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      Integrated malaria vector control with microbial larvicides and insecticide-treated nets in western Kenya: a controlled trial Translated title: Lutte intégrée contre les vecteurs du paludisme au moyen de larvicides microbiens et de moustiquaires imprégnées d'insecticide au Kenya occidental: essai contrôlé Translated title: Lucha antivectorial integrada contra la malaria mediante larvicidas microbianos y mosquiteros tratados con insecticida en Kenya occidental: ensayo controlado

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          Abstract

          OBJECTIVE: To assess the contributions of both microbial larvicides and insecticide-treated nets (ITNs) in terms of reducing malaria incidence in an integrated vector management programme in an area moderately endemic for malaria in the western Kenyan highlands. METHODS: A pre-post, control group design was used. Larval and adult vector populations were surveyed weekly in six separate valley communities. The incidence of Plasmodium infections in children 6 months to 13 years of age was measured during the long and short rainy seasons each year. Baseline data were collected for 17 months, after which Bacillus-based larvicides were applied weekly to aquatic habitats in three of the valleys for another 19 months. At around the same time the larviciding was initiated, ITNs were introduced gradually into all study communities by the National Malaria Control Programme. The effect of larviciding, ITNs and other determinants of malaria risk was assessed by means of generalized estimating equations. FINDINGS: The risk of acquiring new parasite infections in children was substantially and independently reduced by ITN use (odds ratio, OR: 0.69; 95% confidence interval, CI: 0.48-0.99) and larvicide application (OR: 0.44; 95% CI: 0.23-0.82), after adjusting for confounders. CONCLUSION: Vector control with microbial larvicides enhanced the malaria control achieved with ITNs alone. Anti-larval measures are a promising complement to ITN distribution in the economically important highland areas and similar transmission settings in Africa.

          Translated abstract

          OBJECTIF: Évaluer les contributions des larvicides microbiens et des moustiquaires imprégnées d'insecticide (MII) à la réduction de l'incidence du paludisme dans le cadre d'un programme de lutte antivectorielle intégrée, appliqué à une zone d'endémie modérée de cette maladie, dans les hauts plateaux du Kenya occidental. MÉTHODES: On a fait appel à une étude de type avant-après avec groupe témoin. On a surveillé chaque semaine les populations de larves et de vecteurs adultes menaçant les communautés vivant dans six vallées séparées. On a mesuré chaque année l'incidence des infections à Plasmodium chez les enfants de 6 mois à 13 ans au cours des deux saisons des pluies (longue et courte). On a collecté des donnée de référence pendant 17 mois, après quoi on appliqué chaque semaine des larvicides à base de Bacillus sur les habitats aquatiques de trois des vallées pendant 19 autres mois. En même temps à peu près que débutait la destruction des larves, le Programme kenyan de lutte contre le paludisme a commencé à introduire progressivement des MII dans toutes les communautés étudiées. Les effets de la destruction larvaire, des MII et d'autres déterminants du risque de paludisme ont été évalués à l'aide d'équations d'estimation généralisée. RÉSULTATS: Après ajustement pour les facteurs de confusion, le risque de contracter une nouvelle infestation parasitaire chez l'enfant était substantiellement et indépendamment réduit par l'utilisation de MII (Odds ratio, OR: 0,69, intervalle de confiance à 95 %, IC: 0,48-0,99) et par l'application de larvicide (OR: 0,44 ; IC à 95 %: 0,23-0,82). CONCLUSION: La lutte antivectorielle par application de larvicides microbiens a permis de renforcer les résultats obtenus contre le paludisme avec les MII seules. Les mesures de lutte antilarvaire représentent un complément prometteur à la distribution de MII dans les zones importantes sur le plan économique des hauts plateaux et dans d'autres contextes similaires en Afrique où se transmet actuellement le paludisme.

          Translated abstract

          OBJETIVO: Determinar la contribución de los larvicidas microbianos y los mosquiteros tratados con insecticida (MTI) a la reducción de la incidencia de malaria en un programa de lucha antivectorial integrada emprendido en una zona con malaria moderadamente endémica de las tierras altas del oeste de Kenya. MÉTODOS: Se llevó a cabo un estudio pre-post con un grupo de control en el que se procedió a vigilar las poblaciones de larvas y vectores adultos en las comunidades de seis valles. Anualmente se midió la incidencia de infección por Plasmodium en los niños de 6 meses a 13 años durante cada estación de las lluvias cortas y largas. Se reunieron datos de referencia por espacio de 17 meses, tras lo cual se procedió a aplicar todas las semanas larvicidas basados en Bacillus en hábitats acuáticos en tres de los valles durante otros 19 meses. Aproximadamente al mismo tiempo que se iniciaba la aplicación de larvicidas, el Programa Nacional de Control de la Malaria comenzó también a introducir gradualmente los MTI en todas las comunidades estudiadas. El efecto de los larvicidas, los MTI y otros determinantes del riesgo de malaria se evaluó mediante ecuaciones de estimación generalizadas. RESULTADOS: El riesgo de los niños de contraer nuevas infecciones por el parásito se vio reducido de forma sustancial e independiente por el uso de MTI (razón de posibilidades, OR: 0,69; intervalo de confianza [IC] del 95%: 0,48-0,99) y por la aplicación de larvicidas (OR: 0,44; IC95%: 0,23-0,82), después de ajustar por los factores de confusión. CONCLUSIÓN: La lucha antivectorial con larvicidas microbianos potenció el control de la malaria logrado solo con MTI. Las medidas antilarvarias son un complemento prometedor de la distribución de MTI en las zonas montañosas económicamente importantes y otros entornos de transmisión similares en África.

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          Identification of single specimens of the Anopheles gambiae complex by the polymerase chain reaction.

          A ribosomal DNA-polymerase chain reaction (PCR) method has been developed for species identification of individuals of the five most widespread members of the Anopheles gambiae complex, a group of morphologically indistinguishable sibling mosquito species that includes the major vectors of malaria in Africa. The method, which is based on species-specific nucleotide sequences in the ribosomal DNA intergenic spacers, may be used to identify both species and interspecies hybrids, regardless of life stage, using either extracted DNA or fragments of a specimen. Intact portions of a mosquito as small as an egg or the segment of one leg may be placed directly into the PCR mixture for amplification and analysis. The method uses a cocktail of five 20-base oligonucleotides to identify An. gambiae, An. arabiensis, An. quadriannnulatus, and either An. melas in western Africa or An. melas in eastern and southern Africa.
