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  • Journal article
    Najer A, Blight J, Ducker CB, Gasbarri M, Brown JC, Che J, Hogset H, Saunders C, Ojansivu M, Lu Z, Lin Y, Yeow J, Rifaie Graham O, Potter M, Tonkin R, Penders J, Doutch JJ, Georgiadou A, Barriga HMG, Holme MN, Cunnington AJ, Bugeon L, Dallman MJ, Barclay WS, Stellacci F, Baum J, Stevens MMet al.,

    Potent Virustatic Polymer-Lipid Nanomimics Block Viral Entry and Inhibit Malaria Parasites In Vivo

    , ACS Central Science, ISSN: 2374-7943
  • Journal article
    Sherrard-Smith E, Winskill P, Hamlet A, Ngufor C, N'Guessan R, Guelbeogo MW, Sanou A, Nash RK, Hill A, Russell EL, Woodbridge M, Tungu P, Kont MD, McLean T, Fornadel C, Richardson JH, Donnelly MJ, Staedke SG, Gonahasa S, Protopopoff N, Rowland M, Churcher TSet al., 2022,

    Optimising the deployment of vector control tools against malaria: a data-informed modelling study

    , The Lancet Planetary Health, Vol: 6, Pages: e100-e109, ISSN: 2542-5196

    Background Concern that insecticide resistant mosquitoes are threatening malaria control has driven the development of new types of insecticide treated nets (ITNs) and indoor residual spraying (IRS). Malaria control programmes have a choice of vector control interventions though it is unclear which should be used to combat the disease.MethodsThe entomological impact of ITNs combining a pyrethroid insecticide with the synergist piperonyl butoxide (PBO) is characterised from experimental hut trials and used to parameterise a malaria transmission dynamics model. Model projections are validated for two sites by comparing results to data from pyrethroid-PBO ITN and IRS randomised control trials (RCTs). Models are used to identify optimum intervention packages for scenarios with varying budget, price, entomological and epidemiological factors. Findings Combining entomological data and models can reasonably predict changes in malaria in the Tanzanian and Ugandan RCTs. Models indicate switching from pyrethroid-only to pyrethroid-PBO ITNs could avert up to twice as many cases, though the additional benefit is highly variable and depends upon setting. Annual delivery of long-lasting, non-pyrethroid IRS is projected to prevent substantially more cases over 3-years, but pyrethroid-PBO ITNs tend to be the most cost-effective intervention per case averted. An online tool (MINT) provides users with a method of designing intervention packages given their setting and budget. InterpretationThe most cost-effective vector control package will vary locally. Models able to recreate results of RCTs can be used to extrapolate outcomes elsewhere to support evidence-based decision making for investment in vector control.FundingMedical Research Council, IVCC, Wellcome Trust.

  • Journal article
    Mooney JP, DonVito SM, Jahateh M, Bittaye H, Keith M, Galloway LJ, Ndow M, Cunnington AJ, DAlessandro U, Bottomley C, Riley EMet al., 2022,

    ‘Bouncing Back’ from subclinical malaria: inflammation and erythrocytosis after resolution of P. falciparum infection in Gambian children

    , Frontiers in Immunology, Vol: 13, Pages: 1-12, ISSN: 1664-3224

    Recent malaria is associated with an increased risk of systemic bacterial infection. The aetiology of this association is unclear but malaria-related haemolysis may be one contributory factor. To characterise the physiological consequences of persistent and recently resolved malaria infections and associated haemolysis, 1650 healthy Gambian children aged 8–15 years were screened for P. falciparum infection (by 18sRNA PCR) and/or anaemia (by haematocrit) at the end of the annual malaria transmission season (t1). P. falciparum-infected children and children with moderate or severe anaemia (haemoglobin concentration < 11g/dl) were age matched to healthy, uninfected, non-anaemic controls and screened again 2 months later (t2). Persistently infected children (PCR positive at t1 and t2) had stable parasite burdens and did not differ significantly haematologically or in terms of proinflammatory markers from healthy, uninfected children. However, among persistently infected children, IL-10 concentrations were positively correlated with parasite density suggesting a tolerogenic response to persistent infection. By contrast, children who naturally resolved their infections (positive at t1 and negative at t2) exhibited mild erythrocytosis and concentrations of pro-inflammatory markers were raised compared to other groups of children. These findings shed light on a ‘resetting’ and potential overshoot of the homeostatic haematological response following resolution of malaria infection. Interestingly, the majority of parameters tested were highly heterogeneous in uninfected children, suggesting that some may be harbouring cryptic malaria or other infections.

  • Journal article
    Georgiadou A, Dunican C, Sorro-Barrio P, Lee HJ, Kaforou M, Cunnington Aet al., 2022,

    Comparative transcriptomic analysis reveals translationally relevant processes in mouse models of malaria

    , eLife, Vol: 11, ISSN: 2050-084X

    Recent initiatives to improve translation of findings from animal models to human disease have focussed on reproducibility but quantifying the relevance of animal models remains a challenge. Here, we use comparative transcriptomics of blood to evaluate the systemic host response and its concordance between humans with different clinical manifestations of malaria and five commonly used mouse models. Plasmodium yoelii 17XL infection of mice most closely reproduces the profile of gene expression changes seen in the major human severe malaria syndromes, accompanied by high parasite biomass, severe anemia, hyperlactatemia, and cerebral microvascular pathology. However, there is also considerable discordance of changes in gene expression between the different host species and across all models, indicating that the relevance of biological mechanisms of interest in each model should be assessed before conducting experiments. These data will aid the selection of appropriate models for translational malaria research, and the approach is generalizable to other disease models.

