This is a multi-site, multi-disciplinary, Phase-4 two-arm cluster-randomised non-inferiority trial in Burkina Faso and Mali to evaluate the effectiveness and real-life impact of a novel integrated delivery strategy of the R21 malaria vaccine alongside SMC among children in areas with highly seasonal malaria transmission. In this study, a cluster is defined as the catchment area of a health centre. Clusters will be randomised to receive either year-round age-based routine EPI vaccination for children aged 5-36 months (Routine EPI Vaccination) in Burkina Faso or an annual campaign of the 3-dose primary series in children aged 5-36 months prior to the malaria season and SMC delivery (''Routine Pre-SMC vaccination'') in Mali versus an annual campaign of the 3-dose primary series aligned with SMC distribution in children aged 3-59 months (Integrated SMC Vaccination) in each country. Effectiveness will be assessed in terms of clinical malaria, vaccine coverage, acceptability, feasibility, and cost-effectiveness. Malaria incidence will be determined using routine surveillance activities for clinical malaria detection and reporting in each country. Cross-sectional surveys will be conducted to determine the prevalence of parasitaemia in the communities. In addition, the acceptability, feasibility, coverage and cost-effectiveness of the different delivery systems of R21/Matrix-M will be assessed.