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            Reduced Efficacy of Insecticide-treated Nets and Indoor Residual Spraying for Malaria Control in Pyrethroid Resistance Area, Benin

            During the last decade, pyrethroid-treated mosquito nets have become the main method of malaria prevention in many malaria-endemic African countries ( 1 , 2 ). In a few notable exceptions, usually those with a more developed health infrastructure, such as South Africa, a longstanding practice of applying indoor residual spraying (IRS) has been successful ( 3 ). The 2 approaches to malaria prevention, insecticide-treated nets (ITNs) and spraying (IRS), are not mutually exclusive, and in malaria-endemic areas where ITN coverage is still limited, the feasibility of introducing IRS to reduce transmission is being considered, for example, by the President’s Initiative Fund ( 4 ). Trials of IRS and ITNs have shown that in areas with pyrethroid-susceptible Anopheles gambiae the effectiveness of the 2 methods in controlling malaria does not differ ( 5 ). This comparability may not hold true for areas with pyrethroid-resistant populations. In southern Africa, for example, IRS with pyrethroid failed to control pyrethroid-resistant An. funestus and necessitated a switch to an alternative class of insecticide to which there was no resistance ( 6 ). During the last decade, pyrethroid resistance caused by the kdr mechanism has become widespread in An. gambiae in West Africa and is common in some areas ( 7 ). Whether kdr undermines the effectiveness of ITN in areas of high prevalence is unclear. An early experimental hut trial of ITNs in Côte d’Ivoire demonstrated a survival advantage of homozygotes for kdr resistance ( 8 ), whereas subsequent hut trials in adjacent resistant and susceptible populations showed no apparent difference in the effectiveness of ITNs between the 2 localities ( 9 ). Village randomized trials in Côte d’Ivoire showed that ITNs continued to prevent malaria despite a vector population that was kdr resistant ( 10 ). Whether kdr would undermine the effectiveness of IRS in the same way as resistance due to oxidases did against An. funestus in southern Africa ( 6 ) is unknown. To assess the practicability of applying IRS with pyrethroid in West Africa, we need to examine the effectiveness of this approach against a kdr-resistant population of An. gambiae is important. To get a clearer understanding of the influence of kdr resistance on the effectiveness of ITN, further experimental hut trials of ITNs against kdr-resistant populations need to be conducted. We describe 2 experimental hut trials in Benin. One compares the impact of IRS and ITN against a kd- resistant population in the southern part of the country; the other compares IRS and ITNs against a pyrethroid-resistant population several hundred kilometers to the north. Material and Methods Study Sites Ladji is a large village on the outskirts of Cotonou, the capital of Benin. The village floods during the rainy season. An. gambiae comprises the Mopti (M) cytotype and shows resistance to pyrethroids and DDT; kdr is present at high frequency ( 11 ). The nuisance mosquito Culex quinquefasciatus is also present and shows resistance to pyrethroids. Five experimental huts belonging to the Centre de Recherche Entomologique de Cotonou (CREC) are situated in the village. Malanville is in northern Benin, 800 km from Cotonou, in an irrigated rice-growing valley. The local An. gambiae comprises the M cytotype, but the kdr gene is almost absent and mosquitoes are susceptible to lambdacyalothrin and deltamethrin. Six experimental huts are present at Malanville. Experimental Huts The treated nets, residual spray treatments, and their respective untreated controls were evaluated in 4 experimental huts at each field site. Experimental huts are specially designed to test vector control product against freely entering mosquitoes under natural but controlled conditions. Huts were typical of the region. Each was made from concrete bricks, with a corrugated iron roof and a ceiling of thick polyethylene sheeting lined with hessian sackcloth on the interior surface, and each was built on a concrete base surrounded by a water-filled moat to exclude ants ( 12 ). Mosquito access was through 4 window slits, constructed from pieces of plywood fixed at an angle to create a funnel with a 1-cm gap, present on 3 sides of the huts. Mosquitoes had to fly upward to enter through the gaps and downwards to exit; this precluded or limited exodus through the aperture and enabled us to account for most entering mosquitoes. A veranda trap projected from the back wall of each hut. Movement of mosquitoes between a room and the veranda was unimpeded. Mosquito Net Treatments The nets were made of white, 100-denier polyester (SiamDutch Mosquito Netting Co., Bangkok, Thailand). Nets measured 2.0-m long, 1.6-m wide, and 1.8-m tall and had a surface area of 16.9 m2. To simulate badly torn nets, 80 holes, each measuring 2 × 2 cm, were cut in the sides and ends of each net. Insecticides used were formulations of lambdacyhalothrin (Icon, Syngenta, Switzerland): lambdacyhalothrin 2.5% CS, a microencapsulated suspension designed for ITNs, and lambdacyhalothrin 10% WP, a wettable powder designed for IRS. The lambdacyhalothin application rates of 18 mg/m2 for ITNs and 30 mg/m2 for IRS were within the ranges recommended by the manufacturer. Indoor residual treatments were applied with a hand-operated compression sprayer equipped with a flat fan nozzle. The cement walls and sackcloth ceilings were sprayed uniformly after masking the veranda and window slits with protective coverings. The control hut was sprayed with water only. The treated huts were left for 1 week before evaluations were started. Sleepers and Mosquito Collections Preliminary experiments showed the huts to be evenly attractive to mosquitoes. The treatments were randomly allocated to the 4 experimental huts at each site. The main trials were conducted from April to June 2005 at the Ladji site and from September to November 2005 at the Malanville site. Eight adult men employed by CREC slept overnight in the huts and collected mosquitoes from the huts in the mornings. Informed consent to participate in the study was given beforehand, and chemoprophylaxis was provided during the trial. Ethical approval was granted by the London School of Hygiene and Tropical Medicine (LSHTM) and Benin national ethics committees. The trial ran for 50 nights for 8 weeks at each site. The sleepers were rotated between huts to correct for possible variation in individual attractiveness. Each morning, mosquitoes were collected from the floors, walls, and ceilings of rooms, verandas, and nets with aspirators and torches. Mosquitoes were identified and scored as blood-fed or unfed and dead or live. Live mosquitoes were held in netted plastic cups and supplied with 10% honey solution for 24 h before delayed death was recorded. Male mosquitoes were not recorded. The entomologic impact of each treatment on mosquitoes was expressed relative to the control in terms of the following: deterrence, the proportional reduction in the number of mosquitoes entering a treated hut relative to that entering the control hut; induced exophily, the proportion of mosquitoes collected from the veranda trap of the treatment hut relative to the proportion in the veranda of the control hut; blood-feeding inhibition, the reduction in blood-feeding rate relative to the control hut; and mortality, the proportions of mosquitoes found dead in the hut at the time of collection and after a 24-h holding period. If a treatment deters a considerable number of mosquitoes from entering the hut, the values given by proportion blood-feeding or proportion killed in the treatment hut may underestimate the full personal protective effect and overestimate the full insecticidal efficacy of the treatment. The personal protective effect of a treatment is better described by the reduction in the number of blood-fed mosquitoes in the treatment hut relative to the number blood-fed in the control hut: % personal protection = 100 (Bu – Bt)/Bu where Bu = is the total number of blood-fed mosquitoes in the untreated control huts and Bt is the total number blood-fed mosquitoes in the huts with insecticide treatment. The overall insecticidal effect of a treatment needs to take into account that a considerable number of mosquitoes might be deterred from entering the hut and hence not be killed by the treatment. A mass killing effect is desirable to reduce transmission. The overall insecticidal effect of a treatment relative