title: Safety and efficacy of the RTS,S/AS01E candidate malaria vaccine given with expanded-programme-on-immunisation vaccines: 19 month follow-up of a randomised, open-label, phase 2 trial.
abstract: BACKGROUND
  The RTS,S/AS01(E) candidate malaria vaccine is being developed for immunisation of infants in Africa through the expanded programme on immunisation (EPI). 8 month follow-up data have been reported for safety and immunogenicity of RTS,S/AS01(E) when integrated into the EPI. We report extended follow-up to 19 months, including efficacy results.
  
  
  METHODS
  We did a randomised, open-label, phase 2 trial of safety and efficacy of the RTS,S/AS01(E) candidate malaria vaccine given with EPI vaccines between April 30, 2007, and Oct 7, 2009, in Ghana, Tanzania, and Gabon. Eligible children were 6-10 weeks of age at first vaccination, without serious acute or chronic illness. All children received the EPI diphtheria, tetanus, pertussis (inactivated whole-cell), and hepatitis-B vaccines, Haemophilus influenzae type b vaccine, and oral polio vaccine at study months 0, 1, and 2, and measles vaccine and yellow fever vaccines at study month 7. Participants were randomly assigned (1:1:1) to receive three doses of RTS,S/AS01(E) at 6, 10, and 14 weeks (0, 1, 2 month schedule) or at 6 weeks, 10 weeks, and 9 months (0, 2, 7 month schedule) or placebo. Randomisation was according to a predefined block list with a computer-generated randomisation code. Detection of serious adverse events and malaria was by passive case detection. Antibodies against Plasmodium falciparum circumsporozoite protein and HBsAg were monitored for 19 months. This study is registered with ClinicalTrials.gov, number NCT00436007.
  
  
  RESULTS
  511 children were enrolled. Serious adverse events occurred in 57 participants in the RTS,S/AS01(E) 0, 1, 2 month group (34%, 95% CI 27-41), 47 in the 0, 1, 7 month group (28%, 21-35), and 49 (29%, 22-36) in the control group; none were judged to be related to study vaccination. At month 19, anticircumsporozoite immune responses were significantly higher in the RTS,S/AS01(E) groups than in the control group. Vaccine efficacy for the 0, 1, 2 month schedule (2 weeks after dose three to month 19, site-adjusted according-to-protocol analysis) was 53% (95% CI 26-70; p=0·0012) against first malaria episodes and 59% (36-74; p=0·0001) against all malaria episodes. For the entire study period, (total vaccinated cohort) vaccine efficacy against all malaria episodes was higher with the 0, 1, 2 month schedule (57%, 95% CI 33-73; p=0·0002) than with the 0, 1, 7 month schedule (32% CI 16-45; p=0·0003). 1 year after dose three, vaccine efficacy against first malaria episodes was similar for both schedules (0, 1, 2 month group, 61·6% [95% CI 35·6-77·1], p<0·001; 0, 1, 7 month group, 63·8% [40·4-78·0], p<0·001, according-to-protocol cohort).
  
  
  CONCLUSIONS
  Vaccine efficacy was consistent with the target put forward by the WHO-sponsored malaria vaccine technology roadmap for a first-generation malaria vaccine. The 0, 1, 2 month vaccine schedule has been selected for phase 3 candidate vaccine assessment.
  
