Abstract
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.
Highlights
The widespread implementation of malaria prevention and control measures, such as the use of insecticide-treated nets, improved diagnosis, and artemisinin combination therapy, has led to considerable gains in the control of malaria.[1,2] malaria remains a major public health threat, especially in young children in sub-Saharan Africa (SSA)
We further investigated the increased risk of febrile convulsions and the safety signals related to meningitis and cerebral malaria that were previously identified in this trial.[7,8,9,10,12,13]
On further investigation of the timing of the febrile reactions post-vaccination, we found that the increased incidence of fever following RTS,S/AS01 vaccination mainly occurred on the day after vaccination and fever mostly resolved within 1 day (Supplementary figure S1)
Summary
The widespread implementation of malaria prevention and control measures, such as the use of insecticide-treated nets, improved diagnosis, and artemisinin combination therapy, has led to considerable gains in the control of malaria.[1,2] malaria remains a major public health threat, especially in young children in sub-Saharan Africa (SSA). In 2017, an estimated 219 million cases of malaria occurred worldwide, resulting in 435,000 deaths, of which 93%. About 61% of all malaria deaths, mostly caused by Plasmodium falciparum, were estimated to occur in children younger than 5 years.[3,4]. The development and deployment of an effective malaria vaccine is considered a further important step towards reducing the disease burden. RTS,S/AS01 is a malaria vaccine candidate targeting the circumsporozoite protein and has proven efficacy in clinical trials.[5,6,7,8,9,10] In July 2015, RTS,S/
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