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Background Following the World Health Organization (WHO) endorsement of dual active ingredient (AI) nets, an increased uptake of pyrethroid-chlorfenapyr and pyrethroid-pyriproxyfen nets is expected. Studies evaluating their physical and insecticidal durability are essential for making programmatic and procurement decisions. This paper describes the methodology for a prospective study to evaluate the attrition, fabric integrity, insecticidal durability of Interceptor ® G2 (alpha-cypermethrin-chlorfenapyr) and Royal Guard ® (alpha-cypermethrin-pyriproxyfen), compared to Interceptor ® (alpha-cypermethrin), embedded in a 3-arm cluster randomized controlled trial (cRCT) in the Zou Department of Benin. Methods Ten clusters randomly selected from each arm of the cRCT will be used for the study. A total of 750 ITNs per type will be followed in 5 study clusters per arm to assess ITN attrition and fabric integrity at 6-, 12-, 24- and 36-months post distribution, using standard WHO procedures. A second cohort of 1800 nets per type will be withdrawn every 6 months from all 10 clusters per arm and assessed for chemical content and biological activity in laboratory bioassays at each time point. Alpha-cypermethrin bioefficacy in Interceptor ® and Royal Guard ® will be monitored in WHO cone bioassays and tunnel tests using the susceptible Anopheles gambiae Kisumu strain. The bioefficacy of the non-pyrethroid insecticides (chlorfenapyr in Interceptor ® G2 and pyriproxyfen in Royal Guard ® ) will be monitored using the pyrethroid-resistant Anopheles coluzzii Akron strain. Chlorfenapyr activity will be assessed in tunnel tests while pyriproxyfen activity will be assessed in cone bioassays in terms of the reduction in fertility of blood-fed survivors observed by dissecting mosquito ovaries. Nets withdrawn at 12, 24 and 36 months will be tested in experimental hut trials within the cRCT study area against wild free-flying pyrethroid resistant An. gambiae sensu lato to investigate their superiority to Interceptor ® and to compare them to ITNs washed 20 times for experimental hut evaluation studies. Mechanistic models will also be used to investigate whether entomological outcomes with each dual ITN type in experimental hut trials can predict their epidemiological performance in the cRCT. Conclusion This study will provide information on the durability of two dual AI nets (Interceptor ® G2 and Royal Guard ® ) in Benin and will help identify suitable methods for monitoring the durability of their insecticidal activity under operational conditions. The modelling component will determine the capacity of experimental hut trials to predict the epidemiological performance of dual AI nets across their lifespan.

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 Spatial and temporal identification of malaria-endemic areas is a key component of vector-borne disease control. Strategies to target the most vulnerable populations, the periods of high transmission and the most affected geographical areas, should make vector-borne disease control and prevention programmes more cost-effective. The present study focuses on the spatial and temporal dynamics of malaria cases and the exogenous factors influencing the transmission in an area with pyrethroid-resistant mosquito vector populations. Methods A prospective cohort study of 1806 children under 10 years of age was conducted over 20 months to assess the risk of malaria incidence in the Cove-Zagnanado-Ouinhi (CoZO) health zone located in southern Benin. Childhood malaria data were used to identify malaria hotspots according to months of follow-up using spatial scanning methods based on the Kulldoff algorithm. Stability scores were calculated by season to assess incidence heterogeneity. Incidence values by month were aggregated with meteorological data; and demographic data were merged to detect cross-correlation between incidence and meteorological variables. Generalized equation estimators were chosen for their ability to handle intra-group correlation, ensuring robust and interpretable results despite the complexity of the data to identify factors explaining the spatio-temporal heterogeneity of malaria incidence in the CoZO health zone. Results Malaria incidence ranged from 1.41 (95% IC 0.96–2.08) to 13.91 (95% IC 12.22–15.84) cases per 100 child-months. Spatial heterogeneity in malaria transmission hotspots was observed over the study period, with relative risks ranging from 1.59 (p-value = 0.032) to 16.24 (p-value = 0.002). There was a significant negative association (correlation coefficient = − 0.56) between malaria incidence and temperature; and a slightly positive association (correlation coefficient = 0.58) between malaria incidence and rainfall. A significant association between malaria incidence with average house altitude (adjusted incidence rate ratio [aIRR] 1 (95% IC 0.99–1) P < 0.001), soil type aIRR 0.54 (0.39–0.75) p < 0.001 and temperature (incidence rate ratio [IRR] 0.69 (0.66–0.73) p < 0.001). Conclusion This study uses innovative technologies such as remote sensing and geographic information systems (GIS) to analyse the environmental, meteorological and geographical factors influencing malaria transmission, thereby identifying high-risk areas and associated factors. It demonstrates that these tools improve the accuracy of control strategies, while highlighting the crucial role of the environment and human behaviour, paving the way for more targeted interventions against malaria and other vector-borne diseases.

