Advancing spatial repellents for malaria control: effectiveness and cost-effectiveness of a spatial repellent under operational use in Northern Uganda-study protocol for a cluster randomized controlled trial.

BACKGROUND: Spatial repellents (SRs) have been widely used for the prevention of mosquito bites, and preliminary findings suggest efficacy against both malaria (1) and Aedes-borne viruses (2) but their effectiveness in reducing mosquito-borne diseases under operational use has never been evaluated. SRs have the potential of being critical tools in the prevention of mosquito-borne diseases in contexts where typical vector control strategies, such as insecticide-treated nets (ITNs) and indoor residual spraying, are inaccessible or underutilized such as among displaced persons or in emergency relief settings. METHODS: Children will be enrolled in 3 separate cohorts to establish the effectiveness of SRs in reducing malaria infection in different distribution channels. One cohort will estimate the direct effect of the SR distributed through a reference channel (study personnel distribution). The two remaining cohorts will estimate the protection of the SR distributed through a voucher channel and the Village Health Team channel. Cohorts will be followed twice a month (approximately every 15 days): during the first scheduled household visit in the month, a blood sample will be taken for malaria rapid diagnostic test (Monthly Visit #1); and, during the second scheduled household visit, a blood sample will only be taken if the participant has a recent history of fever (Monthly Visit #2). The incidence of malaria in each cohort will be estimated and compared to the reference cohort to determine the benefit of using a SR in an area with high, year-round transmission of malaria. DISCUSSION: This study will address the knowledge gap of whether or not SRs are effective in reducing human malaria disease in humanitarian assistance and emergency response settings in sub-Saharan Africa where underlying transmission rates are historically high and ITNs may or may not be widely deployed. This research will inform policy makers on whether to recommend SRs as a means to further reduce malaria transmission for such operational programs. TRIAL REGISTRATION: ClinicalTrials.gov NCT06122142. Registered on November 8, 2023.

Evaluating human landing catches as a measure of mosquito biting and the importance of considering additional modes of action.

Entomological evaluations of vector control tools often use human landing catches (HLCs) as a standard measure of a direct human-vector contact. However, some tools have additional characteristics, such as mortality, and HLCS are not sensitive for measuring other effects beyond landing inhibition. Therefore, additional measures may need to be considered when evaluating these tools for public health use. This study has two main aims (1) the evaluate the accuracy of HLCs as a proxy for feeding and (2) to compare the predicted reduction in vectorial capacity when we do and do not consider these additional characteristics. To achieve this, we analyse previously published semi-field data from an experiment which used HLCs and another where mosquitoes were allowed to feed in the presence of different dosages of the volatile pyrethroid spatial repellent, transfluthrin. We compare results for two mathematical models: one which only considers the reduction in feeding effect and one which also considers mortality before and after feeding (using data gathered by the aspiration of mosquitoes after the semi-field feeding/landing period and 24 h survival monitoring). These Bayesian hierarchical models are parameterised using Bayesian inference. We observe that, for susceptible mosquitoes, reduction in landing is underestimated by HLCs. For knockdown resistant mosquitoes the relationship is less clear; with HLCs sometimes appearing to overestimate this characteristic. We find HLCs tend to under-predict the relative reduction in vectorial capacity in susceptible mosquitoes while over-predicting this impact in knockdown-resistant mosquitoes. Models without secondary effects have lower predicted relative reductions in vectorial capacities. Overall, this study highlights the importance of considering additional characteristics to reduction in biting of volatile pyrethroid spatial repellents. We recommend that these are considered when evaluating novel vector control tools.

Point Protection with Transfluthrin against Musca domestica L. in a Semi-Field Enclosure.

House flies are notoriously difficult to control, owing to their tendency to live in close relationships with humans and their livestock, and their rapid development of resistance to chemical controls. With this in mind, we explored an alternative chemical control, a spatial repellent to deter Musca domestica L. from points we wanted to protect (i.e., a baited trap). Our results demonstrated that the synthetic spatial repellent, transfluthrin, is effective in preventing M. domestica adults from entering protected traps for both a susceptible strain (CAR21) and a field-acquired permethrin-resistant strain (WHF; 24 h LD50 resistance ratio of 150), comprising 22% and 28% of the total number of flies collected, respectively. These results are promising and demonstrate that transfluthrin can be an effective spatial repellent to protect points of interest where needed.

Experimental hut and field evaluation of a metofluthrin-based spatial repellent against pyrethroid-resistant Anopheles funestus in Siaya County, western Kenya.

