Imperial College London

DrThomasChurcher

Faculty of MedicineSchool of Public Health

Reader in 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

107 results found

Djaafara BA, Whittaker C, Watson OJ, Verity R, Brazeau NF, Widyastuti, 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:p>Measuring COVID-19 spread remains challenging in many countries due to testing limitations. In Java, reported cases and deaths increased throughout 2020 despite intensive control measures, particularly within Jakarta and during Ramadan. However, underlying trends are likely obscured by variations in case ascertainment. COVID-19 protocol funerals in Jakarta provide alternative data indicating a substantially higher burden than observed within confirmed deaths. Transmission estimates using this metric follow mobility trends, suggesting earlier and more sustained intervention impact than observed in routine data. Modelling suggests interventions have lessened spread to rural, older communities with weaker healthcare systems, though predict healthcare capacity will soon be exceeded in much of Java without further control. Our results highlight the important role syndrome-based measures of mortality can play in understanding COVID-19 transmission and burden.</jats:p>

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

Hogan A, Jewell B, Sherrard-Smith E, Vesga J, Watson O, Whittaker C, Hamlet A, Smith J, Ainslie K, Baguelin M, Bhatt S, Boonyasiri A, Brazeau N, Cattarino L, Charles G, Cooper L, Coupland H, Cuomo-Dannenburg G, Dighe A, Djaafara A, Donnelly C, Dorigatti I, Eaton J, van Elsland S, Fitzjohn R, Fu H, Gaythorpe K, Green W, Haw D, Hayes S, Hinsley W, Imai N, Knock E, Laydon D, Lees J, Mangal T, Mellan T, Mishra S, Nedjati Gilani G, Nouvellet P, Okell L, Ower A, Parag K, Pickles M, Stopard I, Thompson H, Unwin H, Verity R, Vollmer M, Walters C, Wang H, Wang Y, Whittles L, Winskill P, Xi X, Ferguson N, Churcher T, Arinaminpathy N, Ghani A, Walker P, Hallett Tet al., 2020, Report 19: The potential impact of the COVID-19 epidemic on HIV, TB and malaria in low- and middle-income countries

COVID-19 has the potential to cause disruptions to health services in different ways; through the health system becoming overwhelmed with COVID-19 patients, through the intervention used to slow transmission of COVID-19 inhibiting access to preventative interventions and services, and through supplies of medicine being interrupted. We aim to quantify the extent to which such disruptions in services for HIV, TB and malaria in high burden low- and middle-income countries could lead to additional loss of life. In high burden settings, HIV, TB and malaria related deaths over 5 years may be increased by up to 10%, 20% and 36%, respectively, compared to if there were no COVID-19 epidemic. We estimate the greatest impact on HIV to be from interruption to ART, which may occur during a period of high or extremely 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 a long period of COVID-19 suppression interventions; for malaria, we estimate that the greatest impact could come from reduced prevention activities including interruption of planned net campaigns, through all phases of the COVID-19 epidemic. In high burden settings, the impact of each type of disruption could be significant and lead to a 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. Maintaining the most critical prevention activities and healthcare services for HIV, TB and malaria could significantly reduce the overall impact of the COVID-19 epidemic.

Report

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

Bradly J, Stone W, Da DF, Morlais I, Dicko A, Cohuet A, Guelbeogo WM, Mahamar A, Nsango S, Soumare HM, Diawara H, Lanke K, Graumans W, Siebelink-Stoter R, van de Vegte-Bolmer M, Chen I, Tiono A, Goncalves BP, Gosling R, Sauerwein RW, Drakeley C, Churcher TS, Bousema Tet al., 2018, Predicting the likelihood and intensity of mosquito infection from sex specific Plasmodium falciparum gametocyte density, ELIFE, Vol: 7, ISSN: 2050-084X

Understanding the importance of gametocyte density on human-to-mosquito transmission is of immediate relevance to malaria control. Previous work (Churcher et al., 2013) indicated a complex relationship between gametocyte density and mosquito infection. Here we use data from 148 feeding experiments on naturally infected gametocyte carriers to show that the relationship is much simpler and depends on both female and male parasite density. The proportion of mosquitoes infected is primarily determined by the density of female gametocytes though transmission from low gametocyte densities may be impeded by a lack of male parasites. Improved precision of gametocyte quantification simplifies the shape of the relationship with infection increasing rapidly before plateauing at higher densities. The mean number of oocysts per mosquito rises quickly with gametocyte density but continues to increase across densities examined. The work highlights the importance of measuring both female and male gametocyte density when estimating the human reservoir of infection.