Severe anaemia is a critical public health issue worldwide, disproportionately affecting children in Africa, where approximately 40% of children aged 6 to 59 months are impacted. It leads to significant hospital and post-hospital complications. However, there is a notable lack of research on its burden and clinical impact, particularly in Benin, where existing data are outdated. This study aims to assess the prevalence and impact of severe anaemia in two areas of perennial transmission in southern Benin. We conducted a retrospective cross-sectional study at two referral hospitals in Benin, Lagune Mother and Child University Hospital Centre (CHU-MEL) and the Departmental Hospital Centre-Zou (CHD-Z). Sociodemographic, clinical and biological information were extracted from medical records of patients admitted to paediatric ward in 2023, using a standardised questionnaire. Clinical severe anaemia was defined as anaemia with decompensation requiring blood transfusion, and biological severe anaemia as haemoglobin < 5 g/dl. A total of 7152 paediatric hospital records were included in the analysis (CHU-MEL = 4388; CHD-Z = 2764). The median (IQR, range) age was 32 (13–61; 1–228) months. Severe malaria (N = 3653/7152 [51.1%]) and clinical severe anaemia (3586/7152 [50.1%]) were the most common diagnoses with four out of five children (2836/3586 [79.0%]) clinically diagnosed with severe anaemia cases had malaria. In children with severe anaemia, the risk of death decreased slightly with year of age (aOR 0.95, 95% CI 0.92–0.99, p  = 0.019). In contrast, severe malnutrition increased the risk of death (aOR 1.80, 95% CI 1.33–2.43, p  < 0.001) being significant risk factors. Severe anaemia is a major contributor to paediatric hospital admissions, with severe malaria being a leading cause in these regions. This study highlights the critical need for a comprehensive management strategy for severe anaemia, particularly in the youngest children. An integrated strategy of effective malaria chemoprevention, such as post-discharge malaria chemotherapy combined with targeted nutritional interventions, are essential to mitigate mortality rates in areas with high malaria transmission, where the dual burden of malaria and nutritional deficiencies exacerbates paediatric morbidity and mortality.

Background Accurate interpretation and recording of malaria rapid diagnostic tests (RDTs) are critical for case management and surveillance in malaria-endemic settings. In Benin, where over 90% of malaria diagnoses rely on RDTs, concerns remain about the accuracy of the reporting and recording of RDT results. This study assessed the fidelity of RDT recording by healthcare workers (HCWs) in public health facilities and explored associated factors. Methods A six-month mixed-methods, prospective observational study was conducted in 16 public health facilities across two departments in Benin. For each RDT performed, an image was captured using a digital RDT reader (HealthPulse, Audere, Seattle, WA USA) and independently interpreted by an external trained panel. HCW-recorded results were compared to panel interpretations. A knowledge, attitudes, practices, and beliefs (KAPB) survey and structured observations of RDT performance were conducted, alongside in-depth interviews with selected HCWs. Results Of 35,720 RDTs assessed, overall agreement between HCW and reference panel interpretations was 94.3% (Cohen’s kappa = 0.88). Results misrecorded as positive (5.0%) were more frequent than results misrecorded as negative (0.7%). Agreement varied by patient age, HCW experience, and facility characteristics. Accuracy was highest with children under 5 years (96.7%) and lowest with patients over 15 years (91.6%). HCWs with ≥ 10 years of experience, and access to electricity and internet performed better. From 226 HCWs surveyed, 89.4% believed a patient with malaria could have a negative RDT, though only 19.5% supported treating such cases with antimalarials. While most HCWs were proficient in performing RDTs, only 40.5% waited the recommended time before reading results, and glove use was low (15.6%) highlighting safety gaps. RDT use was primarily motivated by adherence to guidelines (60.2%), rather than patient or supervisor expectations. Qualitative interviews highlighted contextual challenges including workload, lighting conditions in health facilities, and resource constraints. Conclusion HCWs in Benin showed high accuracy in interpreting and reporting malaria RDT results, likely supported by recent nationwide RDT cassette validations. Performance was strongest among those with more experience, training, and adequate infrastructure. However, negative results misrecorded as positive, especially in adult patients, remains a concern. Targeted training and supportive supervision may help strengthen confidence in negative results and improve overall diagnostic accuracy.

