An experimental hut study evaluating the impact of pyrethroid-only and PBO nets alone and in combination with pirimiphos-methyl-based IRS in Ethiopia.

BACKGROUND: Pyrethroid resistance observed in populations of malaria vectors is widespread in Ethiopia and could potentially compromise the effectiveness of insecticide-based malaria vector control interventions. In this study, the impact of combining indoor residual spraying (IRS) and insecticide-treated nets (ITNs) on mosquito behaviour and mortality was evaluated using experimental huts. METHODS: A Latin Square Design was employed using six experimental huts to collect entomological data. Human volunteers slept in huts with different types of nets (pyrethroid-only net, PBO net, and untreated net) either with or without IRS (Actellic 300CS). The hut with no IRS and an untreated net served as a negative control. The study was conducted for a total of 54 nights. Both alive and dead mosquitoes were collected from inside nets, in the central rooms and verandah the following morning. Data were analysed using Stata/SE 14.0 software package (College Station, TX, USA). RESULTS: The personal protection rate of huts with PermaNet® 2.0 alone and PermaNet® 3.0 alone was 33.3% and 50%, respectively. The mean killing effect of huts with PermaNet® 2.0 alone and PermaNet® 3.0 alone was 2% and 49%, respectively. Huts with PermaNet® 2.0 alone and PermaNet® 3.0 alone demonstrated significantly higher excito-repellency than the control hut. However, mosquito mortality in the hut with IRS + untreated net, hut with IRS + PermaNet® 2.0 and hut with IRS + PermaNet® 3.0 were not significantly different from each other (p > 0.05). Additionally, pre-exposure of both the susceptible Anopheles arabiensis laboratory strain and wild Anopheles gambiae sensu lato to PBO in the cone bioassay tests of Actellic 300CS sprayed surfaces did not reduce mosquito mortality when compared to mortality without pre-exposure to PBO. CONCLUSION: Mosquito mortality rates from the huts with IRS alone were similar to mosquito mortality rates from the huts with the combination of vector control intervention tools (IRS + ITNs) and mosquito mortality rates from huts with PBO nets alone were significantly higher than huts with pyrethroid-only nets. The findings of this study help inform studies to be conducted under field condition for decision-making for future selection of cost-effective vector control intervention tools.

Reduced exposure to malaria vectors following indoor residual spraying of pirimiphos-methyl in a high-burden district of rural Mozambique with high ownership of long-lasting insecticidal nets: entomological surveillance results from a cluster-randomized trial.

BACKGROUND: The need to develop new products and novel approaches for malaria vector control is recognized as a global health priority. One approach to meeting this need has been the development of new products for indoor residual spraying (IRS) with novel active ingredients for public health. While initial results showing the impact of several of these next-generation IRS products have been encouraging, questions remain about how to best deploy them for maximum impact. To help address these questions, a 2-year cluster-randomized controlled trial to measure the impact of IRS with a microencapsulated formulation of pirimiphos-methyl (PM) in an area with high ownership of long-lasting insecticidal nets (LLINs) was conducted in a high-transmission district of central Mozambique with pyrethroid resistant vectors. Presented here are the results of the vector surveillance component of the trial. METHODS: The 2 year, two-armed trial was conducted in Mopeia District, Zambezia Province, Mozambique. In ten sentinel villages, five that received IRS with PM in October-November 2016 and again in October-November 2017 and five that received no IRS, indoor light trap collections and paired indoor-outdoor human landing collections catches (HLCs) were conducted monthly from September 2016 through October 2018. A universal coverage campaign in June 2017, just prior to the second spray round, distributed 131,540 standard alpha-cypermethrin LLINs across all study villages and increased overall net usage rates in children under 5 years old to over 90%. RESULTS: The primary malaria vector during the trial was Anopheles funestus sensu lato (s.l.), and standard World Health Organization (WHO) tube tests with this population indicated variable but increasing resistance to pyrethroids (including alpha-cypermethrin, from > 85% mortality in 2017 to 7% mortality in 2018) and uniform susceptibility to PM (100% mortality in both years). Over the entire duration of the study, IRS reduced An. funestus s.l. densities by 48% (CI95 33-59%; p < 0.001) in indoor light traps and by 74% (CI95 38-90%; p = 0.010) during indoor and outdoor HLC, though in each study year reductions in vector density were consistently greatest in those months immediately following the IRS campaigns and waned over time. Overall there was no strong preference for An. funestus to feed indoors or outdoors, and these biting behaviours did not differ significantly across study arms: observed indoor-outdoor biting ratios were 1.10 (CI95 1.00-1.21) in no-IRS villages and 0.88 (CI95 0.67-1.15) in IRS villages. The impact of IRS was consistent in reducing HLC exposures both indoors (75% reduction: CI95 47-88%; p = 0. < 0.001) and outdoors (68% reduction: CI95 22-87%; p = 0.012). While substantially fewer Anopheles gambiae s.l. were collected during the study, trends show a similar impact of IRS on this key vector group as well, with a 33% (CI95 7-53%; p = 0.019) reduction in mosquitoes collected in light traps and a non-statistically significant 39% reduction (p = 0.249) in HLC landing rates. CONCLUSION: IRS with PM used in addition to pyrethroid-only LLINs substantially reduced human exposures to malaria vectors during both years of the cluster-randomized controlled trial in Mopeia-a high-burden district where the primary vector, An. funestus s.l., was equally likely to feed indoors or outdoors and demonstrated increasing resistance to pyrethroids. Findings suggest that IRS with PM can provide effective vector control, including in some settings where pyrethroid-only ITNs are widely used. Trial registration clinicaltrials.gov , NCT02910934. Registered 22 September 2016, https://www.clinicaltrials.gov/ct2/show/NCT02910934.

