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Unfortunately, the original article [1] contained an error mistakenly carried forward by the Production department handling this article whereby some figures and their captions were interchanged. The correct figures (Figs. 1, 2, 3, 4, 5) and captions are presented in this erratum. The original article has also been updated to reflect this correction. [ABSTRACT FROM AUTHOR]

Background: Insecticide resistance threatens malaria control in sub-Saharan Africa. Knockdown resistance to pyrethroids and organochlorines in Anopheles gambiae sensu lato (s.l.) is commonly caused by mutations in the gene encoding a voltage-gated sodium channel which is the target site for the insecticide. The study aimed to examine risk factors for knockdown resistance in An. gambiae s.l. and its relationship with malaria infection in children in rural Gambia. Point mutations at the Vgsc-1014 locus, were measured in An. gambiae s.l. during a 2-year trial. Cross-sectional surveys were conducted at the end of the transmission season to measure malaria infection in children aged 6 months–14 years. Results: Whilst few Anopheles arabiensis and Anopheles coluzzii had Vgsc-1014 mutations, the proportion of An. gambiae sensu stricto (s.s.) mosquitoes homozygous for the Vgsc-1014F mutation increased from 64.8 to 90.9% during the study. The Vgsc-1014S or 1014F mutation was 80% higher in 2011 compared to 2010, and 27% higher in the villages with indoor residual spraying compared to those without. An increase in the proportion of An. gambiae s.l. mosquitoes with homozygous Vgsc-1014F mutations and an increase in the proportion of An. gambiae s.s. in a cluster were each associated with increased childhood malaria infection. Homozygous Vgsc-1014F mutations were, however, most common in An. gambiae s.s. and almost reached saturation during the study meaning that the two variables were colinear. Conclusions: As a result of colinearity between homozygous Vgsc-1014F mutations and An. gambiae s.s., it was not possible to determine whether insecticide resistance or species composition increased the risk of childhood malaria infection. [ABSTRACT FROM AUTHOR]

An obituary is presented for James Pinder, an organ teacher, church musician, and music director at the Bluecoat School in Liverpool, England.

Abstract: RTS,S/AS02A is a pre-erythrocytic malaria vaccine candidate in which a portion of the circumsporozoite surface protein (CSP) of Plasmodium falciparum is genetically linked to hepatitis B surface antigen (HBsAg) coexpressed in yeast with unfused HBsAg. The resulting particulate antigen is formulated with the adjuvant system AS02A. We have initiated the paediatric clinical development of this vaccine by conducting two sequential Phase I studies in children: a study in older children (6–11 years), followed by a second study in younger children (1–5 years). In each study, a double-blind, randomised controlled, staggered, dose-escalation design was used to evaluate 10μg RTS,S dose (10μg RTS,S in 0.1mL AS02A), 25μg dose (25μg RTS,S in 0.25mL AS02A) and finally a 50μg dose (50μg RTS,S in 0.5mL AS02A) of the RTS,S/AS02A candidate malaria vaccine administered according to a 0-, 1- and 3-month vaccination schedule. Safety and reactogenicity were evaluated before moving to a higher dose level. The RTS,S/AS02A vaccine was safe at all dose levels, in both age groups. No serious adverse events related to vaccination were reported. The frequency of local Grade 3 symptoms was low but tended to increase with increasing dose level. Grade 3 general adverse events in the RTS,S/AS02A groups were infrequent and of short duration. The majority of local and general Grade 3 symptoms resolved or decreased in intensity within 48h. The pattern and intensity of reactogenicity seen in these studies are similar to those of previous studies with RTS,S/AS02A. All doses were highly immunogenic for anti-CSP and anti-HBsAg antibodies. The pooled anti-CSP antibody data from the two studies showed that the 25μg dose and 50μg dose anti-CSP antibody response were similar at both dose levels. However, the immunogenicity of the 10μg dose anti-CSP response was significantly lower than that of either the 50μg or 25μg dose. The 25μg dose was selected for future studies of RTS,S/AS02A in paediatric populations. [Copyright &y& Elsevier]

Background: In rural sub-Saharan Africa, thatch roofs are being replaced by metal roofs. Metal roofing, however, increases indoor temperatures above human comfort levels, and thus makes it more likely that residents will not use an insecticide-treated bed net (ITN) at night. Whether the colour of a metal roof affects indoor temperature and human comfort was assessed. Methods: Two identical, experimental houses were constructed with metal roofs in rural Gambia. Roof types were: (1) original bare-metal, (2) painted with red oxide primer or (3) white gloss, to reflect solar radiation. Pairwise comparisons were run in six, five-night blocks during the malaria season 2018. Indoor climate was measured in each house and multivariate analysis used to compare indoor temperatures during the day and night. Results: From 21.00 to 23.59 h, when most residents decide whether to use an ITN or not, the indoor temperature of a house with a bare metal roof was 31.5 °C (95% CI 31.2–31.8 °C), a red roof, 30.3 °C (95% CI 30.0–30.6) and a white roof, 29.8 °C (95% CI 29.4–30.1). During the same period, red-roofed houses were 1.23 °C cooler (95% CI 1.22–1.23) and white roofs 1.74 °C cooler (95% CI 1.70–1.79) than bare-metal roofed houses (p < 0.001). Similar results were found from 00.00 to 06.00 h. Maximum daily temperatures were 0.93 °C lower in a white-roofed house (95% CI 0.10–0.30, p < 0.001), but not a red roof (mean maximum temperature difference = 0.44 °C warmer, 95% CI 0.43–0.45, p = 0.081), compared with the bare-metal roofed houses. Human comfort analysis showed that from 21.00 to 23.59 h houses with white roofs (comfortable for 87% time) were more comfortable than bare-metal roofed houses (comfortable for 13% time; odds ratio = 43.7, 95% CI 27.5–69.5, p < 0.001). The cost of painting a metal roof white is approximately 31–68 USD. Conclusions: Houses with a white roof were consistently cooler and more comfortable than those with a bare metal roof. Painting the roofs of houses white is a cheap way of making a dwelling more comfortable for the occupants and could potentially increase bed net use in hot humid countries. [ABSTRACT FROM AUTHOR]

Vector-borne diseases (VBDs) such as malaria, dengue, and leishmaniasis cause a high level of morbidity and mortality. Although vector control tools can play a major role in controlling and eliminating these diseases, in many cases the evidence base for assessing the efficacy of vector control interventions is limited or not available. Studies assessing the efficacy of vector control interventions are often poorly conducted, which limits the return on investment of research funding. Here we outline the principal design features of Phase III vector control field studies, highlight major failings and strengths of published studies, and provide guidance on improving the design and conduct of vector control studies. We hope that this critical assessment will increase the impetus for more carefully considered and rigorous design of vector control studies. [ABSTRACT FROM AUTHOR]