to the number of mosquitoes that would ordinarily enter an untreated hut can be estimated by using the following formula and expressed as a percentage: Overall insecticidal effect (%) = 100 (Kt – Ku)/(Tu – Ku) where Kt is the number killed in the treated hut, Ku is the number dying in the untreated control hut, and Tu is the total number collected from the control hut. Residual Activity of Insecticide Treatments To evaluate residual activity, World Health Organization (WHO) cone bioassays were undertaken monthly in the Ladji huts and bimonthly in the Malanville huts with a laboratory-susceptible strain of An. gambiae (Kisumu). An. gambiae females, 3–5 days old, were exposed within the cones to nets for 3 min or to sprayed walls and ceilings for 30 min. Approximately 50 mosquitoes in 5 replicates of 10 mosquitoes were tested on each substrate. Honey solution was provided during the 24-h holding period, and the temperature was kept at 25°C. Biochemical Assays Biochemical tests on individual mosquitoes were conducted to determine the activity of mixed function oxidases and nonspecific esterases present in pyrethroid-resistant and -susceptible samples of An. gambiae from the Ladji and Malanville sites. Tests were conducted on 3-day-old adult females (initially collected as larvae) in microtiter plates ( 13 ). Susceptible (Kisumu) and pyrethroid-resistant (Vkper) An. gambiae served as controls. Genotyping of An. gambiae was carried out to assess kdr frequency at both field stations ( 14 ). Adult Bioassay Data To determine whether a stronger pyrethroid resistance mechanism was present in the Ladji population than in the standard kdr strain Vkper, bioassays with 0.05% lambdacyalothrin-treated papers (18 mg/m2) were conducted in WHO resistance test kits by using a range of exposure times on batches of 25 unfed An. gambiae females 2–5 days of age. One hundred mosquitoes per exposure period were tested. Deaths were scored 24 h later. Log-time mortality curves were generated, and lethal time to kill 50% (LT50), estimated by using probit analysis. Data Analysis Proportional data from the hut trial (exophily, blood-feeding, deaths) were analyzed by using logistic regression (STATA 6 software, Stata Corporation, College Station, TX, USA). Deterrence rates were analyzed by comparing the number of mosquitoes entering each hut by using the Wilcoxon rank sum test. Biochemical activity was analyzed with Kruskal–Wallis and Wilcoxon rank sum tests. The level of resistance to lambdacyalothrin in insecticide bioassays was analyzed by using probit analysis. Results Insecticide Residual Activity Residual activity on ITN as measured by cone bioassay tests showed no decline during the 8 weeks of the trial. Activity of the IRS wettable powder formulation on sackcloth and cement showed a decline in performance by week 4. This trend continued until the end of the trial (Table 1). Table 1 Residual activity of lambdacyalothrin (insecticide)-treated nets (ITNs) and indoor residual spraying over 3 mo in experimental huts, Malanville and Ladji field stations* When and where substrate tested ITNs at 18 mg/m2 Indoor residual spraying at 30 mg/m2 Sides + top of net Ceiling Walls No. tested % Corrected mortality No. tested % Corrected mortality No. tested % Corrected mortality Wk 0 Malanville 77 100 33 100 60 100 Ladji 51 100 30 93.3 54 100 Wk 2 Ladji 52 100 22 100 41 100 Wk 4 Ladji 54 100 21 52.4 47 42.5 Wk 6 Ladji 57 100 25 80.0 45 31.1 Wk 8 Malanville 52 100 29 41.4 54 2.6 Ladji 44 97.7 8 25.0 39 18.5 *As determined by using World Health Organization cone bioassays and susceptible Anopheles gambiae (Kisumu). Efficacy of Treatments in Huts Over the 2-month trial, 1,395 An. gambiae, 3,070 Cx. quinquefasciatus, and small numbers of Mansonia uniformis, An. pharoensis, and Aedes aegypti were collected at Ladji. At Malanvile, 1,523 An. gambiae, 2,804 Mansonia sp., and smaller numbers of An. funestus and Ae. aegypti were collected. Only the malaria vector An. gambiae and the nuisance mosquito Cx. quinquefasciatus were analyzed further. Fewer An. gambiae entered the ITN- and IRS-treated huts than the respective control huts. The treatment induced reduction in hut entry was more evident in the resistance area than in the susceptible area (Table 2). The proportion deterred at each site did not differ between ITN or ITS treatments. Table 2 Experimental hut results of lambdacyhalothrin (insecticide)-treated nets (ITNs) and indoor residual spraying (IRS) against Anopheles gambiae, Ladji (pyrethroid resistance) and Malanville (pyrethroid susceptibility) field stations* Ladji (pyrethroid resistance) Malanville (pyrethroid susceptibility) ITN Untreated net Lambdacyhalothrin 18 mg/m2 Untreated net Lambdacyhalothrin 18 mg/m2 Total collected 689a 386b 363a 267b Deterred, % _ 44.0 ._ 26.4 Exiting, % (CI) 25.0†
(21.7–28.2) 29.0†
(24.5–33.5) 36.1
(31.1–41.0) 46.8‡
(40.8–52.8) Blood-fed, % (CI) 82.0†
(79.1–84.9) 82.1†
(78.3–85.9) 77.7†
(73.4–81.9) 3.0‡
(0.9–5.0) Blood-feeding inhibition, % _ 0 _ 96.1 Personal protection, % (no. bloodfed) – (572) 44.6 (317) – (282) 97.2 (8) % Dead (CI) 13.6† (11.1–16.2) 29.8‡ 25.2–34.4) 3.6† (1.7–5.5) 98.5‡ (97.0–99.9) Insecticidal effect, % (no. dead) – (94) 3.0 (115) – (13) 68.9 (263) IRS Unsprayed hut Lambdacyhalothrin 30 mg/m2 Unsprayed hut Lambdacyhalothrin 30 mg/m2 Total collected 203† 117‡ 498† 395‡ Deterred, % _ 42.4 _ 20.7 Exiting, % (CI) 45.8† (38.9–52.7) 58.1† (49.2–67.1) 54.4† (50.0–58.8) 63.3† (58.5–68.0) Blood-fed, % (CI) 87.7† (83.2–92.2) 73.5‡ (65.5–81.5) 93.8† (91.6–95.9) 69.6‡ (65.1–74.2) Blood-feeding inhibition, % _ 16.2 _ 25.8 Personal protection, % (no. bloodfed) – (178) 51.7 (86) – (467) 41.1 (275) Dead, % (CI) 12.3† (7.8–16.8) 30.8† (22.4–39.1) 1.4† (0.4–2.4) 72.1‡ (67.7–76.6) Insecticidal effect, % (no. dead) – (25) 5.4 (36) – (7) 55.8 (285) *For each untreated–treated pair, values not sharing the same superscript are significantly different at the 5% level.. CI, 95% confidence interval. The untreated net was little or no barrier to blood-feeding of An. gambiae at either field site owing to the large number of holes cut in each net. Treating the holed net with pyrethroid led to a 96% reduction in the number of mosquitoes blood-feeding at the susceptible site (Malanville) but to no reduction in blood-feeding at the resistant site (Ladji). Inhibition of blood-feeding by IRS at either the resistant or susceptible site was limited (Table 2). Natural mortality of An. gambiae occurred in both types of control huts but was notably higher at Ladji than at Malanville. Both modes of treatment were highly insecticidal at Malanville: ITNs treated with 18 mg/m2 lambdacyhalothrin killed 99%, and IRS applied at 30 mg/m2 killed 72% of An. gambiae that entered the huts. At Ladji, the proportions of An. gambiae killed in either the ITN- or IRS-treated hut did not exceed 30% (Table 2). The proportion of An. gambiae collected from the veranda traps in the mornings was greater at Malanville than at Ladji and greater in the huts with untreated nets than in the unsprayed control huts. Relative to the controls, lambdacyalothrin-treated nets and IRS induced little or no exophily of the pyrethroid-resistant An. gambiae into the verandas of the Ladji huts, despite high survival rate of mosquitoes in huts. At Malanville, pyrethroid-induced exophily by ITN or IRS hut was not evident and may have been obscured by the high death rates among the mosquitoes. The personal protection derived from ITN was almost 100% in the susceptible area. Despite the low mortality rate and high rate of blood-feeding observed with ITN in the resistance area, the level of personal protection there was almost 50% because of the deterrent effect of lambdacyhalothin on mosquito entry into huts. The personal protective effect of IRS was low in both areas, and IRS was no barrier to blood-feeding. The overall insecticidal effect of pyrethroid-treated nets and IRS was negligible in the resistance area ( 55.8%). Table 3 breaks down the mortality data into 2-week blocks. Mortality associated with IRS treatments decreased week by week at both sites but started at a lower rate at the Ladji site because of the expression of resistance. Mortality associated with ITN treatments also showed a downward trend over time at Ladji but not at Malanville, where mosquitoes showed high susceptibility throughout the study. Table 3 Mortality rate of free-flying, naturally entering mosquitoes in huts, first 8 weeks of trial Ladji (pyrethroid-resistant Anopheles gambiae) Malanville (pyrethroid-susceptible An. gambiae) ITN IRS ITN IRS Wk No. % Corrected mortality No. % Corrected mortality