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Clinical Trial
. 2019;15(10):2386-2398.
doi: 10.1080/21645515.2019.1586040. Epub 2019 Apr 23.

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

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Free PMC article
Clinical Trial

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

Yolanda Guerra Mendoza et al. Hum Vaccin Immunother. .
Free PMC article

Abstract

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.

Figures

Figure 1.
Figure 1.
Meningitis cases by time-to-onset after dose 1 and by treatment group. R3R, group receiving 4 doses of RTS,S/AS01; R3C, group receiving 3 doses of RTS,S/AS01 plus 1 dose of control vaccine; C3C, group receiving 4 doses of control vaccine.
Figure 2.
Figure 2.
Distribution of meningitis cases by site and etiology in both age categories. R3R, group receiving 4 doses of RTS,S/AS01; R3C, group receiving 3 doses of RTS,S/AS01 plus 1 dose of control vaccine; C3C, group receiving 4 doses of control vaccine. One case with viral etiology is included in the “No pathogen identified” category (R3R group).
Figure 3.
Figure 3.
Cerebral malaria cases (identified per computer algorithm) by time-to-onset after dose 1 and by treatment group (5–17 months age category). R3R, group receiving 4 doses of RTS,S/AS01; R3C, group receiving 3 doses of RTS,S/AS01 plus 1 dose of control vaccine; C3C, group receiving 4 doses of control vaccine.
Figure 4.
Figure 4.
Focus on the patient summary of the findings.

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Grant support

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.
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