Journal article

Lambert B, Sikulu-Lord MT, Mayagaya VS, Devine G, Dowell F, Churcher TSet al., 2018, Monitoring the Age of Mosquito Populations Using Near-Infrared Spectroscopy, SCIENTIFIC REPORTS, Vol: 8, ISSN: 2045-2322

Mosquito control with bednets, residual sprays or fumigation remains the most effective tool for preventing vector-borne diseases such as malaria, dengue and Zika, though there are no widely used entomological methods for directly assessing its efficacy. Mosquito age is the most informative metric for evaluating interventions that kill adult mosquitoes but there is no simple or reliable way of measuring it in the field. Near-Infrared Spectroscopy (NIRS) has been shown to be a promising, high-throughput method that can estimate the age of mosquitoes. Currently the ability of NIRS to measure mosquito age is biased, and has relatively high individual mosquito measurement error, though its capacity to rigorously monitor mosquito populations in the field has never been assessed. In this study, we use machine learning methods from the chemometric literature to generate more accurate, unbiased estimates of individual mosquito age. These unbiased estimates produce precise population-level measurements, which are relatively insensitive to further increases in NIRS accuracy when feasible numbers of mosquitoes are sampled. The utility of NIRS to directly measure the impact of pyrethroid resistance on mosquito control is illustrated, showing how the technology has potential as a highly valuable tool for directly assessing the efficacy of mosquito control interventions.

Journal article

Sala K, Angrisano F, Da DF, Taylor IJ, Churcher T, Blagborough AMet al., 2018, Immunization with Transgenic Rodent Malaria Parasites Expressing Pfs25 Induces Potent Transmission-Blocking Activity, Scientific Reports, Vol: 8, ISSN: 2045-2322

An anti-malarial transmission blocking vaccine (TBV) would be an important tool for disease control or elimination, though current candidates have failed to induce high efficacy in clinical studies. The ookinete surface protein P25 is a primary target for TBV development, but heterologous expression of P25 with appropriate conformation is problematic and a pre-requisite for achieving functional titers. A potential alternative to recombinant/sub-unit vaccine is immunization with a non-pathogenic, whole-parasite vaccine. This study examines the ability of a purified transgenic rodent-malaria parasite (PbPfs25DR3), expressing Plasmodium falciparum P25 in native conformation on the P. berghei ookinete surface, to act as a TBV. Vaccination with purified PbPfs25DR3 ookinetes produces a potent anti-Pfs25 response and high transmission-blocking efficacy in the laboratory, findings that are then translated to experimentation on natural field isolates of P. falciparum from infected individuals in Burkina Faso. Efficacy is demonstrated in the lab and the field (up to 93.3%/97.1% reductions in transmission intensity respectively), with both a homologous strategy with one and two boosts, and as part of a prime-boost regime, providing support for the future development of a whole-parasite TBV.

Journal article

Churcher T, Chanda E, Coetzee M, Davenport M, Diabate A, Djimde A, Dondorp AM, Donnelly M, Hemingway J, Huijben S, Kachur P, Kamau E, Knox TB, Lobo NF, Mayor A, Menard D, Paaijmans K, Picot S, Plowe CV, Price R, Rabinovich R, Ranson H, Reddy M, Rees S, Ringwald P, Rabinovich R, Sibley CH, Simard F, Wondji CSet al., 2017, malERA: An updated research agenda for insecticide and drug resistance in malaria elimination and eradication, PLoS Medicine, Vol: 14, ISSN: 1549-1277