BACKGROUND: Spatial repellents (SR) may complement current vector control tools and provide additional coverage when people are not under their bednets or are outdoors. Here we assessed the efficacy of a metofluthrin-based SR in reducing exposure to pyrethroid-resistant Anopheles funestus in Siaya County, western Kenya. METHODS: Metofluthrin was vaporized using an emanator configured to a liquid petroleum gas (LPG) canister, placed inside experimental huts (phase 1) or outdoors (phase 2), and evaluated for reductions in human landing rate, density, knockdown and mortality rates of An. funestus, which are present in high density in the area. To demonstrate the mosquito recruiting effect of LPG, a hut with only an LPG cooker but no metofluthrin was added as a comparator and compared with an LPG cooker burning alongside the emanator and a third hut with no LPG cooker as control. Phase 2 evaluated the protective range of the SR product while emanating from the centre of a team of mosquito collectors sitting outdoors in north, south, east and west directions at 5, 10 and 20 feet from the emanating device. RESULTS: Combustion of LPG with a cook stove increased the density of An. funestus indoors by 51% over controls with no cook stove. In contrast, huts with metofluthrin vaporized with LPG combustion had lower indoor density of An. funestus (99.3% less than controls), with knockdown and mortality rates of 95.5 and 87.7%, respectively, in the mosquitoes collected in the treated huts. In the outdoor study (phase 2), the outdoor landing rate was significantly lower at 5 and 10 feet than at 20 feet from the emanator. CONCLUSIONS: Vaporized metofluthrin almost completely prevented An. funestus landing indoors and led to 10 times lower landing rates within 10 feet of the emanator outdoors, the first product to demonstrate such potential. Cooking with LPG inside the house could increase exposure to Anopheles mosquito bites, but the use of the metofluthrin canister eliminates this risk.

Transfluthrin diffusers do not protect two-person US military tents from mosquitoes in open field and canopy warm-temperate habitats.

Spatial repellents are volatile or volatilized chemicals that may repel arthropod vectors in free space, preventing bites and reducing the potential for pathogen transmission. In a 21-week field study, we investigated the efficacy of passive transfluthrin-impregnated diffusers placed in two-person United States (US) military tents located in canopy and open field habitats in north Florida to prevent mosquitoes from entering. Mosquito collections with US Centers for Disease Control and Prevention traps baited with light and carbon dioxide were conducted weekly for weeks 0-4, every two weeks for weeks 5-10, and monthly for weeks 11-21. Our results demonstrated that these transfluthrin-impregnated devices did not function as spatial repellents as expected and did not create a mosquito-free zone of protection. Instead, we observed consistently higher collections of mosquitoes from tents with transfluthrin-impregnated diffusers, and higher rates of mosquito mortality in collections from tents with transfluthrin diffusers, compared to untreated control tents. Based on these findings we do not recommend the use of passive transfluthrin-impregnated diffusers for mosquito protection in two-person US military tents in warm-temperate environments similar to north Florida.

Inference for entomological semi-field experiments: Fitting a mathematical model assessing personal and community protection of vector-control interventions.

The effectiveness of vector-control tools is often assessed by experiments as a reduction in mosquito landings using human landing catches (HLCs). However, HLCs alone only quantify a single characteristic and therefore do not provide information on the overall impacts of the intervention product. Using data from a recent semi-field study which used time-stratified HLCs, aspiration of non-landing mosquitoes, and blood feeding, we suggest a Bayesian inference approach for fitting such data to a stochastic model. This model considers both personal protection, through a reduction in biting, and community protection, from mosquito mortality and disarming (prolonged inhibition of blood feeding). Parameter estimates are then used to predict the reduction of vectorial capacity induced by etofenpox-treated clothing, picaridin topical repellents, transfluthrin spatial repellents and metofluthrin spatial repellents, as well as combined interventions for Plasmodium falciparum malaria in Anopleles minimus. Overall, all interventions had both personal and community effects, preventing biting and killing or disarming mosquitoes. This led to large estimated reductions in the vectorial capacity, with substantial impact even at low coverage. As the interventions aged, fewer mosquitoes were killed; however the impact of some interventions changed from killing to disarming mosquitoes. Overall, this inference method allows for additional modes of action, rather than just reduction in biting, to be parameterised and highlights the tools assessed as promising malaria interventions.

Repellency and Toxicity of Vapor-Active Benzaldehydes against Aedes aegypti.