  • Journal article
    Nash RK, Lambert B, NGuessan R, Ngufor C, Rowland M, Oxborough R, Moore S, Tungu P, Sherrard-Smith E, Churcher TSet al., 2021,

    Systematic review of the entomological impact of insecticide-treated nets evaluated using experimental hut trials in Africa

    , Current Research in Parasitology & Vector-Borne Diseases, Vol: 1, Pages: 1-13, ISSN: 2667-114X

    Resistance of anopheline mosquitoes to pyrethroid insecticides is spreading rapidly across sub-Saharan Africa, diminishing the efficacy of insecticide-treated nets (ITNs) – the primary tool for preventing malaria. The entomological efficacy of indoor vector control interventions can be measured in experimental hut trials (EHTs), where hut structures resemble local housing, but allow the collection of mosquitoes that entered, exited, blood-fed and/or died. There is a need to understand how the spread of resistance changes ITN efficacy and to elucidate factors influencing EHT results, including differences in experimental hut design, to support the development of novel vector control tools. A comprehensive database of EHTs was compiled following a systematic review to identify all known trials investigating ITNs or indoor residual spraying across sub-Saharan Africa. This analysis focuses on EHTs investigating ITNs and uses Bayesian statistical models to characterise the complex interaction between ITNs and mosquitoes, the between-study variability, and the impact of pyrethroid resistance. As resistance rises, the entomological efficacy of ITNs declines. They induce less mortality and are less likely to deter mosquitoes from entering huts. Despite this, ITNs continue to offer considerable personal protection by reducing mosquito feeding until resistance reaches high levels. There are clear associations between the different entomological impacts of ITNs, though there is still substantial variability between studies, some of which can be accounted for by hut design. The relationship between EHT outcomes and the level of resistance (as measured by discriminating dose bioassays) is highly uncertain. The meta-analyses show that EHTs are an important reproducible assay for capturing the complex entomological efficacy of ITNs on blood-feeding mosquitoes. The impact of pyrethroid resistance on these measures appears broadly consistent across a wide geographical area onc

  • Journal article
    Okell L, Whittaker C, Ghani A, Slater H, Nash R, Bousema T, Drakeley Cet al., 2021,

    Global patterns of submicroscopic Plasmodium falciparum malaria infection: insights from a systematic review and meta-analysis of population surveys

    , The Lancet Microbe, Vol: 2, Pages: e366-e374, ISSN: 2666-5247

    Background: Adoption of molecular techniques to detect Plasmodium falciparum infection has revealed many previously undetected (by microscopy) yet transmissible low-density infections. The proportion of these infections is typically highest in low transmission settings, but drivers of submicroscopic infection remain unclear. Here, we update a previously conducted systematic review of asexual P. falciparum prevalence by microscopy and polymerase chain reaction (PCR) in the same population. We conduct a meta-analysis to explore potential drivers of submicroscopic infection and identify the locations where submicroscopic infections are most common. Methods: PubMed and Web of Science databases were searched up to 11th October 2020 for cross-sectional studies reporting data on asexual P.falciparum prevalence by both microscopy and PCR. Surveys of pregnant women, where participants had been chosen based on symptoms/treatment or that did not involve a population from a defined location were excluded. Both the number of individuals tested and positive by microscopy and PCR for P. falciparum infection were extracted from each reference. Bayesian regression modelling was used to explore determinants of the size of the submicroscopic reservoir including geography, seasonality, age, methodology and current/historical patterns of transmission.Findings: A total of 166 references containing 551 cross-sectional survey microscopy/PCR prevalence pairs were included. Our results highlight that submicroscopic infections predominate in low transmission settings across all settings, but also reveal marked geographical variation, with the proportion of infections that are submicroscopic being highest in South American surveys and lowest in West African studies. Whilst current transmission levels partly explain these results, we find that historical transmission intensity also represents a crucial determinant of the size of the submicroscopic reservoir, as does the demographic structure of

  • Journal article
    Da DF, McCabe R, Somé BM, Esperança PM, Sala KA, Blight J, Blagborough AM, Dowell F, Yerbanga SR, Lefèvre T, Mouline K, Dabiré RK, Churcher TSet al., 2021,

    Detection of Plasmodium falciparum in laboratory-reared and naturally infected wild mosquitoes using near-infrared spectroscopy.

    , Scientific Reports, Vol: 11, Pages: 10289-10289, ISSN: 2045-2322

    There is an urgent need for high throughput, affordable methods of detecting pathogens inside insect vectors to facilitate surveillance. Near-infrared spectroscopy (NIRS) has shown promise to detect arbovirus and malaria in the laboratory but has not been evaluated in field conditions. Here we investigate the ability of NIRS to identify Plasmodium falciparum in Anopheles coluzzii mosquitoes. NIRS models trained on laboratory-reared mosquitoes infected with wild malaria parasites can detect the parasite in comparable mosquitoes with moderate accuracy though fails to detect oocysts or sporozoites in naturally infected field caught mosquitoes. Models trained on field mosquitoes were unable to predict the infection status of other field mosquitoes. Restricting analyses to mosquitoes of uninfectious and highly-infectious status did improve predictions suggesting sensitivity and specificity may be better in mosquitoes with higher numbers of parasites. Detection of infection appears restricted to homogenous groups of mosquitoes diminishing NIRS utility for detecting malaria within mosquitoes.

  • Journal article
    Georgiadou A, Naidu P, Walsh S, Kamiza S, Barrera V, Harding SP, Moxon CA, Cunnington AJet al., 2021,

    Localized release of matrix metallopeptidase 8 in fatal cerebral malaria

    , Clinical & Translational Immunology, Vol: 10, Pages: 1-7, ISSN: 2050-0068

    ObjectiveCerebral malaria (CM) is a complication of Plasmodium falciparum malaria, in which progressive brain swelling is associated with sequestration of parasites and impaired barrier function of the cerebral microvascular endothelium. To test the hypothesis that localised release of matrix metallopeptidase 8 (MMP8) within the retina is implicated in microvascular leak in CM, we examined its expression and association with extravascular fibrinogen leak in a case–control study of post‐mortem retinal samples from 13 Malawian children who met the clinical case definition of CM during life. Cases were seven children who were found on post‐mortem examination to have ‘true‐CM’ (parasite sequestration in brain blood vessels), whilst controls were six children who had alternative causes of death (‘faux‐CM’, no parasite sequestration in blood vessels).MethodsWe used immunofluorescence microscopy and independent scoring, by two assessors blinded to the CM status, to assess MMP8 expression, extravascular fibrinogen as an indicator of vascular leak and their co‐localisation in the retinal microvasculature.ResultsIn ‘true‐CM’ subjects, MMP8 staining was invariably associated with sequestered parasites and a median of 88% (IQR = 74–91%) of capillaries showed MMP8 staining, compared with 14% (IQR = 3.8–24%) in ‘faux‐CM’ (P‐value = 0.001). 41% (IQR = 28–49%) of capillaries in ‘true‐CM’ subjects showed co‐localisation of extravascular fibrinogen leak and MMP8 staining, compared with 1.8% of capillaries in ‘faux‐CM’ (IQR = 0–3.9%, P‐value = 0.01). Vascular leak was rare in the absence of MMP8 staining.ConclusionMatrix metallopeptidase 8 was extensively expressed in retinal capillaries of Malawian children with malarial retinopathy and strongly associated with vascular leak. Our findings implicate MMP8 as a cause of the vascular endothelial barrier disruption in CM, which may precip

