Gerry F. Killeen

Eradication of Anopheles gambiae from Brazil: lessons for malaria control in Africa?

Current malaria-control strategies emphasise domestic protection against adult mosquitoes with insecticides, and improved access to medical services. Malaria prevention by killing adult mosquitoes is generally favoured because moderately reducing their longevity can radically suppress community-level transmission. By comparison, controlling larvae has a less dramatic effect at any given level of coverage and is often more difficult to implement. Nevertheless, the historically most effective campaign against African vectors is the eradication of accidentally introduced Anopheles gambiae from 54000 km(2) of largely ideal habitat in northeast Brazil in the 1930s and early 1940s. This outstanding success was achieved through an integrated programme but relied overwhelmingly upon larval control. This experience was soon repeated in Egypt and another larval control programme successfully suppressed malaria for over 20 years around a Zambian copper mine. These affordable approaches were neglected after the advent of dichlorodiphenyl trichloroethane (DDT) and global malaria-control policy shifted toward domestic adulticide methods. Larval-control methods should now be re-prioritised for research, development, and implementation as an additional way to roll back malaria.

Advantages of larval control for African malaria vectors: Low mobility and behavioural responsiveness of immature mosquito stages allow high effective coverage

BackgroundBased on sensitivity analysis of the MacDonald-Ross model, it has long been argued that the best way to reduce malaria transmission is to target adult female mosquitoes with insecticides that can reduce the longevity and human-feeding frequency of vectors. However, these analyses have ignored a fundamental biological difference between mosquito adults and the immature stages that precede them: adults are highly mobile flying insects that can readily detect and avoid many intervention measures whereas mosquito eggs, larvae and pupae are confined within relatively small aquatic habitats and cannot readily escape control measures.Presentation of the hypothesisWe hypothesize that the control of adult but not immature mosquitoes is compromised by their ability to avoid interventions such as excito-repellant insecticides.Testing the hypothesisWe apply a simple model of intervention avoidance by mosquitoes and demonstrate that this can substantially reduce effective coverage, in terms of the proportion of the vector population that is covered, and overall impact on malaria transmission. We review historical evidence that larval control of African malaria vectors can be effective and conclude that the only limitations to the effective coverage of larval control are practical rather than fundamental.Implications of the hypothesisLarval control strategies against the vectors of malaria in sub-Saharan Africa could be highly effective, complementary to adult control interventions, and should be prioritized for further development, evaluation and implementation as an integral part of Rolling Back Malaria.

Traditional use of mosquito-repellent plants in western Kenya and their evaluation in semi-field experimental huts against Anopheles gambiae: ethnobotanical studies and application by thermal expulsion and direct burning

Ethnobotanical survey in 2 communities in western Kenya revealed that the most commonly known repellent plants were Ocimum americanum L. (64.1%), Lantana camara L. (17.9%), Tagetes minuta L. (11.3%) and Azadirachta indica A. Juss (8.7%) on Rusinga Island, and Hyptis suaveolens Poit. (49.2%), L. camara (30.9%) and O. basilicum L. (30.4%) in Rambira. Direct burning of plants is the most common method of application for O. americanum (68.8%), L. camara (100%) and O. basilicum (58.8%). Placing branches or whole plants inside houses is most common for H. suaveolens (33.3 and 57.8% for the respective locations), A. indica (66.7 and 100%), and T. minuta (54.8 and 56.0%). The repellency of plants suggested by the ethnobotanical survey and other empirical information was evaluated against the malaria vector Anopheles gambiae s.s. Giles in experimental huts within a screenwalled greenhouse. Thermal expulsion and direct burning were tested as alternative application methods for the selected plants O. americanum, O. kilimandscharicum Guerke, O. suave Willd., L. camara, A. indica, H. suaveolens, Lippia uckambensis Spreng and Corymbia citriodora Hook. When thermally expelled, only H. suaveolens failed to repel mosquitoes, whereas the leaves of C. citriodora (74.5%, P < 0.0001), leaves and seeds of O. suave (53.1%, P < 0.0001) and O. kilimandscharicum (52.0%, P < 0.0001) were the most effective. Leaves of C. citriodora also exhibited the highest repellency (51.3%, P < 0.0001) by direct burning, followed by leaves of L. uckambensis (33.4%, P = 0.0004) and leaves and seeds of O. suave (28.0%, P = 0.0255). The combination of O. kilimandscharicum with L. uckambensis repelled 54.8% of mosquitoes (P < 0.0001) by thermal expulsion. No combination of plants increased repellency by either method. The semi-field system described appears a promising alternative to full-field trials for screening large numbers of candidate repellents without risk of malaria exposure.

