Integrated malaria control and drug resistance in an age- and sex-structured model with seasonal malaria chemoprevention, mass drug administration, and routine case management

Malaria control is increasingly threatened by antimalarial drug resistance. We develop an age- and sex-structured malaria transmission model integrating drug-sensitive and drug-resistant parasites, routine case management, seasonal malaria chemoprevention (SMC), and mass drug administration (MDA). The main novelty is the joint representation of demographic heterogeneity and time since recovery and intervention exposure, allowing waning immunity and drug efficacy to interact with the interventions' deployment and resistance dynamics. We establish the well-posedness of the model and derive the basic reproduction number $\mathcal{R}_0$ using a next-generation operator. Global sensitivity analysis and scenario-based simulations are used to identify the key drivers of clinical burden and resistance and to compare intervention strategies. Under the constant intervention assumption used for the $\mathcal{R}_0$ analysis, neither SMC nor MDA alone reduces $\mathcal{R}_0$ below unity over the coverage ranges considered, whereas their combination can reduce $\mathcal{R}_0$ below unity. Time-dependent simulations further show that the interventions' coverage, timing, and repeated cycles shape both the clinical impact and resistance dynamics. An optimization framework determines the minimal intervention coverage required to achieve predefined reductions in clinical cases. Overall, the framework provides a mechanistic basis for investigating the epidemiological-evolutionary trade-offs of integrated malaria control strategies.