Imperial College London

ProfessorThomasChurcher

Faculty of MedicineSchool of Public Health

Professor of Infectious Disease Dynamics
 
 
 
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Contact

 

+44 (0)20 7594 3265thomas.churcher

 
 
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Location

 

G35Medical SchoolSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
to

115 results found

de Jong RM, Meerstein-Kessel L, Da DF, Nsango S, Challenger JD, van de Vegte-Bolmer M, van Gemert G-J, Duarte E, Teyssier N, Sauerwein RW, Churcher TS, Dabire RK, Morlais I, Locke E, Huynen MA, Bousema T, Jore MMet al., 2021, Monoclonal antibodies block transmission of genetically diverse Plasmodium falciparum strains to mosquitoes, npj Vaccines, Vol: 6, Pages: 1-9, ISSN: 2059-0105

Malaria parasite transmission to mosquitoes relies on the uptake of sexual stage parasites during a blood meal and subsequent formation of oocysts on the mosquito midgut wall. Transmission-blocking vaccines (TBVs) and monoclonal antibodies (mAbs) target sexual stage antigens to interrupt human-to-mosquito transmission and may form important tools for malaria elimination. Although most epitopes of these antigens are considered highly conserved, little is known about the impact of natural genetic diversity on the functional activity of transmission-blocking antibodies. Here we measured the efficacy of three mAbs against leading TBV candidates (Pfs48/45, Pfs25 and Pfs230) in transmission assays with parasites from naturally infected donors compared to their efficacy against the strain they were raised against (NF54). Transmission-reducing activity (TRA) was measured as reduction in mean oocyst intensity. mAb 45.1 (α-Pfs48/45) and mAb 4B7 (α-Pfs25) reduced transmission of field parasites from almost all donors with IC80 values similar to NF54. Sequencing of oocysts that survived high mAb concentrations did not suggest enrichment of escape genotypes. mAb 2A2 (α-Pfs230) only reduced transmission of parasites from a minority of the donors, suggesting that it targets a non-conserved epitope. Using six laboratory-adapted strains, we revealed that mutations in one Pfs230 domain correlate with mAb gamete surface binding and functional TRA. Our findings demonstrate that, despite the conserved nature of sexual stage antigens, minor sequence variation can significantly impact the efficacy of transmission-blocking mAbs. Since mAb 45.1 shows high potency against genetically diverse strains, our findings support its further clinical development and may inform Pfs48/45 vaccine design.

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, Pages: 100047-100047, 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

Djaafara A, Whittaker C, Watson OJ, Verity R, Brazeau N, Widyastuti, Oktavia D, Adrian V, Salama N, Bhatia S, Nouvellet P, Sherrard-Smith E, Churcher T, Surendra H, Lina RN, Ekawati LL, Lestari KD, Andrianto A, Thwaites G, Baird JK, Ghani A, Elyazar IRF, Walker Pet al., 2021, Using syndromic measures of mortality to capture the dynamics of COVID-19 in Java, Indonesia in the context of vaccination roll-out, BMC Medicine, Vol: 19, ISSN: 1741-7015

Background: 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. Methods: 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. Results: 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. Conclusions: 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 being maintained. Increases in control in the relatively short-term will likely yield large, synergistic increases in vaccine impact.

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

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

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

Tadesse FG, Ashine T, Teka H, Esayas E, Messenger LA, Chali W, Meerstein-Kessel L, Walker T, Behaksra SW, Lanke K, Heutink R, Jeffries CL, Mekonnen DA, Hailemeskel E, Tebeje SK, Tafesse T, Gashaw A, Tsegaye T, Emiru T, Simon K, Bogale EA, Yohannes G, Kedir S, Shumie G, Sabir SA, Mumba P, Dengela D, Kolaczinski JH, Wilson A, Churcher TS, Chibsa S, Murphy M, Balkew M, Irish S, Drakeley C, Gadisa E, Bousema Tet al., 2021, Anopheles stephensi Mosquitoes as Vectors of Plasmodium vivax and P. falciparum, Horn of Africa, 2019, EMERGING INFECTIOUS DISEASES, Vol: 27, Pages: 603-607, ISSN: 1080-6040