An individual-based model of Plasmodium falciparum malaria transmission on the coast of Kenya

Individual-based models provide powerful tools to model complex interactions characterized by individual variability. This paper presents an object-oriented design for individual-based modelling of Plasmodium falciparum malaria transmission. Two kinds of objects, human and mosquito, that exhibit variability among individuals for parameters such as recovery and survival rates are defined. The model tracks the dynamics of human hosts and adult female mosquitoes individually. Immunity, modelled as a function of exposure history, is represented by reduced susceptibility and increased recovery rate. The model was calibrated using epidemiological data collected at 30 sites along the coast of Kenya. The sites were grouped into low, intermediate and high transmission based on mean daily human-biting rates. Simulation results show that malaria transmission was stable even in low transmission areas where the human-biting rate is approximately 0.5 bite per day. The model was used to examine the effect of infection control programmes that aim at interrupting transmission by reducing human-vector contact rates and implementing active case detection and drug treatment of infections. With this intervention, local elimination of malaria is likely with a probability of extinction of approximately 0.8 in low transmission areas. However, a small amount of immigration (> 0.3%) by infected people into the community could prevent local extinction of the parasite. In intermediate and high transmission areas, reduction in prevalence is short-lived and the probability of local elimination is low, even at high coverage levels of the intervention.

Behavioural determinants of gene flow in malaria vector populations: Anopheles gambiae males select large females as mates

BackgroundPlasmodium-refractory mosquitoes are being rapidly developed for malaria control but will only succeed if they can successfully compete for mates when released into the wild. Pre-copulatory behavioural traits maintain genetic population structure in wild mosquito populations and mating barriers have foiled previous attempts to control malaria vectors through sterile male release.MethodsVarying numbers of virgin male and female Anopheles gambiae Giles, from two strains of different innate sizes, were allowed to mate under standardized conditions in laboratory cages, following which, the insemination status, oviposition success and egg batch size of each female was assessed. The influence of male and female numbers, strain combination and female size were determined using logistic regression, correlation analysis and a simple mechanistic model of male competition for females.ResultsMale An. gambiae select females on the basis of size because of much greater fecundity among large females. Even under conditions where large numbers of males must compete for a smaller number of females, the largest females are more likely to become inseminated, to successfully oviposit and to produce large egg batches.ConclusionsSexual selection, on the basis of size, could either promote or limit the spread of malaria-refractory genes into wild populations and needs to be considered in the continued development and eventual release of transgenic vectors. Fundamental studies of behavioural ecology in malaria vectors such as An. gambiae can have important implications for malaria control and should be prioritised for more extensive investigation in the future.

SEASONALITY, PARASITE DIVERSITY, AND LOCAL EXTINCTIONS IN PLASMODIUM FALCIPARUM MALARIA

We incorporate stochastic, density-dependent seasonal recruitment in adult Anopheles mosquito populations in a discrete-event model of Plasmodium falciparum malaria transmission and find the probabilities of parasite extinction higher than with perennial transmission. Seasonal fluctuations in vector populations act to synchronize the dynamics of infection and immunity in host populations, leading to fluctuations in parasite prevalence greater than expected solely on the basis of high- and low-season vector densities. This synchronization also biases frequencies of infection with multiple parasite phenotypes or genotypes.

Effects of dietary supplementation with Yucca schidigera Roezl ex Ortgies and its saponin and non-saponin fractions on rat metabolism.

