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This article addresses the evolving challenges in evaluating insecticide-based tools for vector control. In response to the emergence of insecticide resistance in major malaria vectors, novel chemistries and products are coming to market, and there is a need to review the available testing methodologies. Commonly used methods for evaluating insecticides, such as the World Health Organization (WHO) cone bioassay, are inadequate for the diverse range of tools now available. Innovation to Impact (I2I) has studied the variability in laboratory methods, with the aim of identifying key factors that contribute to variation and providing recommendations to tighten up protocols. The I2I Methods Landscape is a living document which presents a review of existing methods for evaluating vector control tools, with the scope currently extending to insecticide-treated nets (ITNs) and indoor residual sprays (IRS). The review reveals a lack of validation for many commonly used vector control methods, highlighting the need for improved protocols to enhance reliability and robustness of the data that is generated to make decisions in product development, evaluation, and implementation. A critical aspect highlighted by this work is the need for tailored methods to measure endpoints relevant to the diverse modes of action of novel insecticides. I2I envisage that the Methods Landscape will serve as a decision-making tool for researchers and product manufacturers in selecting appropriate methods, and a means to prioritise research and development. We call for collective efforts in the pro-active development, validation, and consistent implementation of suitable methods in vector control to produce the data needed to make robust decisions., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Gleave K and Lees RS.)

Background: Pyrethroid long-lasting insecticidal nets (LLINs) have been important in the large reductions in malaria cases in Africa, but insecticide resistance in Anopheles mosquitoes threatens their impact. Insecticide synergists may help control insecticide-resistant populations. Piperonyl butoxide (PBO) is such a synergist; it has been incorporated into pyrethroid-LLINs to form pyrethroid-PBO nets, which are currently produced by five LLIN manufacturers and, following a recommendation from the World Health Organization (WHO) in 2017, are being included in distribution campaigns. This review examines epidemiological and entomological evidence on the addition of PBO to pyrethroid nets on their efficacy., Objectives: To compare effects of pyrethroid-PBO nets currently in commercial development or on the market with effects of their non-PBO equivalent in relation to: 1. malaria parasite infection (prevalence or incidence); and 2. entomological outcomes., Search Methods: We searched the Cochrane Infectious Diseases Group (CIDG) Specialized Register, CENTRAL, MEDLINE, Embase, Web of Science, CAB Abstracts, and two clinical trial registers (ClinicalTrials.gov and WHO International Clinical Trials Registry Platform) up to 25 September 2020. We contacted organizations for unpublished data. We checked the reference lists of trials identified by these methods., Selection Criteria: We included experimental hut trials, village trials, and randomized controlled trials (RCTs) with mosquitoes from the Anopheles gambiae complex or the Anopheles funestus group., Data Collection and Analysis: Two review authors assessed each trial for eligibility, extracted data, and determined the risk of bias for included trials. We resolved disagreements through discussion with a third review author. We analysed data using Review Manager 5 and assessed the certainty of evidence using the GRADE approach., Main Results: Sixteen trials met the inclusion criteria: 10 experimental hut trials, four village trials, and two cluster-RCTs (cRCTs). Three trials are awaiting classification, and four trials are ongoing.  