  • Journal article
    Fraser KJ, Mwandigha L, Traore SF, Traore MM, Doumbia S, Junnila A, Revay E, Beier JC, Marshall JM, Ghani AC, Muller Get al., 2021,

    Estimating the potential impact of Attractive Targeted Sugar Baits (ATSBs) as a new vector control tool for Plasmodium falciparum malaria

    , Malaria Journal, Vol: 20, ISSN: 1475-2875

    BackgroundAttractive targeted sugar baits (ATSBs) are a promising new tool for malaria control as they can target outdoor-feeding mosquito populations, in contrast to current vector control tools which predominantly target indoor-feeding mosquitoes.MethodsIt was sought to estimate the potential impact of these new tools on Plasmodium falciparum malaria prevalence in African settings by combining data from a recent entomological field trial of ATSBs undertaken in Mali with mathematical models of malaria transmission. The key parameter determining impact on the mosquito population is the excess mortality due to ATSBs, which is estimated from the observed reduction in mosquito catch numbers. A mathematical model capturing the life cycle of P. falciparum malaria in mosquitoes and humans and incorporating the excess mortality was used to estimate the potential epidemiological effect of ATSBs.ResultsThe entomological study showed a significant reduction of ~ 57% (95% CI 33–72%) in mosquito catch numbers, and a larger reduction of ~ 89% (95% CI 75–100%) in the entomological inoculation rate due to the fact that, in the presence of ATSBs, most mosquitoes do not live long enough to transmit malaria. The excess mortality due to ATSBs was estimated to be lower (mean 0.09 per mosquito per day, seasonal range 0.07–0.11 per day) than the bait feeding rate obtained from one-day staining tests (mean 0.34 per mosquito per day, seasonal range 0.28–0.38 per day).ConclusionsFrom epidemiological modelling, it was predicted that ATSBs could result in large reductions (> 30% annually) in prevalence and clinical incidence of malaria, even in regions with an existing high malaria burden. These results suggest that this new tool could provide a promising addition to existing vector control tools and result in significant reductions in malaria burden across a range of malaria-endemic settings.

  • Journal article
    Challenger J, Olivera Mesa D, Da DF, Yerbanga RS, Lefèvre T, Cohuet A, Churcher TSet al., 2021,

    Predicting the public health impact of a malaria transmission-blocking vaccine

    , Nature Communications, Vol: 12, Pages: 1-12, ISSN: 2041-1723

    Transmission-blocking vaccines that interrupt malaria transmission from humans to mosquitoes are being tested in early clinical trials. The activity of such a vaccine is commonly evaluated using membrane-feeding assays. Understanding the field efficacy of such a vaccine requires knowledge of how heavily infected wild, naturally blood-fed mosquitoes are, as this indicates how difficult it will be to block transmission. Here we use data on naturally infected mosquitoes collected in Burkina Faso to translate the laboratory-estimated activity into an estimated activity in the field. A transmission dynamics model is then utilised to predict a transmission-blocking vaccine’s public health impact alongside existing interventions. The model suggests that school-aged children are an attractive population to target for vaccination. Benefits of vaccination are distributed across the population, averting the greatest number of cases in younger children. Utilising a transmission-blocking vaccine alongside existing interventions could have a substantial impact against malaria.

  • Journal article
    Winskill P, Mousa A, Oresanya O, Counihan H, Okell L, Walker Pet al., 2021,

    Does integrated community case management (iCCM) target health inequities and treatment delays? Evidence from an analysis of Demographic and Health Surveys data from 21 countries in the period 2010 to 2018

    , Journal of Global Health, Vol: 11, Pages: 1-10, ISSN: 2047-2978

    BackgroundIntegrated community case management (iCCM) is a programme that can, via community health workers (CHWs), increase access to timely and essential treatments for children. As well as improving treatment coverage, iCCM has an additional equity-focus with the aim of targetingunderserved populations. To assess the success of iCCM programmes it is important that we understand the contribution they are making to equitable health coverage.MethodsWe analysed demographic and health survey data from 21 countries over 9 years to assess evidence and evaluate iCCM programmes. We summarise the contribution CHWs are making relative to other healthcare provider groups and what treatment combinations CHWs are commonly prescribing. We assessed the ability of CHWs to target treatment delays and health inequities by evaluating time to treatment following fever onset and relationships between CHWs and wealth, rurality and remoteness.ResultsThere was good evidence that CHWs are being successfully targeted to improve inequities in healthcare coverage. There is a larger contribution of CHWs in areas with higher poverty, rurality and remoteness. In six surveys CHWs were associated with significantly shorter average timebetween fever onset and advice or treatment seeking, whilst in one they were associated with significantly longer times. In areas with active CHW programmes, the contribution of CHWs relative to other healthcare provider groups varied between 11% to 45% of treatment visits. The distribution of types of treatment provided by CHWs was also very variable between countries.ConclusionsThe success of an iCCM programme depends not only on increasing treatment coverage but addressing inequities in access to timely healthcare. Whilst much work is still needed to attain universal healthcare targets, and despite incomplete data, there is evidence that iCCM is successfully addressing treatment delays and targeting underserved populations.