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

Devine GJ, Vazquez-Prokopec GM, Bibiano-Marin W, Pavia-Ruz N, Che-Mendoza A, Medina-Barreiro A, Villegas J, Gonzalez-Olvera G, Dunbar MW, Ong O, Ritchie SA, Churcher TS, Kirstein OD, Manrique-Saide Pet al., 2021, The entomological impact of passive metofluthrin emanators against indoor Aedes aegypti: A randomized field trial, PLOS NEGLECTED TROPICAL DISEASES, Vol: 15, ISSN: 1935-2735

Journal article

Bompard A, Da DF, Yerbanga SR, Morlais I, Awono-Ambéné PH, Dabiré RK, Bosco Ouédraogo J, Lefèvre T, Churcher TS, Cohuet Aet al., 2020, High Plasmodium infection intensity in naturally infected malaria vectors in Africa, International Journal for Parasitology, Vol: 50, Pages: 985-996, ISSN: 0020-7519

The population dynamics of human to mosquito malaria transmission in the field has important implications for the genetics, epidemiology and control of malaria. The number of oocysts in oocyst-positive mosquitoes developing from a single, naturally acquired infectious blood meal (herein referred to as a single-feed infection load) greatly influences the efficacy of transmission blocking interventions but still remains poorly documented. During a year-long analysis of malaria parasite transmission in Burkina Faso we caught and dissected wild malaria vectors to assess Plasmodium oocyst prevalence and load (the number of oocysts counted in mosquitoes with detectable oocysts) and the prevalence of salivary gland sporozoites. This was compared with malaria endemicity in the human population, assessed in cross-sectional surveys. Data were analyzed using a novel transmission mathematical model to estimate the per bite transmission probability and the average single-feed infection load for each location. The observed oocyst load and the estimated single-feed infection load in naturally infected mosquitoes were substantially higher than previous estimates (means ranging from 3.2 to 24.5 according to seasons and locations) and indicate a strong positive association between the single-feed infection load and parasite prevalence in humans. This work suggests that highly infected mosquitoes are not rare in the field and might have a greater influence on the epidemiology and genetics of the parasite, and on the efficacy of novel transmission blocking interventions.

Journal article

Hogan A, Jewell B, Sherrard-Smith E, Watson O, Whittaker C, Hamlet A, Smith J, Winskill P, Verity R, Baguelin M, Lees J, Whittles L, Ainslie K, Bhatt S, Boonyasiri A, Brazeau N, Cattarino L, Cooper L, Coupland H, Cuomo-Dannenburg G, Dighe A, Djaafara A, Donnelly C, Eaton J, van Elsland S, Fitzjohn R, Fu H, Gaythorpe K, Green W, Haw D, Hayes S, Hinsley W, Imai N, Laydon D, Mangal T, Mellan T, Mishra S, Parag K, Thompson H, Unwin H, Vollmer M, Walters C, Wang H, Ferguson N, Okell L, Churcher T, Arinaminpathy N, Ghani A, Walker P, Hallett Tet al., 2020, Potential impact of the COVID-19 pandemic on HIV, TB and malaria in low- and middle-income countries: a modelling study, The Lancet Global Health, Vol: 8, Pages: e1132-e1141, ISSN: 2214-109X

Background: COVID-19 has the potential to cause substantial disruptions to health services, including by cases overburdening the health system or response measures limiting usual programmatic activities. We aimed to quantify the extent to which disruptions in services for human immunodeficiency virus (HIV), tuberculosis (TB) and malaria in low- and middle-income countries with high burdens of those disease could lead to additional loss of life. Methods: We constructed plausible scenarios for the disruptions that could be incurred during the COVID-19 pandemic and used established transmission models for each disease to estimate the additional impact on health that could be caused in selected settings.Findings: In high burden settings, HIV-, TB- and malaria-related deaths over five years may increase by up to 10%, 20% and 36%, respectively, compared to if there were no COVID-19 pandemic. We estimate the greatest impact on HIV to be from interruption to antiretroviral therapy, which may occur during a period of high health system demand. For TB, we estimate the greatest impact is from reductions in timely diagnosis and treatment of new cases, which may result from any prolonged period of COVID-19 suppression interventions. We estimate that the greatest impact on malaria burden could come from interruption of planned net campaigns. These disruptions could lead to loss of life-years over five years that is of the same order of magnitude as the direct impact from COVID-19 in places with a high burden of malaria and large HIV/TB epidemics.Interpretation: Maintaining the most critical prevention activities and healthcare services for HIV, TB and malaria could significantly reduce the overall impact of the COVID-19 pandemic.Funding: Bill & Melinda Gates Foundation, The Wellcome Trust, DFID, MRC

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.

