PRONet Duo insecticide-treated net incorporated with chlorfenapyr and bifenthrin is superior to Interceptor ® G2 nets against pyrethroidresistant Anopheles gambiae sensu lato: a randomized experimental hut trial in Côte d'Ivoire and Tanzania using non-inferiority design

Alphonce Assenga ^1* Ludovic Ahoua Alou ² Soromane Camara ² Alphonsine Koffi ² Raphael N'guessan ³ Dismas Kamande ¹ Safina Ngonyani ¹ Ummi Kibondo ¹ Olukayode Odufuwa ¹ Watson Ntabaliba ¹ Ruth Lekundayo ¹ Faraji Abilah ¹ Edith Madumla ¹ Joseph Muganga ¹ Jason Moore ¹ Sarah Moore ¹

• ¹ Ifakara Health Institute, Ifakara, Tanzania
• ² Vector Control Product Evaluation Centre (VCPEC)-Institut Pierre Richet / Institut National de Santé Publique, Bouaké, Côte d'Ivoire
• ³ Department of Disease Control, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom

The widespread development of pyrethroid-resistant Anopheles populations, has reduced the efficacy of pyrethroid insecticidetreated nets (ITNs), hindering malaria control efforts. This study tested PRONet Duo, a new ITN with two active ingredients-bifenthrin and chlorfenapyr. Bifenthrin is a fluorinated pyrethroid that is highly stable and more slowly detoxified by pyrethroid-resistant mosquitoes.Chlorfenapyr disrupts cellular energy production. The efficacy of PRONet Duo was compared to Interceptor ® G2, an alpha-cypermethrin and chlorfenapyr ITN with proven efficacy in malaria reduction.The study was conducted in two identical 9x9 Latin square experimental hut trials against wild free-flying Anopheles gambiae sensu lato in M'Bé, Côte d'Ivoire, and Lupiro, Tanzania using 18 experimental huts over 108 nights. The primary endpoint was the proportion of 72hour mosquito mortality (M72) and the secondary endpoint was the proportion of mosquito blood-feeding. The study was done following World Health Organization guidelines. Data were analysed using mixed-effect linear regression with a 7% margin of non-inferiority. Data were classified as non-inferior using delta and superior using the line of no difference.Results: PRONet Duo demonstrated a non-inferior and superior mosquito mortality compared to Interceptor ® G2 in both study sites. In Côte d'Ivoire, the M72 of PRONet Duo was 84% [81,88], higher than that of Interceptor ® G2 (72% [68,76], OR: 1. 54 [1.27,1.88]) and it was superior to MAGNet ® (30% [27,34], OR: 13.74 [11.35,16.63], p<0.0001). In Tanzania, M72 of PRONet Duo was 68% [62,73], higher than that induced by Interceptor ® G2 (44% [40,49], Odds Ratio (OR):1.74 [1.54,1.96]), and MAGNet ® (36% [32,41], OR:4.82 [4.06,5.72] p<0.0001). PRONet Duo also induced non-inferior and superior prevention of blood-feeding compared to Interceptor ® G2, with less than 11% feeding success observed in either trial site.PRONet Duo ITNs are non-inferior and superior to the first-in-class Interceptor ® G2 in terms of mosquito mortality and prevention of blood-feeding demonstrating the added benefit of bifenthrin for insecticide resistance management. Both chlorfenapyr nets offered superior mortality compared to the pyrethroid-only ITN. PRONet Duo offers an additional highly effective ITN for control of pyrethroid-resistant mosquitoes in malaria endemic regions