Background. Analysis of genome-wide polymorphism in many organisms has potential to identify genes under recent selection. However, data on historical allele frequency changes are rarely available for direct confirmation.Methods. We genotyped single nucleotide polymorphisms (SNPs) in 4 Plasmodium falciparum drug resistance genes in 668 archived parasite-positive blood samples of a Gambian population between 1984 and 2008. This covered a period before antimalarial resistance was detected locally, through subsequent failure of multiple drugs until introduction of artemisinin combination therapy. We separately performed genome-wide sequence analysis of 52 clinical isolates from 2008 to prospect for loci under recent directional selection.Results. Resistance alleles increased from very low frequencies, peaking in 2000 for chloroquine resistance-associated crt and mdr1 genes and at the end of the survey period for dhfr and dhps genes respectively associated with pyrimethamine and sulfadoxine resistance. Temporal changes fit a model incorporating likely selection coefficients over the period. Three of the drug resistance loci were in the top 4 regions under strong selection implicated by the genome-wide analysis.Conclusions. Genome-wide polymorphism analysis of an endemic population sample robustly identifies loci with detailed documentation of recent selection, demonstrating power to prospectively detect emerging drug resistance genes. [ABSTRACT FROM AUTHOR]

Abstract: This paper describes a malaria research project in The Gambia to provoke thinking on the social value of transnational research. The Larval Control Project (LCP) investigated the efficacy of a microbial insecticide to reduce vector density and, ultimately, clinical malaria in Gambian children. The LCP’s protocol delineated a clinical surveillance scheme that involved Village Health Workers (VHWs) supported by project nurses. Combining insights from ethnographic fieldwork conducted at the Medical Research Council (MRC) Laboratories in Farafenni from 2005 to 2009, open-ended interviews with project nurses, and eight focus group discussions held with participant mothers in October 2007, we consider the social impact of the LCP’s investigative method against the backdrop of several years of research activity. We found that while participants associated the LCP with the clinical care it provided, they also regarded the collaboration between the nurses and VHWs added additional benefits. Organised around the operational functions of the trial, small-scale collaborations provided the platform from which to build local capacity. While ethical guidelines emphasise the considerations that must be added to experimental endeavour in southern countries (e.g. elaborating processes of informed consent, developing strategies of community engagement or providing therapeutic access to participants after the trial concludes), these findings suggest that shifting attention from supplementing ethical protocols to the everyday work of research –embedding ethics through scientific activity – may provide a sounder basis to reinforce the relationship between scientific rigour and social value. [Copyright &y& Elsevier]

The tumor necrosis factor gene (TNF) and lymphotoxin-α gene (LTA) have long attracted attention as candidate genes for susceptibility traits for malaria, and several of their polymorphisms have been found to be associated with severe malaria (SM) phenotypes. In a large study involving>10,000 individuals and encompassing 3 African populations, we found evidence to support the reported associations between the TNF-238 polymorphism and SM in The Gambia. However, no TNF/LTA polymorphisms were found to be associated with SM in cohorts in Kenya and Malawi. It has been suggested that the causal polymorphisms regulating the TNF and LTA responses may be located some distance from the genes. Therefore, more-detailed mapping of variants across TNF/LTA genes and their flanking regions in the Gambian and allied populations may need to be undertaken to find any causal polymorphisms. [ABSTRACT FROM AUTHOR]

The tumour necrosis factor (TNF) gene and other genes flanking it in the major histocompatibility complex (MHC) class III region are potentially important mediators of both immunity and pathogenesis of malaria. We investigated the association of severe malaria with 11 haplotype tagging-polymorphisms for 11 MHC class III candidate genes, including TNF, lymphotoxin alpha (LTA), allograft inflammatory factor 1 (AIF1), and HLA-B associated transcript 2 (BAT2). An analysis of 2,162 case-controls demonstrated the first evidence of association between a BAT2 polymorphism (rs1046089) and severe malaria. [ABSTRACT FROM AUTHOR]

Background. Plasmodium falciparum malaria is a common cause of morbidity in African children, but identifying those who are likely to die is problematic. Previous studies suggested that circulating malarial pigment might be a useful predictor of severity, but none were large enough to detect any association with mortality. Methods. We used thick blood smears performed on admission for 26,296 children hospitalized with P. falciparum at 1 of 6 hospitals in the Severe Malaria in African Children network to assess the prognostic value of pigmentcontaining granulocytes, monocytes, and parasites. Results. Although at all but one of the study sites the risk of mortality for subjects presenting with >5 pigmented granulocytes per 200 white blood cells was higher than in subjects with no pigmented granulocytes, adjusted odds ratios estimated through logistic regression, which included other established markers of severe malaria, suggested that associations between pigmented cells and mortality were moderate to nonexistent in most sites. The predictive ability of pigmented cells was low, as measured by the change in the area under the receiver operating characteristic curve of logistic regression models. Conclusions. Although high levels of pigmented cells were associated with a fatal outcome in some study sites, they were not useful predictors of outcome across Africa. [ABSTRACT FROM AUTHOR]

Functional studies have demonstrated an interaction between the stimulatory G protein alpha subunit (G-alpha-s) and the malaria parasite at a cellular level. Obstruction of signal transduction via the erythrocyte G-alpha-s subunit reduced invasion by Plasmodium falciparum parasites. We sought to determine whether this signal pathway had an impact at the disease level by testing polymorphisms in the gene encoding G-alpha-s ( GNAS) for association with severe malaria in a large multi-centre study encompassing family and case–control studies from The Gambia, Kenya and Malawi, and a case–control study from Ghana. We gained power to detect association using meta-analysis across the seven studies, with an overall sample size approximating 4,000 cases and 4,000 controls. Out of 12 SNPs investigated in the 19 kb GNAS region, four presented signals of association ( P < 0.05) with severe malaria. The strongest single-locus association demonstrated an odds ratio of 1.13 (1.05–1.21), P = 0.001. Three of the loci presenting significant associations were clustered at the 5-prime end of the GNAS gene. Accordingly, haplotypes constructed from these loci demonstrated significant associations with severe malaria [OR = 0.88 (0.81–0.96), P = 0.005 and OR = 1.12 (1.03–1.20), P = 0.005]. The evidence presented here indicates that the influence of G-alpha-s on erythrocyte invasion efficacy may, indeed, alter individual susceptibility to disease. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of this work was to determine the infectivity to mosquitoes of genetically diverse Plasmodium falciparum clones seen in natural infections in the Gambia. Two principal questions were addressed: (i) how infectious are gametocytes of sub-patent infections, particularly at the end of the dry season; and (ii) are all clones in multiclonal infections equally capable of infecting mosquitoes? The work was carried out with two cohorts of infected individuals. Firstly, a group of 31 P. falciparum-infected people were recruited in the middle of the dry season (May, 2003), then examined for P. falciparum at the beginning (August 2003) and middle (October, 2003) of the transmission season. On each occasion, we examined the genotypes of asexual forms and gametocytes by PCR and RT-PCR, as well as their infectivity to Anopheles gambiae using membrane feeds. One individual gave rise to infected mosquitoes in May, and two in August. Different gametocyte genotypes co-existed in the same infection and fluctuated over time. The mean multiplicity of infection was 1.4, 1.7 and 1.5 clones in May, August and October, respectively. Second, a group of patients undergoing drug-treatment during August 2003 was tested for asexual and gametocyte genotypes and their infectivity to mosquitoes. Forty-three out of 100 feeds produced infections. The genetic complexity of the parasites in mosquitoes was sometimes greater than that detectable in the blood on which the mosquitoes had fed. This suggested that gametocytes of clones existing in the blood below PCR detection limits at the time of the feed were at least as infectious to the mosquitoes as the more abundant clones. These findings emphasise the crucial role of gametocyte complexity and infectivity in generating the remarkable diversity of P. falciparum genotypes seen in infected people, even in an area of seasonal transmission. [Copyright &y& Elsevier]

