PROJECT 2 SUMMARY Insecticide-based vector control and antimalarial drug-based case management and prevention are critical pillars supporting malaria control and elimination. Insecticides are used primarily in long-lasting insecticide-treated net (LLIN) and indoor residual spraying (IRS) programs to reduce malaria transmission by mosquitoes. Clinical malaria cases require prompt diagnosis and treatment, while preventive programs target high-risk populations such as children (seasonal/perennial malaria chemoprevention) and pregnant women (intermittent preventive therapy during pregnancy). Although these strategies have been implemented to varying degrees in malaria-endemic countries, their effectiveness is compromised or threatened by the evolution of resistance in mosquitoes to available insecticides and malaria parasites to commonly used antimalarial drugs. To optimize and maximize the effects of the control interventions, it is necessary to understand resistance mechanisms and keep up-to-date with the changing resistance landscape. Thus, we propose to conduct extensive resistance surveillance of vectors and parasites in our established study and sentinel sites, which have highly divergent malaria epidemiology and have used different interventions. This project will test the hypothesis that resistance development in vectors and parasites is influenced by the intensity of transmission and the types of interventions deployed, while resistance progression, in turn, impacts the effectiveness of the current control measures. In selected study sites across Cameroon, we will perform serial surveillance of resistance mediators/markers in vectors and parasites, determine genotype-phenotype associations, look for correlations between marker prevalence and intervention use, and identify and confirm new mutations conferring resistance. Specifically, we will (1) determine the prevalence, distribution, and mechanisms of insecticide resistance in major malaria vectors and evaluate the impact of resistance on vector control interventions, (2) assess the dynamic of antimalarial drug resistance, monitor clinical efficacy in different epidemiological settings, and collaborate with the National Malaria Control Program to develop treatment guidelines for Plasmodium vivax malaria, and (3) determine how the complex interactions between drug and insecticide resistance shape the local malaria transmission patterns. By pursuing these interrelated objectives, we aim to gain insights into how different malaria interventions affect the evolution of resistance across Cameroon over time. Understanding the extent and dynamics of insecticide and drug resistance will provide the critical knowledge base for evidence-based resistance management and guide and refine the selection and implementation of LLINs, IRS, and antimalarial drugs.