Abstract

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

Guerra Mendoza, Y. Garric, E. Leach, A. Lievens, M. Ofori-Anyinam, O. Pircon, J. Y. Stegmann, J. U. Vandoolaeghe, P. Otieno, L. Otieno, W. Owusu-Agyei, S. Sacarlal, J. Masoud, N. S. Sorgho, H. Tanner, M. Tinto, H. Valea, I. Mtoro, A. T. Njuguna, P. Oneko, M. Otieno, G. A. Otieno, K. Gesase, S. Hamel, M. J. Hoffman, I. Kaali, S. Kamthunzi, P. Kremsner, P. Lanaspa, M. Lell, B. Lusingu, J. Malabeja, A. Aide, P. Akoo, P. Ansong, D. Asante, K. P. Berkley, J. A. Adjei, S. Agbenyega, T. Agnandji, S. T. Schuerman, L.
Hum Vaccin Immunother. 2019; 152386-2398

Permanent descriptor

https://doi.org/10.1080/21645515.2019.1586040

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.