BACKGROUND:Primary malaria prevention on a large scale depends on two vector control interventions: indoor residual spraying (IRS) and insecticide-treated mosquito nets (ITNs). Historically, IRS has reduced malaria transmission in many settings in the world, but the health effects of IRS have never been properly quantified. This is important, and will help compare IRS with other vector control interventions. OBJECTIVES:To quantify the impact of IRS alone, and to compare the relative impacts of IRS and ITNs, on key malariological parameters. SEARCH STRATEGY:We searched the Cochrane Infectious Diseases Group Specialized Register (September 2009), CENTRAL (The Cochrane Library 2009, Issue 3), MEDLINE (1966 to September 2009), EMBASE (1974 to September 2009), LILACS (1982 to September 2009), mRCT (September 2009), reference lists, and conference abstracts. We also contacted researchers in the field, organizations, and manufacturers of insecticides (June 2007). SELECTION CRITERIA:Cluster randomized controlled trials (RCTs), controlled before-and-after studies (CBA) and interrupted time series (ITS) of IRS compared to no IRS or ITNs. Studies examining the impact of IRS on special groups not representative of the general population, or using insecticides and dosages not recommended by the World Health Organization (WHO) were excluded. DATA COLLECTION AND ANALYSIS:Two authors independently reviewed trials for inclusion. Two authors extracted data, assessed risk of bias and analysed the data. Where possible, we adjusted confidence intervals (CIs) for clustering. Studies were grouped into those comparing IRS with no IRS, and IRS compared with ITNs, and then stratified by malaria endemicity. MAIN RESULTS:IRS versus no IRSStable malaria (entomological inoculation rate (EIR) > 1): In one RCT in Tanzania IRS reduced re-infection with malaria parasites detected by active surveillance in children following treatment; protective efficacy (PE) 54%. In the same setting, malaria case incidence assessed by passive surveillance was marginally reduced in children aged one to five years; PE 14%, but not in children older than five years (PE -2%). In the IRS group, malaria prevalence was slightly lower but this was not significant (PE 6%), but mean haemoglobin was higher (mean difference 0.85 g/dL).In one CBA trial in Nigeria, IRS showed protection against malaria prevalence during the wet season (PE 26%; 95% CI 20 to 32%) but not in the dry season (PE 6%; 95% CI -4 to 15%). In one ITS in Mozambique, the prevalence was reduced substantially over a period of 7 years (from 60 to 65% prevalence to 4 to 8% prevalence; the weighted PE before-after was 74% (95% CI 72 to 76%).Unstable malaria (EIR < 1): In two RCTs, IRS reduced the incidence rate of all malaria infections;PE 31% in India, and 88% (95% CI 69 to 96%) in Pakistan. By malaria species, IRS also reduced the incidence of P. falciparum (PE 93%, 95% CI 61 to 98% in Pakistan) and P. vivax (PE 79%, 95% CI 45 to 90% in Pakistan); There were similar impacts on malaria prevalence for any infection: PE 76% in Pakistan; PE 28% in India. When looking separately by parasite species, for P. falciparum there was a PE of 92% in Pakistan and 34% in India; for P. vivax there was a PE of 68% in Pakistan and no impact demonstrated in India (PE of -2%).IRS versus Insecticide Treated Nets (ITNs)Stable malaria (EIR > 1): Only one RCT was done in an area of stable transmission (in Tanzania). When comparing parasitological re-infection by active surveillance after treatment in short-term cohorts, ITNs appeared better, but it was likely not to be significant as the unadjusted CIs approached 1 (risk ratio IRS:ITN = 1.22). When the incidence of malaria episodes was measured by passive case detection, no difference was found in children aged one to five years (risk ratio = 0.88, direction in favour of IRS). No difference was found for malaria prevalence or haemoglobin.Unstable malaria (EIR < 1): Two studies; for incidence and prevalence, the malaria rates were higher in the IRS group compared to the ITN group in one study. Malaria incidence was higher in the IRS arm in India (risk ratio IRS:ITN = 1.48) and in South Africa (risk ratio 1.34 but the cluster unadjusted CIs included 1). For malaria prevalence, ITNs appeared to give better protection against any infection compared to IRS in India (risk ratio IRS:ITN = 1.70) and also for both P. falciparum (risk ratio IRS:ITN = 1.78) and P. vivax (risk ratio IRS:ITN = 1.37). AUTHORS' CONCLUSIONS:Historical and programme documentation has clearly established the impact of IRS. However, the number of high-quality trials are too few to quantify the size of effect in different transmission settings. The evidence from randomized comparisons of IRS versus no IRS confirms that IRS reduces malaria incidence in unstable malaria settings, but randomized trial data from stable malaria settings is very limited. Some limited data suggest that ITN give better protection than IRS in unstable areas, but more trials are needed to compare the effects of ITNs with IRS, as well as to quantify their combined effects.