Abstract: Behaviour change is notoriously difficult to initiate and sustain, and the reasons why efforts to promote healthy behaviours fail are coming under increasing scrutiny. To be successful, health interventions should build on existing practices, skills and priorities, recognise the constraints on human behaviour, and either feature community mobilisation or target those most receptive to change. Furthermore, interventions should strive to be culturally compelling, not merely culturally appropriate: they must engage local communities and nestle within social and ecological landscapes. In this paper, we propose a social ecology perspective to make explicit the links between intention to change, actual behaviour change, and subsequent health impact, as relating to both theory-based models and practical strategies for triggering behaviour change. A social ecology model focuses attention on the contexts of behaviour when designing, implementing or critically evaluating interventions. As a case study, we reflect on a community-directed intervention in rural Gambia designed to reduce malaria by promoting a relatively simple and low-cost behaviour: repairing holes in mosquito bednets. In phase 1, contextual information on bednet usage, transactions and repairs (the ‘social lives’ of nets) was documented. In phase 2 (intervention), songs were composed and posters displayed by community members to encourage repairs, creating a sense of ownership and a compelling medium for the transmission of health messages. In phase 3 (evaluation), qualitative and quantitative data showed that household responses were particularly rapid and extensive, with significant increase in bednet repairs (), despite considerable constraints on human agency. We highlight a promising approach—using songs—as a vehicle for change, and present a framework to embed the design, implementation and critical evaluation of interventions within the larger context—or social ecology—of behaviour practices that are the bedrock of health interventions. [Copyright &y& Elsevier]

There is presently much interest in utilizing patterns of linkage disequilibrium (LD) to further genetic association studies. This is particularly pertinent in the class III region of the human major histocompatibility complex (MHC), which has been extensively studied as a disease susceptibility locus in a number of ethnic groups. To date, however, few studies of LD in the MHC have considered non-Caucasian populations. With the advent of large-scale haplotyping of the human genome, the question of utilizing LD patterns across populations has come to the fore. We have previously used LD mapping to direct an MHC class III association study in a UK Caucasian population. As an extension of this, we sought to determine to what extent the pattern of LD observed in that study could be used to conduct a similar study in a West African Gambian population. We found that broad patterns of LD were similar in the two populations, resulting in similar candidate region delineations, but at a higher resolution, marker-specific patterns of LD and population-dependent allele frequencies confounded the choice of regional tagging SNPs. Our results have implications for the applicability of large-scale haplotype maps such as the HapMap to complex regions like the MHC. [ABSTRACT FROM AUTHOR]

There is growing interest in the use of haplotype-based methods for detecting recent selection. Here, we describe a method that uses a sliding window to estimate similarity among the haplotypes associated with any given single- nucleotide polymorphism (SNP) allele. We used simulations of natural selection to provide estimates of the empirical power of the method to detect recently selected alleles and found it to be comparable in power to the popular long-range haplotype test and more powerful than methods based on nucleotide diversity. We then applied the method to a recently selected allele—the sickle mutation at the HBB locus—and found it to have a signal of selection that was significantly stronger than that of simulated models both with and without strong selection. Using this method, we also evaluated >4,000 SNPs on chromosome 20, indicating the applicability of the method to regional data sets. [ABSTRACT FROM AUTHOR]

Two hundred thirty-four Gambian children with severe falciparum malaria who were admitted to the pediatric ward of a rural district hospital each were matched for age with a same-sex control subject presenting as an outpatient with uncomplicated falciparum malaria. Severe malarial anemia (SMA) was the most common presentation (152 cases), followed by cerebral malaria (38 cases) and hyperparasitemia (26 cases). Children presenting with SMA were significantly younger and more likely to carry gametocytes than were children with other severe presentations. Alleles of the genes pfcrt and pfmdr1 associated with chloroquine-resistant parasites occurred together among cases presenting with SMA alone more often than among their matched controls (odds ratio, 2.08 [95% confidence interval, 1.04-4.38]; P = .039). Costs of travel to the hospital of more than US $0.20, use of mosquito repellents, and carriage of resistant parasites were identified as independent risk factors for severe malaria in the case-control analysis. We conclude that, in this setting, poor access to the hospital and a high prevalence of chloroquine-resistant parasites lead to a delay of adequate treatment for young children with malaria, who may then develop SMA. [ABSTRACT FROM AUTHOR]

Successful vaccination against intracellular pathogens, including liver-stage Plasmodium falciparum, will require induction of strong antigen-specific T lymphocyte responses. The multiple epitope (ME)-thrombospondin-related adhesion protein (TRAP) construct includes CD8+ and CD4+ T cell epitopes from pre-erythrocytic P. falciparum antigens fused in-frame to the entire pre-erythrocytic antigen TRAP. Three carriers for this construct--plasmid DNA and 2 recombinant nonreplicating poxviruses (modified vaccinia virus Ankara [MVA] and fowlpox strain 9 [FP9])--were administered at 3-week intervals in a heterologous prime-boost combination to 29 Gambian men aged 18-45 years. Doses of DNA ME-TRAP, MVA ME-TRAP, and FP9 ME-TRAP were 2 mg and 1.5 × 108 and 1 × 108 plaque-forming units, respectively. DNA ME-TRAP was injected intramuscularly; MVA ME-TRAP and FP9 ME-TRAP were injected intradermally. There were no clinically relevant laboratory abnormalities and no severe or serious adverse events related to vaccination. DNA/MVA and FP9/MVA regimens were the most potent inducers of circulating effector T cells seen to date in sub-Saharan Africa. Twelve months after the final vaccination, a single booster vaccination expanded the effector T cell pool to a similar or higher magnitude than that after the primary vaccinations. These results highlight optimized combination regimens with general relevance to the development of vaccines targeting intracellular pathogens. [ABSTRACT FROM AUTHOR]