  • Journal article
    Varghese S, Rahmani R, Drew DR, Beeson JG, Baum J, Smith BJ, Baell Jet al., 2021,

    Structure activity studies of truncated latrunculin analogues with anti-malarial activity

    , ChemMedChem, Vol: 16, Pages: 679-693, ISSN: 0014-827X

    Malarial parasites employ actin dynamics for motility, and any disruption to these dynamics renders the parasites unable to effectively establish infection. Therefore, actin presents a potential target for malarial drug discovery, and naturally occurring actin inhibitors such as latrunculins are a promising starting point. However, the limited availability of the natural product and the laborious route for synthesis of latrunculins have hindered their potential development as drug candidates. In this regard, we recently described novel truncated latrunculins, with superior actin binding potency and selectivity towards P. falciparum actin than the canonical latrunculin B. In this paper, we further explore the truncated latrunculin core to summarize the SAR for inhibition of malaria motility. This study helps further understand the binding pattern of these analogues in order to develop them as drug candidates for malaria.

  • Journal article
    Stopard IJ, Churcher TS, Lambert B, 2021,

    Estimating the extrinsic incubation period of malaria using a mechanistic model of sporogony

    , PLoS Computational Biology, Vol: 17, ISSN: 1553-734X

    During sporogony, malaria-causing parasites infect a mosquito, reproduce and migrate to the mosquito salivary glands where they can be transmitted the next time blood feeding occurs. The time required for sporogony, known as the extrinsic incubation period (EIP), is an important determinant of malaria transmission intensity. The EIP is typically estimated as the time for a given percentile, x, of infected mosquitoes to develop salivary gland sporozoites (the infectious parasite life stage), which is denoted by EIPx. Many mechanisms, however, affect the observed sporozoite prevalence including the human-to-mosquito transmission probability and possibly differences in mosquito mortality according to infection status. To account for these various mechanisms, we present a mechanistic mathematical model, which explicitly models key processes at the parasite, mosquito and observational scales. Fitting this model to experimental data, we find greater variation in the EIP than previously thought: we estimated the range between EIP10 and EIP90 (at 27°C) as 4.5 days compared to 0.9 days using existing statistical methods. This pattern holds over the range of study temperatures included in the dataset. Increasing temperature from 21°C to 34°C decreased the EIP50 from 16.1 to 8.8 days. Our work highlights the importance of mechanistic modelling of sporogony to (1) improve estimates of malaria transmission under different environmental conditions or disease control programs and (2) evaluate novel interventions that target the mosquito life stages of the parasite.

  • Journal article
    Hellewell J, Sherrard-Smith E, Ogoma S, Churcher TSet al., 2021,

    Assessing the impact of low-technology emanators alongside long-lasting insecticidal nets to control malaria

    , Philosophical Transactions of the Royal Society B: Biological Sciences, Vol: 376, Pages: 1-9, ISSN: 0962-8436

    Malaria control in sub-Saharan Africa relies on the widespread use of long-lasting insecticidal nets (LLINs) or the indoor residual spraying of insecticide. Disease transmission may be maintained even when these indoor interventions are universally used as some mosquitoes will bite in the early morning and evening when people are outside. As countries seek to eliminate malaria, they can target outdoor biting using new vector control tools such as spatial repellent emanators, which emit airborne insecticide to form a protective area around the user. Field data are used to incorporate a low-technology emanator into a mathematical model of malaria transmission to predict its public health impact across a range of scenarios. Targeting outdoor biting by repeatedly distributing emanators alongside LLINs increases the chance of elimination, but the additional benefit depends on the level of anthropophagy in the local mosquito population, emanator effectiveness and the pre-intervention proportion of mosquitoes biting outdoors. High proportions of pyrethroid-resistant mosquitoes diminish LLIN impact because of reduced mosquito mortality. When mosquitoes are highly anthropophagic, this reduced mortality leads to more outdoor biting and a reduced additional benefit of emanators, even if emanators are assumed to retain their effectiveness in the presence of pyrethroid resistance. Different target product profiles are examined, which show the extra epidemiological benefits of spatial repellents that induce mosquito mortality.

  • Journal article
    Guglielmo F, Sanou A, Churcher TS, Ferguson HM, Ranson H, Sherrard-Smith Eet al., 2021,

    Quantifying individual variability in exposure risk to mosquito bites in the Cascades region, Burkina Faso

    , Malaria Journal, Vol: 20, Pages: 1-14, ISSN: 1475-2875

    BackgroundThe Cascades region, Burkina Faso, has a high malaria burden despite reported high insecticide-treated mosquito net (ITN) use. Human and vector activities outside the hours when indoor interventions offer direct protection from infectious bites potentially increase exposure risk to bites from malaria-transmitting Anopheles mosquitoes. This work investigated the degree of variation in human behaviour both between individuals and through time (season) to quantify how it impacts exposure to malaria vectors.MethodsPatterns in human overnight activity (18:00–06:00) to quantify time spent using an ITN across 7 successive nights in two rural communities, Niakore (N = 24 participants) and Toma (71 participants), were observed in the dry and rainy seasons, between 2017 and 2018. Hourly human landing Anopheles mosquito catches were conducted in Niakore specifically, and Cascades region generally, between 2016 and 2017. Data were statistically combined to estimate seasonal variation in time spent outdoors and Anopheles bites received per person per night (bpppn).ResultsSubstantial variability in exposure to outdoor Anopheles bites was detected within and between communities across seasons. In October, when Anopheles densities are highest, an individual’s risk of Anopheles bites ranged from 2.2 to 52.2 bites per person per night (bpppn) within the same week with variable risk dependent on hours spent indoors. Comparably higher outdoor human activity was observed in April and July but, due to lower Anopheles densities estimated, bpppn were 0.2–4.7 and 0.5–32.0, respectively. Males and people aged over 21 years were predicted to receive more bites in both sentinel villages.ConclusionThis work presents one of the first clear descriptions of the degree of heterogeneity in time spent outdoors between people and across the year. Appreciation of sociodemographic, cultural and entomological activities will help refine approaches to vector

  • Journal article
    Guglielmo F, Sanou A, Churcher TS, Ferguson HM, Ranson H, Sherrard-Smith Eet al.,

    Quantifying the individual variability in people’s exposure to mosquito bites in Burkina Faso