Incremental impact upon malaria transmission of supplementing pyrethroid-impregnated long-lasting insecticidal nets with indoor residual spraying using pyrethroids or the organophosphate, pirimiphos methyl.

BACKGROUND: Long-lasting, insecticidal nets (LLINs) and indoor residual spraying (IRS) are the most widely accepted and applied malaria vector control methods. However, evidence that incremental impact is achieved when they are combined remains limited and inconsistent. METHODS: Fourteen population clusters of approximately 1000 residents each in Zambia's Luangwa and Nyimba districts, which had high pre-existing usage rates (81.7 %) of pyrethroid-impregnated LLINs were quasi-randomly assigned to receive IRS with either of two pyrethroids, namely deltamethrin [Wetable granules (WG)] and lambdacyhalothrin [capsule suspension (CS)], with an emulsifiable concentrate (EC) or CS formulation of the organophosphate pirimiphos methyl (PM), or with no supplementary vector control measure. Diagnostic positivity of patients tested for malaria by community health workers in these clusters was surveyed longitudinally over pre- and post-treatment periods spanning 29 months, over which the treatments were allocated and re-allocated in advance of three sequential rainy seasons. RESULTS: Supplementation of LLINs with PM CS offered the greatest initial level of protection against malaria in the first 3 months of application (incremental protective efficacy (IPE) [95 % confidence interval (CI)] = 0.63 [CI 0.57, 0.69], P < 0.001), followed by lambdacyhalothrin (IPE [95 % CI] = 0.31 [0.10, 0.47], P = 0.006) and PM EC (IPE, 0.23 [CI 0.15, 0.31], P < 0.001) and then by deltamethrin (IPE [95 % CI] = 0.19 [-0.01, 0.35], P = 0.064). Neither pyrethroid formulation provided protection beyond 3 months after spraying, but the protection provided by both PM formulations persisted undiminished for longer periods: 6 months for CS and 12 months for EC. The CS formulation of PM provided greater protection than the combined pyrethroid IRS formulations throughout its effective life IPE [95 % CI] = 0.79 [0.75, 0.83] over 6 months. The EC formulation of PM provided incremental protection for the first 3 months (IPE [95 % CI] = 0.23 [0.15, 0.31]) that was approximately equivalent to the two pyrethroid formulations (lambdacyhalothrin, IPE [95 % CI] = 0.31 [0.10, 0.47] and deltamethrin, IPE [95 % CI] = 0.19 [-0.01, 0.35]) but the additional protection provided by the former, apparently lasted an entire year. CONCLUSION: Where universal coverage targets for LLIN utilization has been achieved, supplementing LLINs with IRS using pyrethroids may reduce malaria transmission below levels achieved by LLIN use alone, even in settings where pyrethroid resistance occurs in the vector population. However, far greater reduction of transmission can be achieved under such conditions by supplementing LLINs with IRS using non-pyrethroid insecticide classes, such as organophosphates, so this is a viable approach to mitigating and managing pyrethroid resistance.

Applications and limitations of Centers for Disease Control and Prevention miniature light traps for measuring biting densities of African malaria vector populations: a pooled-analysis of 13 comparisons with human landing catches.