Chemical screening efforts recently found that 3-phenoxybenzaldehyde, a breakdown product of alpha-cyano pyrethroids, was a potent spatial repellent against Aedes aegypti mosquitoes in a glass tube repellency assay. In order to characterize this molecule further and identify structure-activity relationships, a set of 12 benzaldehyde analogues were screened for their repellency and toxicity in vapor phase exposures at 100 µg/cm2. Dose-response analyses were performed for the most active compounds in order to better characterize their repellent potency and toxicity compared to those of other commercially available toxicants. The three most toxic compounds (LC50 values) were 3-chlorobenzaldehyde (CBA) (37 µg/cm2), biphenyl-3-carboxaldehyde (BCA) (48 µg/cm2), and 3-vinylbenzaldehyde (66 µg/cm2), which makes them less toxic than bioallethrin (6.1 µg/cm2) but more toxic than sandalwood oil (77 µg/cm2), a repellent/toxic plant essential oil. The most repellent analogues with EC50 values below 30 µg/cm2 were 3-phenoxybenzaldehyde (6.3 µg/cm2), isophthalaldehyde (23 µg/cm2), BCA (17 µg/cm2), and CBA (22 µg/cm2), which makes them about as active as N,N-diethyl-3-methylbenzamide (25.4 µg/cm2). We further investigated the activity of a select group of these benzaldehydes to block the firing of the central nervous system of A. aegypti larvae. Compounds most capable of repelling and killing mosquitoes in the vapor phase were also those most capable of blocking nerve firing in the larval mosquito nervous system. The results demonstrate that benzaldehyde analogues are viable candidate repellent and insecticidal molecules and may lead to the development of future repellent and vapor toxic vector control tools.

Applying the COM-B behaviour change model to a pilot study delivering volatile pyrethroid spatial repellents and insecticide-treated clothing to forest-exposed populations in Mondulkiri Province, Cambodia.

BACKGROUND: Southeast Asia is making tremendous progress towards their 2030 malaria elimination goal but needs new interventions to stop forest malaria. This study trials two new vector control tools, a volatile pyrethroid spatial repellent (VPSR) and insecticide-treated clothing (ITC), amongst forest-exposed populations in Mondulkiri Province Cambodia to inform their potential use for eliminating forest malaria. METHODS: 21 forest-exposed individuals were given a questionnaire on their perceptions of malaria and preventive practices used, after which they trialed two products sequentially. Clothes was treated with ITC by the study team. Mixed methods were used to understand their experience, attitudes, and preferences regarding the products trialed. Quantitative data was summarized and qualitative insights were analysed using thematic analysis, applying the Capability, Opportunity, and Motivation Behaviour Change (COM-B) model and Behaviour Change Wheel Framework to identify intervention functions to support tailored product rollout amongst these populations. RESULTS: Study participants reported a need for protection from mosquito bites in outdoor and forest-exposed settings and perceived both products trialed to be effective for this purpose. The VPSR product was preferred when travel was not required, whereas ITC was preferred for ease of use when going to the forest, especially in rainy conditions. COM-B analysis identified that key enablers for use of both products included their perceived efficacy and ease of use, which required no skill or preparation. For barriers to use, the odour of ITC was sometimes perceived as being toxic, as well as its inability to protect uncovered skin from mosquito bites, while the perceived usefulness of the VPSR product trialed was limited by its water sensitivity in rainy forest settings. Intervention components to encourage appropriate and sustained use of these products include education about how to use these products and what to expect, persuasion to use them from community leaders and targeted channels, and enablement to facilitate convenient and affordable access. CONCLUSION: The rollout of VPSRs and ITC amongst forest-exposed populations can be useful for eliminating malaria in Southeast Asia. Study findings can be applied to increase product uptake among forest exposed populations in Cambodia, while manufacturers can aim to develop products that are rainproof, easy to use in forest settings, and have favourable odour profiles to target users.

Transfluthrin and Metofluthrin as Effective Repellents against Pyrethroid-Susceptible and Pyrethroid-Resistant Aedes aegypti (L.) (Diptera: Culicidae).

Aedes aegypti is a major vector of dengue fever in tropical regions. Spatial repellents (SRs) have shown promise in delaying pesticide resistance. Methods for discriminating concentrations (DCs) are well established using various bioassay tools, while data for high-throughput screening system (HITSS) toxicity bioassay (TOX) are absent. In this study, we compared and optimized lethal (LCs) and sub-lethal concentrations (SLCs) of transfluthrin (TFT) and metofluthrin (MFT) on pyrethroid-susceptible (USDA) and pyrethroid-resistant (Pu-Teuy) Ae. aegypti (L.) strains, using the HITSS-TOX. Mean mortality (MT) was 100% at LC99 and DC, compared to LC50 (45.0 ± 3.7%) and LC75 (65.8 ± 7.0%) for the USDA strain. However, the resistant strain (Pu-Teuy) showed reduced susceptibility against TFT and a significantly lower MT at LC50 (12.5 ± 4.4%; t = 5.665, df = 10, p < 0.001), LC75 (9.2 ± 3.5%; t = 4.844, df = 10, p = 0.001), LC99 (55.0 ± 9.9%; t = 4.538, df = 5, p = 0.006), and DC (75.0 ± 5.2%; U = 3.0, p = 0.007). The DC of TFT (0.15222%) was 4.7-fold higher than for MFT (0.03242%) in USDA strain. The baseline DCs established are useful to better understand susceptibility and the efficacy of various repellents against field populations of Ae. aegypti.