Background: Although the molecular basis of resistance to a number of common antimalarial drugs is well known, a geographic description of the emergence and dispersal of resistance mutations across Africa has not been attempted. To that end we have characterised the evolutionary origins of antifolate resistance mutations in the dihydropteroate synthase (dhps) gene and mapped their contemporary distribution.Methods and Findings: We used microsatellite polymorphism flanking the dhps gene to determine which resistance alleles shared common ancestry and found five major lineages each of which had a unique geographical distribution. The extent to which allelic lineages were shared among 20 African Plasmodium falciparum populations revealed five major geographical groupings. Resistance lineages were common to all sites within these regions. The most marked differentiation was between east and west African P. falciparum, in which resistance alleles were not only of different ancestry but also carried different resistance mutations.Conclusions: Resistant dhps has emerged independently in multiple sites in Africa during the past 10-20 years. Our data show the molecular basis of resistance differs between east and west Africa, which is likely to translate into differing antifolate sensitivity. We have also demonstrated that the dispersal patterns of resistance lineages give unique insights into recent parasite migration patterns.

Malaria is a serious infectious disease that can be fatal if not diagnosed and treated promptly. It is caused by a parasite belonging to the genus Plasmodium, of which four different species are known to affect humans, namely P ovale, P vivax and P malariae and P falciparum. The last one being the most dangerous and unfortunately the most common in Africa.

The prevalence and frequency of the dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps) mutations associated with sulfadoxine-pyrimethamine (SP) resistance at 13 sentinel surveillance sites in southern Mozambique were examined regularly between 1999 and 2004. Frequency of the dhfr triple mutation increased from 0.26 in 1999 to 0.96 in 2003, remaining high in 2004. The dhps double mutation frequency peaked in 2001 (0.22) but declined to baseline levels (0.07) by 2004. Similarly, parasites with both dhfr triple and dhps double mutations had increased in 2001 (0.18) but decreased by 2004 (0.05). The peaking of SP resistance markers in 2001 coincided with a SP-resistant malaria epidemic in neighboring KwaZulu-Natal, South Africa. The decline in dhps (but not dhfr) mutations corresponded with replacement of SP with artemether-lumefantrine as malaria treatment policy in KwaZulu-Natal. Our results show that drug pressure can exert its influence at a regional level rather than merely at a national level.