    , Malaria Journal

    <jats:title>Abstract</jats:title> <jats:p><jats:bold>Background</jats:bold>The Cascades Region, Burkina Faso, has high malaria burden despite reported high insecticide treated bed net (ITN) use. Human and vector activities outside the hours when indoor interventions offer direct protection from infectious bites potentially increase exposure risk to bites from malaria-transmitting <jats:italic>Anopheles </jats:italic>mosquitoes. We investigate the degree of variation in human behaviour both between individuals and through time (season) to quantify how it impacts exposure to malaria vectors.<jats:bold>Methods</jats:bold>Patterns in human overnight activity (18:00-06:00) to quantify time spent using an ITN across 7 successive nights in two rural communities, Niakore (N = 24 participants) and Toma (71 participants), were observed in the dry and rainy seasons, between 2017-2018. Hourly human landing <jats:italic>Anopheles </jats:italic>mosquito catches were conducted in Niakore specifically, and Cascades Region generally, between 2016-2017. Data were statistically combined to estimate seasonal variation in time spent outdoors and <jats:italic>Anopheles </jats:italic>bites received per person per night (bpppn).<jats:bold>Results</jats:bold>Substantial variability in exposure to outdoor <jats:italic>Anopheles</jats:italic> bites was detected within and between communities and across seasons. In October, when <jats:italic>Anopheles </jats:italic>densities are highest, an individual’s risk of <jats:italic>Anopheles</jats:italic> bites ranged from 2.2 to 52.2 bpppn within the same week with variable risk dependent on hours spent indoors. Comparably higher outdoor human activity was observed in April and July but, due to lower <jats:italic>Anopheles </jats:italic>densities estimated bpppn were 0.2 – 4.7 bpppn, and 0.5 &nda

  • Journal article
    Witmer K, Dahalan F, Delves M, Yahiya S, Watson O, Straschil U, Chiwcharoen D, Sorboon B, Pukrittayakamee S, Pearson R, Howick V, Lawniczak M, White N, Dondorp A, Okell L, Chotivanich K, Ruecker A, Baum Jet al., 2021,

    Transmission of artemisinin-resistant malaria parasites to mosquitoes under antimalarial drug pressure

    , Antimicrobial Agents and Chemotherapy, Vol: 65, Pages: 1-17, ISSN: 0066-4804

    Resistance to artemisinin-based combination therapy (ACT) in the Plasmodium falciparum parasite is threatening to reverse recent gains in reducing global deaths from malaria. Whilst resistance manifests as delayed parasite clearance in patients the phenotype can only spread geographically via the sexual stages and mosquito transmission. In addition to their asexual killing properties, artemisinin and its derivatives sterilise sexual male gametocytes. Whether resistant parasites overcome this sterilising effect has not, however, been fully tested. Here, we analysed P. falciparum clinical isolates from the Greater Mekong Subregion, each demonstrating delayed clinical clearance and known resistance-associated polymorphisms in Kelch13 (PfK13var). As well as demonstrating reduced asexual sensitivity to drug, certain PfK13var isolates demonstrated a marked reduction in sensitivity to artemisinin in an in vitro male gamete formation assay. Importantly, this same reduction in sensitivity was observed when the most resistant isolate was tested directly in mosquito feeds. These results indicate that, under artemisinin drug pressure, whilst sensitive parasites are blocked, resistant parasites continue transmission. This selective advantage for resistance transmission could favour acquisition of additional host-specificity or polymorphisms affecting partner drug sensitivity in mixed infections. Favoured resistance transmission under ACT coverage could have profound implications for the spread of multidrug resistant malaria beyond Southeast Asia.

  • Journal article
    Mumtaz R, Okell LC, Challenger J, 2020,

    Asymptomatic recrudescence after artemether-lumefantrine treatment for uncomplicated falciparum malaria: a systematic review and meta-analysis

    , Malaria Journal, Vol: 19, ISSN: 1475-2875

    BackgroundIn clinical trials of therapy for uncomplicated Plasmodium falciparum, there are usually some patients who fail treatment even in the absence of drug resistance. Treatment failures, which can be due to recrudescence or re-infection, are categorized as ‘clinical’ or ‘parasitological’ failures, the former indicating that symptoms have returned. Asymptomatic recrudescence has public health implications for continued malaria transmission and may be important for the spread of drug-resistant malaria. As the number of recrudescences in an individual trial is often low, it is difficult to assess how commonplace asymptomatic recrudescence is, and with what factors it is associated.MethodsA systematic literature review was carried out on clinical trials of artemether-lumefantrine (AL) in patients seeking treatment for symptomatic uncomplicated falciparum malaria, and information on symptoms during treatment failure was recorded. Only treatment failures examined by polymerase chain reaction (PCR) were included, so as to exclude re-infections. A multivariable Bayesian regression model was used to explore factors potentially explaining the proportion of recrudescent infections which are symptomatic across the trials included in the study.ResultsAcross 60 published trials, including 9137 malaria patients, 37.8% [95% CIs (26.6–49.4%)] of recrudescences were symptomatic. A positive association was found between transmission intensity and the observed proportion of recrudescences that were asymptomatic. Symptoms were more likely to return in trials that only enrolled children aged < 72 months [odds ratio = 1.62, 95% CIs (1.01, 2.59)]. However, 84 studies had to be excluded from this analysis, as recrudescences were not specified as symptomatic or asymptomatic.ConclusionsAL, the most widely used treatment for uncomplicated P. falciparum in Africa, remains a highly efficacious drug in most endemic countries. Howev

  • Journal article
    Hogan A, Winskill P, Ghani A, 2020,

    Estimated impact of RTS,S/AS01 malaria vaccine allocation strategies in sub-Saharan Africa: a modelling study