Efficacy of the spatial repellent product Mosquito Shield™ against wild pyrethroid-resistant Anopheles arabiensis in south-eastern Tanzania.

BACKGROUND: Spatial repellents that create airborne concentrations of an active ingredient (AI) within a space offer a scalable solution to further reduce transmission of malaria, by disrupting mosquito behaviours in ways that ultimately lead to reduced human-vector contact. Passive emanator spatial repellents can protect multiple people within the treated space and can last for multiple weeks without the need for daily user touchpoints, making them less intrusive interventions. They may be particularly advantageous in certain use cases where implementation of core tools may be constrained, such as in humanitarian emergencies and among mobile at-risk populations. The purpose of this study was to assess the efficacy of Mosquito Shield™ deployed in experimental huts against wild, free-flying, pyrethroid-resistant Anopheles arabiensis mosquitoes in Tanzania over 1 month. METHODS: The efficacy of Mosquito Shield™ transfluthrin spatial repellent in reducing mosquito lands and blood-feeding was evaluated using 24 huts: sixteen huts were allocated to Human Landing Catch (HLC) collections and eight huts to estimating blood-feeding. In both experiments, half of the huts received no intervention (control) while the remaining received the intervention randomly allocated to huts and remained fixed for the study duration. Outcomes measured were mosquito landings, blood-fed, resting and dead mosquitoes. Data were analysed by multilevel mixed effects regression with appropriate dispersion and link function accounting for volunteer, hut and day. RESULTS: Landing inhibition was estimated to be 70% (57-78%) [IRR 0.30 (95% CI 0.22-0.43); p < 0.0001] and blood-feeding inhibition was estimated to be 69% (56-79%) [IRR 0.31 (95% CI 0.21-0.44; p < 0.0001] There was no difference in the protective efficacy estimates of landing and blood-feeding inhibition [IRR 0.98 (95% CI 0.53-1.82; p = 0.958]. CONCLUSIONS: This study demonstrated that Mosquito Shield™ was efficacious against a wild pyrethroid-resistant strain of An. arabiensis mosquitoes in Tanzania for up to 1 month and could be used as a complementary or stand-alone tool where gaps in protection offered by core malaria vector control tools exist. HLC is a suitable technique for estimating bite reductions conferred by spatial repellents especially where direct blood-feeding measurements are not practical or are ethically limited.

CDC light traps underestimate the protective efficacy of an indoor spatial repellent against bites from wild Anopheles arabiensis mosquitoes in Tanzania.

BACKGROUND: Methods for evaluating efficacy of core malaria interventions in experimental and operational settings are well established but gaps exist for spatial repellents (SR). The objective of this study was to compare three different techniques: (1) collection of blood-fed mosquitoes (feeding), (2) human landing catch (HLC), and (3) CDC light trap (CDC-LT) collections for measuring the indoor protective efficacy (PE) of the volatile pyrethroid SR product Mosquito Shield™ METHODS: The PE of Mosquito Shield™ against a wild population of pyrethroid-resistant Anopheles arabiensis mosquitoes was determined via feeding, HLC, or CDC-LT using four simultaneous 3 by 3 Latin squares (LS) run using 12 experimental huts in Tanzania. On any given night each technique was assigned to two huts with control and two huts with treatment. The LS were run twice over 18 nights to give a sample size of 72 replicates for each technique. Data were analysed by negative binomial regression. RESULTS: The PE of Mosquito Shield™ measured as feeding inhibition was 84% (95% confidence interval (CI) 58-94% [Incidence Rate Ratio (IRR) 0.16 (0.06-0.42), p < 0.001]; landing inhibition 77% [64-86%, (IRR 0.23 (0.14-0.36) p < 0.001]; and reduction in numbers collected by CDC-LT 30% (0-56%) [IRR 0.70 (0.44-1.0) p = 0.160]. Analysis of the agreement of the PE measured by each technique relative to HLC indicated no statistical difference in PE measured by feeding inhibition and landing inhibition [IRR 0.73 (0.25-2.12) p = 0.568], but a significant difference in PE measured by CDC-LT and landing inhibition [IRR 3.13 (1.57-6.26) p = 0.001]. CONCLUSION: HLC gave a similar estimate of PE of Mosquito Shield™ against An. arabiensis mosquitoes when compared to measuring blood-feeding directly, while CDC-LT underestimated PE relative to the other techniques. The results of this study indicate that CDC-LT could not effectively estimate PE of the indoor spatial repellent in this setting. It is critical to first evaluate the use of CDC-LT (and other tools) in local settings prior to their use in entomological studies when evaluating the impact of indoor SR to ensure that they reflect the true PE of the intervention.

