This is a two-arm, cluster-randomised, phase IV trial conducted in Chad to assess theprotective efficacy and impact in real-life conditions of a new strategy foradministering the R21/MM malaria vaccine, synchronized within a seasonal malariachemoprevention (SMC) campaign, among children living in areas of high seasonal malariatransmission.In this study, a cluster is defined as the catchment area of a primary care healthcentre. In Chad, each catchment area is known as a 'zone of responsibility' (French: Zonede Responsibilité' [ZR]).Twenty-six (26) of the total 27 ZRs in the districts of Moïssala and Dembo will berandomized in a 1:1 ratio to receive a 4-dose (3 primary doses + 1 booster) R21/MMschedule either (1) integrated into the routine EPI vaccination program (the "Routine"control arm), or (2) synchronized with an annual seasonal malaria chemoprevention (SMC)campaign (the "Synchronized" intervention arm).Malaria incidence: R21/MM effectiveness will be assessed using the incidence ofbiologically confirmed clinical malaria (trial primary endpoint). The incidence ofclinical malaria will be determined through enhanced surveillance of malaria cases inhealth centres and hospitals over a 17-month period (August 2025 - December 2026).Coverage surveys: Cross-sectional surveys (cluster sampling) will be carried out tomeasure R21/MM vaccine coverage, SMC coverage, coverage of other malaria preventionmeasures, and coverage of other EPI vaccines.Nested case-control study: A sub-sample of children admitted to Moïssala DistrictHospital with severe clinical malaria will be offered the opportunity to participate in anested case-control study designed to estimate the individual protective efficacy ofR21/MM against severe malaria.Aditionnaly, the INTEGREVAC ancillary study's objective is to evaluate thecost-effectiveness, acceptability and feasibility of the synchronised vaccinationstrategy in the context of the ongoing COSAV-R21 trial, to inform policy decisions forthe effective deployment of malaria vaccines in SMC implementation areas.Methodology and planned work:(i) A qualitative study using in-depth interviews (IDIs) and group discussions with keystakeholders at the national, health facility, and community levels, including caregiversof children eligible for vaccination, in Chad, at several points during the trial. Wewill explore stakeholders' and beneficiaries' perceptions and experiences of thesynchronised SMC vaccination strategy (trial intervention arm) compared to age-basedvaccine administration under the routine immunisation programme (trial control arm), aswell as considerations for implementing these strategies. Interviews with healthcareproviders, including those administering R21 and SMC, and community members will assessthe feasibility of implementing the integrated vaccination strategy via SMC.(ii) An economic evaluation including a cost-effectiveness analysis and a nested equityanalysis will be conducted. The economic evaluation will include a cost analysis tocarefully identify and measure the additional costs associated with adding malariavaccination to the EPI delivery platform and, separately, to the SMC delivery channel.Analysis of key cost drivers will enable us to identify potential efficiency savings,provide evidence for country funding requests (e.g., to GAVI and the Global Fund) and forthe malaria vaccine strategy budgeting/planning process. Cost-effectiveness and equityanalyses of each vaccine delivery strategy will provide evidence to help nationalprogrammes plan future malaria vaccine delivery and inform global guidance and on methodsof delivering these vaccines, while providing valuable evidence on the real-worldcost-effectiveness of malaria vaccination.(iii) Impact modelling will estimate the costs, impact, and cost-effectiveness of scalingup the intervention approach to the whole of Chad, under different temporal and spatialscenarios.