Journal article

Suh E, Grossman MK, Waite JL, Dennington NL, Sherrard-Smith E, Churcher TS, Thomas MBet al., 2020, The influence of feeding behaviour and temperature on the capacity of mosquitoes to transmit malaria, Nature Ecology and Evolution, Vol: 4, Pages: 940-951, ISSN: 2397-334X

Insecticide-treated bed nets reduce malaria transmission by limiting contact between mosquito vectors and human hosts when mosquitoes feed during the night. However, malaria vectors can also feed in the early evening and in the morning when people are not protected. Here, we explored how the timing of blood feeding interacts with environmental temperature to influence the capacity of Anopheles mosquitoes to transmit the human malaria parasite Plasmodium falciparum. In laboratory experiments, we found no effect of biting time itself on the proportion of mosquitoes that became infectious (vector competence) at constant temperature. However, when mosquitoes were maintained under more realistic fluctuating temperatures, there was a significant increase in competence for mosquitoes feeding in the evening (18:00), and a significant reduction in competence for those feeding in the morning (06:00), relative to those feeding at midnight (00:00). These effects appear to be due to thermal sensitivity of malaria parasites during the initial stages of parasite development within the mosquito, and the fact that mosquitoes feeding in the evening experience cooling temperatures during the night, whereas mosquitoes feeding in the morning quickly experience warming temperatures that are inhibitory to parasite establishment. A transmission dynamics model illustrates that such differences in competence could have important implications for malaria prevalence, the extent of transmission that persists in the presence of bed nets, and the epidemiological impact of behavioural resistance. These results indicate that the interaction of temperature and feeding behaviour could be a major ecological determinant of the vectorial capacity of malaria mosquitoes.

Journal article

Sherrard-Smith E, Hogan A, Hamlet A, Watson OJ, Whittaker C, Winskill P, Verity R, Lambert B, Cairns M, Okell L, Slater H, Ghani A, Walker P, Churcher T, Imperial College COVID19 response teamet al., 2020, Report 18: The potential public health impact of COVID-19 on malaria in Africa.

The COVID-19 pandemic is likely to severely interrupt health systems in Sub-Saharan Africa (SSA) over the coming weeks and months. Approximately 90% of malaria deaths occur in this region of the world, with an estimated 380,000 deaths from malaria in 2018. Much of the gain made in malaria control over the last decade has been due to the distribution of long-lasting insecticide treated nets (LLINs). Many SSA countries planned to distribute these in 2020. We used COVID-19 and malaria transmission models to understand the likely impact that disruption to these distributions, alongside other core health services, could have on the malaria burden. Results indicate that if all malaria-control activities are highly disrupted then the malaria burden in 2020 could more than double that in the previous year, resulting in large malaria epidemics across the region. These will depend on the course of the COVID-19 epidemic and how it interrupts local health system. Our results also demonstrate that it is essential to prioritise the LLIN distributions either before or as soon as possible into local COVID-19 epidemics to mitigate this risk. Additional planning to ensure other malaria prevention activities are continued where possible, alongside planning to ensure basic access to antimalarial treatment, will further minimise the risk of substantial additional malaria mortality.

Report

Esperança P, Da D, Lambert B, Dabiré R, Churcher Tet al., 2020, Functional data analysis techniques to improve the generalizability of near-infrared spectral data for monitoring mosquito populations, Publisher: bioRxiv

Near infrared spectroscopy is increasingly being used as an economical method to monitormosquito vector populations in support of disease control. Despite this rise in popularity,strong geographical variation in spectra has proven an issue for generalising predictions fromone location to another. Here, we use a functional data analysis approach—which mod-els spectra as smooth curves rather than as a discrete set of points—to develop a methodthat is robust to geographic heterogeneity. Specifically, we use a penalised generalised linearmodelling framework which includes efficient functional representation of spectra, spectralsmoothing and regularisation. To ensure better generalisation of model predictions fromone training set to another, we use cross-validation procedures favouring smoother represen-tation of spectra. To illustrate the performance of our approach, we collected spectra forfield-caught specimens ofAnopheles gambiaecomplex mosquitoes – the most epidemiolog-ically important vector species on the planet – in two sites in Burkina Faso. Using thesespectra, we show how models trained on data from one site can successfully classify mor-phologically identical sibling species in another site, over 250km away. Whilst we apply ourframework to species prediction, our unified statistical framework can, alternatively, handleregression analysis (for example, to determine mosquito age) and other types of multinomialclassification (for example, to determine infection status). To make our methods readilyavailable for field entomologists, we have created an open-source R packagemlevcm. Alldata used is publicly also available.