A cluster-randomized, placebo-controlled trial to evaluate the efficacy of a spatial repellent (Mosquito Shield™) against Aedes-borne virus infection among children ≥ 4-16 years of age in the Gampaha District, Sri Lanka: study protocol (the AEGIS program).

BACKGROUND: Spatial repellents (SRs) have been widely used for prevention of mosquito bites, but their efficacy in reducing Aedes-borne viruses (ABV) has not been tested rigorously at large scale in Asia. To address this knowledge gap, a trial to evaluate the efficacy of Mosquito Shield™, a transfluthrin SR, was developed in Gampaha District of Sri Lanka across three Medical Officer of Health areas; i.e., Negombo, Wattala, and Kelaniya. METHODS: This trial is a cluster-randomized, placebo-controlled, double-blinded clinical trial. A total of ~14,430 subjects aged ≥ 6 months in 30 clusters (15 intervention, 15 placebo) from ~3900 households (HH) will be randomly selected for enrolment into a "febrile surveillance cohort." A subset of the surveillance cohort, ~3570 subjects aged ≥4-16 years that test seronegative (naïve) or are serologically positive for a previous single dengue virus (DENV) infection (monotypic) at baseline sampling, will be enrolled into a "longitudinal cohort" for measuring DENV infection based on laboratory-confirmed seroconversion during the trial. Persons identified positive for antibodies against multiple DENV serotypes (multitypic) at baseline will be monitored for secondary analyses. Active ABV disease will be assessed using an enhanced passive surveillance system with case ascertainment performed in designated healthcare facilities. Serum samples will be taken from longitudinal cohort subjects within 1-2 weeks of when intervention is first deployed (T0) with additional samples taken ~12 (T1) and ~24 months (T2) from baseline sampling. DENV seroconversion and ABV active disease rates from baseline (pre-intervention) and follow-up (post-intervention) samples will be compared between intervention and placebo clusters. Participating houses will be monitored entomologically (indoor adult Aedes aegypti population densities and adult female blood fed status) within 3 months before intervention deployment and monthly during the intervention phase. Entomological surveys will monitor indoor adult Ae. aegypti population densities and blood fed status. Dengue incidence in each cohort will be estimated and compared to determine the public health benefit of using an SR. Entomological parameters will be measured to determine if there are entomological correlates of SR efficacy that may be useful for the evaluation of new SR products. DISCUSSION: The trial will serve as an efficacy assessment of SR products in South Asia. Results will be submitted to the World Health Organization Vector Control Advisory Group for assessment of public health value towards an endorsement to recommend inclusion of SRs in ABV control programs. TRIAL REGISTRATION: Sri Lanka Clinical Trial Registry SLCTR /2022/018. Registered on July 1, 2022. CLINICALTRIALS: gov NCT05452447 . Registered on July 11, 2022. The Universal Trial Number is U1111-1275-3055.

Field Evaluation of Novel Spatial Repellent Controlled Release Devices (CRDs) against Mosquitoes in an Outdoor Setting in the Northern Peruvian Amazon.

U.S. military troops are exposed to mosquito-borne pathogens when deployed to endemic regions. Personal protective measures such as permethrin-treated uniforms and dermal repellents are the cornerstones of mosquito-borne disease prevention for the U.S. military. These measures have limitations and additional personal protection tools, such as spatial repellent devices to decrease the risk of vector-borne pathogen transmission, are required. Novel spatial repellent controlled-release devices formulated with metofluthrin were evaluated in an outdoor setting in the northern Amazon of Peru to evaluate performance under field conditions. The metofluthrin emitting devices lowered the number of mosquitoes captured in protected human landing collections (HLC) compared to blank devices, although there were effect differences between Anopheles spp. and species in other mosquito genera. A computational-experimental model was developed to correlate HLC and active ingredient (AI) concentrations as a function of time and space. Results show a strong correlation between the released AI and the decrease in HLC. This model represents the first effort to obtain a predictive analytical tool on device performance using HLC as the entomological endpoint.

