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The rotational use of insecticides with different modes of action for indoor residual spraying (IRS) is recommended for improving malaria vector control and managing insecticide resistance. Insecticides with new chemistries are urgently needed. Broflanilide is a newly discovered insecticide under consideration. We investigated the efficacy of a wettable powder (WP) formulation of broflanilide (VECTRON T500) for IRS on mud and cement wall substrates in laboratory and experimental hut studies against pyrethroid-resistant malaria vectors in Benin, in comparison with pirimiphos-methyl CS (Actellic 300CS). There was no evidence of cross-resistance to pyrethroids and broflanilide in CDC bottle bioassays. In laboratory cone bioassays, broflanilide WP-treated substrates killed > 80% of susceptible and pyrethroid-resistant An. gambiae sl for 6–14 months. At application rates of 100 mg/m 2 and 150 mg/m 2 , mortality of wild pyrethroid-resistant An. gambiae sl entering experimental huts in Covè, Benin treated with VECTRON T500 was similar to pirimiphos-methyl CS (57–66% vs. 56%, P > 0.05). Throughout the 6-month hut trial, monthly wall cone bioassay mortality on VECTRON T500 treated hut walls remained > 80%. IRS with broflanilide shows potential to significantly improve the control of malaria transmitted by pyrethroid-resistant mosquito vectors and could thus be a crucial addition to the current portfolio of IRS insecticides.

New classes of long-lasting insecticidal nets (LLINs) combining mixtures of insecticides with different modes of action could put malaria control back on track after rebounds in transmission across sub-Saharan Africa. We evaluated the relative efficacy of pyriproxyfen-pyrethroid LLINs and chlorfenapyr-pyrethroid LLINs compared with standard LLINs against malaria transmission in an area of high pyrethroid resistance in Benin. We conducted a cluster-randomised, superiority trial in Zou Department, Benin. Clusters were villages or groups of villages with a minimum of 100 houses. We used restricted randomisation to randomly assign 60 clusters to one of three LLIN groups (1:1:1): to receive nets containing either pyriproxyfen and alpha-cypermethrin (pyrethroid), chlorfenapyr and alpha-cypermethrin, or alpha-cypermethrin only (reference). Households received one LLIN for every two people. The field team, laboratory staff, analyses team, and community members were masked to the group allocation. The primary outcome was malaria case incidence measured over 2 years after net distribution in a cohort of children aged 6 months–10 years, in the intention-to-treat population. This study is ongoing and is registered with ClinicalTrials.gov, NCT03931473. Between May 23 and June 24, 2019, 53 854 households and 216 289 inhabitants were accounted for in the initial census and included in the study. Between March 19 and 22, 2020, 115 323 LLINs were distributed to 54 030 households in an updated census. A cross-sectional survey showed that study LLIN usage was highest at 9 months after distribution (5532 [76·8%] of 7206 participants), but decreased by 24 months (4032 [60·6%] of 6654). Mean malaria incidence over 2 years after LLIN distribution was 1·03 cases per child-year (95% CI 0·96–1·09) in the pyrethroid-only LLIN reference group, 0·84 cases per child-year (0·78–0·90) in the pyriproxyfen-pyrethroid LLIN group (hazard ratio [HR] 0·86, 95% CI 0·65–1·14; p=0·28), and 0·56 cases per child-year (0·51–0·61) in the chlorfenapyr-pyrethroid LLIN group (HR 0·54, 95% CI 0·42–0·70; p<0·0001). Over 2 years, chlorfenapyr-pyrethroid LLINs provided greater protection from malaria than pyrethroid-only LLINs in an area with pyrethroid-resistant mosquitoes. Pyriproxyfen-pyrethroid LLINs conferred protection similar to pyrethroid-only LLINs. These findings provide crucial second-trial evidence to enable WHO to make policy recommendations on these new LLIN classes. This study confirms the importance of chlorfenapyr as an LLIN treatment to control malaria in areas with pyrethroid-resistant vectors. However, an arsenal of new active ingredients is required for successful long-term resistance management, and additional innovations, including pyriproxyfen, need to be further investigated for effective vector control strategies. UNITAID, The Global Fund.