    , PLoS Medicine, Vol: 17, Pages: 1-19, ISSN: 1549-1277

    Background: The RTS,S/AS01 vaccine against P. falciparum malaria infection completed phase 3 trials in 2014, and demonstrated efficacy against clinical malaria of approximately 36% over 4 years for a 4-dose schedule in children aged 5–17 months. Pilot vaccine implementation has recently begun in three African countries. If the pilots demonstrate both a positive health impact and resolve remaining safety concerns, wider roll-out could be recommended from 2021 onwards. Vaccine demand may however outstrip initial supply. We sought to identify where vaccine introduction should be prioritised to maximise public health impact under a range of supply constraints using mathematical modelling. Methods and Findings: Using a mathematical model of P. falciparum malaria transmission and RTS,S vaccine impact, we estimated the clinical cases and deaths averted in children aged 0–5 years in sub-Saharan Africa under two scenarios for vaccine coverage (100% and realistic) and two scenarios for other interventions (current coverage and WHO Global Technical Strategy targets). We used a prioritisation algorithm to identify potential allocative efficiency gains fromprioritising vaccine allocation among countries or administrative units to maximise cases or deaths averted. If malaria burden at introduction is similar to current levels, assuming realistic vaccine coverage and country-level prioritisation in areas with parasite prevalence >10%, we estimate 4.3 million (95% credible interval, CrI 2.8–6.8 million) malaria cases and 22,000 (95% CrI 11,000–35,000) deaths in children younger than 5 years could be averted annually at a dose constraint of 30 million. This decreases to 3.0 million (95% CrI 2.0–4.7 million) cases and14,000 (95% CrI 7,000–23,000) deaths at a dose constraint of 20 million,and increases to 6.6 million (95% CrI 4.2–10.8 million) cases and38,000 (95% CrI 18

  • Journal article
    Morang'a CM, Amenga-Etego L, Bah SY, Appiah V, Amuzu DSY, Amoako N, Abugri J, Oduro AR, Cunnington AJ, Awandare GA, Otto TDet al., 2020,

    Machine learning approaches classify clinical malaria outcomes based on haematological parameters

    , BMC Medicine, Vol: 18, ISSN: 1741-7015

    BACKGROUND: Malaria is still a major global health burden, with more than 3.2 billion people in 91 countries remaining at risk of the disease. Accurately distinguishing malaria from other diseases, especially uncomplicated malaria (UM) from non-malarial infections (nMI), remains a challenge. Furthermore, the success of rapid diagnostic tests (RDTs) is threatened by Pfhrp2/3 deletions and decreased sensitivity at low parasitaemia. Analysis of haematological indices can be used to support the identification of possible malaria cases for further diagnosis, especially in travellers returning from endemic areas. As a new application for precision medicine, we aimed to evaluate machine learning (ML) approaches that can accurately classify nMI, UM, and severe malaria (SM) using haematological parameters. METHODS: We obtained haematological data from 2,207 participants collected in Ghana: nMI (n = 978), SM (n = 526), and UM (n = 703). Six different ML approaches were tested, to select the best approach. An artificial neural network (ANN) with three hidden layers was used for multi-classification of UM, SM, and uMI. Binary classifiers were developed to further identify the parameters that can distinguish UM or SM from nMI. Local interpretable model-agnostic explanations (LIME) were used to explain the binary classifiers. RESULTS: The multi-classification model had greater than 85% training and testing accuracy to distinguish clinical malaria from nMI. To distinguish UM from nMI, our approach identified platelet counts, red blood cell (RBC) counts, lymphocyte counts, and percentages as the top classifiers of UM with 0.801 test accuracy (AUC = 0.866 and F1 score = 0.747). To distinguish SM from nMI, the classifier had a test accuracy of 0.96 (AUC = 0.983 and F1 score = 0.944) with mean platelet volume and mean cell volume being the unique classifiers of SM. Random forest was used

  • Journal article
    Thompson H, Hogan A, Walker P, White M, Cunnington A, Ockenhouse C, Ghani Aet al., 2020,

    Modelling the roles of antibody titre and avidity in protection from Plasmodium falciparum malaria infection following RTS,S/AS01 vaccination

    , Vaccine, Vol: 38, Pages: 7498-7507, ISSN: 0264-410X

    Anti-circumsporozoite antibody titres have been established as an essential indicator for evaluating the immunogenicity and protective capacity of the RTS,S/AS01 malaria vaccine. However, a new delayed-fractional dose regime of the vaccine was recently shown to increase vaccine efficacy, from 62.5% (95% CI 29.4–80.1%) under the original dosing schedule to 86.7% (95% CI, 66.8–94.6%) without a corresponding increase in antibody titres. Here we reanalyse the antibody data from this challenge trial to determine whether IgG avidity may help to explain efficacy better than IgG titre alone by adapting a within-host mathematical model of sporozoite inoculation. We demonstrate that a model incorporating titre and avidity provides a substantially better fit to the data than titre alone. These results also suggest that in individuals with a high antibody titre response that also show high avidity (both metrics in the top tercile of observed values) delayed-fractional vaccination provided near perfect protection upon first challenge (98.2% [95% Credible Interval 91.6–99.7%]). This finding suggests that the quality of the vaccine induced antibody response is likely to be an important determinant in the development of highly efficacious pre-erythrocytic vaccines against malaria.

  • Journal article
    Eagon S, Hammill JT, Sigal M, Ahn KJ, Tryhorn JE, Koch G, Belanger B, Chaplan CA, Loop L, Kashtanova AS, Yniguez K, Lazaro H, Wilkinson SP, Rice AL, Falade MO, Takahashi R, Kim K, Cheung A, DiBernardo C, Kimball JJ, Winzeler EA, Eribez K, Mittal N, Gamo F-J, Crespo B, Churchyard A, Garcia-Barbazan I, Baum J, Anderson MO, Laleu B, Guy RKet al., 2020,

    Synthesis and Structure-Activity Relationship of Dual-Stage Antimalarial Pyrazolo[3,4-b]pyridines

    , JOURNAL OF MEDICINAL CHEMISTRY, Vol: 63, Pages: 11902-11919, ISSN: 0022-2623
  • Journal article
    Mousa A, Al-Taiar A, Anstey NM, Badaut C, Barber BE, Bassat Q, Challenger J, Cunnington AJ, Datta D, Drakeley C, Ghani AC, Gordeuk VR, Grigg MJ, Hugo P, John CC, Mayor A, Migot-Nabias F, Opoka RO, Pasvol G, Rees C, Reyburn H, Riley EM, Shah BN, Sitoe A, Sutherland CJ, Thuma PE, Unger SA, Viwami F, Walther M, Whitty CJM, William T, Okell LCet al., 2020,

