A combined analysis of immunogenicity, antibody kinetics and vaccine efficacy from phase 2 trials of the RTS,S malaria vaccine

BMC Med. 2014 Jul 10;12:117. doi: 10.1186/s12916-014-0117-2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Africa South of the Sahara / epidemiology
  • Antibodies, Protozoan / immunology*
  • Bayes Theorem
  • Child
  • Child, Preschool
  • Clinical Trials, Phase II as Topic
  • Female
  • Humans
  • Infant
  • Malaria Vaccines / administration & dosage*
  • Malaria, Falciparum / epidemiology
  • Malaria, Falciparum / prevention & control*
  • Male
  • Protozoan Proteins / immunology
  • Treatment Outcome
  • Vaccination

Substances

  • Antibodies, Protozoan
  • Malaria Vaccines
  • Protozoan Proteins
  • circumsporozoite protein, Protozoan