Impact of a Spatial Repellent (SR) product on Anopheles and non-Anopheles mosquitoes in Sumba, Indonesia

Background 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. MethodsThe 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 ten-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. ResultsHuman-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, An. balabacensis and An. 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 An. sundaicus s.l.), only five (An. aconitus, An. kochi, An. maculatus, An. tessellatus and An. sundaicus s.l.) demonstrated statistical significance. The SR numerically reduced Anopheles parity rates indoors and outdoors when compared to the placebo. ConclusionEvidence 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.

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.

INSECTICIDE EFFICACY OF SPATIAL REPELLENT COMPOUND-METOFLUTHRIN AGAINST SUSCEPTIBLE AND RESISTANT STRAINS OF AEDES AEGYPTI

Spatial repellents (SR), include pyrethroid insecticides that are highly volatile at low temperatures and with high lethal activities against mosquitoes, mainly Aedes vectors of arboviral diseases. Of these SR, metofluthrin is widely used in various devices for repellent consumer products. This article reports the susceptibility status of Ae. aegypti Puerto Rico permethrin-resistant laboratory strain (PR) and Orlando susceptible laboratory strain (ORL) to metofluthrin and permethrin using the CDC glass bottle bioassay. The time-mortality relationships showed that the permethrin-resistant PR strain is highly resistant to both permethrin and metofluthrin compared to the susceptible ORL strain. The resistant ratio (RR) based on the killing time (KT) (KT50 -PR/KT50 -ORL) was 30- and 5- folds for permethrin and metofluthrin, respectively. The results also showed that the PR strain is less resistance to metofluthrin than to permethrin, with a three-fold RR (KT50 -PR-per/KT50 -PR-met). These results indicate the potential risk of developing cross-resistance of metofluthrin in permethrin-resistant mosquitoes. Integrated vector management in mosquito control should be considerate of how consumer products and field operations interact to accelerate cross resistance to pyrethroids.

The oviposition cue indole inhibits animal-host attraction in Aedes aegypti mosquitoes

Mosquitoes represent a major source of disease transmission and possess the uncanny ability to locate suitable animal-hosts, a feature mediated by their exquisite olfactory system. Insect repellents such as N,N-Diethyl-meta-toluamide, also called DEET, have been shown to activate and inhibit mosquito odorant receptors resulting in behavioral modulation. This and other repellents available for personal protection against mosquitoes are topically applied on the skin and operate at short range. In our search for potential long-range odorant repellents, we have hypothesized that the shared chemical similarities between indole and DEET, may confer the former the ability to block odorant receptor function and inhibit human-host attraction. Using the two-electrode voltage clamp of Xenopus laevis oocytes as a pharmacological platform, we provide evidence that indole inhibits the Aedes aegypti (R)-1-octen-3-ol receptor OR8, a receptor involved in the decision of female mosquitoes to identify human hosts. Coincidentally, we also show that indole inhibits the animal-host seeking behavior of female Aedes aegypti. Together, our findings suggests that indole may be a candidate spatial repellent for the long-range protection of humans against mosquito bites.