Use of mobile data collection systems within large-scale epidemiological field trials: findings and lessons-learned from a vector control trial in Iquitos, Peru.

Vector-borne diseases are among the most burdensome infectious diseases worldwide with high burden to health systems in developing regions in the tropics. For many of these diseases, vector control to reduce human biting rates or arthropod populations remains the primary strategy for prevention. New vector control interventions intended to be marketed through public health channels must be assessed by the World Health Organization for public health value using data generated from large-scale trials integrating epidemiological endpoints of human health impact. Such phase III trials typically follow large numbers of study subjects to meet necessary power requirements for detecting significant differences between treatment arms, thereby generating substantive and complex datasets. Data is often gathered directly in the field, in resource-poor settings, leading to challenges in efficient data reporting and/or quality assurance. With advancing technology, mobile data collection (MDC) systems have been implemented in many studies to overcome these challenges. Here we describe the development and implementation of a MDC system during a randomized-cluster, placebo-controlled clinical trial evaluating the protective efficacy of a spatial repellent intervention in reducing human infection with Aedes-borne viruses (ABV) in the urban setting of Iquitos, Peru, as well as the data management system that supported it. We discuss the benefits, remaining capacity gaps and the key lessons learned from using a MDC system in this context in detail.

Less is more: repellent-treated fabric strips as a substitute for full screening of open eave gaps for indoor and outdoor protection from malaria mosquito bites.

BACKGROUND: Providing protection from malaria vector bites, both indoors and outdoors, is crucial to curbing malaria parasite transmission. Screening of house entry points, especially with incorporated insecticides, confers significant protection but remains a costly and labour-intensive application. Use of spatial repellents has shown promise in creating areas of protection in peri-domestic areas. METHODS: This study aimed at comparing the protection provided by transfluthrin-treated and untreated complete screens over open eave gaps with incomplete transfluthrin-treated eave strips as a potential replacement for a full screen. Human landing catches were implemented independently inside and outside an experimental hut under controlled semi-field conditions, with insectary-reared Anopheles arabiensis mosquitoes. RESULTS: The odds of a female mosquito finding a human volunteer indoors and attempting to bite were similar whether the eaves were completely open or there was an untreated fabric strip fixed around the eaves. However, when the eave gap was completely screened without insecticide, the odds of receiving a bite indoors were reduced by 70% (OR 0.30, 95% CI 0.20-0.47). Adding transfluthrin to the full screen, further increased the protection indoors, with the odds of receiving a bite reduced by 92% (0.08, 95% CI 0.04-0.16) compared to the untreated screen. Importantly, the same protection was conferred when only a narrow transfluthrin-treated fabric strip was loosely fixed around the eave gap (OR 0.07, 95% CI 0.04-0.13). The impact of the transfluthrin treatment on outdoor biting was correlated with evening temperatures during the experiments. At lower evening temperatures, a transfluthrin-treated, complete screen provided moderate and variable protection from bites (OR 0.62, 95% CI 0.37-1.03), whilst at higher evening temperatures the odds of receiving a bite outdoors was over four times lower in the presence of transfluthrin, on either a full screen (OR 0.22 95% 0.12-0.38) or a fabric strip (OR 0.25, 95% 0.15-0.42), than when no treatment was present. CONCLUSION: The findings suggest that transfluthrin-treated fabric strips can provide a substitute for complete eave screens. They are a simple, easy-to-handle tool for protecting people from malaria mosquito bites indoors and potentially around the house in climatic areas where evening and night-time temperatures are relatively high.

Impact of a spatial repellent product on Anopheles and non-Anopheles mosquitoes in Sumba, Indonesia.

