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Journal articleSlater HC, Ross A, Felger I, et al., 2019,
Author Correction: The temporal dynamics and infectiousness of subpatent Plasmodium falciparum infections in relation to parasite density
, Nature Communications, Vol: 10, ISSN: 2041-1723Correction to: Nature Communications https://doi.org/10.1038/s41467-019-09441-1; published online 29 March 2019
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Journal articleGreen N, Sherrard-Smith E, Tanton C, et al., 2019,
Assessing local chlamydia screening performance by combining survey and administrative data to account for differences in local population characteristics
, Scientific Reports, Vol: 9, ISSN: 2045-2322Reducing health inequalities requires improved understanding of the causes of variation. Local-level variation reflects differences in local population characteristics and health system performance. Identifying low- and high-performing localities allows investigation into these differences. We used Multilevel Regression with Post-stratification (MRP) to synthesise data from multiple sources, using chlamydia testing as our example. We used national probability survey data to identify individual-level characteristics associated with chlamydia testing and combined this with local-level census data to calculate expected levels of testing in each local authority (LA) in England, allowing us to identify LAs where observed chlamydia testing rates were lower or higher than expected, given population characteristics. Taking account of multiple covariates, including age, sex, ethnicity, student and cohabiting status, 5.4% and 3.5% of LAs had testing rates higher than expected for 95% and 99% posterior credible intervals, respectively; 60.9% and 50.8% had rates lower than expected. Residual differences between observed and MRP expected values were smallest for LAs with large proportions of non-white ethnic populations. London boroughs that were markedly different from expected MRP values (90% posterior exceedance probability) had actively targeted risk groups. This type of synthesis allows more refined inferences to be made at small-area levels than previously feasible.
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Journal articlevan Eijk AM, Larsen DA, Kayentao K, et al., 2019,
Effect of Plasmodium falciparum sulfadoxine-pyrimethamine resistance on the effectiveness of intermittent preventive therapy for malaria in pregnancy in Africa: a systematic review and meta-analysis.
, Lancet Infectious Diseases, Vol: 19, Pages: 546-556, ISSN: 1473-3099BACKGROUND: Resistance of Plasmodium falciparum to sulfadoxine-pyrimethamine threatens the antimalarial effectiveness of intermittent preventive treatment during pregnancy (IPTp) in sub-Saharan Africa. We aimed to assess the associations between markers of sulfadoxine-pyrimethamine resistance in P falciparum and the effectiveness of sulfadoxine-pyrimethamine IPTp for malaria-associated outcomes. METHODS: For this systematic review and meta-analysis, we searched databases (from Jan 1, 1990 to March 1, 2018) for clinical studies (aggregated data) or surveys (individual participant data) that reported data on low birthweight (primary outcome) and malaria by sulfadoxine-pyrimethamine IPTp dose, and for studies that reported on molecular markers of sulfadoxine-pyrimethamine resistance. Studies that involved only HIV-infected women or combined interventions were excluded. We did a random-effects meta-analysis (clinical studies) or multivariate log-binomial regression (surveys) to obtain summarised dose-response data (relative risk reduction [RRR]) and multivariate meta-regression to explore the modifying effects of sulfadoxine-pyrimethamine resistance (as indicated by Ala437Gly, Lys540Glu, and Ala581Gly substitutions in the dhps gene). This study is registered with PROSPERO, number 42016035540. FINDINGS: Of 1097 records screened, 57 studies were included in the aggregated-data meta-analysis (including 59 457 births). The RRR for low birthweight declined with increasing prevalence of dhps Lys540Glu (ptrend=0·0060) but not Ala437Gly (ptrend=0·35). The RRR was 7% (95% CI 0 to 13) in areas of high resistance to sulfadoxine-pyrimethamine (Lys540Glu ≥90% in east and southern Africa; n=11), 21% (14 to 29) in moderate-resistance areas (Ala437Gly ≥90% [central and west Africa], or Lys540Glu ≥30% to <90% [east and southern Africa]; n=16), and 27% (21 to 33) in low-resistance areas (Ala437Gly <90% [central and west Africa], or Lys540Glu <30% [east and
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Journal articleSlater H, Ross A, Felger I, et al., 2019,
The temporal dynamics and infectiousness of subpatent Plasmodium falciparum infections in relation to parasite density
, Nature Communications, Vol: 10, ISSN: 2041-1723Malaria infections occurring below the limit of detection of standard diagnostics are common in all endemic settings. However, key questions remain surrounding their contribution to sustaining transmission and whether they need to be detected and targeted to achieve malaria elimination. In this study we analyse a range of malaria datasets to quantify the density, detectability, course of infection and infectiousness of subpatent infections. Asymptomatically infected individuals have lower parasite densities on average in low transmission settings compared to individuals in higher transmission settings. In cohort studies, subpatent infections are found to be predictive of future periods of patent infection and in membrane feeding studies, individuals infected with subpatent asexual parasite densities are found to be approximately a third as infectious to mosquitoes as individuals with patent (asexual parasite) infection. These results indicate that subpatent infections contribute to the infectious reservoir, may be long lasting, and require more sensitive diagnostics to detect them in lower transmission settings.
