title: A combined analysis of immunogenicity, antibody kinetics and vaccine efficacy from phase 2 trials of the RTS,S malaria vaccine.
abstract: BACKGROUND
  The RTS,S malaria vaccine is currently undergoing phase 3 trials. High vaccine-induced antibody titres to the circumsporozoite protein (CSP) antigen have been associated with protection from infection and episodes of clinical malaria.
  
  
  METHODS
  Using data from 5,144 participants in nine phase 2 trials, we explore predictors of vaccine immunogenicity (anti-CSP antibody titres), decay in antibody titres, and the association between antibody titres and clinical outcomes. We use empirically-observed relationships between these factors to predict vaccine efficacy in a range of scenarios.
  
  
  RESULTS
  Vaccine-induced anti-CSP antibody titres were significantly associated with age (P = 0.04), adjuvant (P <0.001), pre-vaccination anti-hepatitis B surface antigen titres (P = 0.005) and pre-vaccination anti-CSP titres (P <0.001). Co-administration with other vaccines reduced anti-CSP antibody titres although not significantly (P = 0.095). Antibody titres showed a bi-phasic decay over time with an initial rapid decay in the first three months and a second slower decay over the next three to four years. Antibody titres were significantly associated with protection, with a titre of 51 (95% Credible Interval (CrI): 29 to 85) ELISA units/ml (EU/mL) predicted to prevent 50% of infections in children. Vaccine efficacy was predicted to decline to zero over four years in a setting with entomological inoculation rate (EIR) = 20 infectious bites per year (ibpy). Over a five-year follow-up period at an EIR = 20 ibpy, we predict RTS,S will avert 1,782 cases per 1,000 vaccinated children, 1,452 cases per 1,000 vaccinated infants, and 887 cases per 1,000 infants when co-administered with expanded programme on immunisation (EPI) vaccines. Our main study limitations include an absence of vaccine-induced cellular immune responses and short duration of follow-up in some individuals.
  
  
  CONCLUSIONS
  Vaccine-induced anti-CSP antibody titres and transmission intensity can explain variations in observed vaccine efficacy.
authors.forename: Michael T
authors.initials: MT
authors.lastname: White
authors.forename: Philip
authors.initials: P
authors.lastname: Bejon
authors.forename: Ally
authors.initials: A
authors.lastname: Olotu
authors.forename: Jamie T
authors.initials: JT
authors.lastname: Griffin
authors.forename: Kalifa
authors.initials: K
authors.lastname: Bojang
authors.forename: John
authors.initials: J
authors.lastname: Lusingu
authors.forename: Nahya
authors.initials: N
authors.lastname: Salim
authors.forename: Salim
authors.initials: S
authors.lastname: Abdulla
authors.forename: Nekoye
authors.initials: N
authors.lastname: Otsyula
authors.forename: Selidji T
authors.initials: ST
authors.lastname: Agnandji
authors.forename: Bertrand
authors.initials: B
authors.lastname: Lell
authors.forename: Kwaku Poku
authors.initials: KP
authors.lastname: Asante
authors.forename: Seth
authors.initials: S
authors.lastname: Owusu-Agyei
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mahama
authors.forename: Tsiri
authors.initials: T
authors.lastname: Agbenyega
authors.forename: Daniel
authors.initials: D
authors.lastname: Ansong
authors.forename: Jahit
authors.initials: J
authors.lastname: Sacarlal
authors.forename: John J
authors.initials: JJ
authors.lastname: Aponte
authors.forename: Azra C
authors.initials: AC
authors.lastname: Ghani
mesh_terms: D000328:Adult; D017954:Africa South of the Sahara / Q000453:epidemiology; D000913:Antibodies, Protozoan / Q000276:immunology*; D001499:Bayes Theorem; D002648:Child; D002675:Child, Preschool; D017322:Clinical Trials, Phase II as Topic; D005260:Female; D006801:Humans; D007223:Infant; D017780:Malaria Vaccines / Q000008:administration & dosage*; D016778:Malaria, Falciparum / Q000453:epidemiology / Q000517:prevention & control*; D008297:Male; D015800:Protozoan Proteins / Q000276:immunology; D016896:Treatment Outcome; D014611:Vaccination
chemical_list: D000913:Antibodies, Protozoan; D017780:Malaria Vaccines; D015800:Protozoan Proteins; C041595:circumsporozoite protein, Protozoan