This study provides detailed characteristics of vector populations in preparation for a three-arm cluster randomized controlled trial (RCT) aiming to compare the community impact of dual active-ingredient (AI) long-lasting insecticidal nets (LLINs) that combine two novel insecticide classes-chlorfenapyr or pyriproxifen-with alpha-cypermethrin to improve the prevention of malaria transmitted by insecticide-resistant vectors compared to standard pyrethroid LLINs. The study was carried out in 60 villages across Cove, Zangnanando and Ouinhi districts, southern Benin. Mosquito collections were performed using human landing catches (HLCs). After morphological identification, a sub-sample of Anopheles gambiae s.l. were dissected for parity, analyzed by PCR for species and presence of L1014F kdr mutation and by ELISA-CSP to identify Plasmodium falciparum sporozoite infection. WHO susceptibility tube tests were performed by exposing adult An. gambiae s.l., collected as larvae from each district, to 0.05% alphacypermethrin, 0.75% permethrin, 0.1% bendiocarb and 0.25% pirimiphos-methyl. Synergist assays were also conducted with exposure first to 4% PBO followed by alpha-cypermethrin. An. gambiae s.l. (n = 10807) was the main malaria vector complex found followed by Anopheles funestus s.l. (n = 397) and Anopheles nili (n = 82). An. gambiae s.l. was comprised of An. coluzzii (53.9%) and An. gambiae s.s. (46.1%), both displaying a frequency of the L1014F kdr mutation >80%. Although more than 80% of people slept under standard LLIN, human biting rate (HBR) in An. gambiae s.l. was higher indoors [26.5 bite/person/night (95% CI: 25.2-27.9)] than outdoors [18.5 b/p/n (95% CI: 17.4-19.6)], as were the trends for sporozoite rate (SR) [2.9% (95% CI: 1.7-4.8) vs 1.8% (95% CI: 0.6-3.8)] and entomological inoculation rate (EIR) [21.6 infected bites/person/month (95% CI: 20.4-22.8) vs 5.4 (95% CI: 4.8-6.0)]. Parous rate was 81.6% (95%CI: 75.4-88.4). An. gambiae s.l. was resistant to alpha-cypermethrin and permethrin but, fully susceptible to bendiocarb and pirimiphos-methyl. PBO pre-exposure followed by alpha-cypermethrin treatment induced a higher 24 hours mortality compared to alphacypermethrin alone but not exceeding 40%. Despite a high usage of standard pyrethroid LLINs, the study area is characterized by intense malaria transmission. The main vectors An. coluzzii and An. gambiae s.s. were both highly resistant to pyrethroids and displayed multiple resistance mechanisms, L1014F kdr mutation and mixed function oxidases. These conditions of the study area make it an appropriate site to conduct the trial that aims to assess the effect of novel dual-AI LLINs on malaria transmitted by insecticide-resistant vectors.

Background Long-lasting insecticidal nets (LLINs) are currently the primary method of malaria control in sub-Saharan Africa and have contributed to a significant reduction in malaria burden over the past 15 years. However, this progress is threatened by the wide-scale selection of insecticide-resistant malaria vectors. It is, therefore, important to accelerate the generation of evidence for new classes of LLINs. Methods This protocol presents a three-arm superiority, single-blinded, cluster randomized controlled trial to evaluate the impact of 2 novel dual-active ingredient LLINs on epidemiological and entomological outcomes in Benin, a malaria-endemic area with highly pyrethroid-resistant vector populations. The study arms consist of (i) Royal Guard® LLIN, a net combining a pyrethroid (alpha-cypermethrin) plus an insect growth regulator (pyriproxyfen), which in the adult female is known to disrupt reproduction and egg fertility; (ii) Interceptor G2® LLIN, a net incorporating two adulticides (alpha-cypermethrin and chlorfenapyr) with different modes of action; and (iii) the control arm, Interceptor® LLIN, a pyrethroid (alpha-cypermethrin) only LLIN. In all arms, one net for every 2 people will be distributed to each household. Sixty clusters were identified and randomised 1:1:1 to each study arm. The primary outcome is malaria case incidence measured over 24 months through active case detection in a cohort of 25 children aged 6 months to 10 years, randomly selected from each cluster. Secondary outcomes include 1) malaria infection prevalence (all ages) and prevalence of moderate to severe anaemia in children under 5 years old, measured at 6 and 18 months post-intervention; 2) entomological indices measured every 3 months using human landing catches over 24 months. Insecticide resistance intensity will also be monitored over the study period. Discussion This study is the second cluster randomised controlled trial to evaluate the efficacy of these next-generation LLINs to control malaria transmitted by insecticide-resistant mosquitoes. The results of this study will form part of the WHO evidence-based review to support potential public health recommendations of these nets and shape malaria control strategies of sub-Saharan Africa for the next decade. Trial registration ClinicalTrials.gov, NCT03931473 , registered on 30 April 2019.