Working paper

Ong OTC, Kho EA, Esperanca PM, Freebairn C, Dowell FE, Devine GJ, Churcher TSet al., 2020, Ability of near-infrared spectroscopy and chemometrics to predict the age of mosquitoes reared under different conditions, Parasites and Vectors, Vol: 13, ISSN: 1756-3305

BackgroundPractical, field-ready age-grading tools for mosquito vectors of disease are urgently needed because of the impact that daily survival has on vectorial capacity. Previous studies have shown that near-infrared spectroscopy (NIRS), in combination with chemometrics and predictive modeling, can forecast the age of laboratory-reared mosquitoes with moderate to high accuracy. It remains unclear whether the technique has utility for identifying shifts in the age structure of wild-caught mosquitoes. Here we investigate whether models derived from the laboratory strain of mosquitoes can be used to predict the age of mosquitoes grown from pupae collected in the field.MethodsNIRS data from adult female Aedes albopictus mosquitoes reared in the laboratory (2, 5, 8, 12 and 15 days-old) were analysed against spectra from mosquitoes emerging from wild-caught pupae (1, 7 and 14 days-old). Different partial least squares (PLS) regression methods trained on spectra from laboratory mosquitoes were evaluated on their ability to predict the age of mosquitoes from more natural environments.ResultsModels trained on spectra from laboratory-reared material were able to predict the age of other laboratory-reared mosquitoes with moderate accuracy and successfully differentiated all day 2 and 15 mosquitoes. Models derived with laboratory mosquitoes could not differentiate between field-derived age groups, with age predictions relatively indistinguishable for day 1–14. Pre-processing of spectral data and improving the PLS regression framework to avoid overfitting can increase accuracy, but predictions of mosquitoes reared in different environments remained poor. Principal components analysis confirms substantial spectral variations between laboratory and field-derived mosquitoes despite both originating from the same island population.ConclusionsModels trained on laboratory mosquitoes were able to predict ages of laboratory mosquitoes with good sensitivity and specificity though

Journal article

Esperanca P, Da D, Lambert B, Dabire R, Churcher Tet al., 2020, Functional data analysis techniques to improve the generalizability of near-infrared spectral data for monitoring mosquito populations

Report

Johnson BJ, Hugo LE, Churcher TS, Ong OTW, Devine GJet al., 2020, Mosquito age grading and vector-control programmes, Trends in Parasitology, Vol: 36, Pages: 39-51, ISSN: 0169-4758

Journal article

Murray GPD, Lissenden N, Jones J, Voloshin V, Toé KH, Sherrard-Smith E, Foster GM, Churcher TS, Parker JEA, Towers CE, NFalé S, Guelbeogo WM, Ranson H, Towers D, McCall PJet al., 2020, Barrier bednets target malaria vectors and expand the range of usable insecticides, Nature Microbiology, Vol: 5, Pages: 40-47, ISSN: 2058-5276

Transmission of Plasmodium falciparum malaria parasites occurs when nocturnal Anopheles mosquito vectors feed on human blood. In Africa, where malaria burden is highest, bednets treated with pyrethroid insecticide were highly effective in preventing mosquito bites and reducing transmission, and essential to achieving unprecedented reductions in malaria until 2015 (ref. 1). Since then, progress has stalled2, and with insecticidal bednets losing efficacy against pyrethroid-resistant Anopheles vectors3,4, methods that restore performance are urgently needed to eliminate any risk of malaria returning to the levels seen before their widespread use throughout sub-Saharan Africa5. Here, we show that the primary malaria vector Anopheles gambiae is targeted and killed by small insecticidal net barriers positioned above a standard bednet in a spatial region of high mosquito activity but zero contact with sleepers, opening the way for deploying many more insecticides on bednets than is currently possible. Tested against wild pyrethroid-resistant A. gambiae in Burkina Faso, pyrethroid bednets with organophosphate barriers achieved significantly higher killing rates than bednets alone. Treated barriers on untreated bednets were equally effective, without significant loss of personal protection. Mathematical modelling of transmission dynamics predicted reductions in clinical malaria incidence with barrier bednets that matched those of ‘next-generation’ nets recommended by the World Health Organization against resistant vectors. Mathematical models of mosquito–barrier interactions identified alternative barrier designs to increase performance. Barrier bednets that overcome insecticide resistance are feasible using existing insecticides and production technology, and early implementation of affordable vector control tools is a realistic prospect.