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Journal articleSherrard-Smith E, Griffin J, Winskill P, et al., 2018,
Systematic review of indoor residual spray efficacy and effectiveness against Plasmodium falciparum in Africa
, Nature Communications, Vol: 9, ISSN: 2041-1723Indoor residual spraying (IRS) is an important part of malaria control. There is a growing list of insecticide classes; pyrethroids remain the principal insecticide used in bednets but recently, novel non-pyrethroid IRS products, with contrasting impacts, have been introduced. There is an urgent need to better assess product efficacy to help decision makers choose effective and relevant tools for mosquito control. Here we use experimental hut trial data to characterise the entomological efficacy of widely-used, novel IRS insecticides. We quantify their impact against pyrethroid-resistant mosquitoes and use a Plasmodium falciparum transmission model to predict the public health impact of different IRS insecticides. We report that long-lasting IRS formulations substantially reduce malaria, though their benefit over cheaper, shorter-lived formulations depends on local factors including bednet use, seasonality, endemicity and pyrethroid resistance status of local mosquito populations. We provide a framework to help decision makers evaluate IRS product effectiveness.
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Journal articlevan Eijk AM, Larsen D, Kayentao K, et al.,
Impact of Plasmodium falciparum Sulphadoxine-Pyrimethamine Resistance on the Effectiveness of Intermittent Preventive Therapy for Malaria in Pregnancy in Africa: A Systematic Review and Meta-Analysis
, Lancet Infectious Diseases, ISSN: 1473-3099BackgroundPlasmodium falciparum resistance to sulphadoxine-pyrimethamine (SP) threatens the efficacy of intermittent preventive treatment (IPTp) for malaria in pregnancy in Africa. We conducted a meta-analysis to assess the impact of SP resistance on IPTp-SP effectiveness.MethodsWe searched databases (1990 to March-01-2018) for clinical studies (aggregated data) or surveys (individual-participant data) containing information on low birthweight (LBW, primary outcome) and malaria by IPTp-SP dose, and for studies reporting SP-resistance molecular markers. We performed random-effects meta-analysis (clinical studies) or multivariate log-binomial regression (surveys) to obtain summarized dose-response data (Relative-Risk-Reduction:RRR) and multivariate meta-regression to explore modifying effects of SP-resistance (dhps substitutions A437G, K540E, A581G). FindingsOf 1097 records, 57 studies were included in the aggregated-data meta-analysis (59,457 births). The RRR for LBW declined with increasing prevalence of Pfdhps-K540E (P-trend=0.0060) but not with Pfdhps-A437G (P-trend=0.35). The RRR in areas of high (Pfdhps-K540E >90%, n=11), moderate (Central/West Africa:Pfdhps-A437G≥90% or East/southern Africa:Pfdhps-K540E 30-90%, n=16) and low SP-resistances (n=30) were 7% (95% CI 0-13), 21% (14-29) and 27% (21-33) respectively (P-trend=0.0054, I2=69.5%). In the individual-participant analysis of 13 surveys (42,394 births), IPTp-SP was associated with reduced LBW in areas with Pfdhps-K540E>90% & Pfdhps-A581G<10% (RRR=10%, 7-12), but not those with Pfdhps-A581G>=10% (pooled Pfdhps-A581G prevalence:37%, range 29-46) (RRR=0.5%, -16-14, n=3). InterpretationThe effectiveness of IPTp-SP is reduced in areas with high SP-resistance, but IPTp-SP remains associated with reduced LBW in areas where Pfdhps-K540E prevalence exceeds 90%. IPTp-SP is not effective in areas with ≥37% prevalence of the highly-resistant sextuple Pfdhps-A581G-containing genotype.