    The impact of delayed treatment of uncomplicated P. falciparum malaria on progression to severe malaria: a systematic review and a pooled multicentre individual-patient meta-analysis

    , PLoS Medicine, Vol: 17, Pages: 1-28, ISSN: 1549-1277

    Background: Delay in receiving treatment for uncomplicated malaria is often reported to increase the risk of developing severe malaria, but access to treatment remains low in most high-burden areas. Understanding the contribution of treatment delay on progression to severe disease is critical to determine how quickly patients need to receive treatment and to quantify the impact of widely implemented treatment interventions, such as “test-and-treat” policies administered by community health workers. We conducted a pooled individual-participant meta-analysis to estimate the association between treatment delay and presenting with severe malaria.Methods and Findings: A search using Ovid MEDLINE and Embase was initially conducted to identify studies on severe P. falciparum malaria which included information on treatment delay, such as fever duration 12(inceptions to 22nd September 2017). Studies identified included five case-control and eight other observational clinical studies of severe and uncomplicated malaria cases. Risk of bias was assessed using the Newcastle–Ottawa scale and all studies were ranked as “Good”, scoring ≥7/10. Individual-patient data were pooled from thirteen studies of 3,989(94.1% aged <15 years)severe malaria patients and 5,780(79.6% aged <15 years)uncomplicated malaria cases in Benin, Malaysia, Mozambique, Tanzania, The Gambia, Uganda, Yemen and Zambia. Definitions of severe malaria were standardised across studies to compare treatment delay in patients with uncomplicated malaria and different severe malaria phenotypes using age-adjusted mixed-effects regression. The odds of any severe malaria phenotype were significantly higher in children with longer delays between initial symptoms and arrival at the health facility (OR=1.33, 95%CI:1.07-1.64 for a delay of >24 hours vs. ≤24 hours;p=0.009). Reported illness duration was a strong predictor of presenting with severe malarial anaemia (SMA) in children

  • Journal article
    Prah DA, Amoah LE, Gibbins MP, Bediako Y, Cunnington AJ, Awandare GA, Hafalla JCRet al., 2020,

    Comparison of leucocyte profiles between healthy children and those with asymptomatic and symptomatic Plasmodium falciparum infections.

    , Malaria Journal, Vol: 19, Pages: 364-364, ISSN: 1475-2875

    BACKGROUND: The immune mechanisms that determine whether a Plasmodium falciparum infection would be symptomatic or asymptomatic are not fully understood. Several studies have been carried out to characterize the associations between disease outcomes and leucocyte numbers. However, the majority of these studies have been conducted in adults with acute uncomplicated malaria, despite children being the most vulnerable group. METHODS: Peripheral blood leucocyte subpopulations were characterized in children with acute uncomplicated (symptomatic; n = 25) or asymptomatic (n = 67) P. falciparum malaria, as well as malaria-free (uninfected) children (n = 16) from Obom, a sub-district of Accra, Ghana. Leucocyte subpopulations were enumerated by flow cytometry and correlated with two measures of parasite load: (a) plasma levels of P. falciparum histidine-rich protein 2 (PfHRP2) as a proxy for parasite biomass and (b) peripheral blood parasite densities determined by microscopy. RESULTS: In children with symptomatic P. falciparum infections, the proportions and absolute cell counts of total (CD3 +) T cells, CD4 + T cells, CD8 + T cells, CD19 + B cells and CD11c + dendritic cells (DCs) were significantly lower as compared to asymptomatic P. falciparum-infected and uninfected children. Notably, CD15 + neutrophil proportions and cell counts were significantly increased in symptomatic children. There was no significant difference in the proportions and absolute counts of CD14 + monocytes amongst the three study groups. As expected, measures of parasite load were significantly higher in symptomatic cases. Remarkably, PfHRP2 levels and parasite densities negatively correlated with both the proportions and absolute numbers of peripheral leucocyte subsets: CD3 + T, CD4 + T, CD8 + T, CD19 + B, CD56&th

  • Journal article
    Djaafara BA, Whittaker C, Watson OJ, Verity R, Brazeau NF, Widyastuti W, Oktavia D, Adrian V, Salama N, Bhatia S, Nouvellet P, Sherrard-Smith E, Churcher TS, Surendra H, Lina RN, Ekawati LL, Lestari KD, Andrianto A, Thwaites G, Baird JK, Ghani AC, Elyazar IRF, Walker PGTet al., 2020,

    Quantifying the dynamics of COVID-19 burden and impact of interventions in Java, Indonesia

    <jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>As in many countries, quantifying COVID-19 spread in Indonesia remains challenging due to testing limitations. In Java, non-pharmaceutical interventions (NPIs) were implemented throughout 2020. However, as a vaccination campaign launches, cases and deaths are rising across the island.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We used modelling to explore the extent to which data on burials in Jakarta using strict COVID-19 protocols (C19P) provide additional insight into the transmissibility of the disease, epidemic trajectory, and the impact of NPIs. We assess how implementation of NPIs in early 2021 will shape the epidemic during the period of likely vaccine roll-out.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>C19P burial data in Jakarta suggest a death toll approximately 3.3 times higher than reported. Transmission estimates using these data suggest earlier, larger, and more sustained impact of NPIs. Measures to reduce sub-national spread, particularly during Ramadan, substantially mitigated spread to more vulnerable rural areas. Given current trajectory, daily cases and deaths are likely to increase in most regions as the vaccine is rolled-out. Transmission may peak in early 2021 in Jakarta if current levels of control are maintained. However, relaxation of control measures is likely to lead to a subsequent resurgence in the absence of an effective vaccination campaign.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Syndromic measures of mortality provide a more complete picture of COVID-19 severity upon which to base decision-making. The high potential impact of the vaccine in Java is attributable to reductions in transmission to date and dependent on these be

  • Journal article
    Ashdown G, Gaboriau D, Baum J, 2020,

    A machine learning approach to define antimalarial drug action from heterogeneous cell-based screens

    , Science Advances, Vol: 6, ISSN: 2375-2548

    Drug resistance threatens the effective prevention and treatment of an ever-increasing range ofhuman infections. This highlights an urgent need for new and improved drugs with novelmechanisms of action to avoid cross-resistance. Current cell-based drug screens are,however, restricted to binary live/dead readouts with no provision for mechanism of actionprediction. Machine learning methods are increasingly being used to improve informationextraction from imaging data. Such methods, however, work poorly with heterogeneouscellular phenotypes and generally require time-consuming human-led training. We havedeveloped a semi-supervised machine learning approach, combining human- and machinelabelled training data from mixed human malaria parasite cultures. Designed for highthroughput and high-resolution screening, our semi-supervised approach is robust to naturalparasite morphological heterogeneity and correctly orders parasite developmental stages. Ourapproach also reproducibly detects and clusters drug-induced morphological outliers bymechanism of action, demonstrating the potential power of machine learning for acceleratingcell-based drug discovery.