Background Cluster-randomized controlled trials (cluster-RCTs) have demonstrated variation in the epidemiological efficacy of different next-generation insecticide-treated net (ITN) types, with some providing shorter-lived impact than others. Further studies are needed to assess changes in the insecticidal durability of these ITNs over time to complement cluster-RCT results. Methods A series of experimental hut trials were performed to evaluate the bioefficacy of new and field-aged next-generation ITNs (PermaNet ® 3.0, Royal Guard ® , Interceptor ® G2) compared to a pyrethroid-only net (Interceptor ® ) against pyrethroid-resistant malaria vectors in Covè, southern Benin. Field-aged nets were withdrawn from households at 12, 24 and 36 months. Net pieces cut from whole ITNs were analysed for chemical content, and susceptibility bioassays were performed during each trial to assess changes in insecticide resistance in the Covè vector population. Results Interceptor ® G2 induced superior mosquito mortality than the other ITNs across all time points. The improved mortality with Interceptor ® G2 compared to Interceptor ® was evident across all time points but was greater with new nets (odds ratio (OR) = 8.6, 95% CI [7.4, 10.1]) than field-aged nets (OR = 2.5, 95% CI [1.8, 3.5] at 12 months, OR = 2.4, 95% CI [1.6, 3.7] at 24 months and OR = 2.9, 95% CI [1.6, 5.1] at 36 months). New Royal Guard ® reduced mosquito fertility compared to the other ITNs, but this improvement fell after field-ageing, particularly at 24 months when it was similar to Interceptor ® (11% vs 3%, p = 0.08). When new, mortality was significantly higher with PermaNet ® 3.0 compared to Interceptor ® (OR = 3.6, 95% CI [3.0, 4.2]); however, this benefit was lost with field-aged nets at 12 months (OR = 1.1, 95% CI [0.8, 1.5]) and 24 months (OR = 0.6, 95% CI [0.4, 0.9]). Retention of the non-pyrethroid compound in next-generation nets was low after 36 months (27% for PermaNet ® 3.0, 26% for Royal Guard ® and 15% for Interceptor ® G2). Conclusions Interceptor ® G2 outperformed the other ITNs, confirming the superiority of pyrethroid-chlorfenapyr nets over other net types. When new, all next-generation ITNs showed superior bioefficacy compared to Interceptor ® ; however, the size of this improvement fell after field-ageing due to poor durability of the non-pyrethroid compound. These findings emphasize the need to enhance the insecticidal durability of next-generation ITNs.

Cluster randomised trials (CRTs) are important tools for evaluating the community-wide effect of malaria interventions. During the design stage, CRT sample sizes need to be inflated to account for the cluster heterogeneity in measured outcomes. The coefficient of variation (k), a measure of such heterogeneity, is typically used in malaria CRTs yet is often predicted without prior data. Underestimation of k decreases study power, thus increases the probability of generating null results. In this meta-analysis of cluster-summary data from 24 malaria CRTs, we calculate true prevalence and incidence k values using methods-of-moments and regression modelling approaches. Using random effects regression modelling, we investigate the impact of empirical k values on original trial power and explore factors associated with elevated k. Results show empirical estimates of k often exceed those used in sample size calculations, which reduces study power and effect size precision. Elevated k values are associated with incidence outcomes (compared to prevalence), lower endemicity settings, and uneven intervention coverage across clusters. Study findings can enhance the robustness of future malaria CRT sample size calculations by providing informed k estimates based on expected prevalence or incidence, in the absence of cluster-level data. This meta-analysis of malaria cluster trials highlights that underestimating between-cluster variation reduces statistical power. It provides refined coefficient of variation estimates to inform sample size calculations for future evaluations.