Background: Indoor residual spraying (IRS) has again become popular for malaria control in Africa. This combined with the affirmation by WHO that DDT is appropriate for use in the absence of longer lasting insecticide formulations in some malaria endemic settings, has resulted in an increase in IRS with DDT as a major malaria vector control intervention in Africa. DDT was reintroduced into Mozambique's IRS programme in 2005 and is increasingly becoming the main insecticide used for malaria vector control in Mozambique. The selection of DDT as the insecticide of choice in Mozambique is evidence-based, taking account of the susceptibility of Anopheles funestus to all available insecticide choices, as well as operational costs of spraying.Previously lambda cyhalothrin had replaced DDT in Mozambique in 1993. However, resistance appeared quickly to this insecticide and, in 2000, the pyrethroid was phased out and the carbamate bendiocarb introduced. Low level resistance was detected by biochemical assay to bendiocarb in 1999 in both An. funestus and Anopheles arabiensis, although this was not evident in WHO bioassays of the same population.Methods: Sentinel sites were established and monitored for insecticide resistance using WHO bioassays. These assays were conducted on 1-3 day old F1 offspring of field collected adult caught An. funestus females to determine levels of insecticide resistance in the malaria vector population. WHO biochemical assays were carried out to determine the frequency of insecticide resistance genes within the same population.Results: In surveys conducted between 2002 and 2006, low levels of bendiocarb resistance were detected in An. funestus, populations using WHO bioassays. This is probably due to significantly elevated levels of Acetylcholinesterase levels found in the same populations. Pyrethroid resistance was also detected in populations and linked to elevated levels of p450 monooxygenase activity. One site had shown reduction in pyrethroid resistance since the base line in 1999.

With the increase in indoor residual spraying in many internationally and nationally funded malaria control programs, and affirmation by World Health Organization (WHO) that DDT is appropriate for use in the absence of longer lasting insecticide formulations in some malaria endemic settings, DDT has been reintroduced as a major malaria control intervention in Africa. Indoor residual spraying with DDT was reintroduced into Mozambique for malaria control in 2005, and it is increasingly becoming the main insecticide used for malaria vector control in Mozambique. The selection of DDT in Mozambique is evidence-based, taking account of the susceptibility of Anopheles arabiensis (Patton) and Anopheles gambiae (Giles) s.s. to all the available insecticide choices, as well as relative costs of the insecticide and the logistical costs of spraying. Before this time in Mozambique, DDT was replaced by λ-cyhalothrin in 1993. Resistance occurred quickly to this insecticide, and in 2000 the pyrethroid was phased out and the carbamate bendiocarb was introduced. Low-level resistance was detected by biochemical assay to bendiocarb in 1999 in both Anopheles funestus (Giles) and An. arabiensis, although this was not evident in WHO bioassays of the same population. In the 2000–2006 surveys the levels of bendiocarb resistance had been selected to a higher level in An. arabiensis, with resistance detectable by both biochemical and WHO bioassay. The insecticide resistance monitoring program includes assessment of field populations by standard WHO insecticide susceptibility assays and biochemical assays. Monitoring was established in 1999, and it was maintained as part of an operational monitoring and evaluation program thereafter.

Background Five large insecticide-treated net (ITN) programmes and two indoor residual spraying (IRS) programmes were compared using a standardized costing methodology. Methods Costs were measured locally or derived from existing studies and focused on the provider perspective, but included the direct costs of net purchases by users, and are reported in 2005 USD. Effectiveness was estimated by combining programme outputs with standard impact indicators. Findings Conventional ITNs: The cost per treated net-year of protection ranged from USD 1.21 in Eritrea to USD 6.05 in Senegal. The cost per child death averted ranged from USD 438 to USD 2,199 when targeting to children was successful. Long-lasting insecticidal nets (LLIN) of five years duration: The cost per treated-net year of protection ranged from USD 1.38 in Eritrea to USD 1.90 in Togo. The cost per child death averted ranged from USD 502 to USD 692. IRS: The costs per person-year of protection for all ages were USD 3.27 in KwaZulu Natal and USD 3.90 in Mozambique. If only children under five years of age were included in the denominator the cost per person-year of protection was higher: USD 23.96 and USD 21.63. As a result, the cost per child death averted was higher than for ITNs: USD 3,933–4,357. Conclusion Both ITNs and IRS are highly cost-effective vector control strategies. Integrated ITN free distribution campaigns appeared to be the most efficient way to rapidly increase ITN coverage. Other approaches were as or more cost-effective, and appeared better suited to "keep-up" coverage levels. ITNs are more cost-effective than IRS for highly endemic settings, especially if high ITN coverage can be achieved with some demographic targeting.