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Journal articleMagombedze G, Ferguson NM, Ghani AC, 2018,
A trade-off between dry season survival longevity and wet season high net reproduction can explain the persistence of Anopheles mosquitoes.
, Parasites & Vectors, Vol: 11, ISSN: 1756-3305BACKGROUND: Plasmodium falciparum malaria remains a leading cause of death in tropical regions of the world. Despite efforts to reduce transmission, rebounds associated with the persistence of malaria vectors have remained a major impediment to local elimination. One area that remains poorly understood is how Anopheles populations survive long dry seasons to re-emerge following the onset of the rains. METHODS: We developed a suite of mathematical models to explore the impact of different dry-season mosquito survival strategies on the dynamics of vector populations. We fitted these models to an Anopheles population data set from Mali to estimate the model parameters and evaluate whether incorporating aestivation improved the fit of the model to the observed seasonal dynamics. We used the fitted models to explore the impact of intervention strategies that target aestivating mosquitoes in addition to targeting active mosquitoes and larvae. RESULTS: Including aestivation in the model significantly improved our ability to reproduce the observed seasonal dynamics of vector populations as judged by the deviance information criterion (DIC). Furthermore, such a model resulted in more biologically plausible active mosquito survival times (for A. coluzzii median wet season survival time of 10.9 days, 95% credible interval (CrI): 10.0-14.5 days in a model with aestivation versus 38.1 days, 95% CrI: 35.8-42.5 days in a model without aestivation; similar patterns were observed for A. arabiensis). Aestivation also generated enhanced persistence of the vector population over a wider range of both survival times and fecundity levels. Adding vector control interventions that target the aestivating mosquito population is shown to have the potential to enhance the impact of existing vector control. CONCLUSIONS: Dry season survival attributes appear to drive vector population persistence and therefore have implications for vector control. Further research is therefore needed to better u
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Journal articleOkell L, Reiter LM, Ebbe LS, et al., 2018,
Emerging implications of policies on malaria treatment: genetic changes in the Pfmdr-1 gene affecting susceptibility to artemether-lumefantrine and artesunate-amodiaquine in Africa
, BMJ Global Health, Vol: 3, ISSN: 2059-7908Artemether–lumefantrine (AL) and artesunate–amodiaquine (AS-AQ) are the most commonly used artemisinin-based combination therapies (ACT) for treatment of Plasmodium falciparum in Africa. Both treatments remain efficacious, but single nucleotide polymorphisms (SNPs) in the Plasmodium falciparum multidrug resistance 1 (Pfmdr1) gene may compromise sensitivity. AL and AS-AQ exert opposing selective pressures: parasites with genotype 86Y, Y184 and 1246Y are partially resistant to AS-AQ treatment, while N86, 184 F and D1246 are favoured by AL treatment. Through a systematic review, we identified 397 surveys measuring the prevalence of Pfmdr1 polymorphisms at positions 86 184 or 1246 in 30 countries in Africa. Temporal trends in SNP frequencies after introduction of AL or AS-AQ as first-line treatment were analysed in 32 locations, and selection coefficients estimated. We examined associations between antimalarial policies, consumption, transmission intensity and rate of SNP selection. 1246Y frequency decreased on average more rapidly in locations where national policy recommended AL (median selection coefficient(s) of −0.083), compared with policies of AS-AQ or both AL and AS-AQ (median s=−0.035 and 0.021, p<0.001 respectively). 86Y frequency declined markedly after ACT policy introduction, with a borderline significant trend for a more rapid decline in countries with AL policies (p=0.055). However, these trends could also be explained by a difference in initial SNP frequencies at the time of ACT introduction. There were non-significant trends for faster selection of N86 and D1246 in areas with higher AL consumption and no trend with transmission intensity. Recorded consumption of AS-AQ was low in the locations and times Pfmdr1 data were collected. SNP trends in countries with AL policies suggest a broad increase in sensitivity of parasites to AS-AQ, by 7–10 years after AL introduction. Observed rates of selection have implications for pla
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Journal articleAydemir O, Janko M, Hathaway NJ, et al., 2018,
Drug-resistance and population structure of plasmodium falciparum across the Democratic Republic of Congo using high-throughput molecular inversion probes
, Journal of Infectious Diseases, Vol: 218, Pages: 946-955, ISSN: 0022-1899A better understanding of the drivers of the spread of malaria parasites and drug resistance across space and time is needed. These drivers can be elucidated using genetic tools. Here, a novel molecular inversion probe (MIP) panel targeting all major drug-resistance mutations and a set of microsatellites was used to genotype Plasmodium falciparum infections of 552 children from the 2013–2014 Demographic and Health Survey conducted in the Democratic Republic of the Congo (DRC). Microsatellite-based analysis of population structure suggests that parasites within the DRC form a homogeneous population. In contrast, sulfadoxine-resistance markers in dihydropteroate synthase show marked spatial structure with ongoing spread of double and triple mutants compared with 2007. These findings suggest that parasites in the DRC remain panmictic despite rapidly spreading antimalarial-resistance mutations. Moreover, highly multiplexed targeted sequencing using MIPs emerges as a cost-effective method for elucidating pathogen genetics in complex infections in large cohorts.
