title: Randomized, controlled trial of the long term safety, immunogenicity and efficacy of RTS,S/AS02(D) malaria vaccine in infants living in a malaria-endemic region.
abstract: BACKGROUND
  The RTS,S/AS malaria candidate vaccine is being developed with the intent to be delivered, if approved, through the Expanded Programme on Immunization (EPI) of the World Health Organization. Safety, immunogenicity and efficacy of the RTS,S/AS02(D) vaccine candidate when integrated into a standard EPI schedule for infants have been reported over a nine-month surveillance period. This paper describes results following 20 months of follow up.
  
  
  METHODS
  This Phase IIb, single-centre, randomized controlled trial enrolled 340 infants in Tanzania to receive three doses of RTS,S/AS02(D) or hepatitis B vaccine at 8, 12, and 16 weeks of age. All infants also received DTPw/Hib (diphtheria and tetanus toxoids, whole-cell pertussis vaccine, conjugated Haemophilus influenzae type b vaccine) at the same timepoints. The study was double-blinded to month 9 and single-blinded from months 9 to 20.
  
  
  RESULTS
  From month 0 to 20, at least one SAE was reported in 57/170 infants who received RTS,S/AS02(D) (33.5%; 95% confidence interval [CI]: 26.5, 41.2) and 62/170 infants who received hepatitis B vaccine (36.5%; 95% CI: 29.2, 44.2). The SAE profile was similar in both vaccine groups; none were considered to be related to vaccination. At month 20, 18 months after completion of vaccination, 71.8% of recipients of RTS,S/AS02(D) and 3.8% of recipients of hepatitis B vaccine had seropositive titres for anti-CS antibodies; seroprotective levels of anti-HBs antibodies remained in 100% of recipients of RTS,S/AS02(D) and 97.7% recipients of hepatitis B vaccine. Anti-HBs antibody GMTs were higher in the RTS,S/AS02(D) group at all post-vaccination time points compared to control. According to protocol population, vaccine efficacy against multiple episodes of malaria disease was 50.7% (95% CI: -6.5 to 77.1, p = 0.072) and 26.7% (95% CI: -33.1 to 59.6, p = 0.307) over 12 and 18 months post vaccination, respectively. In the Intention to Treat population, over the 20-month follow up, vaccine efficacy against multiple episodes of malaria disease was 14.4% (95% CI: -41.9 to 48.4, p = 0.545).
  
  
  CONCLUSIONS
  The acceptable safety profile and good tolerability of RTS,S/AS02(D) in combination with EPI vaccines previously reported from month 0 to 9 was confirmed over a 20 month surveillance period in this infant population. Antibodies against both CS and HBsAg in the RTS,S/AS02(D) group remained significantly higher compared to control for the study duration. Over 18 months follow up, RTS,S/AS02(D) prevented approximately a quarter of malaria cases in the study population.
  
  
  RESULTS
  Gov identifier: NCT00289185.
authors.affiliation: Bagamoyo Research and Training Centre of Ifakara Health Institute, Pwani, Tanzania. sabdulla@ihi.or.tz
authors.forename: Salim
authors.initials: S
authors.lastname: Abdulla
authors.forename: Nahya
authors.initials: N
authors.lastname: Salim
authors.forename: Francisca
authors.initials: F
authors.lastname: Machera
authors.forename: Richard
authors.initials: R
authors.lastname: Kamata
authors.forename: Omar
authors.initials: O
authors.lastname: Juma
authors.forename: Mwanajaa
authors.initials: M
authors.lastname: Shomari
authors.forename: Sulende
authors.initials: S
authors.lastname: Kubhoja
authors.forename: Ali
authors.initials: A
authors.lastname: Mohammed
authors.forename: Grace
authors.initials: G
authors.lastname: Mwangoka
authors.forename: Thomas
authors.initials: T
authors.lastname: Aebi
authors.forename: Hassan
authors.initials: H
authors.lastname: Mshinda
authors.forename: David
authors.initials: D
authors.lastname: Schellenberg
authors.forename: Terrell
authors.initials: T
authors.lastname: Carter
authors.forename: Tonya
authors.initials: T
authors.lastname: Villafana
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Dubois
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: Joe
authors.initials: J
authors.lastname: Cohen
authors.forename: W Ripley
authors.initials: WR
authors.lastname: Ballou
authors.forename: Marcel
authors.initials: M
authors.lastname: Tanner
mesh_terms: D000913:Antibodies, Protozoan / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D015721:Diphtheria-Tetanus-Pertussis Vaccine / Q000008:administration & dosage; D004311:Double-Blind Method; D004347:Drug Interactions; D019353:Endemic Diseases; D005260:Female; D018073:Haemophilus Vaccines / Q000008:administration & dosage; D017325:Hepatitis B Vaccines / Q000008:administration & dosage; D006801:Humans; D007223:Infant; D008288:Malaria / Q000453:epidemiology / Q000517:prevention & control*; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology*; D008297:Male; D013636:Tanzania / Q000453:epidemiology; D014611:Vaccination / Q000009:adverse effects / Q000379:methods*
chemical_list: D000913:Antibodies, Protozoan; D000914:Antibodies, Viral; D015721:Diphtheria-Tetanus-Pertussis Vaccine; D018073:Haemophilus Vaccines; D017325:Hepatitis B Vaccines; D017780:Malaria Vaccines; C533817:RTS,S-AS02D vaccine; C080881:diphtheria-tetanus-pertussis-haemophilus b conjugate vaccine