The Lubombo Spatial Development Initiative is a joint development program between the governments of Mozambique, Swaziland, and South Africa, which includes malaria control as a core component of the initiative. Vector control through indoor residual spraying (IRS) was incrementally introduced in southern Mozambique between November 2000 and February 2004. Surveillance to monitor its impact was conducted by annual cross-sectional surveys to assess the prevalence of Plasmodium falciparum infection, entomologic monitoring, and malaria case notification in neighboring South Africa and Swaziland. In southern Mozambique, there was a significant reduction in P. falciparum prevalence after the implementation of IRS, with an overall relative risk of 0.74 for each intervention year (P < 0.001), ranging from 0.66 after the first year to 0.93 after the fifth intervention year. Substantial reductions in notified malaria cases were reported in South Africa and Swaziland over the same period. The success of the program in reducing malaria transmission throughout the target area provides a strong argument for investment in regional malaria control.

The Bioko Island Malaria Control Project (BIMCP) has carried out intensive interventions since early 2004 to reduce malaria transmission through indoor residual spraying (IRS) and case management. Annual parasite prevalence surveys have been carried out to monitor the effectiveness of the program. Significant overall reductions in prevalence of infection have been observed, with 42% fewer infections occurring in 2006 compared with baseline. Nevertheless, there is evidence of considerable heterogeneity in impact of the intervention. Prevalence of infection was significantly associated with spray status of the child's house, spray coverage with effective insecticide of the neighborhood of the house, bed net use, and time elapsed since last spray. Careful scheduling of spray coverage is therefore essential to maximize the effectiveness of IRS and to ensure consistent reductions in parasite prevalence. This can only be achieved if comprehensive monitoring systems are in place for both the management and evaluation of the intervention.

Background. Although the regional approach to malaria control between South Africa, Swaziland, and Mozambique has significantly decreased malaria risk in the Lubombo corridor, many facility owners' and tourists' malaria risk perception has remained unchanged. A large percentage are still unaware of the extensive malaria control efforts in the region and subsequent malaria reductions in the Lubombo corridor.Methods. A questionnaire-based follow-up survey was carried out in northern KwaZulu-Natal in the 1999/2000 and 2002/2003 malaria seasons. Tourists and tourist facility owners/managers were interviewed on their perceptions pertaining to malaria risk.Results. In the 1999/2000 malaria season, 18% of tourist facilities in northern KwaZulu-Natal were in areas where 5 to 25 malaria cases per 1,000 population were recorded, and 68% were in areas where < 5 malaria cases per 1,000 population were recorded. A major reduction in malaria cases was achieved by the end of the 2002/2003 malaria season. None (0%) of the tourist facilities were in areas where 5 to 25 malaria cases per 1,000 population were recorded, and 98% were in areas where malaria cases were lower than five cases per 1,000 population.Conclusion. The survey of local and international tourists and tourist facility operators in northern KwaZulu-Natal revealed that there was a discrepancy between perceived and actual malaria risk. The perceived malaria risk among both local and international tourists and facility operators needs to be addressed by distributing updated malaria risk information on an annual basis.