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Journal articleHellewell J, Walker P, Ghani A, et al., 2018,
Using ante-natal clinic prevalence data to monitor temporal changes in malaria incidence in a humanitarian setting in the Democratic Republic of Congo
, Malaria Journal, Vol: 17, ISSN: 1475-2875BackgroundThe number of clinical cases of malaria is often recorded in resource constrained or conflict settings as a proxy for disease burden. Interpreting case count data in areas of humanitarian need is challenging due to uncertainties in population size caused by security concerns, resource constraints and population movement. Malaria prevalence in women visiting ante-natal care (ANC) clinics has the potential to be an easier and more accurate metric for malaria surveillance that is unbiased by population size if malaria testing is routinely conducted irrespective of symptoms. MethodsA suite of distributed lag non-linear models was fitted to clinical incidence time-series data in children under 5 years and ANC prevalence data from health centres run by Médecins Sans Frontières in the Democratic Republic of Congo, which implement routine intermittent screening and treatment (IST) alongside intermittent preventative treatment in pregnancy (IPTp). These statistical models enable the temporal relationship between the two metrics to be disentangled. ResultsThere was a strong relationship between the ANC prevalence and clinical incidence suggesting that both can be used to describe current malaria endemicity. There was no evidence that ANC prevalence could predict future clinical incidence, though a change in clinical incidence was shown to influence ANC prevalence up to 3 months into the future. ConclusionsThe results indicate that ANC prevalence may be a suitable metric for retrospective evaluations of the impact of malaria interventions and is a useful method for evaluating long-term malaria trends in resource constrained settings.
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Journal articleWhite MT, Walker PGT, Karl S, et al., 2018,
Mathematical modelling of the impact of expanding levels of malaria control interventions on Plasmodium vivax
, Nature Communications, Vol: 9, ISSN: 2041-1723Plasmodium vivax poses unique challenges for malaria control and elimination, notably the potential for relapses to maintain transmission in the face of drug-based treatment and vector control strategies. We developed an individual-based mathematical model of P. vivax transmission calibrated to epidemiological data from Papua New Guinea (PNG). In many settings in PNG, increasing bed net coverage is predicted to reduce transmission to less than 0.1% prevalence by light microscopy, however there is substantial risk of rebounds in transmission if interventions are removed prematurely. In several high transmission settings, model simulations predict that combinations of existing interventions are not sufficient to interrupt P. vivax transmission. This analysis highlights the potential options for the future of P. vivax control: maintaining existing public health gains by keeping transmission suppressed through indefinite distribution of interventions; or continued development of strategies based on existing and new interventions to push for further reduction and towards elimination.
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Journal articleWitmer K, Sherrard-Smith E, Straschil U, et al., 2018,
An inexpensive open source 3D printed membrane feeder for human malaria transmission studies
, Malaria Journal, Vol: 17, ISSN: 1475-2875BackgroundThe study of malaria transmission requires the experimental infection of mosquitoes with Plasmodium gametocytes. In the laboratory, this is achieved using artificial membrane feeding apparatus that simulate body temperature and skin of the host, and so permit mosquito feeding on reconstituted gametocyte-containing blood. Membrane feeders either use electric heating elements or complex glass chambers to warm the infected blood; both of which are expensive to purchase and can only be sourced from a handful of specialized companies. Presented and tested here is a membrane feeder that can be inexpensively printed using 3D-printing technology.ResultsUsing the Plasmodium falciparum laboratory strain NF54, three independent standard membrane feeding assays (SMFAs) were performed comparing the 3D-printed feeder against a commercial glass feeder. Exflagellation rates did not differ between the two feeders. Furthermore, no statistically significant difference was found in the oocyst load nor oocyst intensity of Anopheles stephensi mosquitoes (mean oocyst range 1.3–6.2 per mosquito; infection prevalence range 41–79%).ConclusionsOpen source provision of the design files of the 3D-printed feeder will facilitate a wider range of laboratories to perform SMFAs in laboratory and field settings, and enable them to freely customize the design to their own requirements.
