title: Safety of the RTS,S/AS02D candidate malaria vaccine in infants living in a highly endemic area of Mozambique: a double blind randomised controlled phase I/IIb trial.
abstract: BACKGROUND
  Malaria remains a leading global health problem that requires the improved use of existing interventions and the accelerated development of new control methods. We aimed to assess the safety, immunogenicity, and initial efficacy of the malaria vaccine RTS,S/AS02D in infants in Africa.
  
  
  METHODS
  We did a phase I/IIb double-blind randomised trial of 214 infants in Mozambique. Infants were randomly assigned to receive three doses either of RTS,S/AS02D or the hepatitis B vaccine Engerix-B at ages 10 weeks, 14 weeks, and 18 weeks of age, as well as routine immunisation vaccines given at 8, 12, and 16 weeks of age. The primary endpoint was safety of the RTS,S/AS02D during the first 6 months of the study, and analysis was by intention to treat. Secondary endpoints included immunogenicity and analysis of new Plasmodium falciparum infections during a 3-month follow up after the third dose. Time to new infections in the per-protocol cohort were compared between groups using Cox regression models. This study is registered with ClinicalTrials.gov, number NCT00197028.
  
  
  RESULTS
  There were 17 children (15.9%; 95% CI 9.5-24.2) with serious adverse events in each group. In the follow-up which ended on March 6, 2007, there were 31 serious adverse events in the RTS,S/AS02D group and 30 serious adverse events in the Engerix-B group, none of which were reported as related to vaccination. There were four deaths during this same follow-up period; all of them after the active detection of infection period had finished at study month 6 (two in RTSS/AS02D group and two in the Engerix-B group). RTS,S/AS02D induced high titres of anti-circumsporozoite antibodies. 68 first or only P falciparum infections were documented: 22 in the RTS,S/AS02D group and 46 in the control group. The adjusted vaccine efficacy was 65.9% (95% CI 42.6-79.8%, p<0.0001).
  
  
  CONCLUSIONS
  The RTS,S/AS02D malaria vaccine was safe, well tolerated, and immunogenic in young infants. These findings set the stage for expanded phase III efficacy studies to confirm vaccine efficacy against clinical malaria disease.
authors.affiliation: Barcelona Centre for International Health Research (CRESIB), Hospital Clínic/Institut d'Investigacions Biomediques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain.
authors.forename: John J
authors.initials: JJ
authors.lastname: Aponte
authors.forename: Pedro
authors.initials: P
authors.lastname: Aide
authors.forename: Montse
authors.initials: M
authors.lastname: Renom
authors.forename: Inacio
authors.initials: I
authors.lastname: Mandomando
authors.forename: Quique
authors.initials: Q
authors.lastname: Bassat
authors.forename: Jahit
authors.initials: J
authors.lastname: Sacarlal
authors.forename: M Nelia
authors.initials: MN
authors.lastname: Manaca
authors.forename: Sarah
authors.initials: S
authors.lastname: Lafuente
authors.forename: Arnoldo
authors.initials: A
authors.lastname: Barbosa
authors.forename: Amanda
authors.initials: A
authors.lastname: Leach
authors.forename: Marc
authors.initials: M
authors.lastname: Lievens
authors.forename: Johan
authors.initials: J
authors.lastname: Vekemans
authors.forename: Betuel
authors.initials: B
authors.lastname: Sigauque
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Dubois
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Demoitié
authors.forename: Marla
authors.initials: M
authors.lastname: Sillman
authors.forename: Barbara
authors.initials: B
authors.lastname: Savarese
authors.forename: John G
authors.initials: JG
authors.lastname: McNeil
authors.forename: Eusebio
authors.initials: E
authors.lastname: Macete
authors.forename: W Ripley
authors.initials: WR
authors.lastname: Ballou
authors.forename: Joe
authors.initials: J
authors.lastname: Cohen
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Alonso
mesh_terms: D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007115:Immunization Schedule; D007223:Infant; D008288:Malaria / Q000517:prevention & control*; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D009073:Mozambique; D010963:Plasmodium falciparum / Q000276:immunology*
chemical_list: D000913:Antibodies, Protozoan; D017780:Malaria Vaccines