Objectives: Combination therapy using existing anti-malarials together with artesunate (AS) has been advocated as a method to slow the spread of drug resistance. We assessed the effect on Plasmodium falciparum transmissibility of the addition of AS to chloroquine (CQ) in an area of The Gambia where resistance to CQ is increasing.Methods: Gambian children with acute uncomplicated P. falciparum malaria were treated with either CQ monotherapy (n=120) or the combination of CQ plus three doses of AS (CQ/AS; n=352). Post-treatment sexual-stage parasitaemia was assessed during a 4-week follow-up period. Experimental infections of Anopheles gambiae s.s. mosquitoes were performed with blood from patients who were carrying gametocytes 7 days after starting treatment (n=69).Results: The addition of AS significantly reduced post-treatment prevalence and mean density of gametocytes in the first 14 days (day 7: 43.7% vs. 12.4%, 62.4/microl vs. 6.2/microl; day 14: 32.9% vs. 3.7%; 21.9/microl vs. 5.2/microl; CQ vs. CQ/AS), although by day 28 the benefits of the combination were substantially less marked (40.5% vs. 21.8%; 23.0/microl vs. 63.1/microl; CQ vs. CQ/AS). The duration of gametocyte carriage over the study period was significantly lower in the CQ/AS group (5.2 days vs. 1.5 days; CQ vs. CQ/AS). The estimated infectious proportion of children at day 7 was also lower in the combination group (19.2% vs. 3.4%; CQ vs. CQ/AS), as were the proportion of mosquitoes infected and mean oocyst density (11.5% vs. 0.9%; 0.3 vs. 0.01; CQ vs. CQ/AS). Treatment failure was associated with threefold and twofold higher gametocyte carriage rates during follow-up in CQ and CQ/AS groups, respectively (P<0.001 in both cases), and 26-fold and 2.3-fold higher intensity of infection at day 7 among CQ- and CQ/AS-treated children, respectively (P=0.002 and 0.30, respectively).Conclusion: The benefits of adding AS to CQ monotherapy in lowering gametocyte prevalence and density were transient, suggesting that the addition of AS delayed, but did not prevent, the emergence of gametocytes. This is consistent with our finding that treatment failure, and thus the presence of CQ-resistant parasites, was significantly associated with a higher gametocyte carriage rate in both treatment groups. At day 7, CQ monotherapy significantly favoured transmission of resistant infections, which showed an 11-fold greater intensity of transmission compared with infections that were successfully treated. In contrast, the combination of CQ/AS did not significantly favour resistant infections at day 7. We conclude that significant transmission-reduction is achieved by the combination but is not maintained because of the recrudescence of CQ-resistant parasites. [ABSTRACT FROM AUTHOR]

To assess the hypothesis that nitric oxide is critical in the pathogenesis of cerebral malaria, we analysed genetic variation in the proximal promoter region of NOS2A, the gene encoding inducible nitric oxide synthase. Sequencing 72 Gambian chromosomes revealed 11 single nucleotide polymorphisms in 2.5 kB (θ=8.6×10-4). Genotyping 104 nuclear families identified six common haplotypes. A single haplotype, uniquely defined by the NOS2A-1659T allele, was associated with cerebral malaria by a transmission disequilibrium test of 334 affected children and their parents (P=0.02). An independent case-control study of 505 different children from the same population replicated the allelic association with cerebral malaria (odds ratio: 1.31, P=0.04). Taken together these data indicate a weak but significant association of the NOS2A locus with susceptibility to cerebral malaria. Despite high linkage disequilibrium across the region studied, this association would not have been detected without the initial construction of a dense marker set for haplotype tagging. [ABSTRACT FROM AUTHOR]

To find out what proportion of Plasmodium falciparum infections are treated in rural Gambia. Subjects from four villages in the Gambia were followed over nine months through visits to village health workers. Monthly cross-sectional malaria surveys measured the prevalence of P. falciparum infection. Linked databases were searched for treatment requests. Treated cases were individuals with parasitaemia who requested treatment during narrow or extended periods (14 or 28 days, respectively) before or after a positive blood film was obtained. Parasite prevalence peaked in November 1998, when 399/653 (61%) individuals had parasitaemia. Parasite prevalence was highest throughout the study in children aged 5–10 years. Although access to treatment was better than in most of sub-Saharan Africa, only 20% of infected individuals sought medical treatment up to 14 days before or after a positive blood film. Within two months of a positive blood film, 199/726 (27%) individuals with parasitaemia requested treatment. Despite easy access to health care, less than half (42%) of those with parasite densities consistent with malaria attacks (>5000/µl) requested treatment. High parasite density and infection during October-November were associated with more frequent treatment requests. Self-treatment was infrequent in study villages: in 3/120 (2.5%) households antimalarial drugs had been used in the preceding malaria season. Many P. falciparum infections may be untreated because of their subclinical nature. Intermittent presumptive treatment may reduce morbidity and mortality. It is likely that not all untreated infections were asymptomatic. Qualitative research should explore barriers to treatment uptake, to allow educational interventions to be planned. [ABSTRACT FROM AUTHOR]

Interferon (IFN)--γ is a critical mediator of immunity to malaria. This study explored the relationship between polymorphisms in the promoter region of the gene encoding IFN-γ receptor 1 (IFNGRI) and susceptibility to malaria in African children. Four polymorphisms were found in the region between -1400 and +100 nt of the translational start site by sequencing, and analysis of 562 nuclear families revealed 6 haplotypes. Case-control analysis of 562 Gambian children with severe malaria and 569 umbilical cord blood samples (controls) showed that in Mandinka, the major Gambian ethnic group, heterozygotes for the IFNGR1 -56 polymorphism were protected against cerebral malaria (odds ratio, 0.54; P = .016) and against death resulting from cerebral malaria (odds ratio, 0.22; P = .006). Analysis of a family study by transmission disequilibrium testing revealed a similar result. Further data are needed to validate this finding, but these results are reminiscent of those for other well-established heterozygote advantages, such as that associated with hemoglobin S. [ABSTRACT FROM AUTHOR]

Two hundred thirteen mother-baby pairs in The Gambia were studied to determine the influence of placental malaria infection and maternal hypergammaglobulinemia on transplacental antibody transfer. Antibody transfer for herpes simplex virus 1 (HSV-1), respiratory syncytial virus (RSV), and varicella-zoster virus (VZV) was significantly reduced by placental malaria infection by 69%, 58%, and 55%, respectively. Maternal hypergammaglobulinemia was associated with a significant reduction in antibody transfer for HSV-1, RSV, VZV, and pneumococcus by 89%, 90%, 91%, and 88%, respectively. In addition, placental malaria infection was associated with a significant reduction in transfer of IgG1, IgG2, and IgG4 (P < .01, P = .01, and P = .03, respectively) but not of IgG3 (P = .59). Maternal hypergammaglobulinemia significantly impaired the transfer of IgG1 and IgG2 (P = .01) but not of IgG3 or IgG4 (P = .62 and P = .59, respectively). Placental malaria infection and maternal hypergammaglobulinemia were associated with reduction in the transplacental transfer of these specific antibodies, IgG1, and IgG2 in this Gambian population. [ABSTRACT FROM AUTHOR]