Background Malaria remains a major public health problem in sub-Saharan Africa, particularly in Benin. The present study aims to evaluate the different Plasmodium species transmitted by malaria vectors in the communes of Cove, Zagnanado and Ouinhi, Southern Benin. Methods The study was conducted between December 2021 and October 2022 in 60 villages spread over the three study communes. Adult mosquitoes were collected from four houses in each village using human landing catches (HLCs). After morphological identification, a subsample of Anopheles gambiae , Anopheles funestus and Anopheles nili was analysed by PCR to test for their infection to the different Plasmodium species. Results Anopheles gambiae was collected at higher frequency in all the three study communes, representing 93.5% (95% CI 92.9–94) of all collected mosquitoes (n = 10,465). In total, five molecular species were found, An. gambiae sensu stricto (s.s.) and Anopheles coluzzii of the Gambiae complex, An. funestus and Anopheles leesoni of the Funestus group, and An. nili s.s., the sole species of the Nili group. From the five molecular species, four ( An. gambiae s.s., An. coluzzii , An. funestus s.s. and An. nili s.s.) were found to be infected. Plasmodium falciparum was the main Plasmodium species in the study area, followed by Plasmodium vivax and Plasmodium ovale. Only An. gambiae s.s. was infected with all three Plasmodium species, while An. coluzzii was infected with two species, P. falciparum and P. vivax . Conclusions Plasmodium falciparum was the only species tested for in malaria vectors in Benin, and remains the only one against which most control tools are directed. It is, therefore, necessary that particular attention be paid to secondary Plasmodium species for an efficient control of the disease. The presence of P. vivax emphasizes the need for an update of case management for malaria.

Background This study aimed to investigate the relationship between the physicochemical characteristics of An. gambiae s.s. and An. coluzzii breeding sites, the susceptibility profiles to commonly used insecticides in public health, and the underlying insecticide resistance mechanisms. Methods Anopheles breeding sites surveys were conducted in Cotonou and Natitingou in September 2020, January and August 2021. Physicochemical properties and bacterial loads were determined in individual breeding sites. The WHO susceptibility assays were carried out using the female of the emerging adult mosquitoes. Anopheles species were identified through PCR techniques. Kdr L1014F/S , N1575Y and G119S mutations were investigated using TaqMan genotyping assays. Results Molecular analysis showed that all mosquitoes analyzed in Cotonou were Anopheles coluzzii , while those of Natitingou were Anopheles gambiae s.s. Fecal coliforms were identified as playing a role in this distribution through their significant influence on the presence of An. coluzzii larvae. WHO susceptibility assay indicated a high level of resistance to deltamethrin in the two cities. The resistance levels to deltamethrin were higher in Cotonou (X 2  = 31.689; DF = 1; P  < 0.0001). There was a suspected resistance to bendiocarb in Cotonou, whereas the mosquito population in Natitingou was resistant. The kdr L1014F mutation was highly observed in both mosquito populations (frequence: 86–91%), while the Ace-1 mutation was found in a small proportion of mosquitoes. In Cotonou, salinity was the only recorded physicochemical parameter that significantly correlated with the resistance of Anopheles mosquitoes to deltamethrin ( P  < 0.05). In Natitingou, significant correlations were observed between the allelic frequencies of the kdr L1014F mutation and pH, conductivity, and TDS. Conclusion These results indicate a high level of pyrethroid resistance in the anopheles populations of both Cotonou and Natitingou. Moreover, this study report the involvement of abiotic factors influencing Anopheles susceptibility profile.

