Safety of RTS,S/AS01E malaria vaccine up to 1 year after the third dose in Ghana, Kenya, and Malawi (EPI-MAL-003): a phase 4 cohort event monitoring study

<h4>Background</h4>RTS,S/AS01_E has been successfully administered to over two million children since 2019 through the Malaria Vaccine Implementation Programme (MVIP). In this Article, we report the safety results of a study evaluating RTS,S/AS01_E safety and effectiveness in real-world settings.<h4>Methods</h4>EPI-MAL-003 is an ongoing phase 4 disease surveillance study with prospective cohort event monitoring and hospital-based surveillance, done in the setting of routine health-care practice in Ghana, Kenya, and Malawi and fully embedded in the MVIP. The study design was dependent on the cluster-randomised vaccine implementation. In active surveillance, we enrolled children younger than 18 months from exposed (where RTS,S/AS01_E was offered) and unexposed clusters. The coprimary endpoints were the occurrence of predefined adverse events of special interest and aetiology-confirmed meningitis. We report primary and secondary safety results up to 1 year after the primary vaccine schedule (three doses). The study is registered with ClinicalTrials.gov, NCT03855995.<h4>Findings</h4>The first participant was enrolled on March 21, 2019. The cutoff date for the current analysis was 1 year after the third RTS,S/AS01_E dose for each participant. In total, 44 912 children (19 993 in Ghana, 11 990 in Kenya, and 12 929 in Malawi) were included in the analysis set for the cluster-randomised comparison: 22 508 from exposed clusters and 22 404 from unexposed clusters. Incidence rates (expressed per 100 000 person-years) for generalised convulsive seizures and intussusception were similar between vaccinated and unvaccinated children. Aetiology-confirmed meningitis was reported in two children: one case of bacterial meningitis due to Streptococcus pneumoniae in an RTS,S/AS01_E-vaccinated child in the exposed clusters, and one case of viral meningitis due to human herpesvirus 6 in an unvaccinated child in the unexposed clusters. Both cases occurred within 12 months after vaccination in children in the cluster-design analysis set, leading to incidence rates of 4·1 (95% CI 0·1-23·0) per 100 000 person-years in RTS,S/AS01_E-vaccinated children and 4·0 (0·1-22·6) per 100 000 person-years in unvaccinated children, and a country-adjusted incidence rate ratio (IRR) of 0·96 (95% CI 0·06-15·34; p=0·98). Cerebral malaria cases were reported for four (<0·1%) of 20 639 RTS,S/AS01_E-vaccinated children in the exposed clusters and two (<0·1%) of 22 137 unvaccinated children in the unexposed clusters. These included three and two cases occurring within 12 months after the primary vaccination, in RTS,S/AS01_E-vaccinated children and unvaccinated children, respectively (IRR 1·43, 95% CI 0·24-8·58, p=0·70). Incidence rates for all-cause mortality were 659·7 (95% CI 561·5-770·3) in vaccinated children versus 724·5 (622·3-838·8) in unvaccinated children, with similar incidence rates for boys and girls.<h4>Interpretation</h4>We found no evidence of vaccination being associated with an increased risk of meningitis, cerebral malaria, or mortality among vaccinated children, and no new safety risks were identified.<h4>Funding</h4>GSK.