No. % Corrected mortality No. % Corrected mortality 1–2 41 43.2 15 53.3 67 100 91 100 3–4 83 50.5 42 47.6 93 100 108 88.7 5–6 209 28.7 39 24.2 54 92.6 78 57.8 7–8 53 5.7 21 23.8 53 98.8 118 39.0 *ITN, insecticide-treated net; IRS, indoor residual spraying. Both ITN and IRS treatments at Ladji showed poor efficacy against Cx. quinquefasciatus (this species was not encountered in Malanville). Insecticide-induced deterrence was greater for ITN than for IRS (Table 4). Neither method killed many Culex nor stimulated repellency into verandas. The IRS treatment produced an unusually high level of blood-feeding inhibition. Table 4 Experimental hut results of lambdacyalothrin (insecticide)-treated nets (ITNs) and indoor residual spraying (IRS) against Culex quinquefasciatus, Ladji (pyrethroid resistance) field station* Results Treatments ITNs IRS Untreated net Lambdacyhalothrin 18 mg/m2 Unsprayed hut Lambdacyhalothrin 30 mg/m2 Total entered 845 598 858 769 Deterred, % _ 29.2 _ 10.4 Exiting, % (CI) 29.8 (26.7–32.9) 35.9 (32.1–39.8) 52.7 (49.3–56.0) 54.6 (51.1–58.1) Blood-fed, % (CI) 62.8 (59.6–56.1) 59.5 (55.6–63.5) 85.1 (82.7–87.5) 42.9 (39.4–46.4) Blood-feeding inhibition – NS – 49.6 Personal protection, % (no. blood-fed – (531) 33.1 (355) – (730) 54.8 (330) Dead, % (CI) 4.3 (2.9–5.6) 8.5 (6.3–10.8) 3.4 (2.2–4.6) 16.3 (13.7–18.9) Insecticidal effect, % (no. dead) – (36) 1.9 (51) – (29) 11.6 (125) *CI, 95% confidence interval. Biochemical Assays and kdr Genotyping An. gambiae from Ladji expressed a significantly higher level of oxidase activity than the standard susceptible (Kisumu) and the laboratory kdr (Vkper) strains, which had a similar level of oxidase activity. However, the pyrethroid-susceptible strain from Malanville showed a level of oxidase activity that was not significantly different from that of the Ladji strain. This finding would appear to rule out any contribution from oxidases to the pyrethroid resistance observed in An. gambiae from Ladji. The level of α-esterase activity in An. gambiae from Ladji was significantly higher than that expressed in Malanville or Kisumu strains, whereas the level of β-esterase activity in Ladji, Vkper, and Kisumu strains was similar and clearly played no part in resistance (Table 5). Overall, the mean level of esterase activity at Malanville was significantly lower than that of the susceptible reference strain (p 95%, a degree of personal protection associated with ITNs and IRS was still evident (45%–50%) relative to the untreated net or unsprayed hut owing to a partial deterrent effect of treatments on entry of mosquitoes rather than to any inhibition of blood-feeding once the insects were inside the huts. Indeed, on entering the huts, most mosquitoes did go on to blood-feed, and the deliberately holed ITN was no barrier to resistant mosquitoes. By contrast, in northern Benin, only 4% of the insecticide-susceptible mosquitoes that entered the hut fed through the holed ITN. The loss of personal protection and loss of mosquito mortality associated with resistance would presumably combine to make ITNs unattractive from the perspective of both the individual user and the malaria control manager. Incision of 80 holes per net is the standard for ITN trials in West Africa ( 8 , 9 , 12 ), and such nets have given a degree of personal protection in earlier trials. An ITN with no or few holes might be expected to give some protection against resistant mosquitoes from Ladji, but there were insufficient huts available to test this idea. These experimental hut results from southern Benin stand in contrast to results from an area of Côte d’Ivoire (Yaokoffikro) that had a comparable frequency of kdr (78%) to that of Ladji (83%) ( 15 ) and where lambdacyhalothrin-treated nets and other ITN showed continuing efficacy, with mortality rates of 45%–68% ( 8 , 16 – 19 ). We sought evidence that other resistance mechanisms than kdr might be contributing to the reduced efficacy of pyrethroids at Ladji. Metabolic resistance due to mixed function oxidases (MFO) has, for example, undermined attempts at malaria control with deltamethrin residual spraying in southern Africa caused by An. funestus ( 6 ), and elevated MFO activity in a strain of An. gambiae from Cameroon reduced the efficacy of permethrin-treated netting in laboratory tests ( 20 ). The combined elevated activity of MFOs, glutathione S–transferase, and esterases resulted in a failure of the S. Mexican IRS program against An. albimanus ( 21 ). Our examination of enzymatic activity in An. gambiae showed no evidence that MFO activity is any greater in mosquitoes from Ladji than in mosquitoes from Malanville, nor did esterase activity differ between Ladji and Vkper (kdr) strains. Thus, there was no evidence of metabolic resistance enhancing the resistance already caused by kdr in mosquitoes from Ladji. Lambdacyhalothin bioassay tests showed no evidence of resistance level differing between Ladji and Vkper strains, and we conclude that metabolic mechanisms made no contribution to the observations in Ladji. In East Africa a different type of kdr based on a leucine-to-serine mutation, which confers resistance to permethrin and DDT ( 22 ), has been detected in several countries. However, no mosquitoes of this genotype were detected in tests on samples of An. gambiae from Ladji ( 23 ). The complete absence of efficacy of lambdacyalothrin against Cx. quinquefasciatus in Ladji merely confirms earlier findings involving other types of pyrethroid in experimental huts in West Africa ( 6 , 9 , 16 , 18 ). The contribution of kdr to pyrethroid resistance in An. gambiae needs to be reappraised. While lambdacyhalothin-treated nets (reported here) and permethrin-treated nets reported earlier ( 24 ) were less effective in hut trials in the kdr area of Benin (Ladji) than in a corresponding area of Côte d’Ivoire (Yaokoffikro), pyrethroid-treated nets were more effective in the susceptible area of Benin (Malanville) than in the corresponding susceptible area of Côte d’Ivoire (M’Be) ( 9 ) for reasons that are presently unknown. Other differences between the biology of An. gambiae from Côte d’Ivoire and Benin exist. Ivorian An. gambiae with kdr is mainly of the S molecular form, whereas Beninoise An. gambiae is of the M form (V. Corbel, unpub. data). M and S forms differ in ecologic distribution and habitat. While mosquitoes of the M form with kdr might behave differently from those of the S form with kdr when exposed to pyrethroids, this is mere speculation. Moreover, the M form in Malanville showed higher vulnerability to ITN than did the corresponding S form in Côte d’Ivoire, a finding that seems at odds with a behavioral hypothesis. Our study provides persuasive evidence that pyrethroid resistance in Benin is capable of undermining control measures based on ITN. Nor is there reassurance to be taken from IRS, and any attempt to switch vector control strategy would seem doomed to fail. Whereas the earlier phase 3 malaria control trials of ITN in Côte d’Ivoire showed continuing effectiveness despite kdr at high levels ( 10 ), our phase 2 results from Benin give no grounds for optimism. However, only phase 3 can provide a definitive answer. Further phase 3 trials using pyrethroid-treated nets and IRS need to be undertaken in Benin in an area of pyrethroid resistance. The normal practice with phase 3 is to aim at complete community coverage. Coverage in real life is usually less than total, and the danger with the type of pyrethroid resistance found in Benin is that at lower levels of coverage the important mass protective effect of ITNs ( 25 , 26 ) may be lost and transmission may continue unabated among those who do not have ITNs. To establish whether this is true, phase 3 trials on resistant mosquito populations should ideally set the coverage level at <100%. If it is considered unacceptable to deny a section of the trial population access to ITNs, an alternative but much less rigorous approach would be to monitor malaria incidence among users and non-users of long-lasting insecticide nets (LLIN) during the proposed scaling up of LLIN coverage in Benin currently being considered. Pyrethroid resistance in Benin is far from homogeneous, and LLIN should give good protection wherever mosquito populations are susceptible. Use of LLIN should be encouraged but scale-up of treated nets may ultimately select for further resistance. The need to develop alternative insecticides to replace or supplement pyrethroids on nets is urgent and should be put on a par with the seeking of new antimalarial drugs or vaccines that have received far greater attention and resources in recent years.