BACKGROUND: The East Nusa Tenggara province, Indonesia, contributed to 5% of malaria cases nationally in 2020, with other mosquito-borne diseases, such as dengue and filariasis also being endemic. Monitoring of spatial and temporal vector species compositions and bionomic traits is an efficient method for generating evidence towards intervention strategy optimization and meeting disease elimination goals. METHODS: The impact of a spatial repellent (SR) on human biting mosquitoes was evaluated as part of a parent cluster-randomized, double-blinded, placebo-controlled trial, in Sumba, East Nusa Tenggara. A 10-month (June 2015-March 2016) baseline study was followed by a 24-month intervention period (April 2016 to April 2018)-where half the clusters were randomly assigned either a passive transfluthrin emanator or a placebo control. RESULTS: Human-landing mosquito catches documented a reduction in landing rates related to the SR. Overall, there was a 16.4% reduction (21% indoors, and 11.3% outdoors) in human biting rates (HBR) for Anopheles. For Aedes, there was a 44.3% HBR reduction indoors and a 35.6% reduction outdoors. This reduction was 38.3% indoors and 39.1% outdoors for Armigeres, and 36.0% indoors and 32.3% outdoors for Culex species. Intervention impacts on the HBRs were not significant and are attributed to large inter-household and inter cluster variation. Anopheles flavirostris, Anopheles balabacensis and Anopheles maculatus individually impacted the overall malaria infections hazard rate with statistically significance. Though there was SR-based protection against malaria for all Anopheles species (except Anopheles sundaicus), only five (Anopheles aconitus, Anopheles kochi, Anopheles tessellatus, An. maculatus and An. sundaicus) demonstrated statistical significance. The SR numerically reduced Anopheles parity rates indoors and outdoors when compared to the placebo. CONCLUSION: Evidence demonstrating that Anopheles vectors bite both indoors and outdoors indicates that currently implemented indoor-based vector control tools may not be sufficient to eliminate malaria. The documented impact of the SR intervention on Aedes, Armigeres and Culex species points to its importance in combatting other vector borne diseases. Studies to determine the impact of spatial repellents on other mosquito-borne diseases is recommended.

Efficacy of a spatial repellent for control of Aedes-borne virus transmission: A cluster-randomized trial in Iquitos, Peru.

Over half the world's population is at risk for viruses transmitted by Aedes mosquitoes, such as dengue and Zika. The primary vector, Aedes aegypti, thrives in urban environments. Despite decades of effort, cases and geographic range of Aedes-borne viruses (ABVs) continue to expand. Rigorously proven vector control interventions that measure protective efficacy against ABV diseases are limited to Wolbachia in a single trial in Indonesia and do not include any chemical intervention. Spatial repellents, a new option for efficient deployment, are designed to decrease human exposure to ABVs by releasing active ingredients into the air that disrupt mosquito-human contact. A parallel, cluster-randomized controlled trial was conducted in Iquitos, Peru, to quantify the impact of a transfluthrin-based spatial repellent on human ABV infection. From 2,907 households across 26 clusters (13 per arm), 1,578 participants were assessed for seroconversion (primary endpoint) by survival analysis. Incidence of acute disease was calculated among 16,683 participants (secondary endpoint). Adult mosquito collections were conducted to compare Ae. aegypti abundance, blood-fed rate, and parity status through mixed-effect difference-in-difference analyses. The spatial repellent significantly reduced ABV infection by 34.1% (one-sided 95% CI lower limit, 6.9%; one-sided P value = 0.0236, z = 1.98). Aedes aegypti abundance and blood-fed rates were significantly reduced by 28.6 (95% CI 24.1%, ∞); z = -9.11) and 12.4% (95% CI 4.2%, ∞); z = -2.43), respectively. Our trial provides conclusive statistical evidence from an appropriately powered, preplanned cluster-randomized controlled clinical trial of the impact of a chemical intervention, in this case a spatial repellent, to reduce the risk of ABV transmission compared to a placebo.

Evaluation of the protective efficacy of a spatial repellent to reduce malaria incidence in children in Mali compared to placebo: study protocol for a cluster-randomized double-blinded control trial (the AEGIS program).

BACKGROUND: Spatial repellents have been widely used for the prevention of mosquito bites but their efficacy in reducing mosquito-borne diseases has never been evaluated in Africa. Additionally, spatial repellents have the potential of being critical tools in the prevention of mosquito-borne diseases in contexts where typical vectors control efforts such as insecticide-treated nets (ITNs) and indoor residual spray (IRS) are inaccessible or underutilized such as among displaced populations or in emergency relief settings. To address this knowledge gap, Kolondieba District, Sikasso Region, Mali was selected as a site to estimate the impact of the Mosquito Shield™, a spatial repellent that incorporates transfluthrin on a plastic sheet, on malaria-related outcomes. Over the past decade, the Region of Sikasso, Health districts of Kadiolo, Yorosso, and Kolondieba have remained among the most afflicted, characterized by an annual parasite incidence of more than 116 cases per 1000 population [1] and a Plasmodium falciparum prevalence rate of 29.7% [2]. METHODS: Cluster-randomized, placebo-controlled, double-blinded clinical trial, whereby children ≥ 6 months to < 10 years old will be enrolled and followed to determine the time to malaria infection with monthly blood samples for microscopic diagnosis. A total of 1920 subjects (HHs) will be enrolled in 60 clusters (30 spatial repellent, 30 placebo). Malaria incidence will be estimated and compared to demonstrate and quantify the protective efficacy (PE) of a spatial repellent, in reducing malaria infection. Monthly mosquito collections using CDC light traps will be conducted to determine if there are entomological correlates of spatial repellent efficacy that may be useful for the evaluation of new spatial repellents. Quarterly human landing catches (HLC) will assess the behavioral effects of the intervention. DISCUSSION: Findings will serve as an efficacy trial of spatial repellent products for sub-Saharan Africa. Findings will be submitted to the World Health Organization Vector Control Advisory Group (WHO VCAG) for assessment of whether spatial repellents have "public health value." Entomological outcomes will also be measured as proxies of malaria transmission to help develop guidelines for the evaluation of future spatial repellent products. TRIAL REGISTRATION: ClinicalTrials.gov NCT04795648 . Registered on March 12, 2021.