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Journal articleHogan AB, Winskill P, Verity R, et al., 2018,
Modelling population-level impact to inform target product profiles for childhood malaria vaccines
, BMC Medicine, Vol: 16, ISSN: 1741-7015BackgroundThe RTS,S/AS01 vaccine for Plasmodium falciparum malaria demonstrated moderate efficacy in 5–17-month-old children in phase 3 trials, and from 2018, the vaccine will be evaluated through a large-scale pilot implementation program. Work is ongoing to optimise this vaccine, with higher efficacy for a different schedule demonstrated in a phase 2a challenge study. The objective of our study was to investigate the population-level impact of a modified RTS,S/AS01 schedule and dose amount in order to inform the target product profile for a second-generation malaria vaccine.MethodsWe used a mathematical modelling approach as the basis for our study. We simulated the changing anti-circumsporozoite antibody titre following vaccination and related the titre to vaccine efficacy. We then implemented this efficacy profile within an individual-based model of malaria transmission. We compared initial efficacy, duration and dose timing, and evaluated the potential public health impact of a modified vaccine in children aged 5–17 months, measuring clinical cases averted in children younger than 5 years.ResultsIn the first decade of delivery, initial efficacy was associated with a higher reduction in childhood clinical cases compared to vaccine duration. This effect was more pronounced in high transmission settings and was due to the efficacy benefit occurring in younger ages where disease burden is highest. However, the low initial efficacy and long duration schedule averted more cases across all age cohorts if a longer time horizon was considered. We observed an age-shifting effect due to the changing immunological profile in higher transmission settings, in scenarios where initial efficacy was higher, and the fourth dose administered earlier.ConclusionsOur findings indicate that, for an imperfect childhood malaria vaccine with suboptimal efficacy, it may be advantageous to prioritise initial efficacy over duration. We predict that a modified vaccine could outpe
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Journal articleRoutledge I, Chevez JER, Cucunubá ZM, et al., 2018,
Estimating spatiotemporally varying malaria reproduction numbers in a near elimination setting
, Nature Communications, Vol: 9, Pages: 1-8, ISSN: 2041-1723In 2016 the World Health Organization identified 21 countries that could eliminate malaria by 2020. Monitoring progress towards this goal requires tracking ongoing transmission. Here we develop methods that estimate individual reproduction numbers and their variation through time and space. Individual reproduction numbers, Rc, describe the state of transmission at a point in time and differ from mean reproduction numbers, which are averages of the number of people infected by a typical case. We assess elimination progress in El Salvador using data for confirmed cases of malaria from 2010 to 2016. Our results demonstrate that whilst the average number of secondary malaria cases was below one (0.61, 95% CI 0.55–0.65), individual reproduction numbers often exceeded one. We estimate a decline in Rc between 2010 and 2016. However we also show that if importation is maintained at the same rate, the country may not achieve malaria elimination by 2020.
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Journal articleSherrard-Smith E, Sala KA, Betancourt M, et al., 2018,
Synergy in anti-malarial pre-erythrocytic and transmission-blocking antibodies is achieved by reducing parasite density
, eLife, Vol: 7, ISSN: 2050-084XAnti-malarial pre-erythrocytic vaccines (PEV) target transmission by inhibiting human infection but are currently partially protective. It has been posited, but never demonstrated, that co-administering transmission-blocking vaccines (TBV) would enhance malaria control. We hypothesized a mechanism that TBV could reduce parasite density in the mosquito salivary glands, thereby enhancing PEV efficacy. This was tested using a multigenerational population assay, passaging Plasmodium berghei to Anopheles stephensi mosquitoes. A combined efficacy of 90.8% (86.7–94.2%) was observed in the PEV +TBV antibody group, higher than the estimated efficacy of 83.3% (95% CrI 79.1–87.0%) if the two antibodies acted independently. Higher PEV efficacy at lower mosquito parasite loads was observed, comprising the first direct evidence that co-administering anti-sporozoite and anti-transmission interventions act synergistically, enhancing PEV efficacy across a range of TBV doses and transmission intensities. Combining partially effective vaccines of differing anti-parasitic classes is a pragmatic, powerful way to accelerate malaria elimination efforts.
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