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              Preventing Childhood Malaria in Africa by Protecting Adults from Mosquitoes with Insecticide-Treated Nets

              Introduction The massive malaria burden in Africa merits particular attention as the world struggles to realize a better life for the poorest [1,2]. The Anopheles mosquitoes that act as vectors for human Plasmodium parasites must access sugar, blood, and aquatic oviposition sites to complete their life cycle and maintain parasite transmission. The availability of such ecological resources to mosquitoes has long been recognized as a crucial determinant of malaria transmission [3], but quantitative understanding of this process, as well as viable means to prevent it, remain poorly developed compared with other disease [4] and pest systems [5]. Recent theoretical work highlights the enormous influence of blood source and aquatic habitat availability in determining malaria transmission intensity, disease burden, and their responsiveness to various forms of control [6–12]. Here we apply field-parameterized kinetic models of mosquito host availability [11,13] to identify important shortcomings of current global targets for delivering insecticide treated nets (ITNs) [2,14,15], the most important vector control tool in Africa today. Not only does the model outline the limitations of existing strategies that emphasize targeting of vulnerable groups such as young children and pregnant women [16–18], it also indicates how complementary strategies to promote coverage of whole populations, including nonvulnerable adults and older children [19], will achieve greater and more equitable reduction of disease burden than otherwise would be possible. Insecticide-treated nets (ITNs) represent a practical and effective means to prevent malaria in Africa [20], so scaling up coverage to at least 80% use by young children and pregnant women by 2010 is a consensus target of the Millennium Development Goals (MDGs), the Roll Back Malaria Partnership, and the US President's Malaria Initiative [2,14,15]. Targeting individual protection to these vulnerable groups [16–18] is a well-founded and explicitly accepted priority of all three initiatives, because these groups bear the highest risk of morbidity and mortality from malaria. However, this strategy largely ignores the potentially greater community-wide benefits of broader population coverage [19], and no explicit resources, targets, or strategies have been proposed to achieve these benefits. ITNs can protect not only the individuals and households that use them, but also members of the surrounding community [19,21–26]. This is because they kill adult mosquitoes directly or force them to undertake longer, more hazardous foraging expeditions in search of vertebrate blood and aquatic habits [11]. Plasmodium falciparum, the malaria parasite responsible for the bulk of deaths in Africa, requires at least 8 d to develop from imbibed gametocytes into mature sporozoites within the salivary glands of the vector mosquito. This means that most malaria transmission is carried out by mosquitoes that are at least 10 d old and have taken several previous blood meals at intervals of 2–5 d [27,28]. By even modestly increasing mosquito mortality while they attempt to feed on humans, ITNs can greatly reduce the number of mosquitoes that survive repeated hazardous encounters with protected humans [11]. Also, the excito-repellent properties of ITNs can reduce the frequency with which mosquitoes successfully acquire blood, often diverting them to feed on other mammals that do not host the malaria parasite, resulting in greatly reduced prevalence of sporozoite infection [11]. This theoretical rationale is strongly supported by detailed observations from experimental hut studies [29–34] and from larger village-scale trials: ITNs have been clearly shown to reduce malaria risk among unprotected individuals by suppressing the density [35–37], survival [35–37], human blood indices [38,39], and feeding frequency [39] of malaria vector populations. Large reductions of transmission are required to appreciably reduce malaria burden in most of Africa [17,40], particularly in the longer term as exposure and immunity re-equilibrate [41]. ITNs can address this challenging need through direct personal protection and area-wide suppression of the malaria transmission intensity that benefits even nonusers. It has been suggested that such communal benefits can make large impacts on disease burden only if appreciable levels of coverage are achieved in the human population as a whole [11,12,19], but precise coverage targets for achieving this remain to be determined. So how much coverage is enough to protect individuals who do not use an ITN? Methods Overview Here we used recently developed kinetic models of mosquito behaviour and mortality [11,13] to answer this question by considering the impact of ITNs on human host availability and feeding hazards to mosquitoes, as well as the consequences of such changes for malaria transmission intensity. Protection was estimated in terms of protection against exposure to infectious mosquito bites, expressed as the relative change in the entomological inoculation rate (EIR). EIR is a proven epidemiological indicator of malaria transmission intensity and a key determinant of disease burden [17,40]. Two common but ecologically distinct African malaria transmission systems are considered. First, we modelled an Anopheles gambiae Giles or An. arabienis Patton (sibling species from the same species complex known as An. gambiae sensu lato) population with access to human blood only. Second, we considered An. arabiensis populations in the presence of abundant cattle, which can act as alternative blood sources. An. gambiae greatly prefers humans, but An. arabiensis will readily feed upon cattle [42,43], so populations of these species respond quite differently to increasing ITN coverage, with malaria transmission by the latter typically being lower to begin with but less sensitive to control with ITNs [11]. In both transmission systems we considered ITNs with properties typical of those evaluated in rigorous clinical trials [20] or those of emerging technologies with improved operational durability [44–47]. Note that coverage is expressed as the proportion of the total human population using an ITN each night, rather than in terms of ownership, because this value is the most direct indicator of both personal and communal protection. Figure 1 provides an overview of how mosquito behaviour and survival were modelled as a function of host availability, ITN properties, compliance, and coverage. The approach described is essentially a behaviourally explicit extension of existing vector biodemography [48] models, which predict epidemiologically relevant outcomes such as exposure to transmission (the biodemography–epidemiology model). The principles and utility of the biodemography–epidemiology models we have used [27,49,50], as well as several others that are based on similar assumptions [6,18,28,51], are well established. Notably, this family of models realistically assumes that mosquito behaviour cycles between host seeking, feeding, resting, oviposition-site seeking, oviposition, and back to host seeking again [51]. Similarly to recent analyses of the importance of oviposition [7,8,10] and host acquisition [11,12] processes, here we explicitly modelled the underlying behavioural events that determine the input parameters of these biodemographic processes (the behaviour–biodemography model). Detailed consideration of mosquito behaviour and mortality upon encounter with individual hosts (the individual-level submodel) allows simulation of the impact of ITNs upon the foraging requirements and risks for mosquito populations at the community level (the community-level submodel). This hierarchical approach links individual- and community-level submodels into an integrated behaviour–biodemography model, which drives the outcome of the biodemography–epidemiology model and allows the influence of ITNs upon malaria transmission intensity to be estimated in terms of EIR experienced by both users and nonusers [11,27,50]. Figure 1 A Schematic Outline of the Two-Tier Model Used for This Analysis, Adapted from Previous Detailed Descriptions A detailed model of mosquito behaviour and survival as a function of host availability, ITN properties, compliance, and coverage [11,13] was used to estimate the key biodemographic parameters that determine malaria transmission intensity (behaviour–biodemography model). This model allowed the influence of ITN usage upon malaria transmission intensity to be estimated (biodemography–epidemiology model) in terms of EIR experienced by both users and nonusers [11,27,50]. All terms and symbols are defined in detail elsewhere [11,27,50,52] and are summarized in Methods. The specific modelling approach described here is almost identical to our recent exploration of the optimal properties of ITNs as a function of local ecology [11], apart from subtle improvements in terms calculating mosquito diversion, mortality, and feeding probabilities per host encounter. It is also similar to and consistent with the approaches of others [6,12] but accounts for the fact that ITNs can act only during times of the night when they are actually in use, so that their overall protection is also influenced by subtle variations in the behavioural interactions between humans and mosquitoes [13]. This model has already been evaluated through improved iterations in terms of sensitivity to variations in the assumed parameter values for the insecticidal and excito-repellent properties of ITNs [11], the survival rate of mosquitoes while foraging for resources [11], the innate resource preferences of vector populations [11,50,52], and the availability of those resources, including oviposition sites [50] and alternative blood meal hosts [11,50]. While the analysis outlined here could be implemented with either of the recently developed (and perhaps more elegant) alternative models [6,12], this particular form captures all of the same processes without necessitating the mathematical subtleties of integration, differentiation, equilibrium analysis, or limits. While these are inherently valuable tools for mathematical modelling, they often constitute “black boxes” to nonmathematicians, including several authors of this article. We therefore chose a model that does not require mathematical complexities that might limit accessibility to some of the field biologists and epidemiologists for whom this analysis is most relevant. The model is presented as a downloadable spreadsheet (see Protocol S1) and has proven valuable for teaching the ecological basis of malaria epidemiology and control to students in both the developed and developing world. Modelling Mosquito Behaviour and Mortality at the Individual Level Here we describe a submodel of behavioural and mortality processes that