A retail audit of mosquito control products in Busia County, western Kenya

Background Approximately 70% of Kenya’s population is at risk for malaria. The core vector control methods in Kenya are insecticide-treated mosquito nets (ITNs) and indoor residual spraying, with supplementary larval source management. In 2015, 21% of ITNs were accessed through the private retail sector. Despite the private sector role in supplying mosquito control products (MCPs), there is little evidence on the availability, sales trends, and consumer preferences for MCPs other than ITNs. This study, a component of a larger research programme focused on evaluating a spatial repellent intervention class for mosquito-borne disease control, addressed this evidence gap on the role of the private sector in supplying MCPs. Methods A cross-sectional survey was deployed in a range of retail outlets in Busia County to characterize MCP availability, sales trends, and distribution channels. The questionnaire included 32 closed-ended and four open-ended questions with short answer responses. Descriptive analysis of frequency counts and percentages was carried out to glean insights about commercially available MCPs and the weighted average rank was used to determine consumer preferences for MCPs. Open-ended data was analysed thematically. Results Retail outlets that stocked MCPs commonly stocked mosquito coils (73.0%), topical repellents (38.1%), aerosol insecticide sprays (23.8%) and ITNs (14.3%). Overall, retailers reported the profits from selling MCPs were adequate and they overwhelmingly planned to continue stocking the products. Of respondents who stocked MCPs, 96.8% responded that sales increased during long rains and 36.5% that sales also surged during short rains. ITNs and baby-size nets were often delivered by the wholesaler. Retailers of aerosol sprays, mosquito coils, and topical repellents either collected stock from the wholesaler or products were delivered to them. Other commercially available MCPs included insecticide incense sticks, electric mosquito strikers, insecticide soaps, electrically heated insecticide mats, and electric insecticide emanators, indicating a well-established market. Conclusions The wide range of MCPs in local retail outlets within the study area suggests the need and demand for mosquito control tools, in addition to ITNs, that are affordable, easy to use and effective. The presence of a wide range of MCPs, is a promising sign for the introduction of a spatial repellent intervention class of products that meets consumer needs and preferences.

Efficacy of a Spatial Repellent for Control of Aedes-Borne Virus Transmission: A Cluster Randomized Trial in Iquitos, Peru

ABSTRACTBackgroundOver 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 the geographic range of Aedes-borne viruses (ABV) continue to expand. To date, there are no rigorously proven vector control interventions that prevent ABV diseases. Spatial repellents, a new option, are designed to decrease human exposure to ABV by releasing active ingredients into the air that disrupt mosquito-human contact.MethodsA parallel, cluster-randomized controlled trial was conducted in Iquitos, Peru to quantify the impact of a transfluthrin-based spatial repellent on 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). Bi-monthly adult mosquito collections were conducted to compare Ae. aegypti abundance, blood-fed capture rate and parity status through mixed effect difference-in-difference analyses.ResultsThe spatial repellent significantly reduced ABV infection by 34.1% (95% CI 6.9%, ∞); p = 0.0236, z=1.98). Aedes aegypti abundance and blood-fed capture 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.ConclusionsOur trial provides the first conclusive evidence of significant protective efficacy by any chemical vector control intervention, in this case a spatial repellent, to reduce the risk of ABV transmission. Results support vector control as a beneficial component to ABV disease prevention.Trial registration numberNCT03553277 (clinicaltrials.gov)

Behavioral response of insecticide-resistant mosquitoes against spatial repellent: A modified self-propelled particle model simulation

Rapidly increasing pyrethroid insecticide resistance and changes in vector biting and resting behavior pose serious challenges in malaria control. Mosquito repellents, especially spatial repellents, have received much attention from industry. We attempted to simulate interactions between mosquitoes and repellents using a machine learning method, the Self-Propelled Particle (SPP) model, which we modified to include attractiveness/repellency effects. We simulated a random walk scenario and scenarios with insecticide susceptible/resistant mosquitoes against repellent alone and against repellent plus attractant (to mimic a human host). Simulation results indicated that without attractant/repellent, mosquitoes would fly anywhere in the cage at random. With attractant, all mosquitoes were attracted to the source of the odor by the end. With repellent, all insecticide-susceptible mosquitoes eventually moved to the corner of the cage farthest from the repellent release point, whereas, a high proportion of highly resistant mosquitoes might reach the attractant release point (the human) earlier in the simulation. At fixed concentration, a high proportion of mosquitoes could be able to reach the host when the relative repellency efficacy (compare to attractant efficacy) was <1, whereas, no mosquitoes reached the host when the relative repellency efficacy was > 1. This result implies that repellent may not be sufficient against highly physiologically insecticide resistant mosquitoes, since very high concentrations of repellent are neither practically feasible nor cost-effective.