Two cRCTs examined the effects of pyrethroid-PBO nets on parasite prevalence in people living in areas with highly pyrethroid-resistant mosquitoes (< 30% mosquito mortality in discriminating dose assays). At 21 to 25 months post intervention, parasite prevalence was lower in the intervention arm (odds ratio (OR) 0.79, 95% confidence interval (CI) 0.67 to 0.95; 2 trials, 2 comparisons; moderate-certainty evidence). In highly pyrethroid-resistant areas, unwashed pyrethroid-PBO nets led to higher mosquito mortality compared to unwashed standard-LLINs (risk ratio (RR) 1.84, 95% CI 1.60 to 2.11; 14,620 mosquitoes, 5 trials, 9 comparisons; high-certainty evidence) and lower blood feeding success (RR 0.60, 95% CI 0.50 to 0.71; 14,000 mosquitoes, 4 trials, 8 comparisons; high-certainty evidence). However, in comparisons of washed pyrethroid-PBO nets to washed LLINs, we do not know if PBO nets had a greater effect on mosquito mortality (RR 1.20, 95% CI 0.88 to 1.63; 10,268 mosquitoes, 4 trials, 5 comparisons; very low-certainty evidence), although the washed pyrethroid-PBO nets did decrease blood-feeding success compared to standard-LLINs (RR 0.81, 95% CI 0.72 to 0.92; 9674 mosquitoes, 3 trials, 4 comparisons; high-certainty evidence). In areas where pyrethroid resistance is moderate (31% to 60% mosquito mortality), mosquito mortality was higher with unwashed pyrethroid-PBO nets compared to unwashed standard-LLINs (RR 1.68, 95% CI 1.33 to 2.11; 751 mosquitoes, 2 trials, 3 comparisons; moderate-certainty evidence), but there was little to no difference in effects on blood-feeding success (RR 0.90, 95% CI 0.72 to 1.11; 652 mosquitoes, 2 trials, 3 comparisons; moderate-certainty evidence). For washed pyrethroid-PBO nets compared to washed standard-LLINs, we found little to no evidence for higher mosquito mortality or reduced blood feeding (mortality: RR 1.07, 95% CI 0.74 to 1.54; 329 mosquitoes, 1 trial, 1 comparison, low-certainty evidence; blood feeding success: RR 0.91, 95% CI 0.74 to 1.13; 329 mosquitoes, 1 trial, 1 comparison; low-certainty evidence). In areas where pyrethroid resistance is low (61% to 90% mosquito mortality), studies reported little to no difference in the effects of unwashed pyrethroid-PBO nets compared to unwashed standard-LLINs on mosquito mortality (RR 1.25, 95% CI 0.99 to 1.57; 948 mosquitoes, 2 trials, 3 comparisons; moderate-certainty evidence), and we do not know if there was any effect on blood-feeding success (RR 0.75, 95% CI 0.27 to 2.11; 948 mosquitoes, 2 trials, 3 comparisons; very low-certainty evidence). For washed pyrethroid-PBO nets compared to washed standard-LLINs, we do not know if there was any difference in mosquito mortality (RR 1.39, 95% CI 0.95 to 2.04; 1022 mosquitoes, 2 trials, 3 comparisons; very low-certainty evidence) or on blood feeding (RR 1.07, 95% CI 0.49 to 2.33; 1022 mosquitoes, 2 trials, 3 comparisons; low-certainty evidence). In areas where mosquito populations are susceptible to insecticides (> 90% mosquito mortality), there may be little to no difference in the effects of unwashed pyrethroid-PBO nets compared to unwashed standard-LLINs on mosquito mortality (RR 1.20, 95% CI 0.64 to 2.26; 2791 mosquitoes, 2 trials, 2 comparisons; low-certainty evidence). This is similar for washed nets (RR 1.07, 95% CI 0.92 to 1.25; 2644 mosquitoes, 2 trials, 2 comparisons; low-certainty evidence). We do not know if unwashed pyrethroid-PBO nets had any effect on the blood-feeding success of susceptible mosquitoes (RR 0.52, 95% CI 0.12 to 2.22; 2791 mosquitoes, 2 trials, 2 comparisons; very low-certainty evidence). The same applies to washed nets (RR 1.25, 95% CI 0.82 to 1.91; 2644 mosquitoes, 2 trials, 2 comparisons; low-certainty evidence). In village trials comparing pyrethroid-PBO nets to LLINs, there was no difference in