occur at the level of individual mosquitoes seeking, encountering, attacking, and feeding upon individual blood hosts. Another important simplification to consider is that, like most deterministic malaria transmission models, our approach assumed a “malaria in a bottle” scenario in which populations of identical parasites, vectors, and hosts are mixed homogenously within an enclosed system [53]. One important corollary of this assumption is that well-established variations of vulnerability to malaria infection within human populations [16,17] or associated variations in attractiveness and availability to mosquitoes [9,54–56] are not explicitly modelled. As defined previously [52], the availability (a) of any host (j) of any species (s) is the product of the rate at which individual vectors encounter it (ɛs,j) and the probability that, once encountered, they will feed upon it (φs,j): Note that this kinetic definition of availability as a rate per unit time is consistent with applications of the same term to acquisition of oviposition sites [10], the term attraction rate for blood sources [6,57], and the terms feeding rate and oviposition rate for both resources [8,12]. We considered successful feeding as just one of three possible outcomes of a host encounter by a female vector, the other two being death while attempting to feed and diversion to seek another host (Figure 1). We considered this a two-stage process in which the vector first either attacks the encountered host or is diverted away and searches for another, the probabilities of which we denote as γ and Δ, respectively. This definition of diversion includes the combined effects of noncontact repellency and contact-mediated irritancy, often referred to as excito-repellency [58,59]. Considering mean values for hosts of any given species (s), the sum of these two probabilities is: We then considered the second stage of the blood acquisition process, namely feeding. Knowing the probabilities that the vector will either feed successfully (φs) or die in the attempt (μs) per attack (rather than per encounter) allowed us to calculate the probability of a successful feed per encounter: Specifically, the cases of cattle (c) and unprotected humans (h,u) were dealt with in a straightforward manner as follows, where Δu and μu represent a common parameter value for both types of host (Table 1): Table 1 Behavioural and Host Availability Input Parameters for Both Vector Species Personal protection measures such as bed nets, repellents, or domestic insecticide use were envisaged as three possible outcomes, the probabilities of which sum to 1: For a vector that would normally choose to feed upon an encountered unprotected human with a probability of φh,u, the presence of a net or other intervention is expected to influence this probability for protected humans (φh,p) as a function of the excess probability of diverting (Δp) and killing (μp) that vector (Figure 1). The combined baseline and net-induced probabilities of diversion (Δu  + p ) or mortality (μu + p) were calculated as follows: and These parameters allowed us to calculate the feeding probability for a human who always uses and is protected by a net (φh,p): These equations are parameterized using data from experimental hut trials in which the human participants slept within the net throughout the period of data collection (Table 1). However, very few human beings spend their entire day asleep or using a net [13] so the true probability of feeding upon a typical net user ( ) is calculated by weighting φh,u and φh,p according to the proportion of normal exposure during which the host is actually covered (πi): Equations 5-7 differ slightly from those previously proposed [11], which treated diversion and killing as independent events, conditional on the host having and using a net. At low values of πi these changes relative to [11] make little difference, but the model described here is more realistic at high values of πi . Extrapolating Impacts of Insecticide-Treated Nets to the Community Level Given the above submodel for the interactions of mosquitoes with individual mammalian hosts, it was possible to extrapolate the likely large-area effects of these small-scale influences on entire vector populations and the human communities they feed upon. For any given number of cattle (Nc), unprotected humans (Nh,u), and protected humans (Nh,p), the mean seeking interval for vertebrate hosts (ηv) can be calculated as the reciprocal of total host availability (A) [52], using estimates of these feeding probabilities and their corresponding encounter rates, adapting Equation 1 from our original formulation [50]: where As refers to the total availability of all hosts of species s. In this case, the species or species categories considered were unprotected humans (h,u), protected humans (h,p), and cattle (c). Values for ac and ah,u (previously ah [50]) were estimated exactly as described previously [50] and ah,p was calculated as follows: where λp is the relative availability of protected versus unprotected hosts, estimated in terms of the ratio of their feeding probabilities: Foraging for resources is an intrinsically dangerous undertaking for mosquitoes, and it is commonly assumed that survival during these phases is lower than while resting in houses [6,60]. We adapted Equation 3 from our previous formulation [50] to estimate the survival rate per feeding cycle (Pf) as the product of the probability of surviving the eventual attack on a host that may be protected (Pγ) and the probabilities of surviving the gestation (g), oviposition site-seeking (ηo), and vertebrate host-seeking (ηv) intervals, with distinct daily survival probabilities for the resting (P), foraging for either oviposition sites or vertebrate hosts (Pov), and attacking (Pγ) phases: The mean probability of mosquitoes surviving their eventual chosen host attack (Pγ) was calculated assuming that the proportion of all attacks that end in death is the sum of the mortality probabilities for attacking protected and unprotected hosts, weighted according to the proportion of all encounters that will occur on such hosts. Assuming that protection does not affect encounter rates, and that these rates are proportional to availability when unprotected, we applied this weighting approach to estimate total attack-related mortality rate and consequent survival as follows: Similarly, the human blood index is calculated as the proportion of total host availability accounted for by humans [52], similarly to Equation 9: The EIR for protected and unprotected individuals was then calculated from the total number of infectious bites upon humans that occur in the population as a whole (β E) [27,49], the share of the total human availability represented by that group, and the population size of that group: where β is the mean number of infectious human bites each emerging mosquito takes in its lifetime and E is the emergence rate of mosquitoes [27]. Dividing Equation 16 by Equation 15, substituting with Equation 10, and rearranging also leads to an intuitively satisfactory solution, consistent with independently formulated models of personal protection [13]: Otherwise, we modelled malaria transmission exactly as previously described [50]. Note that this model has been adapted [11,50] from its original formulation [27] to account for superinfection of mosquitoes [28] and daily time increments to smooth the effects of changing host availability patterns on feeding cycle length [50]. For ease of comparison and interpretation, the impact of ITNs is presented in terms of the relative transmission intensity EIR C /EIR 0 at a given coverage level (C; note distinction from c, which denotes cattle hosts) as a result of personal and communal protection amongst users and nonusers: Baseline Mosquito Behaviour, Host Availability, and Survival Parameters The parameter definitions and values used to implement this analysis are summarized in Table 1. Namwawala, in the Kilombero Valley, southern Tanzania is the primary centre for parameterising our model because of the exceptionally detailed quantitative characterisation of malaria transmission and vector biodemography in this village and the surrounding area. This is a holoendemic village with intense seasonal transmission, stable high parasite prevalence in humans, and a heavy burden of clinical malaria [61–68]. At this site the bulk of transmission is mediated by An. gambiae sensu lato (of which the main species involved in transmission is An. arabiensis) and transmission intensity has been modelled with available field data [27,49]. As previously described [27,49], we based our estimate of human population size [62] approximately upon those reported for this particular village during the early 1990s. Nevertheless, we used a human population size of 1,000 and, where relevant, a bovine population of the same size so that the EIR experienced by users and nonusers could be easily calculated at net coverage levels approaching 0% and 100%. By setting coverage to 0.001 or 0.999, this model simulates a single user or nonuser in the population, respectively. Infectiousness of humans (κ) is set to 0.030, reflecting a more precise recent estimate [69] than was available previously [61,63]. In a typical holoendemic scenario, the infectiousness of the human population is thought to be largely insensitive to reductions in transmission intensity [69]. In the interests of making conservative and generalizable predictions, we assumed that increasing coverage with ITNs will not affect κ [69], even though reduction of κ is likely at EIR values below 10 infectious bites per person per year [56]. We set mean daily survival of the resting phase (P) at 0.90, reflecting a median value of daily survival at four well-characterised holoendemic sites [27] and estimated daily indoor survival for An. gambiae s.l. in Tanzania [70]. As previously described, the daily survival rate of mosquitoes while foraging for blood or oviposition sites (Pov) was set at 0.80, representing a median value of plausible field values [11]. The results of experimental hut studies [34] were combined with host-choice evaluations [71] and appropriate analytical models [50,52] to define the attack and mortality probabilities of An. arabiensis encountering cattle or humans: we set the probability that An. arabiensis will attack unprotected cattle or humans (γu), conditional upon encountering them, to be 0.90 and the chance that they will die in the attempt (μu) at 0.10. Using these parameters and Equation 3, we calculated that, for An. arabiensis, the overall feeding probability upon either cattle (φc) or unprotected humans (φh,u) would be 0.81, a value similar to previous estimates of approximately 0.80–0.85 for the feeding success of An. gambiae sensu lato on sleeping humans in Tanzania [34,62]. We also applied these same probabilities of attacking (γu), feeding (φh,u), and dying (μu) to An. gambiae sensu stricto encountering unprotected