Background: A comprehensive malaria control intervention was initiated in February 2004 on Bioko Island, Equatorial Guinea. This manuscript reports on the continuous entomological monitoring of the indoor residual spray ( IRS) programme during the first two years of its implementation.Methods: Mosquitoes were captured daily using window traps at 16 sentinel sites and analysed for species identification, sporozoite rates and knockdown resistance ( kdr) using polymerase chain reaction ( PCR) to assess the efficacy of the vector control initiative from December 2003 to December 2005.Results: A total of 2,807 and 10,293 Anopheles funestus and Anopheles gambiae s. l. respectively were captured throughout the study period. Both M and S molecular forms of An. gambiae s. s. and Anopheles melas were identified. Prior to the first round of IRS, sporozoite rates were 6.0, 8.3 and 4.0 for An. gambiae s. s., An. melas and An. funestus respectively showing An. melas to be an important vector in areas in which it occurred. After the third spray round, no infective mosquitoes were identified. After the first spray round using a pyrethroid spray the number of An. gambiae s. s. were not reduced due to the presence of the kdr gene but An funestus and An. melas populations declined from 23.5 to 3.1 and 5.3 to 0.8 per trap per 100 nights respectively. After the introduction of a carbamate insecticide in the second round, An. gambiae s. s. reduced from 25.5 to 1.9 per trap per 100 nights and An. funestus and An. melas remained at very low levels. Kdr was found only in the M-form of An. gambiae s. s. with the highest frequency at Punta Europa ( 85%).Conclusion: All three vectors that were responsible for malaria transmission before the start of the intervention were successfully controlled once an effective insecticide was used. Continuous entomological surveillance including resistance monitoring is of critical importance in any IRS based malaria vector control programme. This paper demonstrates that sufficient resources for such monitoring should be included in any proposal in order to avoid programme failures.

We evaluated the association between annual malaria incidence and El Niño Southern Oscillation (ENSO) as measured by the Southern Oscillation Index (SOI) in five countries in Southern Africa from 1988 to 1999. Below normal incidence of malaria synchronised with a negative SOI (El Niño) and above normal incidence with a positive SOI (La Niña), which lead to dry and wet weather conditions, respectively. In most countries there was a positive relationship between SOI and annual malaria incidence, especially where Anopheles arabiensis is a major vector. This mosquito breeds in temporary rain pools and is highly sensitive to fluctuations in weather conditions. South Africa and Swaziland have the most reliable data and showed the strongest associations, but the picture there may also be compounded by the moderating effect of other oscillatory systems in the Indian Ocean. The impact of ENSO also varies over time within countries, depending on existing malaria control efforts and response capacity. There remains a need for quantitative studies that at the same time consider both ENSO-driven climate anomalies and non-ENSO factors influencing epidemic risk potential to assess their relative importance in order to provide an empirical basis for malaria epidemic forecasting models.

Background: Several malaria risk maps have been developed in recent years, many from the prevalence of infection data collated by the MARA (Mapping Malaria Risk in Africa) project, and using various environmental data sets as predictors. Variable selection is a major obstacle due to analytical problems caused by over-fitting, confounding and non-independence in the data. Testing and comparing every combination of explanatory variables in a Bayesian spatial framework remains unfeasible for most researchers. The aim of this study was to develop a malaria risk map using a systematic and practicable variable selection process for spatial analysis and mapping of historical malaria risk in Botswana.Results: Of 50 potential explanatory variables from eight environmental data themes, 42 were significantly associated with malaria prevalence in univariate logistic regression and were ranked by the Akaike Information Criterion. Those correlated with higher-ranking relatives of the same environmental theme, were temporarily excluded. The remaining 14 candidates were ranked by selection frequency after running automated step-wise selection procedures on 1000 bootstrap samples drawn from the data. A non-spatial multiple-variable model was developed through step-wise inclusion in order of selection frequency. Previously excluded variables were then re-evaluated for inclusion, using further step-wise bootstrap procedures, resulting in the exclusion of another variable. Finally a Bayesian geo-statistical model using Markov Chain Monte Carlo simulation was fitted to the data, resulting in a final model of three predictor variables, namely summer rainfall, mean annual temperature and altitude. Each was independently and significantly associated with malaria prevalence after allowing for spatial correlation. This model was used to predict malaria prevalence at unobserved locations, producing a smooth risk map for the whole country.Conclusion: We have produced a highly plausible and parsimonious model of historical malaria risk for Botswana from point-referenced data from a 1961/2 prevalence survey of malaria infection in 1-14 year old children. After starting with a list of 50 potential variables we ended with three highly plausible predictors, by applying a systematic and repeatable staged variable selection procedure that included a spatial analysis, which has application for other environmentally determined infectious diseases. All this was accomplished using general-purpose statistical software.