To test the hypothesis that widespread treatment with artemisinin derivatives can reduce malaria transmission, a mass drug administration (MDA) campaign was undertaken in an area of The Gambia in 1999. Coverage of 85% of the target population was achieved, but the intervention did not reduce overall malaria transmission. We studied the perceptions, knowledge and attitudes of the community to the MDA campaign. A validated questionnaire was administered to randomly selected MDA participants (n = 90) and MDA refusers (n = 71). Individuals who believed in the importance of the MDA (adjusted OR 58.3%; 95% CI 17.4-195.8) and those who were aware that a high level of participation was needed for the MDA to be successful (adjusted OR 28.1; 95% CI 10.3-75.9) were more likely to participate. Understanding that the purpose of the MDA was to reduce malaria (adjusted OR 13.9; 95% CI 5.5-35.1) and knowledge of the fact that malaria is transmitted by mosquitoes and of the clinical signs of malaria (adjusted OR 3.4; 95% CI 3.1-9.0) were associated with participation. Individuals who discussed the MDA with other villagers (adjusted OR 5.5; 95% CI 2.2-13.5) and those who attended the sensitization meeting (adjusted OR 2.6; 95% CI 1.1-6.0) were also more likely to participate. Women were significantly more likely to participate in the MDA than men (adjusted OR 3.1; 95% CI 1.5-6.2). Individuals who refused to participate were unlikely to plan participation in future MDAs. One of the most difficult challenges in the implementation of a malaria control strategy such as an MDA is to convince villagers to participate and to make them aware that a high level of participation by the community is needed for success. We found that our sensitization meetings could be improved by giving more information on how the MDA works and finding means to generate small group discussions after the meeting. [ABSTRACT FROM AUTHOR]

Studies the effect of combination therapy including artemisinin derivatives on transmission of falciparum malaria infections, in Gambian children with Plasmodim falciparum malaria, treated with chloroquine or pyrimethamine-sulfadoxine alone or in combination with artesunate. Materials and methods; Results.

Normal respiratory rates (RR) for children under five in the tropics are well-documented, but data for older children are limited. This study tracked RR changes with age and examined associations with nutritional status and environmental factors. We monitored rural Gambian children aged 6 months to 14 years, recording RR during home visits twice weekly over two rainy seasons. Using a generalized additive model, we constructed RR reference curves, and a linear mixed-effect model identified factors influencing RR. A total of 830 children provided 67,512 RR measurements. Their median age was 6.07 years (interquartile range 4.21-8.55) and 400 (48.2%) were female. Age, stunting, ambient temperature, and time of RR measurement were independent predictors of respiratory rate. Strikingly, children showing signs of illness had greater variability in repeat RR measurements. We constructed a RR reference chart for children aged one to 13 years and proposed a cutoff of > 26 breaths/min for raised RR among children aged > 5 years bridging an important gap in this age group. Although the time of data collection, nutritional status, and ambient temperature were predictors of RR, their effect size is not clinically significant enough to warrant a change in the current WHO guidelines owing to the prevailing uncertainty in the measurement of RR. The finding that RRs between repeat measurements were more variable among children with signs of illness suggests that a single RR measurement may be inadequate to reliably assess the status of sick children-a population in which accurate diagnosis is essential to enable targeted interventions with lifesaving treatment., (© 2024. The Author(s).)

Rural houses in sub-Saharan Africa are typically hot and allow malaria mosquitoes inside. We assessed whether passive or active ventilation can reduce house entry of malaria mosquitoes and cool a bedroom at night in rural Gambia. Two identical experimental houses were used: one ventilated and one unventilated (control). We evaluated the impact of (i) passive ventilation (solar chimney) and (ii) active ventilation (ceiling fan) on the number of mosquitoes collected indoors and environmental parameters (temperature, humidity, CO 2 , evaporation). Although the solar chimney did not reduce entry of Anopheles gambiae sensu lato , the ceiling fan reduced house entry by 91% compared with the control house. There were no differences in indoor nightly temperature, humidity or CO 2 between intervention and control houses in either experiment. The solar chimney did not improve human comfort assessed using psychrometric analysis. While the ceiling fan improved human comfort pre-midnight, in the morning it was too cool compared with the control house, although this could be remedied through provision of blankets. Further improvements to the design of the solar chimney are needed. High air velocity in the ceiling fan house probably reduced mosquito house entry by preventing mosquito flight. Improved ventilation in houses may reduce malaria transmission.

Background: The housing stock of rural sub-Saharan Africa is changing rapidly. With millions of new homes required over the coming decades, there is an opportunity to protect residents by screening homes from malaria mosquitoes. This study, undertaken in the Upper River Region of The Gambia, explores local perceptions of what a good house should provide for its inhabitants and responses to living in a house that has been modified as part of a randomized control trial designed to assess whether improved housing provided additional protection against clinical malaria in children (the RooPfs trial)., Methods: This descriptive, exploratory study was undertaken over 22 months using mixed-methods (informal conversations, observations, focus group discussions, photovoice, and a questionnaire survey) in a parallel convergent design. Analysis was conducted across the data sets using a framework approach. Following coding, the textual data were charted by a priori and emerging themes. These themes were compared with the quantitative survey results. The nature and range of views about housing and the RooPfs study modifications and the relationships among them were identified and described., Results: The data were derived from a total of 35 sets of observations and informal conversations in 10 villages, 12 discussions with the photovoice photographers, 26 focus group discussions (across 13 villages) and 391 completed questionnaires. The study participants described a 'good house' as one with a corrugate-metal roof, cement walls (preferably cement block, but mud block covered with cement plaster was also an acceptable and cheaper substitute) and well-fitting doors. These features align with local perceptions of a modern house that provides social status and protection from physical harms. The RooPfs modifications were largely appreciated, although poor workmanship caused concerns that houses had become insecure. However, the long-term trusting relationship with the implementing institution and the actions taken to rectify problems provided reassurance and enhanced acceptability., Conclusion: In developing housing to address population needs in Africa, attention should be paid to local perceptions of what is required to make a house secure for its inhabitants, as well as providing a healthy environment., (© 2022. The Author(s).)