Field Evaluation of a Spatial Repellent Emanation Vest for Personal Protection Against Outdoor Biting Mosquitoes

Exophilic vectors are an important contributor to residual malaria transmission. Wearable spatial repellents (SR) can potentially provide personal protection in early evening hours before people retire indoors. An SR prototype for passive delivery of transfluthrin (TFT) for protecting humans against nocturnal mosquitoes in Kanchanaburi, western Thailand, is evaluated. A plastic polyethylene terephthalate (PET) sheet (676 cm2) treated with 55-mg TFT (TFT-PET), attached to the back of short-sleeve vest worn by human collector, was evaluated under semifield and outdoor conditions. Field-caught, nonblood-fed female Anopheles minimus s.l. were released in a 40 m length, semifield screened enclosure. Two collectors positioned at opposite ends conducted 12-h human-landing collections (HLC). The outdoor experiment was conducted between treatments among four collectors at four equidistant positions who performed HLC. Both trials were conducted for 30 consecutive nights. TFT-PET provided 67% greater protection (P &lt; 0.001) for 12 h compared with unprotected control, a threefold reduction in the attack. In outdoor trials, TFT-PET provided only 16% protection against An. harrisoni Harbach & Manguin (Diptera: Culicidae) compared with unprotected collector (P = 0.0213). The TFT-PET vest reduced nonanophelines landing by 1.4-fold compared with the PET control with a 29% protective efficacy. These findings suggest that TFT-PET had diminished protective efficacy in an open field environment. Nonetheless, the concept of a wearable TFT emanatory device has the potential for protecting against outdoor biting mosquitoes. Further development of portable SR tools is required, active ingredient selection and dose optimization, and more suitable device design and materials for advancing product feasibility.

Evaluating Putative Repellent ‘Push’ and Attractive ‘Pull’ Components for Manipulating the Odour-orientation of Host-seeking Malaria Vectors in the Peri-domestic Space

Background Novel malaria vector control approaches aim to combine tools to work in synergy for maximum protection. This study aimed to evaluate novel and re-evaluate existing, putative repellent ‘push’ and attractive ‘pull’ components for manipulating the odour-orientation of malaria vectors in the peri-domestic space. Methods Anopheles arabiensis outdoor human landing catches and trap comparisons were implemented in large semi-field systems to (1) test the efficacy of citriodiol or transfluthrin-treated fabric strips positioned in house eave gaps as push components for preventing bites; (2) understand the efficacy of an MB5-baited Suna-trap in attracting vectors in the presence of a human being; (3) assess 2-butanone as a CO2 replacement for trapping; and (4) determine the protection provided by a full push-pull set up. The air-concentrations of the chemical constituents of the push-pull mosquito control tool were quantified.Results Microencapsulated citriodiol eave strips did not provide any outdoor protection against host-seeking An. arabiensis. Transfluthrin-treated strips significantly reduced the odds of a mosquito landing on the human volunteer (OR 0.17; 95% CI 0.12-0.23). This impact was lower (OR 0.59; 95% CI 0.52-0.66) during the push-pull experiment which was associated with low night-time temperatures likely affecting the transfluthrin vaporisation. The MB5-baited Suna trap supplemented with CO2 attracted only a third of the released mosquitoes in the absence of a human being, however, with a human volunteer in the same system, the trap caught less than 1% of all released mosquitoes. The volunteer consistently attracted over two-thirds of all mosquitoes released. This was the case in the absence (‘pull’ only) and in the presence of a spatial repellent (‘push-pull’), indicating that in its current configuration the tested ‘pull’ does not provide a valuable addition to a spatial repellent. The chemical 2-butanone was ineffective in replacing CO2. Transfluthrin was detectable in the air space but with a strong linear reduction in concentrations over 5 metres from release. The MB5 constituent chemicals were only irregularly detected, potentially suggesting insufficient release and concentration in the air for attraction.Conclusion This step-by-step evaluation of the selected ‘push’ and ‘pull’ components led to a better understanding of their ability to affect host-seeking behaviours of the malaria vector Anopheles arabiensis in the peri-domestic space and helps to gauge the impact such tools would have when used in the field for monitoring or control.