sporozoite rate (4 trials, 5 comparisons) nor in mosquito parity (3 trials, 4 comparisons)., Authors' Conclusions: In areas of high insecticide resistance, pyrethroid-PBO nets have greater entomological and epidemiological efficacy compared to standard LLINs, with sustained reduction in parasite prevalence, higher mosquito mortality and reduction in mosquito blood feeding rates 21 to 25 months post intervention. Questions remain about the durability of PBO on nets, as the impact of pyrethroid-PBO nets on mosquito mortality was not sustained over 20 washes in experimental hut trials, and epidemiological data on pyrethroid-PBO nets for the full intended three-year life span of the nets is not available. Little evidence is available to support greater entomological efficacy of pyrethroid-PBO nets in areas where mosquitoes show lower levels of resistance to pyrethroids., (Copyright © 2021 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Background: Public health strategies that target mosquito vectors, particularly pyrethroid long-lasting insecticidal nets (LLINs), have been largely responsible for the substantial reduction in the number of people in Africa developing malaria. The spread of insecticide resistance in Anopheles mosquitoes threatens these impacts. One way to control insecticide-resistant populations is by using insecticide synergists. Piperonyl butoxide (PBO) is a synergist that inhibits specific metabolic enzymes within mosquitoes and has been incorporated into pyrethroid-LLINs to form pyrethroid-PBO nets. Pyrethroid-PBO nets are currently produced by four LLIN manufacturers and, following a recommendation from the World Health Organization (WHO) in 2017, are being included in distribution campaigns in countries. This review examines epidemiological and entomological evidence on whether the addition of PBO to LLINs improves their efficacy., Objectives: 1. Evaluate whether adding PBO to pyrethroid LLINs increases the epidemiological and entomological effectiveness of the nets.2. Compare the effects of pyrethroid-PBO nets currently in commercial development or on the market with their non-PBO equivalent in relation to:a. malaria infection (prevalence or incidence);b. entomological outcomes., Search Methods: We searched the Cochrane Infectious Diseases Group (CIDG) Specialized Register; CENTRAL, MEDLINE, Embase, Web of Science, CAB Abstracts, and two clinical trial registers (ClinicalTrials.gov and WHO International Clinical Trials Registry Platform) up to 24 August 2018. We contacted organizations for unpublished data. We checked the reference lists of trials identified by the above methods., Selection Criteria: We included laboratory trials, experimental hut trials, village trials, and randomized clinical trials with mosquitoes from the Anopheles gambiae complex or Anopheles funestus group., Data Collection and Analysis: Two review authors assessed each trial for eligibility, extracted data, and determined the risk of bias for included trials. We resolved disagreements through discussion with a third review author. We analysed the data using Review Manager 5 and assessed the certainty of the evidence using the GRADE approach., Main Results: Fifteen trials met the inclusion criteria: two laboratory trials, eight experimental hut trials, and five cluster-randomized controlled village trials.One village trial examined the effect of pyrethroid-PBO nets on malaria infection prevalence in an area with highly pyrethroid-resistant mosquitoes. The latest endpoint at 21 months post-intervention showed that malaria prevalence probably decreased in the intervention arm (OR 0.40, 95% CI 0.20 to 0.80; 1 trial, 1 comparison, moderate-certainty evidence).In highly pyrethroid-resistant areas (< 30% mosquito mortality), in comparisons of unwashed pyrethroid-PBO nets to unwashed standard-LLINs, PBO nets resulted in higher mosquito mortality (risk ratio (RR) 1.84, 95% CI 1.60 to 2.11; 14,620 mosquitoes, 5 trials, 9 comparisons, high-certainty evidence) and lower blood feeding success (RR 0.60, 95% CI 0.50 to 0.71; 14,000 mosquitoes, 4 trials, 8 comparisons, high-certainty evidence). However, in comparisons of washed pyrethroid-PBO nets to washed LLINs we do not know if PBO nets have a greater effect on mosquito mortality (RR 1.20, 95% CI 0.88 to 1.63; 10,268 mosquitoes, 4 trials, 5 comparisons, very low-certainty evidence), although the washed pyrethroid-PBO nets do decrease blood feeding success compared to standard-LLINs (RR 0.81, 95% CI 0.72 to 0.92; 9674 mosquitoes, 3 trials, 4 comparisons, high-certainty evidence).In areas where pyrethroid resistance is considered moderate (31% to 60% mosquito mortality), there may be little or no difference in effects of unwashed pyrethroid-PBO nets compared to unwashed standard-LLINs on mosquito mortality (RR 1.16, 95% CI 0.88 to 1.54; 242 mosquitoes, 1 trial, 1 comparison, low-certainty evidence), and there may be little or no difference in the effects on blood feeding success (RR 0.87, 95% CI 0.67 to 1.13; 242 mosquitoes, 1 trial, 1 comparison, low-certainty evidence). The same pattern is apparent for washed pyrethroid-PBO nets compared to washed standard-LLINs (mortality: RR 1.07, 95% CI 0.74 to 1.54; 329 mosquitoes, 1 trial, 1 comparison, low-certainty evidence; blood feeding success: RR 0.91, 95% CI 0.74 to 1.13; 329 mosquitoes, 1 trial, 1 comparison, low-certainty evidence).In areas where pyrethroid resistance is low (61% to 90% mosquito mortality), there is probably little or no difference in the effect of unwashed pyrethroid-PBO nets compared to unwashed standard-LLINs on mosquito mortality (RR 1.10, 95% CI 1.05 to 1.16; 708 mosquitoes, 1 trial, 2 comparisons, moderate-certainty evidence), but there is no evidence for an effect on blood feeding success (RR 0.67, 95% CI 0.06 to 7.37; 708 mosquitoes, 1 trial, 2 comparisons, very low-certainty evidence). For washed pyrethroid-PBO nets compared to washed standard-LLINs we do not know if there is any difference in mosquito mortality (RR 1.16, 96% CI 0.83 to 1.63; 878 mosquitoes, 1 trial, 2 comparisons, very low-certainty evidence), but blood feeding may decrease (RR 1.50, 95% CI 0.89 to 2.54; 878 mosquitoes, 1 trial, 2 comparisons, low-certainty evidence).In areas were mosquito populations are susceptible to insecticides (> 90% mosquito mortality), there may be little or no difference in the effect of unwashed pyrethroid-PBO nets compared to unwashed standard-LLINs on mosquito mortality (RR 1.20, 95% CI 0.64 to 2.26; 2791 mosquitoes, 2 trials, 2 comparisons, low-certainty evidence). This is similar for washed nets (RR 1.07, 95% CI 0.92 to 1.25; 2644 mosquitoes, 2 trials, 2 comparisons, low-certainty evidence). We do not know if unwashed pyrethroid-PBO nets have any effect on blood feeding success of susceptible mosquitoes (RR 0.50, 95% CI 0.11 to 2.32; 2791 mosquitoes, 2 trials, 2 comparisons, very low-certainty evidence). The same applies to washed nets (RR 1.28, 95% CI 0.81 to 2.04; 2644 mosquitoes, 2 trials, 2 comparisons, low-certainty evidence).In village trials comparing pyrethroid-PBO nets to LLINs, there was no difference in sporozoite rate (4 trials, 5 comparison) and mosquito parity (3 trials, 4 comparisons)., Authors' Conclusions: In areas of high insecticide resistance, pyrethroid-PBO nets reduce mosquito mortality and blood feeding rates, and results from a single clinical trial demonstrate that this leads to lower malaria prevalence. Questions remain about the durability of PBO on nets, as the impact of pyrethroid-PBO LLINs on mosquito mortality was not sustained over 20 washes in experimental hut trials. There is little evidence to support higher entomological efficacy of pyrethroid-PBO nets in areas where the mosquitoes show lower levels of resistance to pyrethroids.