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.
Guerra Mendoza, Y., Garric, E., Leach, A., Lievens, M., Ofori-Anyinam, O., Pirçon, 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.