  
  BACKGROUND
  Program for Appropriate Technology in Health Malaria Vaccine Initiative; GlaxoSmithKline Biologicals.
authors.affiliation: Kintampo Health Research Centre, Kintampo, Ghana. kwakupoku.asante@kintampo-hrc.org
authors.forename: Kwaku Poku
authors.initials: KP
authors.lastname: Asante
authors.forename: Salim
authors.initials: S
authors.lastname: Abdulla
authors.forename: Selidji
authors.initials: S
authors.lastname: Agnandji
authors.forename: John
authors.initials: J
authors.lastname: Lyimo
authors.forename: Johan
authors.initials: J
authors.lastname: Vekemans
authors.forename: Solange
authors.initials: S
authors.lastname: Soulanoudjingar
authors.forename: Ruth
authors.initials: R
authors.lastname: Owusu
authors.forename: Mwanajaa
authors.initials: M
authors.lastname: Shomari
authors.forename: Amanda
authors.initials: A
authors.lastname: Leach
authors.forename: Erik
authors.initials: E
authors.lastname: Jongert
authors.forename: Nahya
authors.initials: N
authors.lastname: Salim
authors.forename: Jose F
authors.initials: JF
authors.lastname: Fernandes
authors.forename: David
authors.initials: D
authors.lastname: Dosoo
authors.forename: Maria
authors.initials: M
authors.lastname: Chikawe
authors.forename: Saadou
authors.initials: S
authors.lastname: Issifou
authors.forename: Kingsley
authors.initials: K
authors.lastname: Osei-Kwakye
authors.forename: Marc
authors.initials: M
authors.lastname: Lievens
authors.forename: Maria
authors.initials: M
authors.lastname: Paricek
authors.forename: Tina
authors.initials: T
authors.lastname: Möller
authors.forename: Stephen
authors.initials: S
authors.lastname: Apanga
authors.forename: Grace
authors.initials: G
authors.lastname: Mwangoka
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Dubois
authors.forename: Tigani
authors.initials: T
authors.lastname: Madi
authors.forename: Evans
authors.initials: E
authors.lastname: Kwara
authors.forename: Rose
authors.initials: R
authors.lastname: Minja
authors.forename: Aurore B
authors.initials: AB
authors.lastname: Hounkpatin
authors.forename: Owusu
authors.initials: O
authors.lastname: Boahen
authors.forename: Kingsley
authors.initials: K
authors.lastname: Kayan
authors.forename: George
authors.initials: G
authors.lastname: Adjei
authors.forename: Daniel
authors.initials: D
authors.lastname: Chandramohan
authors.forename: Terrell
authors.initials: T
authors.lastname: Carter
authors.forename: Preeti
authors.initials: P
authors.lastname: Vansadia
authors.forename: Marla
authors.initials: M
authors.lastname: Sillman
authors.forename: Barbara
authors.initials: B
authors.lastname: Savarese
authors.forename: Christian
authors.initials: C
authors.lastname: Loucq
authors.forename: Didier
authors.initials: D
authors.lastname: Lapierre
authors.forename: Brian
authors.initials: B
authors.lastname: Greenwood
authors.forename: Joe
authors.initials: J
authors.lastname: Cohen
authors.forename: Peter
authors.initials: P
authors.lastname: Kremsner
authors.forename: Seth
authors.initials: S
authors.lastname: Owusu-Agyei
authors.forename: Marcel
authors.initials: M
authors.lastname: Tanner
authors.forename: Bertrand
authors.initials: B
authors.lastname: Lell
mesh_terms: D000913:Antibodies, Protozoan / Q000097:blood*; D015721:Diphtheria-Tetanus-Pertussis Vaccine / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D005681:Gabon / Q000453:epidemiology; D005869:Ghana / Q000453:epidemiology; D018073:Haemophilus Vaccines / Q000008:administration & dosage; D017325:Hepatitis B Vaccines / Q000008:administration & dosage; D006801:Humans; D017589:Immunization Programs; D007115:Immunization Schedule; D007223:Infant; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology*; D016778:Malaria, Falciparum / Q000175:diagnosis / Q000453:epidemiology / Q000276:immunology* / Q000517:prevention & control*; D008297:Male; D011055:Poliovirus Vaccine, Oral / Q000008:administration & dosage; D015397:Program Evaluation; D015800:Protozoan Proteins / Q000276:immunology*; D012720:Severity of Illness Index; D013636:Tanzania / Q000453:epidemiology; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000913:Antibodies, Protozoan; D015721:Diphtheria-Tetanus-Pertussis Vaccine; D018073:Haemophilus Vaccines; D017325:Hepatitis B Vaccines; D017780:Malaria Vaccines; D011055:Poliovirus Vaccine, Oral; D015800:Protozoan Proteins; C526041:RTS,S-AS01B vaccine; C041595:circumsporozoite protein, Protozoan