Background Insecticide-based interventions have averted more than 500 million malaria cases since 2000, but insecticide resistance in mosquitoes could bring about a rebound in disease and mortality. This study investigated whether insecticide resistance was associated with increased incidence of clinical malaria. Methods In an area of southern Benin with insecticide resistance and high use of insecticide-treated nets (ITNs), malaria morbidity and insecticide resistance were measured simultaneously in 30 clusters (villages or collections of villages) multiple times over the course of 2 years. Insecticide resistance frequencies were measured using the standard World Health Organization bioassay test. Malaria morbidity was measured by cases recorded at health facilities both in the whole population using routinely collected data and in a passively followed cohort of children under 5 years old. Results There was no evidence that incidence of malaria from routinely collected data was higher in clusters with resistance frequencies above the median, either in children aged under 5 (RR = 1.27 (95% CI 0.81–2.00) p = 0.276) or in individuals aged 5 or over (RR = 1.74 (95% CI 0.91–3.34) p = 0.093). There was also no evidence that incidence was higher in clusters with resistance frequencies above the median in the passively followed cohort (RR = 1.11 (0.52–2.35) p = 0.777). Conclusions This study found no association between frequency of resistance and incidence of clinical malaria in an area where ITNs are the principal form of vector control. This may be because, as other studies have shown, ITNs continue to offer some protection from malaria even in the presence of insecticide resistance. Irrespective of resistance, nets provide only partial protection so the development of improved or supplementary vector control tools is required to reduce Africa’s unacceptably high malaria burden.

Background Long-lasting insecticidal nets (LLINs) are designed to survive and sustain their physical barrier for 3 years in household conditions. However, studies have shown that most of these nets are usually torn or no longer present in the households in less than 3 years. This study was initiated in Benin to compare the survivorship and physical integrity of seven types of LLINs in a same socio-geographic area. Methods In August 2017, 1890 households were selected in 9 villages in the municipality of Zagnanado in central Benin. Each one of the selected households received one of the seven LLIN products: Aspirational ® , DawaPlus ® 2.0, OlysetNet ® , PermaNet ® 2.0, PermaNet ® 3.0, Royal Sentry ® and Yorkool ® . Overall, 270 LLINs of each type were freely distributed in Zagnanado, at a rate of 30 LLINs per type per village. These bed nets have been monitored and evaluated every 6 months to identify the most resilient and preferred LLINs in the community. Net survivorship was assessed using the rate of net loss and physical condition. Results The survivorship of all types of LLIN was estimated at 92% (95% CI 90.33–92.96) after 6 months and 70% (95% CI 67.25–71.81) after a year of use. At 12 months, all bed nets monitored were below the NetCalc model threshold of 92.8% for an LLIN with a lifespan of 3 years. Only 1.73% of all types of LLIN had a visible loss of integrity after 6 months with a median proportionate hole index (PHI) estimated at zero. The percentage significantly increased after 12 months with 10.41% of damaged nets (all types of LLINs). The median PHI for each brand of net was 23, 196, 141, 23, 23, 121 and 72, respectively for Aspirational ® , DawaPlus ® 2.0, OlysetNet ® , PermaNet ® 2.0, PermaNet ® 3.0, Royal Sentry ® and Yorkool ® . A significant difference was noted between the PHI at 6 and 12 months (p < 0.0001). After 12 months, the DawaPlus ® 2.0, OlysetNet ® and Royal Sentry ® suffered significantly more damage compared to the others (p < 0.001). Conclusion The results of this study showed that after a year of use, the survivorship of the 7 LLIN products in households was lower than expected. However, all the LLIN products successfully met WHO standards for physical integrity after 12 months of use. The monitoring continues. The next steps will help to identify the most sustainable LLINs.