BACKGROUND: Measurement of densities of host-seeking malaria vectors is important for estimating levels of disease transmission, for appropriately allocating interventions, and for quantifying their impact. The gold standard for estimating mosquito-human contact rates is the human landing catch (HLC), where human volunteers catch mosquitoes that land on their exposed body parts. This approach necessitates exposure to potentially infectious mosquitoes, and is very labour intensive. There are several safer and less labour-intensive methods, with Centers for Disease Control light traps (LT) placed indoors near occupied bed nets being the most widely used. METHODS: This paper presents analyses of 13 studies with paired mosquito collections of LT and HLC to evaluate these methods for their consistency in sampling indoor-feeding mosquitoes belonging to the two major taxa of malaria vectors across Africa, the Anopheles gambiae sensu lato complex and the Anopheles funestus s.l. group. Both overall and study-specific sampling efficiencies of LT compared with HLC were computed, and regression methods that allow for the substantial variations in mosquito counts made by either method were used to test whether the sampling efficacy varies with mosquito density. RESULTS: Generally, LT were able to collect similar numbers of mosquitoes to the HLC indoors, although the relative sampling efficacy, measured by the ratio of LT:HLC varied considerably between studies. The overall best estimate for An. gambiae s.l. was 1.06 (95% credible interval: 0.68-1.64) and for An. funestus s.l. was 1.37 (0.70-2.68). Local calibration exercises are not reproducible, since only in a few studies did LT sample proportionally to HLC, and there was no geographical pattern or consistent trend with average density in the tendency for LT to either under- or over-sample. CONCLUSIONS: LT are a crude tool at best, but are relatively easy to deploy on a large scale. Spatial and temporal variation in mosquito densities and human malaria transmission exposure span several orders of magnitude, compared to which the inconsistencies of LT are relatively small. LT, therefore, remain an invaluable and safe alternative to HLC for measuring indoor malaria transmission exposure in Africa.

Made-to-measure malaria vector control strategies: rational design based on insecticide properties and coverage of blood resources for mosquitoes.

Eliminating malaria from highly endemic settings will require unprecedented levels of vector control. To suppress mosquito populations, vector control products targeting their blood hosts must attain high biological coverage of all available sources, rather than merely high demographic coverage of a targeted resource subset, such as humans while asleep indoors. Beyond defining biological coverage in a measurable way, the proportion of blood meals obtained from humans and the proportion of bites upon unprotected humans occurring indoors also suggest optimal target product profiles for delivering insecticides to humans or livestock. For vectors that feed only occasionally upon humans, preferred animal hosts may be optimal targets for mosquito-toxic insecticides, and vapour-phase insecticides optimized to maximize repellency, rather than toxicity, may be ideal for directly protecting people against indoor and outdoor exposure. However, for vectors that primarily feed upon people, repellent vapour-phase insecticides may be inferior to toxic ones and may undermine the impact of contact insecticides applied to human sleeping spaces, houses or clothing if combined in the same time and place. These concepts are also applicable to other mosquito-borne anthroponoses so that diverse target species could be simultaneously controlled with integrated vector management programmes. Measurements of these two crucial mosquito behavioural parameters should now be integrated into programmatically funded, longitudinal, national-scale entomological monitoring systems to inform selection of available technologies and investment in developing new ones.

Comparative assessment of diverse strategies for malaria vector population control based on measured rates at which mosquitoes utilize targeted resource subsets.

BACKGROUND: Eliminating malaria requires vector control interventions that dramatically reduce adult mosquito population densities and survival rates. Indoor applications of insecticidal nets and sprays are effective against an important minority of mosquito species that rely heavily upon human blood and habitations for survival. However, complementary approaches are needed to tackle a broader diversity of less human-specialized vectors by killing them at other resource targets. METHODS: Impacts of strategies that target insecticides to humans or animals can be rationalized in terms of biological coverage of blood resources, quantified as proportional coverage of all blood resources mosquito vectors utilize. Here, this concept is adapted to enable impact prediction for diverse vector control strategies based on measurements of utilization rates for any definable, targetable resource subset, even if that overall resource is not quantifiable. RESULTS: The usefulness of this approach is illustrated by deriving utilization rate estimates for various blood, resting site, and sugar resource subsets from existing entomological survey data. Reported impacts of insecticidal nets upon human-feeding vectors, and insecticide-treated livestock upon animal-feeding vectors, are approximately consistent with model predictions based on measured utilization rates for those human and animal blood resource subsets. Utilization rates for artificial sugar baits compare well with blood resources, and are consistent with observed impact when insecticide is added. While existing data was used to indirectly measure utilization rates for a variety of resting site subsets, by comparison with measured rates of blood resource utilization in the same settings, current techniques for capturing resting mosquitoes underestimate this quantity, and reliance upon complex models with numerous input parameters may limit the applicability of this approach. CONCLUSIONS: While blood and sugar consumption can be readily quantified using existing methods for detecting natural markers or artificial tracers, improved techniques for labelling mosquitoes, or other arthropod pathogen vectors, will be required to assess vector control measures which target them when they utilize non-nutritional resources such as resting, oviposition, and mating sites.