Resistance to first-line treatments for Plasmodium falciparum malaria and the insecticidesused for Anopheles vector control are threatening malaria elimination efforts. Suboptimalresponses to drugs and insecticides are both spreading geographically and emerging independentlyand are being seen at increasing intensities. Whilst resistance is unavoidable, itseffects can be mitigated through resistance management practices, such as exposing theparasite or vector to more than one selective agent. Resistance contributed to the failure ofthe 20th century Global Malaria Eradication Programme, and yet the global response to thisissue continues to be slow and poorly coordinated—too often, too little, too late. The MalariaEradication Research Agenda (malERA) Refresh process convened a panel on resistanceof both insecticides and antimalarial drugs. This paper outlines developments in the fieldover the past 5 years, highlights gaps in knowledge, and proposes a research agendafocused on managing resistance. A deeper understanding of the complex biological processesinvolved and how resistance is selected is needed, together with evidence of its publichealth impact. Resistance management will require improved use of entomological andparasitological data in decision making, and optimisation of the useful life of new and existingproducts through careful implementation, combination, and evaluation. A proactive, collaborativeapproach is needed from basic science and the development of new tools toprogramme and policy interventions that will ensure that the armamentarium of drugs andinsecticides is sufficient to deal with the challenges of malaria control and its elimination.

Journal article

Gonçalves BP, Kapulu MC, Sawa P, Guelbéogo WM, Tiono AB, Grignard L, Stone W, Hellewell J, Lanke K, Bastiaens GJH, Bradley J, Nébié I, Ngoi JM, Oriango R, Mkabili D, Nyaurah M, Midega J, Wirth DF, Marsh K, Churcher TS, Bejon P, Sirima SB, Drakeley C, Bousema Tet al., 2017, Examining the human infectious reservoir for Plasmodium falciparum malaria in areas of differing transmission intensity., Nature Communications, Vol: 8, ISSN: 2041-1723

A detailed understanding of the human infectious reservoir is essential for improving malaria transmission-reducing interventions. Here we report a multi-regional assessment of population-wide malaria transmission potential based on 1209 mosquito feeding assays in endemic areas of Burkina Faso and Kenya. Across both sites, we identified 39 infectious individuals. In high endemicity settings, infectious individuals were identifiable by research-grade microscopy (92.6%; 25/27), whilst one of three infectious individuals in the lowest endemicity setting was detected by molecular techniques alone. The percentages of infected mosquitoes in the different surveys ranged from 0.05 (4/7716) to 1.6% (121/7749), and correlate positively with transmission intensity. We also estimated exposure to malaria vectors through genetic matching of blood from 1094 wild-caught bloodfed mosquitoes with that of humans resident in the same houses. Although adults transmitted fewer parasites to mosquitoes than children, they received more mosquito bites, thus balancing their contribution to the infectious reservoir.

Journal article

Eldering M, Bompard A, Miura K, Stone W, Morlais I, Cohuet A, van Gemert G-J, Brock PM, Rijpma SR, van de Vegte-Bolmer M, Graumans W, Siebelink-Stoter R, Da DF, Long CA, Morin MJ, Sauerwein RW, Churcher TS, Bousema Tet al., 2017, Comparative assessment of An. gambiae and An. stephensi mosquitoes to determine transmission-reducing activity of antibodies against P. falciparum sexual stage antigens., Parasites & Vectors, Vol: 10, ISSN: 1756-3305