Background: In malaria-endemic areas, residents of modern houses have less malaria than those living in traditional houses. We aimed to assess whether children in The Gambia received an incremental benefit from improved housing, where current best practice of insecticide-treated nets, indoor residual spraying, seasonal malaria chemoprevention in children younger than 5 years, and prompt treatment against clinical malaria was in place., Methods: In this randomised controlled study, 800 households with traditional thatched-roofed houses were randomly selected from 91 villages in the Upper River Region of The Gambia. Within each village, equal numbers of houses were randomly allocated to the control and intervention groups using a sampling frame. Houses in the intervention group were modified with metal roofs and screened doors and windows, whereas houses in the control group received no modifications. In each group, clinical malaria in children aged 6 months to 13 years was monitored by active case detection over 2 years (2016-17). We did monthly collections from indoor light traps to estimate vector densities. Primary endpoints were the incidence of clinical malaria in study children with more than 50% of observations each year and household vector density. The trial is registered at ISRCTN02622179., Findings: In June, 2016, 785 houses had one child each recruited into the study (398 in unmodified houses and 402 in modified houses). 26 children in unmodified houses and 28 children in modified houses did not have at least 50% of visits in a year and so were excluded from analysis. 38 children in unmodified houses were recruited after study commencement, as were 21 children in modified houses, meaning 410 children in unmodified houses and 395 in modified houses were included in the parasitological analyses. At the end of the study, 659 (94%) of 702 children were reported to have slept under an insecticide-treated net; 662 (88%) of 755 children lived in houses that received indoor residual spraying; and 151 (90%) of 168 children younger than 5 years had seasonal malaria chemoprevention. Incidence of clinical malaria was 0·12 episodes per child-year in children in the unmodified houses and 0·20 episodes per child-year in the modified houses (unadjusted incidence rate ratio [RR] 1·68 [95% CI 1·11-2·55], p=0·014). Household vector density was 3·30 Anopheles gambiae per house per night in the unmodified houses compared with 3·60 in modified houses (unadjusted RR 1·28 [0·87-1·89], p=0·21)., Interpretation: Improved housing did not provide protection against clinical malaria in this area of low seasonal transmission with high coverage of insecticide-treated nets, indoor residual spraying, and seasonal malaria chemoprevention., Funding: Global Health Trials funded by Medical Research Council, UK Department for International Development, and Wellcome Trust., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: African houses are frequently too hot and uncomfortable to use a bed net at night. Indoor thermal comfort is often evaluated by measuring temperature and humidity, ignoring ventilation. This study explored ways to measure ventilation in single-roomed rural Gambian houses during the malaria transmission season and evaluated building designs that could increase airflow at night and help keep the occupants comfortable., Methods: Two identical mud-walled houses were constructed with a metal roof, three doors and closed eaves. Experiment 1 compared five methods for measuring ventilation in a building: (1) using a blower door, (2) increasing carbon dioxide (CO 2 ) levels indoors using an artificial source of CO 2 and then measuring the rate of gas decay, (3) using a similar approach with a natural source of CO 2 , (4) measuring the rise of CO 2 when people enter a building and (5) using hot-wire anemometers. Experiment 2 used CO 2 data loggers to compare ventilation in a reference metal-roofed house with closed eaves and badly-fitting doors with a similar house with (1) thatched roof and open eaves, (2) eaves tubes, (3) screened doors and (4) screened doors and windows., Results: In experiment 1, CO 2 data loggers placed indoors in two identical houses showed similar changes in airflow (p > 0.05) for all three methods recording either decreasing or increasing CO 2 . Blower doors were unable to measure airflow in houses with open eaves or screened windows and the anemometers broke down under field conditions. In experiment 2, open eaves in thatched houses, screened doors alone, and screened doors and windows increased indoor ventilation compared to the reference metal-roofed house with closed eaves and badly fitting doors (p < 0.05). Eaves tubes did not increase ventilation in comparison to the reference house., Conclusion: CO 2 data loggers proved to be a simple and efficient method for measuring ventilation in rural houses at night. Ventilation of metal-roofed houses can be improved by adding two screened doors and windows on opposite walls. Improved ventilation will result in increased thermal comfort making it more likely that people will sleep under a bed net.

Background: Recording behaviours that have the potential to impact health can be doubly challenging if the behaviour takes place in private spaces that cannot be observed directly, and where respondents answer what they think the recorder may want to hear. Sleeping under a long-lasting insecticidal net (LLIN) is an important intervention for malaria prevention, yet it is difficult to gauge the extent to which coverage (how many nets are in the community) differs from usage (how many people actually sleep under a net). List randomization, a novel method which partially obscures respondents' answers to sensitive questions, was employed to estimate LLIN usage in The Gambia., Methods: 802 heads-of-household from 15 villages were recruited into a randomized controlled trial assessing the effect of a housing intervention on malaria. These houses were randomly assigned to a housing intervention versus control, with stratification by village so as to ensure balance between arms. From these, 125 households (63 intervention, 52 control) were randomly selected for participation in the list randomization experiment, along with 68 households from the same villages but which were not part of the housing improvement study, resulting in a total of 196 households for the list randomization experiment. Approximately half (n = 97) of the 196 study participants were randomly assigned to the control group and received a four-question list about non-sensitive behaviours; the intervention group (n = 99) received the same list, with the addition of one question on a sensitive behaviour: whether or not they had used a bed net the previous night. Participants were read the list of questions and then said how many of the statements were true. Bed net usage was estimated by calculating the difference in means between the number of affirmative responses between the two groups., Results: The mean number of affirmative responses in the control group was 2.60 of four statements (95% confidence interval, 95% CI 2.50-2.70), compared with 3.68 (95% CI 3.59-3.78) in the intervention group. Such difference (1.08; 95% CI 94.9-100%) suggests near universal bed net usage., Conclusions: Bed net usage by household heads in these rural villages was found to be high. Though not entirely unexpected given other studies' estimates of high bed net usage in the area, the list randomization method should be further validated in an area with lower coverage.

In The Gambia, metal-roof houses were hotter during the day than thatched-roof houses. After 24 h, the mortality of Anopheles gambiae, the principal African malaria vector, was 38% higher in metal-roof houses than thatched ones. During the day, mosquitoes in metal-roof houses moved from the hot roof to cooler places near the floor, where the temperature was still high, reaching 35 °C. In laboratory studies, at 35 °C few mosquitoes survived 10 days, the minimum period required for malaria parasite development. Analysis of epidemiological data showed there was less malaria and lower vector survival rates in Gambian villages with a higher proportion of metal roofs. Our findings are consistent with the hypothesis that the indoor climate of metal-roof houses, with higher temperatures and lower humidity, reduces survivorship of indoor-resting mosquitoes and may have contributed to the observed reduction in malaria burden in parts of sub-Saharan Africa.