Malaria continues to kill approximately 650 000 people each year. There is evidence that some second-generation insecticide-treated nets, which combine insecticide formulations with different modes of action, are protective against malaria while the nets are new; however, evidence for their impact over 3 years is scarce. In this study, we report the third-year results of a cluster-randomised controlled trial assessing the long-term effectiveness of dual-active ingredient long-lasting insecticidal nets (LLINs). This is a secondary analysis of a cluster-randomised controlled trial, carried out between May 23, 2019, and April 30, 2023, in southern Benin. Restricted randomisation was used to assign 60 clusters (villages or groups of villages with a minimum of 100 households) to the three study groups (1:1:1) to evaluate the efficacy of pyriproxyfen-pyrethroid LLINs and chlorfenapyr-pyrethroid LLINs compared with pyrethroid-only LLINs (reference) against malaria transmission. The study staff and communities were masked to the group allocation. The primary outcome was malaria incidence measured over the third year after LLIN distribution, in a cohort of children aged 6 months to 9 years at the time of enrolment, in the intention-to-treat population. Here, we present the data of the third year post-LLIN distribution. The trial was registered with ClinicalTrials.gov, NCT03931473. Study net use declined over the 3 years and was consistently lowest in the pyriproxyfen-pyrethroid LLIN group (at 36 months: 889 [39·4%] of 2257 participants vs 1278 [52·2%] of 2450 participants for the chlorfenapyr-pyrethroid LLIN group and 1400 [57·6%] of 2430 participants for the pyrethroid-only LLIN group). The cohort of children for the third year of follow-up (600 per group) were enrolled between April 9 and 30, 2022. Mean malaria incidence during the third year after distribution was 1·19 cases per child-year (95% CI 1·09–1·29) in the pyrethroid-only LLIN reference group, 1·21 cases per child-year (1·12–1·31) in the pyriproxyfen-pyrethroid LLIN group (hazard ratio [HR] 1·02, 95% CI 0·71–1·44; p=0·92), and 0·96 cases per child-year (0·88–1·05) in the chlorfenapyr-pyrethroid LLIN group (HR 0·80, 0·56–1·17; p=0·25). No adverse events related to study nets were reported by participants. During the third year, as was also observed during the first 2 years, the pyriproxyfen-pyrethroid LLIN group did not have superior protection against malaria cases compared with the standard LLIN group. In the third year, people living in the chlorfenapyr-pyrethroid LLIN group no longer benefited from greater protection against malaria cases and infections than those living in the pyrethroid-only LLIN group. This was probably influenced by lower study net use than previous years and the declining concentration of partner insecticides in the nets. UNITAID, The Global Fund. For the French translation of the abstract see Supplementary Materials section.

Background In Alibori and Donga, two departments of high malaria incidence of Northern Benin, pirimiphos-methyl, mixture deltamethrin + clothianidin, as well as clothianidin were used at large scale for IRS. The present study aimed to assess the residual efficacy of these products. Methods Immatures of Anopheles gambiae sensu lato ( s.l .) collected in the communes of Kandi and Gogounou (Department of Alibori), Djougou and Copargo (Department of Donga) were reared until adulthood. Females aged 2–5 days were used for susceptibility tube tests following the WHO protocol. The tests were conducted with deltamethrin (0.05%), bendiocarb (0.1%), pirimiphos-methyl (0.25%) and clothianidin (2% weight per volume). For cone tests performed on cement and mud walls, the An. gambiae Kisumu susceptible strain was used. After the quality control of the IRS performed 1-week post-campaign, the evaluation of the residual activity of the different tested insecticides/mixture of insecticides was conducted on a monthly basis. Results Over the three study years, deltamethrin resistance was observed in all the communes. With bendiocarb, resistance or possible resistance was observed. In 2019 and 2020, full susceptibility to pirimiphos-methyl was observed, while possible resistance to the same product was detected in 2021 in Djougou, Gogounou and Kandi. With clothianidin, full susceptibility was observed 4–6 days post-exposure. The residual activity lasted 4–5 months for pirimiphos-methyl, and 8–10 months for clothianidin and the mixture deltamethrin + clothianidin. A slightly better efficacy of the different tested products was observed on cement walls compared to the mud walls. Conclusion Overall, An. gambiae s.l. was fully susceptible to clothianidin, while resistance/possible resistance was observed the other tested insecticides. In addition, clothianidin-based insecticides showed a better residual activity compared to pirimiphos-methyl, showing thus their ability to provide an improved and prolonged control of pyrethroid resistant vectors.