Journal article

Dahalan FA, Churcher TS, Windbichler N, Lawniczak MKNet al., 2019, The male mosquito contribution towards malaria transmission: Mating influences the Anopheles female midgut transcriptome and increases female susceptibility to human malaria parasites., PLoS Pathogens, Vol: 15, Pages: 1-19, ISSN: 1553-7366

Mating causes dramatic changes in female physiology, behaviour, and immunity in many insects, inducing oogenesis, oviposition, and refractoriness to further mating. Females from the Anopheles gambiae species complex typically mate only once in their lifetime during which they receive sperm and seminal fluid proteins as well as a mating plug that contains the steroid hormone 20-hydroxyecdysone. This hormone, which is also induced by blood-feeding, plays a major role in activating vitellogenesis for egg production. Here we show that female Anopheles coluzzii susceptibility to Plasmodium falciparum infection is significantly higher in mated females compared to virgins. We also find that mating status has a major impact on the midgut transcriptome, detectable only under sugar-fed conditions: once females have blood-fed, the transcriptional changes that are induced by mating are likely masked by the widespread effects of blood-feeding on gene expression. To determine whether increased susceptibility to parasites could be driven by the additional 20E that mated females receive from males, we mimicked mating by injecting virgin females with 20E, finding that these females are significantly more susceptible to human malaria parasites than virgin females injected with the control 20E carrier. Further RNAseq was carried out to examine whether the genes that change upon 20E injection in the midgut are similar to those that change upon mating. We find that 79 midgut-expressed genes are regulated in common by both mating and 20E, and 96% (n = 76) of these are regulated in the same direction (up vs down in 20E/mated). Together, these findings show that male Anopheles mosquitoes induce changes in the female midgut that can affect female susceptibility to P. falciparum. This implies that in nature, males might contribute to malaria transmission in previously unappreciated ways, and that vector control strategies that target males may have additional benefits towards reducing transm

Journal article

Bradley J, Soumaré HM, Mahamar A, Diawara H, Roh M, Delves M, Drakeley C, Churcher TS, Dicko A, Gosling R, Bousema Tet al., 2019, Transmission-blocking effects of primaquine and methylene blue suggest P. falciparum gametocyte sterilisation rather than effects on sex ratio, Clinical Infectious Diseases, Vol: 69, Pages: 1436-1439, ISSN: 1058-4838

Gametocyte density and sex-ratio can predict the proportion of mosquitoes that become infected after feeding on blood of patients receiving non-gametocytocidal drugs. Because primaquine and methylene blue sterilize gametocytes before affecting their density and sex-ratio, mosquito feeding experiments are required to demonstrate their early transmission-blocking effects.

Journal article

Sherrard-Smith E, Skarp JE, Beale AD, Fornadel C, Norris LC, Moore SJ, Mihreteab S, Charlwood JD, Bhatt S, Winskill P, Griffin JT, Churcher TSet al., 2019, Mosquito feeding behavior and how it influences residual malaria transmission across Africa, Proceedings of the National Academy of Sciences, Vol: 116, Pages: 15086-15095, ISSN: 0027-8424