Multi-country assessment of residual bio-efficacy of insecticides used for indoor residual spraying in malaria control on different surface types: results from program monitoring in 17 PMI/USAID-supported IRS countries.

BACKGROUND: Indoor residual spraying (IRS) is the application of insecticide to the interior walls of household structures that often serve as resting sites for mosquito vectors of malaria. Human exposure to malaria vectors is reduced when IRS involves proper application of pre-determined concentrations of the active ingredient specific to the insecticide formulation of choice. The impact of IRS can be affected by the dosage of insecticide, spray coverage, vector behavior, vector susceptibility to insecticides, and the residual efficacy of the insecticide applied. This report compiles data on the residual efficacy of insecticides used in IRS campaigns implemented by the United States President's Malaria Initiative (PMI)/United States Agency for International Development (USAID) in 17 African countries and compares observed length of efficacy to ranges proposed in World Health Organization (WHO) guidelines. Additionally, this study provides initial analysis on variation of mosquito mortality depending on the surface material of sprayed structures, country spray program, year of implementation, source of tested mosquitoes, and type of insecticide. METHODS: Residual efficacy of the insecticides used for PMI/USAID-supported IRS campaigns was measured in Benin, Burkina Faso, Ethiopia, Ghana, Kenya, Liberia, Madagascar, Malawi, Mali, Mozambique, Nigeria, Rwanda, Senegal, Tanzania, Uganda, Zambia and Zimbabwe. The WHO cone bioassay tests were used to assess the mortality rate of mosquitoes exposed to insecticide-treated mud, wood, cement, and other commonly used housing materials. Baseline tests were performed within weeks of IRS application and follow-up tests were continued until the mortality of exposed mosquitoes dropped below 80% or the program monitoring period ended. Residual efficacy in months was then evaluated with respect to WHO guidelines that provide suggested ranges of residual efficacy for insecticide formulations recommended for use in IRS. Where the data allowed, direct comparisons of mosquito mortality rates were then made to determine any significant differences when comparing insecticide formulation, country, year, surface type, and the source of the mosquitoes used in testing. RESULTS: The residual efficacy of alpha-cypermethrin ranged from 4 to 10 months (average = 6.4 months), with no reported incidents of underperformance when compared to the efficacy range provided in WHO guidelines. Deltamethrin residual efficacy results reported a range of 1 to 10 months (average = 4.9 months), with two instances of underperformance. The residual efficacy of bendiocarb ranged from 2 weeks to 7 months (average = 2.8 months) and failed to achieve proposed minimum efficacy on 14 occasions. Lastly, long-lasting pirimiphos-methyl efficacy ranged from 2 months to 9 months (average = 5.3 months), but reported 13 incidents of underperformance. CONCLUSIONS: Much of the data used to determine application rate and expected efficacy of insecticides approved for use in IRS programs are collected in controlled laboratory or pilot field studies. However, the generalizability of the results obtained under controlled conditions are limited and unlikely to account for variation in locally sourced housing materials, climate, and the myriad other factors that may influence the bio-efficacy of insecticides. Here, data are presented that confirm the variation in residual efficacy observed when monitoring household surfaces sprayed during PMI/USAID-supported IRS campaigns. All insecticides except alpha-cypermethrin showed evidence of failing to meet the minimum range of residual efficacy proposed in WHO criteria at least once. However, this initial effort in characterizing program-wide insecticide bio-efficacy indicates that some insecticides, such as bendiocarb and pirimiphos-methyl, may be vulnerable to variations in the local environment. Additionally, the comparative analysis performed in this study provides evidence that mosquito mortality rates differ with respect to factors including: the types of insecticide sprayed, surface material, geographical location, year of spraying, and tested mosquitoes. It is, therefore, important to locally assess the residual efficacy of insecticides on various surfaces to inform IRS programming.

Eliminating malaria vectors.

Malaria vectors which predominantly feed indoors upon humans have been locally eliminated from several settings with insecticide treated nets (ITNs), indoor residual spraying or larval source management. Recent dramatic declines of An. gambiae in east Africa with imperfect ITN coverage suggest mosquito populations can rapidly collapse when forced below realistically achievable, non-zero thresholds of density and supporting resource availability. Here we explain why insecticide-based mosquito elimination strategies are feasible, desirable and can be extended to a wider variety of species by expanding the vector control arsenal to cover a broader spectrum of the resources they need to survive. The greatest advantage of eliminating mosquitoes, rather than merely controlling them, is that this precludes local selection for behavioural or physiological resistance traits. The greatest challenges are therefore to achieve high biological coverage of targeted resources rapidly enough to prevent local emergence of resistance and to then continually exclude, monitor for and respond to re-invasion from external populations.