Integrating Malaria Vaccine with Seasonal Malaria Chemoprevention in West Africa (IMVACS): study protocol for a cluster-randomized trial

Abstract Background Despite wide-scale implementation of malaria prevention strategies, including seasonal malaria chemoprevention (SMC), a substantial disease burden persists. The R21/Matrix-M (R21/MM) malaria vaccine, recommended by the World Health Organization in 2023, is expected to substantially reduce this burden in children. However, the optimal delivery strategy in highly seasonal transmission settings remains uncertain. Integrating vaccine delivery with SMC campaigns may improve access, timeliness, and coverage, especially for the fourth dose. This trial will evaluate whether integrated delivery of R21/MM through SMC campaigns will provide non-inferior protection against malaria compared with routine Essential Program on Immunization (EPI)-based delivery or routine pre-seasonal delivery before SMC campaigns. Feasibility, acceptability, and cost-effectiveness will also be assessed. Methods This trial is a multi-site, phase IV, open-label, two-arm, cluster-randomized, non-inferiority trial conducted in the rural health districts of Boussé (Burkina Faso) and Dioila (Mali). Clusters, defined as peripheral health centers catchment areas, will be randomized separately within each country (1:1) and stratified by cluster size, with 20 clusters in Burkina Faso and 16 in Mali. Following written informed consent, trained study staff will enroll eligible children. Children aged 3–59 months living in intervention clusters and those aged 5–36 months living in control clusters will be eligible for vaccination. Children with previous malaria vaccination or conditions compromising participation will be excluded. Vaccination will be delivered through integrated SMC campaigns in the intervention arm and through year-round EPI-based delivery in Burkina Faso or pre-seasonal delivery before SMC campaigns followed by year-round EPI-based delivery in Mali. Power calculations will assume a non-inferiority margin of 0.10. The primary outcome will be the incidence of clinical malaria among children aged 5–36 months over 12 months after the first dose. Secondary outcomes will include adverse events following immunization, adverse events of special interest, serious adverse events, vaccine coverage, dropout rates, barriers and facilitators to implementation, stakeholder perceptions, and cost per disability-adjusted life year averted. Discussion Beyond effectiveness and safety, the study will provide evidence to support integrated R21/MM delivery with SMC in highly seasonal transmission settings. The findings are expected to inform national and global malaria vaccine policies. Trial registration ClinicalTrials.gov, NCT06860178 . Registered on 20 January 2025.