The antimalarial efficacy of the most important vector control interventions—long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS)—primarily protect against mosquitoes’ biting people when they are in bed and indoors. Mosquito bites taken outside of these times contribute to residual transmission which determines the maximum effectiveness of current malaria prevention. The likelihood mosquitoes feed outside the time of day when LLINs and IRS can protect people is poorly understood, and the proportion of bites received outdoors may be higher after prolonged vector control. A systematic review of mosquito and human behavior is used to quantify and estimate the public health impact of outdoor biting across Africa. On average 79% of bites by the major malaria vectors occur during the time when people are in bed. This estimate is substantially lower than previous predictions, with results suggesting a nearly 10% lower proportion of bites taken at the time when people are beneath LLINs since the year 2000. Across Africa, this higher outdoor transmission is predicted to result in an estimated 10.6 million additional malaria cases annually if universal LLIN and IRS coverage was achieved. Higher outdoor biting diminishes the cases of malaria averted by vector control. This reduction in LLIN effectiveness appears to be exacerbated in areas where mosquito populations are resistant to insecticides used in bed nets, but no association was found between physiological resistance and outdoor biting. Substantial spatial heterogeneity in mosquito biting behavior between communities could contribute to differences in effectiveness of malaria control across Africa.

Journal article

Sanz S, Aquilini E, Tweedell RE, Verma G, Hamerly T, Hritzo B, Tripathi A, Machado M, Churcher TS, Rodrigues JA, Izquierdo L, Dinglasan RRet al., 2019, Protein O-fucosyltransferase 2 is not essential for plasmodium berghei development, Frontiers in Cellular and Infection Microbiology, Vol: 9, Pages: 1-9, ISSN: 2235-2988

Thrombospondin type I repeat (TSR) domains are commonly O-fucosylated by protein O-fucosyltransferase 2 (PoFUT2), and this modification is required for optimal folding and secretion of TSR-containing proteins. The human malaria parasite Plasmodium falciparum expresses proteins containing TSR domains, such as the thrombospondin-related anonymous protein (TRAP) and circumsporozoite surface protein (CSP), which are O-fucosylated. TRAP and CSP are present on the surface of sporozoites and play essential roles in mosquito and human host invasion processes during the transmission stages. Here, we have generated PoFUT2 null-mutant P. falciparum and Plasmodium berghei (rodent) malaria parasites and, by phenotyping them throughout their complete life cycle, we show that PoFUT2 disruption does not affect the growth through the mosquito stages for both species. However, contrary to what has been described previously by others, P. berghei PoFUT2 null mutant sporozoites showed no deleterious motility phenotypes and successfully established blood stage infection in mice. This unexpected result indicates that the importance of O-fucosylation of TSR domains may differ between human and RODENT malaria parasites; complicating our understanding of glycosylation modifications in malaria biology.

Journal article

Suh E, Grossman MK, Waite JL, Dennington NL, Sherrard-Smith E, Churcher TS, Thomas MBet al., 2019, The influence of feeding behaviour and temperature on the capacity of mosquitoes to transmit malaria, Publisher: Cold Spring Harbor Laboratory

<jats:title>Abstract</jats:title><jats:p>Insecticide-treated bed nets reduce malaria transmission by limiting contact between mosquito vectors and human hosts when mosquitoes feed during the night. However, malaria vectors can also feed in the early evening and in the morning when people are not protected. Here, we explored how timing of blood feeding interacts with environmental temperature to influence the capacity of <jats:italic>Anopheles</jats:italic> mosquitoes to transmit the human malaria parasite, <jats:italic>Plasmodium falciparum</jats:italic>. We found no effect of biting time itself on the proportion of mosquitoes that became infectious (vector competence) at constant temperature. However, when mosquitoes were maintained under more realistic fluctuating temperatures there was a significant increase in competence for mosquitoes feeding in the evening, and a significant reduction in competence for those feeding in the morning, relative to those feeding at midnight. These effects appear to be due to thermal sensitivity of malaria parasites during the initial stages of parasite development within the mosquito, and the fact that mosquitoes feeding in the evening experience cooling temperatures during the night, whereas mosquitoes feeding in the morning quickly experience warming temperatures that are inhibitory to parasite establishment. A transmission dynamics model illustrates that such differences in competence could have important implications for disease endemicity, the extent of transmission that persists in the presence of bed nets, and the epidemiological impact of behavioural resistance. These results indicate the interaction of temperature and feeding behaviour to be a major ecological determinant of the vectorial capacity of malaria mosquitoes.</jats:p>

Working paper

Sherrard-Smith E, Griffin J, Winskill P, Corbel V, Pennetier C, Djénontin A, Moore S, Richardson J, Müller P, Edi C, Protopopoff N, Oxborough R, Agossa F, N'Guessan R, Rowland M, Churcher Tet al., 2018, Systematic review of indoor residual spray efficacy and effectiveness against Plasmodium falciparum in Africa, Nature Communications, Vol: 9, ISSN: 2041-1723

Indoor 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.

