title: A randomised, double-blind, controlled vaccine efficacy trial of DNA/MVA ME-TRAP against malaria infection in Gambian adults.
abstract: BACKGROUND
  Many malaria vaccines are currently in development, although very few have been evaluated for efficacy in the field. Plasmodium falciparum multiple epitope (ME)- thrombospondin-related adhesion protein (TRAP) candidate vaccines are designed to potently induce effector T cells and so are a departure from earlier malaria vaccines evaluated in the field in terms of their mechanism of action. ME-TRAP vaccines encode a polyepitope string and the TRAP sporozoite antigen. Two vaccine vectors encoding ME-TRAP, plasmid DNA and modified vaccinia virus Ankara (MVA), when used sequentially in a prime-boost immunisation regime, induce high frequencies of effector T cells and partial protection, manifest as delay in time to parasitaemia, in a clinical challenge model.
  
  
  RESULTS
  A total of 372 Gambian men aged 15-45 y were randomised to receive either DNA ME-TRAP followed by MVA ME-TRAP or rabies vaccine (control). Of these men, 296 received three doses of vaccine timed to coincide with the beginning of the transmission season (141 in the DNA/MVA group and 155 in the rabies group) and were followed up. Volunteers were given sulphadoxine/pyrimethamine 2 wk before the final vaccination. Blood smears were collected weekly for 11 wk and whenever a volunteer developed symptoms compatible with malaria during the transmission season. The primary endpoint was time to first infection with asexual P. falciparum. Analysis was per protocol. DNA ME-TRAP and MVA ME-TRAP were safe and well-tolerated. Effector T cell responses to a non-vaccine strain of TRAP were 50-fold higher postvaccination in the malaria vaccine group than in the rabies vaccine group. Vaccine efficacy, adjusted for confounding factors, was 10.3% (95% confidence interval, -22% to +34%; p = 0.49). Incidence of malaria infection decreased with increasing age and was associated with ethnicity.
  
  
  CONCLUSIONS
  DNA/MVA heterologous prime-boost vaccination is safe and highly immunogenic for effector T cell induction in a malaria-endemic area. But despite having produced a substantial reduction in liver-stage parasites in challenge studies of non-immune volunteers, this first generation T cell-inducing vaccine was ineffective at reducing the natural infection rate in semi-immune African adults.
authors.affiliation: Medical Research Council Laboratories, Banjul, Gambia. vmoorthy@malariavaccine.org
authors.forename: Vasee S
authors.initials: VS
authors.lastname: Moorthy
authors.forename: Egeruan B
authors.initials: EB
authors.lastname: Imoukhuede
authors.forename: Paul
authors.initials: P
authors.lastname: Milligan
authors.forename: Kalifa
authors.initials: K
authors.lastname: Bojang
authors.forename: Sheila
authors.initials: S
authors.lastname: Keating
authors.forename: Pauline
authors.initials: P
authors.lastname: Kaye
authors.forename: Margaret
authors.initials: M
authors.lastname: Pinder
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Gilbert
authors.forename: Gijs
authors.initials: G
authors.lastname: Walraven
authors.forename: Brian M
authors.initials: BM
authors.lastname: Greenwood
authors.forename: Adrian S V
authors.initials: AS
authors.lastname: Hill
mesh_terms: D000293:Adolescent; D000328:Adult; D004311:Double-Blind Method; D000939:Epitopes; D005714:Gambia; D006801:Humans; D007113:Immunity, Innate; D017780:Malaria Vaccines / Q000009:adverse effects / Q000276:immunology* / Q000627:therapeutic use*; D016778:Malaria, Falciparum / Q000276:immunology / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D015800:Protozoan Proteins / Q000276:immunology*; D013601:T-Lymphocytes; D014611:Vaccination
chemical_list: D000939:Epitopes; D017780:Malaria Vaccines; D015800:Protozoan Proteins; C069428:thrombospondin-related adhesive protein, protozoan