The present cluster-randomised control trial aims to assess the entomological efficacy of pyrethroid-pyriproxyfen and pyrethroid-chlorfenapyr LLINs compared to the standard pyrethroid-only LLINs, in their third year of community usage. Adult mosquito collections were performed every 3 months, in 4 randomly selected houses in each of the 60 trial clusters, using human landing catches. Adult mosquitoes were morphologically identified and Anopheles vectors were molecularly speciated and screened for the presence of the L1014F kdr mutation using PCR. Plasmodium falciparum sporozoite infection was assessed using ELISA. A subset of An. gambiae s.l. was also dissected to examine parity and fertility rates across study arms. There was no evidence of a significant reduction in indoor vector density and entomological inoculation rate by the pyrethroid-pyriproxyfen [DR 0.94 (95% CI 0.46–1.88), p = 0.8527; and RR 1.10 (95% CI 0.44–2.72), p = 0.8380], and pyrethroid-chlorfenapyr [DR 0.74 (95% CI 0.37–1.48), p = 0.3946; and RR 1.00 (95% CI 0.40–2.50), p = 0.9957] LLINs, respectively. The same trend was observed outdoors. Frequencies of the L1014F kdr mutation, as well as parous and fertility rates, were similar between study arms. In the third year after net distribution, entomological indicators show that the two dual active-ingredients nets performed similarly to the standard pyrethroid-only LLIN. To maintain malaria gains, it is crucial that net distribution cycles fit with their operational lifespan.

Background Pregnant women are a vulnerable population to COVID-19 given an increased susceptibility to severe SARS-CoV-2 infection and pregnancy complications. However, few SARS-CoV-2 serological surveys have been performed among this population to assess the extent of the infection in sub-Saharan countries. The objectives of this study were to determine SARS-CoV-2 seroprevalence among Beninese pregnant women, to identify spatial seropositivity clusters and to analyse factors associated with the infection. Methods A cross-sectional study including women in their third trimester of pregnancy attending the antenatal care (ANC) clinics at Allada (south Benin) and Natitingou (north Benin) was conducted. Rapid diagnostic tests (RDT) for detection of IgG/IgM against the SARS-CoV-2 spike protein were performed using capillary blood. Seroprevalence of SARS-CoV-2 antibodies and associations between SARS-CoV-2 serostatus and maternal characteristics were analyzed by multivariate logistic regression. Spatial analyses were performed using the spatial scan statistics to identify spatial clusters of SARS-CoV-2 infection. Results A total of 861 pregnant women were enrolled between May 4 and June 29, 2022. 58/861 (6.7%) participants reported having received COVID-19 vaccine. None of the participants had been diagnosed with COVID-19 during their pregnancy. SARS-CoV-2 antibodies were detected in 607/802 (75.7%; 95% CI 72.56%–78.62%) of unvaccinated participants. Several urban and rural spatial clusters of SARS-CoV-2 cases were identified in Allada and one urban spatial cluster was identified in Natitingou. Unvaccinated participants from Allada with at least one previous morbidity were at a three-times higher risk of presenting SARS-CoV-2 antibodies (OR = 2.89; 95%CI 1.19%-7.00%). Conclusion Three out of four pregnant women had SARS-CoV-2 antibodies, suggesting a high virus circulation among pregnant women in Benin, while COVID-19 vaccination coverage was low. Pregnant women with comorbidities may be at increased risk of SARS-CoV-2 infection. This population should be prioritized for COVID-19 diagnosis and vaccination in order to prevent its deleterious effects. Trial registration NCT06170320 (retrospectively registered on December 21, 2023).