  • Journal article
    Watson O, Okell L, Hellewell J, Slater H, Unwin H, Omedo I, Bejon P, Snow R, Noor A, Rockett K, Hubbart C, Joaniter N, Greenhouse B, Chang H-H, Ghani A, Verity Aet al., 2020,

    Evaluating the performance of malaria genetics for inferring changes in transmission intensity using transmission modelling

    , Molecular Biology and Evolution, Vol: 38, Pages: 274-289, ISSN: 0737-4038

    Substantial progress has been made globally to control malaria, however there is a growing need for innovative new tools to ensure continued progress. One approach is to harness genetic sequencing and accompanying methodological approaches as have been used in the control of other infectious diseases. However, to utilise these methodologies for malaria we first need to extend the methods to capture the complex interactions between parasites, human and vector hosts, and environment, which all impact the level of genetic diversity and relatedness of malaria parasites. We develop an individual-based transmission model to simulate malaria parasite genetics parameterised using estimated relationships between complexity of infection and age from 5 regions in Uganda and Kenya. We predict that cotransmission and superinfection contribute equally to within-host parasite genetic diversity at 11.5% PCR prevalence, above which superinfections dominate. Finally, we characterise the predictive power of six metrics of parasite genetics for detecting changes in transmission intensity, before grouping them in an ensemble statistical model. The model predicted malaria prevalence with a mean absolute error of 0.055. Different assumptions about the availability of sample metadata were considered, with the most accurate predictions of malaria prevalence made when the clinical status and age of sampled individuals is known. Parasite genetics may provide a novel surveillance tool for estimating the prevalence of malaria in areas in which prevalence surveys are not feasible. However, the findings presented here reinforce the need for patient metadata to be recorded and made available within all future attempts to use parasite genetics for surveillance.

  • Journal article
    Mumtaz R, Okell LC, Challenger JD, 2020,

    How often do symptoms return after unsuccessful drug treatment for malaria? A systematic review and meta-analysis

    <jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>In clinical trials of therapies for uncomplicated <jats:italic>Plasmodium falciparum</jats:italic>, there are usually some patients who fail treatment even in the absence of drug resistance. Treatment failures are categorised as ‘clinical’ or ‘parasitological’ failures, the latter indicating that recrudescence of the infection has occurred without inducing the return of symptoms. Asymptomatic treatment failure has public health implications for continued malaria transmission and may be important for the spread of drug-resistant malaria. As the number of treatment failures in an individual trial is often low, it is difficult to assess how commonplace asymptomatic treatment failure is, and with what factors it is associated.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>A systematic literature review was carried out on clinical trials of artemether-lumefantrine (AL) in patients seeking treatment for symptomatic uncomplicated falciparum malaria, and information on symptoms during treatment failure was recorded. Only treatment failures examined by polymerase chain reaction (PCR) were included, so as to exclude reinfections. Using a multivariable Bayesian regression model, we explored factors potentially explaining the proportion of recrudescent infections which are symptomatic across the trials included in our study.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Across 60 published trials including 9137 malaria patients we found that 40.8% (95% CIs [35.9-45.8%]) of late treatment failures were symptomatic. We found a positive association between transmission intensity and the observed proportion of treatment failures that were asymptomatic. We also found that symptoms were more likely to return in t

  • Journal article
    Wang X, Wilkinson MD, Lin X, Ren R, Willison KR, Ivanov AP, Baum J, Edel JBet al., 2020,

    Correction: Single-molecule nanopore sensing of actin dynamics and drug binding

    , Chemical Science, Vol: 11, Pages: 8036-8038, ISSN: 2041-6520

    Correction for ‘Single-molecule nanopore sensing of actin dynamics and drug binding’ by Xiaoyi Wang et al., Chem. Sci., 2020, 11, 970–979, DOI: 10.1039/C9SC05710B.

  • Journal article
    Sherrard-Smith E, Hogan AB, Hamlet A, Watson OJ, Whittaker C, Winskill P, Ali F, Mohammad AB, Uhomoibhi P, Maikore I, Ogbulafor N, Nikau J, Kont MD, Challenger JD, Verity R, Lambert B, Cairns M, Rao B, Baguelin M, Whittles LK, Lees JA, Bhatia S, Knock ES, Okell L, Slater HC, Ghani AC, Walker PGT, Okoko OO, Churcher TSet al., 2020,

    The potential public health consequences of COVID-19 on malaria in Africa.

    , Nature Medicine, Vol: 26, Pages: 1411-1416, ISSN: 1078-8956

    The burden of malaria is heavily concentrated in sub-Saharan Africa (SSA) where cases and deaths associated with COVID-19 are rising1. In response, countries are implementing societal measures aimed at curtailing transmission of SARS-CoV-22,3. Despite these measures, the COVID-19 epidemic could still result in millions of deaths as local health facilities become overwhelmed4. Advances in malaria control this century have been largely due to distribution of long-lasting insecticidal nets (LLINs)5, with many SSA countries having planned campaigns for 2020. In the present study, we use COVID-19 and malaria transmission models to estimate the impact of disruption of malaria prevention activities and other core health services under four different COVID-19 epidemic scenarios. If activities are halted, the malaria burden in 2020 could be more than double that of 2019. In Nigeria alone, reducing case management for 6 months and delaying LLIN campaigns could result in 81,000 (44,000-119,000) additional deaths. Mitigating these negative impacts is achievable, and LLIN distributions in particular should be prioritized alongside access to antimalarial treatments to prevent substantial malaria epidemics.

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