Impact of Indoor Residual Spraying and Insecticide-Treated Nets on Malaria Burden in Uganda: A Quasi-Experimental Study in 8 Districts in West Nile and Acholi Regions

Background: In Uganda, where malaria transmission is high, insecticide treated nets (ITNs) have been distributed nationwide every three years since 2013. In West Nile, northern Uganda, indoor residual spraying (IRS) was first implemented with clothianidin-deltamethrin (Fludora Fusion®) in 2022, followed by pirimiphos-methyl (Actellic 300CS®) in 2023. We utilized a quasi-experimental study to assess the impact of IRS+ITNs on malaria incidence in West Nile. Methods: Data were collected from three malaria reference centres (MRCs) in West Nile (IRS+ITNs, intervention) and five MRCs in neighbouring Acholi (ITNs only, control) over 4 years: (1) Baseline (December 2018-November 2020), prior to IRS; (2) IRS-1 (December 2022-December 2023) following IRS with clothianidin-deltamethrin; (3) IRS-2 (January 2024-December 2024) following IRS with pirimiphos-methyl. The primary outcome was monthly malaria incidence (number of laboratory-confirmed malaria cases from each MRC target area per 1000 person-years). Data were analysed using negative binomial regression models with a difference-in-difference approach, comparing pre-post trends in malaria incidence between intervention and control groups. Adjusted models accounted for seasonality and care-seeking behaviours. Results: During IRS-1, mean observed malaria incidence fell from baseline in both arms (intervention: 720.9 to 547.9; and control: 523.4 to 455.2 per 1000 person-years). We detected a 14% difference in predicted mean malaria incidence between intervention and control during IRS-1 relative to baseline, but this was not significant (adjusted IRR = 0.86, 95% CI 0.70–1.06, p=0.17). During IRS-2, incidence in the intervention arm declined by 79.3% compared to baseline (720.9 to 149.1), while in the control arm, incidence fell by 24.3% (523.4 to 396.2). We detected a 70% reduction in predicted mean malaria incidence in the intervention arm compared to control relative to baseline (aIRR 0.30, 95% CI 0.24 – 0.38, p<0.01). During IRS-2, there was strong evidence of an immediate and sustained reduction in incidence in the intervention arm over one year. Conclusion: In West Nile, the reduction in malaria incidence after clothianidin-based IRS (plus ITNs) was modest and non-significant. Subsequent IRS with pirimiphos-methyl (plus ITNs) substantially reduced malaria incidence. These results highlight the importance of selecting context-specific insecticides for vector control programs and the potential synergistic effect of dual interventions in areas of high pyrethroid resistance.