Malaria is the most important of the parasitic diseases of humans, with 107 countries and territories having areas at risk of transmission containing close to 50 percent of the world's population (Hay and others 2004; WHO 2005). More than 3 billion people live in malarious areas and the disease causes between 1 million and 3 million deaths each year (Breman, Alilio, and Mills 2004; Snow and others 2003). Recent esti- mates of the global falciparum malaria morbidity burden have increased the number to 515 million cases, with Africa suffer- ing the vast majority of this toll (Snow and others 2005). In addition, almost 5 billion clinical episodes resembling malaria occur in endemic areas annually, with more than 90 percent of this burden occurring in Africa (Breman 2001; Breman, Alilio, and Mills 2004; Carter and Mendis 2002; Snow and others 1999, 2003; Snow, Trape, and Marsh 2001). The disease has resurged in many parts of the tropics, and nonmalarious countries face continual danger from importa- tion. Contributing to this resurgence are the increasing prob- lems of Plasmodium falciparum resistance to drugs and of the Anopheles vectors' resistance to insecticides. The recent findings that insecticide-treated nets (ITNs) are extremely cost-effective in preventing malaria and overall deaths and that intermittent preventive therapy (IPT) (treatment doses given during periods of vulnerability) is effective for protecting pregnant women and their fetuses, along with the discovery of new drugs (artemisinins) and their use in combination with other antimalarials and promising vaccine trials, have given great impetus to the battle against this scourge (Alonso and others 2004; Armstrong-Schellenberg and others 2001; Lengeler 2004; Newman and others 2003; Yeung and others 2004).

Current malaria control initiatives aim at reducing malaria burden by half by the year 2010. Effective control requires evidence-based utilisation of resources. Characterizing spatial patterns of risk, through maps, is an important tool to guide control programmes. To this end an analysis was carried out to predict and map malaria risk in Malawi using empirical data with the aim of identifying areas where greatest effort should be focussed.

Few new insecticides have been produced for control of disease vectors for public health in developing countries over the past three decades, owing to market constraints, and the available insecticides are often poorly deployed. The Innovative Vector Control Consortium will address these market failures by developing a portfolio of chemical and technological tools that will be directly and immediately accessible to populations in the developing world. The Bill and Melinda Gates Foundation has supported this new initiative to enable industry and academia to change the vector control paradigm for malaria and dengue and to ensure that vector control, alongside drugs, case management and vaccines, can be better used to reduce disease.

Malaria control in southern Mozambique is currently by indoor residual carbamate insecticide treatment, with pyrethroid-treated bed-nets distributed to pregnant women and children under five in northern Mozambique. The susceptibility of Anopheles funestus s.s. to pyrethroid, carbamate, organochlorine, and organophosphorus insecticides was determined by World Health Organization adult mosquito susceptibility tests at 19 localities in Mozambique, from March 2000 to July 2002. Biochemical assays were carried out on mosquitoes from the same families to detect shifts in the quantity or activity of enzyme families involved in insecticide detoxification. An. funestus from all localities remained fully susceptible to DDT and the organophosphorus insecticide malathion. A high level of pyrethroid resistance was detected in An. funestus populations in southern Mozambique. An. funestus outside Maputo province were still susceptible to pyrethroids. An. funestus from six localities also were resistant to carbamate insecticides propoxur and bendiocarb. Both pyrethroid and carbamate resistance occurred in five of these six localities. Mosquitoes from five of the localities with elevated p450 estimates, compared with the insecticide-susceptible Durban strain, were pyrethroid-resistant. The only exception to this trend was Mozal, which had elevated p450 estimates but full pyrethroid susceptibility by bioassay. The lack of cross-resistance between pyrethroids and DDT in Mozambican An. funestus suggests that a kdr-type target site resistance mechanism has not been selected. Low levels of insecticide-insensitive acetylcholinesterase, the target site for carbamates and organophosphates, were found in all populations tested. The high level of metabolically based pyrethroid resistance has implications for current malaria control programs in Mozambique.