Yucca schidigera Roezl ex Ortgies, family Lillaceae, was fractionated with butan-1-ol to yield a butanol extractable fraction (BE; saponin fraction) and a non-butanol fraction (NBE; non-saponin fraction). Four groups of eight male rats were allowed ad libitum access to diets supplemented with water (control) or 200 mg x kg(-1) total Y. schidigera (TOT) or 200 mg x kg(-1) of each of the fractions (NBE or BE). The effects of dietary supplementation with the fractions and their interactions in TOT were analyzed according to the factorial experimental design by two-way analysis of variance. All three supplementation groups displayed significantly reduced serum urea levels (P < 0.05). The TOT and NBE fractions were found to significantly increase serum insulin levels (P < 0.01) in the absence of any fluctuations in serum glucose levels. Urea cycle enzyme activities, namely, arginase (EC 3.5.3.1) and argininosuccinate lyase (EC 4.3.2.1), were significantly decreased (P < 0.05) in vivo, although no effect was observed in vitro. Both fractions displayed effects, indicating that the active constituents are present in both fractions.

The effects of dietary supplementation with Yucca schidigera extract or fractions thereof on nitrogen metabolism and gastrointestinal fermentation processes in the rat

Yucca schidigera was fractionated with butan-1-ol, yielding a butanol-extractable (BE) fraction, containing all the in vitro antimicrobial activity, and the aqueous, non-butanol-extractable (NBE) fraction. Four groups of five female rats (12 weeks old) were allowed ad libitum access to diets supplemented with water (control) or 200 mg kg -1 total Y. schidigera (TOT) or its fraction equivalent of NBE or BE for 64 days. The effects of the fractions and their interactions in the TOT treatment were analysed according to the factorial experimental structure by two-way ANOVA. NBE reduced serum urea (-50%, P = 0.019) and ammonia (-46%, P = 0.037) concentrations, serum/urine concentration quotients of urea (-79%, P = 0.009) and ammonia (-57%, P = 0.002). NBE also reduced hindgut acetate/propionate (-12%, P = 0.007) but increased faecal ammonia concentration (+87%, P = 0.039). BE reduced hindgut indoles (-25%, P = 0.023) and interacted synergystically with NBE in the TOT treatment to further reduce hindgut acetate/propionate by 6% (P = 0.006). NBE increased (+27%, P = 0.002) and BE decreased (-57%, P = 0.005) hindgut urease activity levels, resulting in essentially no change (+4%) in the TOT treatment. The in vitro antimicrobial activity of Y. schidigera is an unlikely explanation for most of its effects in vivo because these are caused by NBE and in vitro antimicrobial activity is exclusive to BE. Sarsasapogenin and smilagenin were also exclusive (>98%) to BE and cannot account for the effects of Y. schidigera on N metabolism.

Monitoring, characterization and control of chronic, symptomatic malaria infections in rural Zambia through monthly household visits by paid community health workers

BackgroundActive, population-wide mass screening and treatment (MSAT) for chronic Plasmodium falciparum carriage to eliminate infectious reservoirs of malaria transmission have proven difficult to apply on large national scales through trained clinicians from central health authorities.MethodologyFourteen population clusters of approximately 1,000 residents centred around health facilities (HF) in two rural Zambian districts were each provided with three modestly remunerated community health workers (CHWs) conducting active monthly household visits to screen and treat all consenting residents for malaria infection with rapid diagnostic tests (RDT). Both CHWs and HFs also conducted passive case detection among residents who self-reported for screening and treatment.ResultsDiagnostic positivity was higher among symptomatic patients self-reporting to CHWs (42.5%) and HFs (24%) than actively screened residents (20.3%), but spatial and temporal variations of diagnostic positivity were highly consistent across all three systems. However, most malaria infections (55.6%) were identified through active home visits by CHWs rather than self-reporting to CHWs or HFs. Most (62%) malaria infections detected actively by CHWs reported one or more symptoms of illness. Most reports of fever and vomiting, plus more than a quarter of history of fever, headache and diarrhoea, were attributable to malaria infection. The minority of residents who participated >12 times had lower rates of malaria infection and associated symptoms in later contacts but most residents were tested <4 times and high malaria diagnostic positivity (32%) in active surveys, as well as incidence (1.7 detected infections per person per year) persisted in the population. Per capita cost for active service delivery by CHWs was US

Characterization of a unique human single-chain antibody isolated by phage-display selection on membrane-bound mosquito midgut antigens.

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