Safety profile of the RTS,S/AS01 malaria vaccine in infants and children: additional data from a phase III randomized controlled trial in sub-Saharan Africa

Hum Vaccin Immunother. 2019;15(10):2386-2398. doi: 10.1080/21645515.2019.1586040. Epub 2019 Apr 23.


A phase III, double-blind, randomized, controlled trial (NCT00866619) in sub-Saharan Africa showed RTS,S/AS01 vaccine efficacy against malaria. We now present in-depth safety results from this study. 8922 children (enrolled at 5-17 months) and 6537 infants (enrolled at 6-12 weeks) were 1:1:1-randomized to receive 4 doses of RTS,S/AS01 (R3R) or non-malaria control vaccine (C3C), or 3 RTS,S/AS01 doses plus control (R3C). Aggregate safety data were reviewed by a multi-functional team. Severe malaria with Blantyre Coma Score ≤2 (cerebral malaria [CM]) and gender-specific mortality were assessed post-hoc. Serious adverse event (SAE) and fatal SAE incidences throughout the study were 24.2%-28.4% and 1.5%-2.5%, respectively across groups; 0.0%-0.3% of participants reported vaccination-related SAEs. The incidence of febrile convulsions in children was higher during the first 2-3 days post-vaccination with RTS,S/AS01 than with control vaccine, consistent with the time window of post-vaccination febrile reactions in this study (mostly the day after vaccination). A statistically significant numerical imbalance was observed for meningitis cases in children (R3R: 11, R3C: 10, C3C: 1) but not in infants. CM cases were more frequent in RTS,S/AS01-vaccinated children (R3R: 19, R3C: 24, C3C: 10) but not in infants. All-cause mortality was higher in RTS,S/AS01-vaccinated versus control girls (2.4% vs 1.3%, all ages) in our setting with low overall mortality. The observed meningitis and CM signals are considered likely chance findings, that - given their severity - warrant further evaluation in phase IV studies and WHO-led pilot implementation programs to establish the RTS,S/AS01 benefit-risk profile in real-life settings.

Keywords: (5–10): Malaria; RTS,S/AS01 vaccine; cerebral malaria; febrile convulsions; meningitis; safety.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Africa South of the Sahara
  • Double-Blind Method
  • Female
  • Fever / chemically induced
  • Humans
  • Immunization Schedule*
  • Incidence
  • Infant
  • Malaria Vaccines / adverse effects*
  • Malaria Vaccines / immunology
  • Malaria, Cerebral / mortality
  • Malaria, Cerebral / prevention & control
  • Malaria, Falciparum / mortality
  • Malaria, Falciparum / prevention & control*
  • Male
  • Meningitis / chemically induced
  • Plasmodium falciparum
  • Seizures, Febrile / chemically induced
  • Vaccination


  • Malaria Vaccines

Grants and funding

The trial was supported by GlaxoSmithKline Biologicals SA and was funded by both GlaxoSmithKline Biologicals SA and the PATH Malaria Vaccine Initiative. All centers received a grant from the MVI for running the trial. Author travel and accommodation related to this trial were financed by the MVI. GlaxoSmithKline Biologicals SA received a grant from the MVI to run the trial. The MVI received a grant from the Bill & Melinda Gates Foundation to run this trial and to compensate MVI authors for trial-related travel. GlaxoSmithKline Biologicals SA developed and manufactured the vaccine. GlaxoSmithKline Biologicals SA took in charge all costs related to the development and publication of this article.