Introduction: Unprecedented improvements in housing are occurring across much of rural sub-Saharan Africa, but the consequences of these changes on malaria transmission remain poorly explored. We examined how different typologies of rural housing affect mosquito house entry and indoor climate., Methods: Five typologies of mud-block houses were constructed in rural Gambia: four were traditional designs with poorly fitted doors and one was a novel design with gable windows to improve ventilation. In each house, one male volunteer slept under a bednet and mosquitoes were collected indoors with a light trap. Typologies were rotated between houses weekly. Indoor conditions were monitored with data loggers and the perceived comfort of sleepers recorded with questionnaires. We used pyschrometric modelling to quantify the comfort of the indoor climate using the logger data. Primary measurements were mean number of Anopheles gambiae and mean temperature for each house typology., Findings: In thatched-roofed houses, closing the eaves reduced A gambiae house entry by 94% (95% CI 89-97) but increased the temperature compared with thatched-roofed houses with open eaves. In houses with closed eaves, those with metal roofs had more A gambiae, were hotter (1·5°C hotter [95% CI 1·3-1·7]) between 2100h and 2300 h, and had 25% higher concentrations of carbon dioxide (211·1 ppm higher [117·8-304·6]) than those with thatched roofs. In metal-roofed houses with closed eaves, mosquito house entry was reduced by 96% (91-98) by well fitted screened doors. Improved ventilation of metal-roofed houses made them as cool as thatched houses with open eaves. Metal-roofed houses with closed eaves were considered more uncomfortable than thatched ones with closed eaves. In metal-roofed houses, ventilated houses were more comfortable than unventilated houses before midnight, when people retired to bed., Interpretation: Closing the eaves reduced vector entry in thatched houses but increased entry in metal-roofed houses. Metal-roofed houses with closed eaves were, however, protected against malaria vectors by well fitted screened doors and were made comfortable by increasing ventilation. House designs that exclude mosquitoes and are comfortable to live in should be a priority in sub-Saharan Africa., Funding: Sir Halley Stewart Trust, Global Clinical Trials, and Global Challenges Research Fund., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Insecticide resistance threatens malaria control in sub-Saharan Africa. Knockdown resistance to pyrethroids and organochlorines in Anopheles gambiae sensu lato (s.l.) is commonly caused by mutations in the gene encoding a voltage-gated sodium channel which is the target site for the insecticide. The study aimed to examine risk factors for knockdown resistance in An. gambiae s.l. and its relationship with malaria infection in children in rural Gambia. Point mutations at the Vgsc-1014 locus, were measured in An. gambiae s.l. during a 2-year trial. Cross-sectional surveys were conducted at the end of the transmission season to measure malaria infection in children aged 6 months-14 years., Results: Whilst few Anopheles arabiensis and Anopheles coluzzii had Vgsc-1014 mutations, the proportion of An. gambiae sensu stricto (s.s.) mosquitoes homozygous for the Vgsc-1014F mutation increased from 64.8 to 90.9% during the study. The Vgsc-1014S or 1014F mutation was 80% higher in 2011 compared to 2010, and 27% higher in the villages with indoor residual spraying compared to those without. An increase in the proportion of An. gambiae s.l. mosquitoes with homozygous Vgsc-1014F mutations and an increase in the proportion of An. gambiae s.s. in a cluster were each associated with increased childhood malaria infection. Homozygous Vgsc-1014F mutations were, however, most common in An. gambiae s.s. and almost reached saturation during the study meaning that the two variables were colinear., Conclusions: As a result of colinearity between homozygous Vgsc-1014F mutations and An. gambiae s.s., it was not possible to determine whether insecticide resistance or species composition increased the risk of childhood malaria infection.

Background: Although many malaria control programmes in sub-Saharan Africa use indoor residual spraying with long-lasting insecticidal nets (LLINs), the two studies assessing the benefit of the combination of these two interventions gave conflicting results. We aimed to assess whether the addition of indoor residual spraying to LLINs provided a significantly different level of protection against clinical malaria in children or against house entry by vector mosquitoes., Methods: In this two-arm cluster, randomised, controlled efficacy trial we randomly allocated clusters of Gambian villages using a computerised algorithm to LLINs alone (n=35) or indoor residual spraying with dichlorodiphenyltrichloroethane plus LLINs (n=35). In each cluster, 65-213 children, aged 6 months to 14 years, were surveyed at the start of the 2010 transmission season and followed in 2010 and 2011 by passive case detection for clinical malaria. Exposure to parasite transmission was assessed by collection of vector mosquitoes with both light and exit traps indoors. Primary endpoints were the incidence of clinical malaria assessed by passive case detection and number of Anopheles gambiae sensu lato mosquitoes collected per light trap per night. Intervention teams had no role in data collection and the data collection teams were not informed of the spray status of villages. The trial is registered at the ISRCTN registry, number ISRCTN01738840., Findings: LLIN coverage in 2011 was 3510 (93%) of 3777 children in the indoor residual spraying plus LLIN group and 3622 (95.5%) of 3791 in the LLIN group. In 2010, 7845 children were enrolled, 7829 completed passive case detection, and 7697 (98%) had complete clinical and covariate data. In 2011, 7009 children remained in the study, 648 more were enrolled, 7657 completed passive case detection, and 7545 (98.5%) had complete data. Indoor residual spraying coverage per cluster was more than 80% for both years in the indoor residual spraying plus LLIN group. Incidence of clinical malaria was 0.047 per child-month at risk in the LLIN group and 0.044 per child-month at risk in the indoor residual spraying plus LLIN group in 2010, and 0.032 per child-month at risk in the LLIN group and 0.034 per child-month at risk in the indoor residual spraying plus LLIN group in 2011. The incident rate ratio was 1.08 (95% CI 0.80-1.46) controlling for confounders and cluster by mixed-effect negative binomial regression on all malaria attacks for both years. No significant difference was recorded in the density of vector mosquitoes caught in light traps in houses over the two transmission seasons; the mean number of A gambiae sensu lato mosquitoes per trap per night was 6.7 (4.0-10.1) in the LLIN group and 4.5 (2.4-7.4) in the indoor residual spraying plus LLIN group (p=0.281 in the random-effects linear regression model)., Interpretation: We identified no significant difference in clinical malaria or vector density between study groups. In this area with high LLIN coverage, moderate seasonal transmission, and susceptible vectors, indoor residual spraying did not provide additional benefit., Funding: UK Medical Research Council., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

RTS,S is a pre-erythrocytic malaria vaccine candidate antigen based on the circumsporozoite surface protein of Plasmodium falciparum fused to HBsAg, incorporating a novel Adjuvant System (AS02). The first field efficacy of RTS,S/AS02 against infection was demonstrated in a trial initiated in The Gambia in 1998. This paper presents the five-year safety and immunogenicity follow up of the 306 men who were enrolled in the original trial. In the primary study men aged 18 to 45 years were randomized to receive either RTS,S/AS02 or rabies vaccine at 0, 1, 5 months followed by a booster dose at month 19. The subjects were observed for long term safety and immunogenicity continuously until month 58. Of the 153 subjects in each group at enrollment, 80 (52%) subjects in the RTS,S/AS02 group and 83 (54%) subjects in the rabies group returned for the final long-term follow-up visit at month 58. The main reason for non-attendance at month 58 was migration (76% of all drop-outs). Nine subjects in the RTS,S/AS02 group and seven in the rabies group experienced serious adverse events (SAEs) over the 58 month surveillance period, of which seven had a fatal outcome (five RTS,S/AS02 and two rabies group). None of the SAEs with fatal outcome were attributed to the study vaccine. Anti-CS antibody persistence compared to control was observed for five years, although titres had waned from post-booster levels; similar responses in anti-HBs antibody persistence were observed in initially HBsAg seronegative subjects. This study provides the first indication of the long-term safety and persistence of anti-CS and anti-HBs antibodies of the RTS,S vaccine candidate in combination with the novel AS02 Adjuvant System.