humans. The availabilities of unprotected humans and cattle were calculated for An. arabiensis using field measurements of the duration of the feeding cycle and were extended to An. gambiae s.s., accounting for the lower estimated relative availability of cattle (λc) to this mosquito species as previously described [52]. Note that λc is assumed to modify a c by affecting the encounter rate only, indicating that these mosquitoes can differentiate between preferred and nonpreferred hosts at long ranges [72–74]. In the case of An. arabiensis this assumption is consistent with the longer spatial range of attraction of cows relative to humans for zoophilic members of the An. gambiae complex [72–74]. Parameters Reflecting the Effects of Insecticide-Treated Bed Nets The parameter definitions and values describing the impacts of ITNs on vector behaviour and mortality at the level of individual interactions are listed in Table 1. The impacts of ITNs very much depend on their excito-repellent and insecticidal properties, which are most representatively evaluated using well-established experimental hut methodologies [59,75,76] that have been extensively applied to this particular intervention [29–34]. Furthermore, the interaction of these two properties, to yield varying levels of personal and communal protection, is complex and has crucial implications for ITN programmes across Africa [11]. Sensitivity analysis of models similar to those used in this paper [11] have previously been used to explore the influence that these properties might have upon the magnitude and equity of protection afforded by ITNs (Figure 2). In order to validate this slightly revised model (see Equations 4-8) and similarly investigate such interactions at ITN coverage levels that can be plausibly sustained, we examined usage data collected during routine socioeconomic status surveys of a long-standing demographic surveillance system in the Kilombero Valley, southern Tanzania, where social marketing programmes have been well established since 1997 [77,78]. Data from the annual ITN usage survey in 2004 were used because they overlap with detailed entomological surveys of malaria transmission (which will be reported elsewhere). These surveys of randomly sampled residents from across two rural districts indicate that 75% (11,982/16,086) net use was achieved although most of these nets were not effectively treated [79]. In this sensitivity analysis, we assumed that new long-lasting ITN technologies [44–47] will enable sustained coverage with nets that are effectively treated even under the most rigorous programmatic field conditions. Figure 2 The Simulated Protection ITNs Afford against Exposure to Malaria Transmission as a Function of Their Ability to Divert and Kill Host-Seeking Mosquitoes Protection is expressed as relative exposure to malaria transmission (EIR C /EIR o ) for individuals with (Equation 19) and without (Equation 18) nets is plotted as a function of their ability to divert (Δp) and kill (μp) mosquitoes attacking protected humans. To simulate the likely field properties of existing long-lasting insecticidal nets with a full range of insecticidal and excito-repellent properties, the parameters of this model reflecting increased mosquito mortality (μp) and diversion (Δp) were varied across a plausible range of 0–0.8. As described in the main text and previous publications, these results represent simulations in two distinctive scenarios: An. gambiae sensu lato in the absence of cattle (results for both sibling species are identical) and An. arabiensis in the presence of one head of cattle per person. The biodemographic parameters of the interacting vector and parasite are also exactly as described previously [11,13] with survival of foraging mosquitoes (Pov) set at 0.8 per day. Coverage levels of 75% net usage was assumed, consistent with the results of surveys in the Kilombero Valley, southern Tanzania (see Methods: Parameters Reflecting the Effects of Insecticide-Treated Bed Nets). Figure 2 shows that, for the comparatively zoophilic vector An. arabiensis, in the presence of alternative hosts, excito-repellency consistently enhances the benefits for both users and nonusers, regardless of the insecticidal properties of the net. Consistent with previous analyses using this model [11], this simulation suggests that nets that are purely excito-repellent and lack insecticidal properties could slightly increase exposure of nonusers to An. gambiae sensu lato by diverting mosquitoes to them where no alternative sources of blood are available. Thus, purely diversionary vector control strategies may indeed be ethically questionable, as was previously suggested [31,34,80,81]. Nevertheless, even modest insecticidal properties are expected to counterbalance this inequity and confer a useful communal reduction of EIR. While repellent properties do slightly reduce the benefits to nonusers exposed to anthropophagic vectors lacking an alternative host, this slight disadvantage is likely to be outweighed in practice by the advantage of improved personal protection for users: Excito-repellent properties and physical barriers add to the effectiveness of insecticides for personal protection because these two incentives constitute the major motivating force behind ITN uptake and use at the individual and subsequently the community level. It is also reassuring to note that the predictions and epidemiological implications of this slightly revised model are very similar to those reported for its previous iteration [11]. We therefore concluded that the simulations described in the main text should consider ITNs with both insecticidal and excito-repellent properties, consistent with those of products currently on the market that have been evaluated in a variety of settings and experimental designs. To simulate the likely properties of established ITNs under programmatic conditions, we conservatively assumed they will both divert and kill 40% more mosquitoes than an unprotected human (μp = 0.4 and Δp = 0.4). A net with such proper-ties would protect against 64% of indoor exposure (1 − [(1 − 0.4) × (1 − 0.4)] = 0.64), as measured in a typical experimental hut trial [46,76]. To explore the best possible future scenario for the development of highly durable ITNs [44–47] or regular retreatment services [82], we also simulated increasing co-verage with nets that divert and kill 80% more mosquitoes than with an unprotected human (μp = 0.8 and Δp = 0.8), providing 96% protection (1 − [(1 − 0.8) × (1 − 0.8)] = 0.96). The proportion of normal biting exposure that occurs while nets are actually in use (πi) has been estimated as 90% for A. gambiae in southern Tanzania [13], so we set πi to a value of 0.90. Results Figure 3 illustrates how increasing community-level protection of ITN nonusers and users alike combines with constant individual protection to reduce exposure to malaria. Regardless of vector species or the availability of alternative hosts, modestly effective conventional ITNs achieve much greater impact upon human exposure, even that of users, if approximately half or more of the whole human population is covered. While this principle has already been suggested by field trials [19] and two independently formulated models [11,12], here we have identified specific coverage thresholds at which communal protection becomes greater than or equal to individual personal protection. Where alternative hosts for vector mosquitoes are absent, 35% of the human population must sleep under regular ITNs to achieve equivalence of personal and communal protection mechanisms, resulting in major community-wide suppression of exposure. The same target is achieved at 55% coverage where alternative hosts such as cattle are present. Figure 3 Relative Exposure to Malaria Transmission (EIR C /EIR o ) as a Function of Increasing Coverage with Insecticide-Treated Nets We express coverage as the proportion of the total human population using an ITN each night, and protection as the proportional reduction of infectious bites to which a resident is exposed (see Methods). Individual protection afforded to users (thin solid line; Equation 20) and communal protection afforded to nonusers (thick dashed line; Equation 18), as well as their combined effect on users (thick solid line; Equation 19) are separately calculated [11,13]. Two distinct but common and broadly distributed ecological scenarios in Africa are considered: (1) An. gambiae or An. arabienis (sibling species of the same species complex known as An. gambiae sensu lato) populations in the absence of alternative blood sources and (2) vector populations dominated by An. arabiensis in the presence of abundant cattle as alternative hosts. Both scenarios are simulated with ITNs that have either standard or improved properties (See Methods). Grey shading represents an approximate absolute maximum for community-level coverage achievable by covering vulnerable under five years of age and pregnant population groups only with perfect targeting efficiency. Arrows extrapolate the thresholds at which communal and personal protection are equivalent. The insecticidal and excito-repellent properties of ITNs that define levels of personal protection also determine the extent of community-wide alleviation of exposure amongst users and nonusers alike [11], so improved ITN properties consistently result in improved overall impact. In our model, slightly higher usage rates were required to achieve equivalence of individual and communal effects, with thresholds of 40% and 64% coverage for vector populations with and without alternative hosts, respectively (Figure 3). While emerging ITN technologies with long-lasting insecticidal properties under programmatic conditions [44] would confer useful personal protection even at low coverage levels, personal protection was greatly enhanced by communal protection. At the 75% total population coverage recently achieved with largely untreated nets in southern Tanzania (Killeen et al., unpublished data), net users and nonusers are predicted to receive >98% and >90% protection, respectively, regardless of ecological scenario, if those nets were to be replaced with improved long-lasting insecticidal nets. Even for users of improved ITNs, this level of protection against African vector species is impossible without the contribution of community-level transmission suppression, because at least 10% of exposure occurs outdoors during times of the night when nets are not in use [13,83]. We conclude that modest coverage (thresholds of approximately 35%–65% use, depending on ecological scenario) of entire malaria-endemic populations, rather than just the most vulnerable minority, is needed to realize the full potential of ITNs, even with longer-lasting products or regular retreatment services [14,44]. This range of modelled thresholds is remarkably consistent with the figure of 50% suggested by large-scale field trials using approximately equivalent technology [19]. Discussion