“Breaking the Resistance Barrier”: Superior Efficacy of Chlorfenapyr Bednets Against Highly Resistant Anopheles malaria vectors in Uganda

Background Insecticide resistance and its escalation poses a great challenge to bednets’ efficacy in malaria control. Methods We conducted experimental the first hut trials in Uganda using highly resistant free-flying wild Anopheles mosquitoes and F2 hybrids of FANG and Uganda An. funestus to evaluate the performance of bednets. Results The chlorfenapyr-based Interceptor G2 bednet demonstrated superior efficacy compared to pyrethroid-only net [mortality odds ratio (OR): 18.7 (8.05–48.6) P  < 0.0001], achieving an overall mortality rate of 70.6% and 63.2% against An. funestus and An. gambiae respectively. In contrast, piperonyl butoxide (PBO)-based and pyriproxyfen (PPF)-treated bednets exhibited significantly lower mortality against An. funestus [Olyset Plus: 36.1%, PermaNet 3.0: 31.0% and Royal Guard (37.6%], though performance against An. gambiae was moderate [PermaNet 3.0: 61.4%, Olyset Plus: 50.0%, Royal Guard: 51.6%]. Pyrethroid-only Interceptor nets produced the lowest mortality (~ 25%) against both species. Regarding blood-feeding inhibition (BFI), PBO nets, particularly Olyset Plus, outperformed Interceptor G2 and Royal Guard, while Interceptor produced minimal BFI (< 36%). Further evaluation of Royal Guard’s PPF effect on oviposition revealed no significant reduction in oviposition rates compared to controls with An. funestus (63.9% vs. 63.3%, P  > 0.05). Genetic analysis revealed that pyrethroid resistance markers ( 4.3Kb-SV and G454A-Cyp9k1 ) were associated with mosquito survival and blood-feeding success against pyrethroid-only and PBO nets but showed no significant association with chlorfenapyr-based (Interceptor G2) net. Conclusions These findings establish Interceptor G2 as the ideal intervention for regions dominated by both highly resistant An. funestus s.l. and An. gambiae s.l. Piperonyl butoxide and PPF nets emerge as an ideal alternative for areas with only resistant An. gambiae s.l. populations. Critically, the demonstrated variable impact of insecticide resistance on bednet efficacy underscores the imperative need for a comprehensive vector distribution mapping, continuous field efficacy assessments, and systematic resistance monitoring. This evidence-based triad should guide strategic LLIN distribution and rotations to sustain malaria control efficacy in resistance-prone settings.