title: Four-year efficacy of RTS,S/AS01E and its interaction with malaria exposure.
abstract: BACKGROUND
  The candidate malaria vaccine RTS,S/AS01E has entered phase 3 trials, but data on long-term outcomes are limited.
  
  
  METHODS
  For 4 years, we followed children who had been randomly assigned, at 5 to 17 months of age, to receive three doses of RTS,S/AS01E vaccine (223 children) or rabies vaccine (224 controls). The end point was clinical malaria (temperature of ≥37.5°C and Plasmodium falciparum parasitemia density of >2500 parasites per cubic millimeter). Each child's exposure to malaria was estimated with the use of the distance-weighted local prevalence of malaria.
  
  
  RESULTS
  Over a period of 4 years, 118 of 223 children who received the RTS,S/AS01E vaccine and 138 of 224 of the controls had at least 1 episode of clinical malaria. Vaccine efficacies in the intention-to-treat and per-protocol analyses were 29.9% (95% confidence interval [CI], 10.3 to 45.3; P=0.005) and 32.1% (95% CI, 11.6 to 47.8; P=0.004), respectively, calculated by Cox regression. Multiple episodes were common, with 551 and 618 malarial episodes in the RTS,S/AS01E and control groups, respectively; vaccine efficacies in the intention-to-treat and per-protocol analyses were 16.8% (95% CI, -8.6 to 36.3; P=0.18) and 24.3% (95% CI, 1.9 to 41.6; P=0.04), respectively, calculated by the Andersen-Gill extension of the Cox model. For every 100 vaccinated children, 65 cases of clinical malaria were averted. Vaccine efficacy declined over time (P=0.004) and with increasing exposure to malaria (P=0.001) in the per-protocol analysis. Vaccine efficacy was 43.6% (95% CI, 15.5 to 62.3) in the first year but was -0.4% (95% CI, -32.1 to 45.3) in the fourth year. Among children with a malaria-exposure index that was average or lower than average, the vaccine efficacy was 45.1% (95% CI, 11.3 to 66.0), but among children with a malaria-exposure index that was higher than average it was 15.9% (95% CI, -11.0 to 36.4).
  
  
  CONCLUSIONS
  The efficacy of RTS,S/AS01E vaccine over the 4-year period was 16.8%. Efficacy declined over time and with increasing malaria exposure. (Funded by the PATH Malaria Vaccine Initiative and Wellcome Trust; ClinicalTrials.gov number, NCT00872963.).
authors.affiliation: Centre for Geographic Medicine Research, Kenya Medical Research Institute (KEMRI)-Wellcome Trust Research Programme, Kilifi, Kenya. aolotu@kemri-wellcome.org
authors.forename: Ally
authors.initials: A
authors.lastname: Olotu
authors.forename: Gregory
authors.initials: G
authors.lastname: Fegan
authors.forename: Juliana
authors.initials: J
authors.lastname: Wambua
authors.forename: George
authors.initials: G
authors.lastname: Nyangweso
authors.forename: Ken O
authors.initials: KO
authors.lastname: Awuondo
authors.forename: Amanda
authors.initials: A
authors.lastname: Leach
authors.forename: Marc
authors.initials: M
authors.lastname: Lievens
authors.forename: Didier
authors.initials: D
authors.lastname: Leboulleux
authors.forename: Patricia
authors.initials: P
authors.lastname: Njuguna
authors.forename: Norbert
authors.initials: N
authors.lastname: Peshu
authors.forename: Kevin
authors.initials: K
authors.lastname: Marsh
authors.forename: Philip
authors.initials: P
authors.lastname: Bejon
mesh_terms: D000913:Antibodies, Protozoan; D002648:Child; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D007223:Infant; D057194:Intention to Treat Analysis; D017780:Malaria Vaccines / Q000276:immunology*; D016778:Malaria, Falciparum / Q000453:epidemiology / Q000276:immunology / Q000517:prevention & control*; D008297:Male; D059208:Parasite Load; D018512:Parasitemia; D010963:Plasmodium falciparum / Q000276:immunology*; D012044:Regression Analysis; D016896:Treatment Outcome; D014614:Vaccines, Synthetic / Q000276:immunology*
chemical_list: D000913:Antibodies, Protozoan; D017780:Malaria Vaccines; C577001:RTS,S-AS01 vaccine; D014614:Vaccines, Synthetic