In addition to the direct impacts on vector populations explicitly modelled above, coverage of adults and older children is likely to have further benefits arising from subtleties of mosquito resource utilization that are often under-appreciated. Over 80% of human-to-mosquito transmission originates from adults and children over five years of age, because these groups constitute the bulk of the population and are more attractive to mosquitoes [56]. Where the entomological inoculation rate is fewer than ten infectious bites per person per year, the distributions of infectiousness [56,69], morbidity, and mortality will all shift into these older age groups, necessitating protection of all members of the population. Under such conditions, ITNs could suppress transmission not only through direct impacts on mosquito mortality, host choice, and feeding frequency [11], but also by limiting the prevalence, density, and infectiousness of malaria parasites in the human population [56]. An under-emphasized feature of communal protection is the enhancement of ITN programme equity, regardless of ecological scenario or ITN effectiveness: If the majority of people living in malaria-endemic Africa regularly used existing ITN technologies, nonusers would receive communal protection at least equivalent to using the only ITN in an otherwise unprotected population (Figure 3). This means that all children would equitably receive communal protection at least equivalent to the personal protection of an ITN, with users receiving multiplicative combined effects on exposure of both personal and communal benefits. While the wisdom of targeting interventions to protect at-risk individuals is based on solid scientific grounds [9,18,84] and is widely accepted [16], this approach should not preclude efforts to maximize communal protection through less selective delivery mechanisms. Targeting limited subsidies to maximize personal protection of the most vulnerable should remain a priority, but more equitable and effective suppression of risk for entire populations, including vulnerable groups, can be attained with quite modest coverage across all ages. Most field evaluations of ITNs have been conducted at reasonably high coverage levels [19], and all five mortality trials [21,85–88] that estimated that ITNs save 5.5 lives for every 1,000 children protected [20] covered large portions of entire communities rather than only the children themselves. The choice of ITN delivery strategy has proven contentious in recent years [89,90], but proponents of both market-based and public-sector approaches equally emphasize targeting strategies [9,16,84] to enhance equity and minimize leakage of subsidized ITNs beyond intended target groups [91–94]. While optimal targeting of finite subsidies is highly desirable, there are fundamental limitations to the impact that can be achieved: Even if resources were perfectly targeted, 80% coverage of pregnant women and children under five years of age could be accomplished with less than 20% coverage of the whole population, and even less of the total human host availability [11,56], as well as the infectious parasite reservoir [56,69]. Even if the ITN coverage targets of the MDGs were attained with flawless targeting efficiency, the substantial and equitable benefits of communal protection would not be achieved. Specifically, the target of 70% less exposure to transmission [13] would not be attained by the remaining minority of vulnerable individuals who are not covered and do not use an ITN, regardless of ecological scenario or ITN properties (Figure 3). We therefore highlight an important caveat to the following conclusion of the current Global Strategic Framework for ITN scaleup in Africa [95]: “In order to achieve maximum public health impact, ITN coverage needs to be maximized amongst those population groups that are most vulnerable to malaria infection and its consequences, primarily pregnant women and children under five years of age.” Specifically, we conclude that protecting the vulnerable can achieve maximum public health impact only if complemented by strategies that also achieve broad coverage of the population as a whole. In reality, the targets for coverage of vulnerable groups will not be reached without some leakage and inequity. Our analysis suggests that such concerns may be less of a problem than the targets themselves and may be minimized by extending coverage priorities to include all age groups. Fortunately, consensus is finally emerging that a range of approaches to ITN deployment merit investigation, development, and comparative evaluation at scales for which no precedent yet exists [95]. Note that this analysis supports the implementation of any of the diverse and rapidly emerging delivery strategies as long as high coverage with long-lasting ITNs is sustained across entire malaria-endemic populations on national scales. Perhaps the most important remaining question is: How can such population-wide coverage levels be affordably and cost-effectively sustained? Growing financial support for malaria control globally [14,15,95] may enable fully subsidized provision to entire populations [82] of the world's most impoverished, malaria-afflicted nations. Existing evidence, based largely on individual protection alone, indicates that ITNs are as cost-effective as childhood immunization [96], and future analyses should explicitly consider the additional benefits of communal protection. Implementing this goal may be relatively straightforward for programmes that are primarily subsidized and implemented through the public sector, such as recent successful initiatives associated with vaccination campaigns [91]. By comparison, social marketing approaches, including hybrid systems that deliver public subsidies through the private sector, may require more detailed consideration, particularly where cost sharing with the target population is substantial and biased toward the nonpregnant adults and older children who are key to communal protection. Although social marketing approaches to ITN distribution face substantial challenges [93,97,98], notable success in terms of coverage and impact have been reported in a variety of settings [94,99,100], including the KINET programme in Kilombero Valley, southern Tanzania where ITNs have been promoted and subsidized since 1996 [77,78]. Much of the essential experience generated by KINET was later integrated into the ITN promotion strategy of the National Malaria Control Programme of Tanzania, which supports private sector distribution through a voucher system that subsidizes purchase by vulnerable priority groups [101]. In the meantime, the preceding KINET pilot in Kilombero has achieved 75 % net use amongst randomly sampled residents of all ages (Killeen et al., unpublished data). It is particularly noteworthy that substantial levels of communal protection were achieved [102] (unpublished data) even though most of these nets were untreated or poorly treated at the time of evaluation [79] (unpublished data). Reassuringly, the model applied here approximately reproduces these patterns of communal protection using plausible parameter estimates for the net properties, vector behaviours, and host demographics of the area (unpublished data). We therefore recommend that the cost-effectiveness of such hybrid approaches be explicitly evaluated in terms of the complementary respective contributions of public-sector subsidies and cost-sharing by target populations to personal and communal protection. While appropriate engagement and sensitization of malaria-afflicted populations is essential to the success of any ITN promotion programme, this is likely to be especially true where cost-sharing by the target population will be needed to complement limited public subsidies. Such cost-sharing schemes may be the only affordable means to support full population coverage where available subsidies are inadequate. In such resource-limited circumstances, high levels of awareness, acceptance, and willingness to pay will be essential to enable concerted use of ITNs by adults and shared protection of all children within their communities. Overly confident extrapolation from mathematical models to set operational targets for malaria control has proved to be a grave mistake in the past [103]. A number of complications not captured by this model could emerge as ITN coverage increases, not least of which might be increased selection for insecticide resistance [104,105]. While we urge caution in interpreting the numerical results of our analysis, the phenomenon outlined is well established and has clear implications for malaria control in Africa and beyond [19]. In fact, the analysis presented here provides a generalizable rationale that strongly supports the conclusions of the most recent and meticulous evaluations of the community-level benefits of ITNs: “High coverage with ITNs will do more for public health in Africa than previously imagined” [19]. We therefore suggest that further field data, analyzed with appropriate theoretical models and cost-effectiveness frameworks, are required to verify and quantify the levels of communal protection afforded by increasing ITN use across Africa. International targets [2,14,15] should be amended to include thresholds for coverage of entire populations and monitored accordingly. By making life increasingly difficult for mosquitoes through programmes that promote ITN use by the majority of their human victims, it may be possible to protect the 15%–20% of children and pregnant women in African communities who would not otherwise be covered even if existing personal protection targets of the MDGs [2], the Roll Back Malaria Partnership [14], or the U.S. President's Malaria Initiative [15] were to be achieved. Supporting Information Protocol S1 Model Spreadsheet A Microsoft Excel spreadsheet version of all model simulations presented here is available to download. (1.1 MB XLS) Click here for additional data file.
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                Author and article information

                Journal
                bwho
                Bulletin of the World Health Organization
                Bull World Health Organ
                World Health Organization (Genebra, Genebra, Switzerland )
                0042-9686
                September 2009
                : 87
                : 9
                : 655-665
                Affiliations
                London orgnameLondon School of Hygiene and Tropical Medicine orgdiv1Disease Control and Vector Biology Unit England
                Nairobi orgnameKenya Medical Research Institute orgdiv1Centre for Vector Biology and Control Research Kenya
                Article
                S0042-96862009000900009 S0042-9686(09)08700909
                2739910
                19784445

                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 48, Pages: 11
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