Journal article

Janko MM, Churcher TS, Emch ME, Meshnick SRet al., 2018, Strengthening long-lasting insecticidal nets effectiveness monitoring using retrospective analysis of cross-sectional, population-based surveys across sub-Saharan Africa, Scientific Reports, Vol: 8, ISSN: 2045-2322

Bed nets averted 68% of malaria cases in Africa between 2000 and 2015. However, concerns over insecticide resistance, bed net durability and the effectiveness of long-lasting insecticidal nets (LLIN) are growing. To assess the effectiveness of LLINs of different ages and insecticides against malaria, we conducted a population-based, cross-sectional study using data from 162,963 children younger than 5 years of age participating in 33 Demographic and Health and Malaria Indicator Surveys conducted in 21 countries between 2009 and 2016. We used Bayesian logistic regression to estimate associations between LLIN age, insecticide type, and malaria. Children sleeping under LLINs the previous night experienced 21% lower odds of malaria infection than children who did not (odds ratio [OR] 0.79; 95% Uncertainty Interval [UI] 0.76–0.82). Nets less than one year of age exhibited the strongest protective effect (OR 0.75; 95% UI 0.72–0.79), and protection weakened as net age increased. LLINs containing different insecticides exhibited similar protection (ORdeltamethrin 0.78 [0.75–0.82]; ORpermethrin 0.79 [0.75–0.83]; ORalphacypermethrin 0.85 [0.76–0.94]). Freely-available, population-based surveys can enhance and guide current entomological monitoring amid concerns of insecticide resistance and bed net durability, and be used with locally-collected data to support decisions on LLIN redistribution campaign timing which insecticide to use.

Journal article

Hellewell J, Walker P, Ghani A, Rao BV, Churcher Tet 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: 1475-2875

BackgroundThe 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.

Journal article

Esperanca PM, Blagborough AM, Da DF, Dowell FE, Churcher TSet al., 2018, Detection of Plasmodium berghei infected Anopheles stephensi using near-infrared spectroscopy, Parasites and Vectors, Vol: 11, ISSN: 1756-3305

BackgroundThe proportion of mosquitoes infected with malaria is an important entomological metric used to assess the intensity of transmission and the impact of vector control interventions. Currently, the prevalence of mosquitoes with salivary gland sporozoites is estimated by dissecting mosquitoes under a microscope or using molecular methods. These techniques are laborious, subjective, and require either expensive equipment or training. This study evaluates the potential of near-infrared spectroscopy (NIRS) to identify laboratory reared mosquitoes infected with rodent malaria.MethodsAnopheles stephensi mosquitoes were reared in the laboratory and fed on Plasmodium berghei infected blood. After 12 and 21 days post-feeding mosquitoes were killed, scanned and analysed using NIRS and immediately dissected by microscopy to determine the number of oocysts on the midgut wall or sporozoites in the salivary glands. A predictive classification model was used to determine parasite prevalence and intensity status from spectra.ResultsThe predictive model correctly classifies infectious and uninfectious mosquitoes with an overall accuracy of 72%. The false negative and false positive rates were 30 and 26%, respectively. While NIRS was able to differentiate between uninfectious and highly infectious mosquitoes, differentiating between mid-range infectious groups was less accurate. Multiple scans of the same specimen, with repositioning the mosquito between scans, is shown to improve accuracy. On a smaller dataset NIRS was unable to predict whether mosquitoes harboured oocysts.ConclusionsTo our knowledge, we provide the first evidence that NIRS can differentiate between infectious and uninfectious mosquitoes. Currently, distinguishing between different intensities of infection is challenging. The classification model provides a flexible framework and allows for different error rates to be optimised, enabling the sensitivity and specificity of the technique to be varied according

Journal article

Sherrard-Smith E, Sala KA, Betancourt M, Upton LM, Angrisano F, Morin MJ, Ghani AC, Churcher TS, Blagborough AMet al., 2018, Synergy in anti-malarial pre-erythrocytic and transmission-blocking antibodies is achieved by reducing parasite density, eLife, Vol: 7, ISSN: 2050-084X

Anti-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.

Journal article

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