There is growing epidemiological and molecular evidence that ABO blood group affects host susceptibility to severe Plasmodium falciparum infection. The high frequency of common ABO alleles means that even modest differences in susceptibility could have a significant impact on the health of people living in malaria endemic regions. We performed an association study, the first to utilize key molecular genetic variation underlying the ABO system, genotyping >9000 individuals across three African populations. Using population- and family-based tests, we demonstrated that alleles producing functional ABO enzymes are associated with greater risk of severe malaria phenotypes (particularly malarial anemia) in comparison with the frameshift deletion underlying blood group O: case-control allelic odds ratio (OR), 1.2; 95% confidence interval (CI), 1.09-1.32; P = 0.0003; family-studies allelic OR, 1.19; 95% CI, 1.08-1.32; P = 0.001; pooled across all studies allelic OR, 1.18; 95% CI, 1.11-1.26; P = 2 x 10(-7). We found suggestive evidence of a parent-of-origin effect at the ABO locus by analyzing the family trios. Non-O haplotypes inherited from mothers, but not fathers, are significantly associated with severe malaria (likelihood ratio test of Weinberg, P = 0.046). Finally, we used HapMap data to demonstrate a region of low F(ST) (-0.001) between the three main HapMap population groups across the ABO locus, an outlier in the empirical distribution of F(ST) across chromosome 9 (approximately 99.5-99.9th centile). This low F(ST) region may be a signal of long-standing balancing selection at the ABO locus, caused by multiple infectious pathogens including P. falciparum.

The Severe Malaria in African Children (SMAC) network was established to conduct mortality-based trials. Although falciparum malaria kills more than one million children each year, single centers cannot enroll enough patients to detect reductions of 20-30% in mortality rates. Our aim was to quantify and describe severe malaria across a variety of epidemiological settings so that we could design intervention studies with more precise sample size estimates. We used a standardized surveillance mechanism to capture clinical, laboratory and outcome data on all parasitemic children admitted to hospital. Between December 2000 and December 2003, 20333 patients were enrolled at five sites. The frequency of severe malaria syndromes (cerebral malaria, severe malarial anemia and acidosis) differed between sites, as did the syndrome-specific mortality rates. Intervention studies targeted at reducing mortality in one or a combination of severe malaria syndromes would require 3-4 years to complete within the existing network. These data provide more accurate estimates of the disease burden of children hospitalized for malaria in sub-Saharan Africa. Networks are required to recruit enough patients for mortality-based studies and to encompass the epidemiological diversity of malaria in sub-Saharan Africa. SMAC represents the first effort to develop this capacity.

Many human T-cell responses specific for epitopes in Plasmodium falciparum have been described, but none has yet been shown to be predictive of protection against natural malaria infection. Here we report a peptide-specific T-cell assay that is strongly associated with protection of humans in The Gambia, West Africa, from both malaria infection and disease. The assay detects interferon-gamma-secreting CD4(+) T cells specific for a conserved sequence from the circumsporozoite protein, which binds to many human leukocyte antigen (HLA)-DR types. The correlation was observed using a cultured, rather than an ex vivo, ELISPOT assay that measures central memory-'type T cells rather than activated effector T cells. These findings provide direct evidence for a protective role for CD4(+) T cells in humans, and a precise target for the design of improved vaccines against P. falciparum.

A double-blind, community-randomized, placebo-controlled trial was conducted in a rural area of The Gambia between June and December 1999 to test whether a reduction in the infectious reservoir can reduce malaria transmission. Overall 14,017 (85%) individuals living in the study area were treated with either placebo or sulfadoxine-pyrimethamine (SP) combined with a single dose of artesunate (AS). Following the mass drug administration (MDA) 1375 children aged 6 months to 10 years were kept under surveillance for clinical malaria in 18 villages throughout the 1999 malaria transmission season. During a 20-week surveillance period 637 episodes of malaria were detected. The mean incidence rate was 2.5/100 child-weeks in the placebo villages, and 2.3/100 child-weeks in villages that received SP + AS. The mean rate ratio, adjusted for individual and village-level covariates, was 0.91 (95% CI 0.68-1.22, P = 0.49). During the first 2 months of surveillance, the malaria incidence was lower in treated villages. After 2 months the incidence was slightly higher in the MDA group but this was not statistically significant. Overall, no benefit of the MDA could be detected. The reason for the absence of an impact on malaria transmission is probably the very high basic reproductive number of malaria, and the persistence of mature gametocytes, which are not affected by AS treatment.

Objective: To find out what proportion of Plasmodium falciparum infections are treated in rural Gambia., Methods: Subjects from four villages in the Gambia were followed over nine months through visits to village health workers. Monthly cross-sectional malaria surveys measured the prevalence of P. falciparum infection. Linked databases were searched for treatment requests. Treated cases were individuals with parasitaemia who requested treatment during narrow or extended periods (14 or 28 days, respectively) before or after a positive blood film was obtained., Findings: Parasite prevalence peaked in November 1998, when 399/653 (61%) individuals had parasitaemia. Parasite prevalence was highest throughout the study in children aged 5-10 years. Although access to treatment was better than in most of sub-Saharan Africa, only 20% of infected individuals sought medical treatment up to 14 days before or after a positive blood film. Within two months of a positive blood film, 199/726 (27%) individuals with parasitaemia requested treatment. Despite easy access to health care, less than half (42%) of those with parasite densities consistent with malaria attacks (5000/ l) requested treatment. High parasite density and infection during October-November were associated with more frequent treatment requests. Self-treatment was infrequent in study villages: in 3/120 (2.5%) households antimalarial drugs had been used in the preceding malaria season., Conclusion: Many P. falciparum infections may be untreated because of their subclinical nature. Intermittent presumptive treatment may reduce morbidity and mortality. It is likely that not all untreated infections were asymptomatic. Qualitative research should explore barriers to treatment uptake, to allow educational interventions to be planned.