Evaluation of the protective efficacy of a spatial repellent to reduce malaria incidence in children in western Kenya compared to placebo: study protocol for a cluster-randomized double-blinded control trial (the AEGIS program).

BACKGROUND: Spatial repellents are widely used for prevention of mosquito bites and evidence is building on their public health value, but their efficacy against malaria incidence has never been evaluated in Africa. To address this knowledge gap, a trial to evaluate the efficacy of Mosquito Shield™, a spatial repellent incorporating transfluthrin, was developed for implementation in Busia County, western Kenya where long-lasting insecticidal net coverage is high and baseline malaria transmission is moderate to high year-round. METHODS: This trial is designed as a cluster-randomized, placebo-controlled, double-blinded clinical trial. Sixty clusters will be randomly assigned in a 1:1 ratio to receive spatial repellent or placebo. A total of 6120 children aged ≥6 months to 10 years of age will be randomly selected from the study clusters, enrolled into an active cohort (baseline, cohort 1, and cohort 2), and sampled monthly to determine time to first infection by smear microscopy. Each cohort following the implementation of the intervention will be split into two groups, one to estimate direct effect of the spatial repellent and the other to estimate degree of diversion of mosquitoes and malaria transmission to unprotected persons. Malaria incidence in each cohort will be estimated and compared (primary indicator) to determine benefit of using a spatial repellent in a high, year-round malaria transmission setting. Mosquitoes will be collected monthly using CDC light traps to determine if there are entomological correlates of spatial repellent efficacy that may be useful for the evaluation of new spatial repellents. Quarterly human landing catches will assess behavioral effects of the intervention. DISCUSSION: Findings will serve as the first cluster-randomized controlled trial powered to detect spatial repellent efficacy to reduce malaria in sub-Saharan Africa where transmission rates are high, insecticide-treated nets are widely deployed, and mosquitoes are resistant to insecticides. Results will be submitted to the World Health Organization Vector Control Advisory Group for assessment of public health value towards an endorsement to recommend inclusion of spatial repellents in malaria control programs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04766879 . Registered February 23, 2021.

Assessing transfluthrin mortality against Aedes aegypti and Culex quinquefasciatus inside and outside US military tents in a northern Florida environment.

Mortality caused by passive resin transfluthrin diffusers (∼5 mg AI per 24 h release rate) suspended in small 2-person tents was measured for colony-reared sentinel pyrethroid susceptible Aedes aegypti and Culex quinquefasciatus female mosquitoes, as well as a pyrethroid-resistant strain of Aedes aegypti, in a USA military field camp scenario. Mortality effects were investigated for impact by factors such as sentinel cage location (inside tent, tent doorway and outside tent), exposure time (15, 30, 45 and 60 min), and environmental temperature (°C), all of which were examined over an 8-week period. Analyses determined there was a significant interaction between mosquito strain and transfluthrin susceptibility, with the two susceptible strains experiencing significantly greater mean mortality than the resistant Ae. aegypti strain. Significant differences were likewise observed between the mosquito strains over the 8-week study period, where study week and temperature were both positively correlated with an increase in observed mean mosquito mortality. Mosquito proximity to the transfluthrin diffusers was also influenced by week and showed that sentinel cage placement in the environment demonstrates different mortality measurements, depending on the environmental conditions. The length of exposure to transfluthrin, however, was determined to not significantly impact transfluthrin efficacy on the examined mosquito strains, although increased exposure did result in increased susceptible strain mortality. These results suggest that transfluthrin is highly effective in causing mortality against susceptible Ae. aegypti and Cx. quinquefasciatus mosquitoes under field conditions but is minimally effective against pyrethroid-resistant Ae. aegypti mosquitoes. Transfluthrin-infused devices are influenced by environmental factors that can combine to impact mosquito mortality in the field.