ChAd63-MVA ME-TRAP remains the most promising antigenic insert for a vectored liver-stage vaccine. Detailed analyses of parasite kinetics may allow detection of smaller but biologically important differences in vaccine efficacy that can influence future vaccine development.
  
  
  BACKGROUND
  NCT01623557.
authors.affiliation: Jenner Institute.
authors.forename: Susanne H
authors.initials: SH
authors.lastname: Hodgson
authors.affiliation: Jenner Institute.
authors.forename: Katie J
authors.initials: KJ
authors.lastname: Ewer
authors.affiliation: Jenner Institute.
authors.forename: Carly M
authors.initials: CM
authors.lastname: Bliss
authors.affiliation: Jenner Institute.
authors.forename: Nick J
authors.initials: NJ
authors.lastname: Edwards
authors.affiliation: Jenner Institute.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rampling
authors.affiliation: Jenner Institute.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Anagnostou
authors.affiliation: Jenner Institute Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Eoghan
authors.initials: E
authors.lastname: de Barra
authors.affiliation: NIHR Wellcome Trust Clinical Research Facility, University of Southampton and University Hospital Southampton NHS Foundation Trust.
authors.forename: Tom
authors.initials: T
authors.lastname: Havelock
authors.affiliation: Jenner Institute.
authors.forename: Georgina
authors.initials: G
authors.lastname: Bowyer
authors.affiliation: Jenner Institute.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Poulton
authors.affiliation: Jenner Institute.
authors.forename: Simone
authors.initials: S
authors.lastname: de Cassan
authors.affiliation: Jenner Institute.
authors.forename: Rhea
authors.initials: R
authors.lastname: Longley
authors.affiliation: Jenner Institute.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Illingworth
authors.affiliation: Jenner Institute.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Douglas
authors.affiliation: Jenner Institute.
authors.forename: Pooja B
authors.initials: PB
authors.lastname: Mange
authors.affiliation: Jenner Institute.
authors.forename: Katharine A
authors.initials: KA
authors.lastname: Collins
authors.affiliation: Jenner Institute.
authors.forename: Rachel
authors.initials: R
authors.lastname: Roberts
authors.affiliation: Centre for Statistics in Medicine.
authors.forename: Stephen
authors.initials: S
authors.lastname: Gerry
authors.affiliation: Clinical Biomanufacturing Facility, University of Oxford.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Berrie
authors.affiliation: Clinical Biomanufacturing Facility, University of Oxford.
authors.forename: Sarah
authors.initials: S
authors.lastname: Moyle
authors.affiliation: Okairos, Rome.
authors.forename: Stefano
authors.initials: S
authors.lastname: Colloca
authors.affiliation: Okairos, Basel, Switzerland.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Cortese
authors.affiliation: Jenner Institute Division of Cell and Molecular Biology, Imperial College London, United Kingdom.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Sinden
authors.affiliation: Jenner Institute.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Gilbert
authors.affiliation: Centre for Geographical Medical Research (Coast), Kenya Medical Research Institute-Wellcome Trust, Kilifi.
authors.forename: Philip
authors.initials: P
authors.lastname: Bejon
authors.affiliation: Jenner Institute.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Lawrie
authors.affiliation: Okairos, Rome CEINGE Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Nicosia
authors.affiliation: NIHR Wellcome Trust Clinical Research Facility, University of Southampton and University Hospital Southampton NHS Foundation Trust.
authors.forename: Saul N
authors.initials: SN
authors.lastname: Faust
authors.affiliation: Jenner Institute.
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
mesh_terms: D000261:Adenoviruses, Simian / Q000235:genetics / Q000276:immunology; D000293:Adolescent; D000328:Adult; D000913:Antibodies, Protozoan / Q000096:biosynthesis; D000939:Epitopes / Q000276:immunology; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D008099:Liver / Q000821:virology; D017780:Malaria Vaccines / Q000276:immunology*; D016778:Malaria, Falciparum / Q000276:immunology / Q000469:parasitology / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D010963:Plasmodium falciparum / Q000235:genetics / Q000276:immunology*; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology*; D055815:Young Adult
chemical_list: D000913:Antibodies, Protozoan; D000939:Epitopes; D017780:Malaria Vaccines; D015800:Protozoan Proteins; C041595:circumsporozoite protein, Protozoan; C069428:thrombospondin-related adhesive protein, protozoan; D007371:Interferon-gamma
keywords: CHMI; CS; ChAd63; ME-TRAP; MVA; P. falciparum; malaria; vaccine