BACKGROUND: With the increasing interest in vaccines to interrupt malaria transmission, there is a demand for harmonization of current methods to assess Plasmodium transmission in laboratory settings. Potential vaccine candidates are currently tested in the standard membrane feeding assay (SMFA) that commonly relies on Anopheles stephensi mosquitoes. Other mosquito species including Anopheles gambiae are the dominant malaria vectors for Plasmodium falciparum in sub-Saharan Africa. METHODS: Using human serum and monoclonal pre-fertilization (anti-Pfs48/45) and post-fertilization (anti-Pfs25) antibodies known to effectively inhibit sporogony, we directly compared SMFA based estimates of transmission-reducing activity (TRA) for An. stephensi and An. gambiae mosquitoes. RESULTS: In the absence of transmission-reducing antibodies, average numbers of oocysts were similar between An. gambiae and An. stephensi. Antibody-mediated TRA was strongly correlated between both mosquito species, and absolute TRA estimates for pre-fertilisation monoclonal antibodies (mAb) showed no significant difference between the two species. TRA estimates for IgG of naturally exposed individuals and partially effective concentrations of anti-Pfs25 mAb were higher for An. stephensi than for An. gambiae. CONCLUSION: Our findings support the use of An. stephensi in the SMFA for target prioritization. As a vaccine moves through product development, better estimates of TRA and transmission-blocking activity (TBA) may need to be obtained in epidemiologically relevant parasite-species combination.

Journal article

Bompard A, Da DF, Yerbanga RS, Biswas S, Kapulu M, Bousema T, Lefèvre T, Cohuet A, Churcher TSet al., 2017, Evaluation of two lead malaria transmission blocking vaccine candidate antibodies in natural parasite-vector combinations., Scientific Reports, Vol: 7, ISSN: 2045-2322

Transmission blocking vaccines (TBV) which aim to control malaria by inhibiting human-to-mosquito transmission show considerable promise though their utility against naturally circulating parasites remains unknown. The efficacy of two lead candidates targeting Pfs25 and Pfs230 antigens to prevent onwards transmission of naturally occurring parasites to a local mosquito strain is assessed using direct membrane feeding assays and murine antibodies in Burkina Faso. The transmission blocking activity of both candidates depends on the level of parasite exposure (as assessed by the mean number of oocysts in control mosquitoes) and antibody titers. A mathematical framework is devised to allow the efficacy of different candidates to be directly compared and determine the minimal antibody titers required to halt transmission in different settings. The increased efficacy with diminishing parasite exposure indicates that the efficacy of vaccines targeting either Pfs25 or Pfs230 may increase as malaria transmission declines. This has important implications for late-stage candidate selection and assessing how they can support the drive for malaria elimination.

Journal article

Sherrard-Smith E, Churcher TS, Upton LM, Sala KA, Zakutansky SE, Slater HC, Blagborough AM, Betancourt Met al., 2017, A novel model itted to multiple life stages of malaria for assessing eicacy of transmission-blocking interventions, Malaria Journal, Vol: 16, ISSN: 1475-2875

BackgroundTransmission-blocking interventions (TBIs) aim to eliminate malaria by reducing transmission of the parasite between the host and the invertebrate vector. TBIs include transmission-blocking drugs and vaccines that, when given to humans, are taken up by mosquitoes and inhibit parasitic development within the vector. Accurate methodologies are key to assess TBI efficacy to ensure that only the most potent candidates progress to expensive and time-consuming clinical trials. Measuring intervention efficacy can be problematic because there is substantial variation in the number of parasites in both the host and vector populations, which can impact transmission even in laboratory settings.MethodsA statistically robust empirical method is introduced for estimating intervention efficacy from standardised population assay experiments. This method will be more reliable than simple summary statistics as it captures changes in parasite density in different life-stages. It also allows efficacy estimates at a finer resolution than previous methods enabling the impact of the intervention over successive generations to be tracked. A major advantage of the new methodology is that it makes no assumptions on the population dynamics of infection. This enables both host-to-vector and vector-to-host transmission to be density-dependent (or other) processes and generates easy-to-understand estimates of intervention efficacy.ResultsThis method increases the precision of intervention efficacy estimates and demonstrates that relying on changes in infection prevalence (the proportion of infected hosts) alone may be insufficient to capture the impact of TBIs, which also suppress parasite density in secondarily infected hosts.ConclusionsThe method indicates that potentially useful, partially effective TBIs may require multiple infection cycles before substantial reductions in prevalence are observed, despite more rapidly suppressing parasite density. Accurate models to quantify effica

Journal article

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