Publications

Journal article

OMahony E, Ryan F, Hemandas H, Al-Sabbagh A, Cunnington A, Fitzgerald Fet al., 2024,

Cryptic congenital malaria infection causing fever of unknown origin in an infant

, Journal of Pediatrics, Vol: 275, ISSN: 0022-3476

A 10-week-old male infant presented multiple times to a United Kingdom (UK)hospital with prolonged fever for one month, occurring at irregular intervals and in the absence of any other noticeable symptoms. He was the first child of non-consanguineous, Nigerian parents, with neither parent having traveled outside the UK for two years prior to pregnancy. Routine antenatal serology and scans were unremarkable, and the mother was well during pregnancy with no febrile illnesses or health concerns reported. The boy was born at term via elective cesarean section due to breech positioning (birth weight 3.75 kg), with an uncomplicated perinatal period. He received the BCG vaccine at 6 weeks of age as standard care due to having parents born in a country with high rates of tuberculosis, but was otherwise unvaccinated; his initial 8-week vaccinations were delayed because he was febrile.

Journal article

Cunnington A, Abbara A, Kaduni Bawa F, Achan Jet al., 2024,

Identification and management of co-infections in people with malaria

, BMJ: British Medical Journal, Vol: 384, Pages: 1-10, ISSN: 0959-535X

A 16 year old Ugandan girl is brought to the emergency department with a three day history of fever, headache, cough, and myalgia. She has had several episodes of malaria in the past. On admission, she is febrile, tachycardic, tachypnoeic, and has oxygen saturations of 90% in air. A malaria rapid antigen test is positive for Plasmodium falciparum and a chest radiograph shows left sided pneumonia. She is admitted and treated with antimalarials, antibiotics, and oxygen. She makes a full recovery over five days. At discharge, the cause of the pneumonia and the contribution of malaria to the illness remain unresolved.

Journal article

Baldeh M, Bawa F, Bawah F, Chamai M, Dzabeng F, Jebreel W, Kabuya J-B, Molemodile Dele Olowu S, Rakotomalala Robinson D, Cunnington Aet al., 2024,

Lessons from the pandemic: new best practices in selecting molecular diagnostics for point-of-care testing of infectious diseases in sub-Saharan Africa

, Expert Review of Molecular Diagnostics: new diagnostic technologies are set to revolutionise healthcare, Vol: 24, Pages: 153-159, ISSN: 1473-7159

Introduction:Point-of-care molecular diagnostics offer solutions to the limited diagnostic availability and accessibility in resource-limited settings. During the COVID-19 pandemic, molecular diagnostics became essential tools for accurate detection and monitoring of SARS-CoV-2. The unprecedented demand for molecular diagnostics presented challenges and catalyzed innovations which may provide lessons for the future selection of point-of-care molecular diagnostics.Areas Covered:We searched PubMed from January 2020 to August 2023 to identify lessons learned from the COVID-19 pandemic which may impact the selection of point-of-care molecular diagnostics for future use in sub-Saharan Africa. We evaluated this in the context of REASSURED criteria (Real-time connectivity; Ease of specimen collection; Affordable; Sensitive; Specific; User-friendly; Rapid and robust; Equipment free; and Deliverable to users at the point of need) for point-of-care diagnostics for resource-limited settings.Expert Opinion:The diagnostic challenges and successes during the COVID-19 pandemic affirmed the importance of the REASSURED criteria but demonstrated that these are not sufficient to ensure new diagnostics will be appropriate for public health emergencies. Capacity for rapid scale-up of diagnostic testing and transferability of assays, data, and technology are also important, resulting in updated REST-ASSURED criteria. Few diagnostics will meet all criteria, and trade-offs between criteria will need to be context-specific.

Journal article

Winskill P, Dhabangi A, Kwambai TK, Mori AT, Mousa A, Okell LCet al., 2023,

Estimating the burden of severe malarial anaemia and access to hospital care in East Africa.

, Nat Commun, Vol: 14

Severe malarial anaemia can be fatal if not promptly treated. Hospital studies may under-represent the true burden because cases often occur in settings with poor access to healthcare. We estimate the relationship of community prevalence of malaria infection and severe malarial anaemia with the incidence of severe malarial anaemia cases in hospital, using survey data from 21 countries and hospital data from Kenya, Tanzania and Uganda. The estimated percentage of severe malarial anaemia cases that were hospitalised is low and consistent for Kenya (21% (95% CrI: 7%, 47%)), Tanzania (18% (95% CrI: 5%, 52%)) and Uganda (23% (95% CrI: 9%, 48%)). The majority of severe malarial anaemia cases remain in the community, with the consequent public health burden being contingent upon the severity of these cases. Alongside health system strengthening, research to better understand the spectrum of disease associated with severe malarial anaemia cases in the community is a priority.

Journal article

Malpartida-Cardenas K, Baum J, Cunnington A, Georgiou P, Rodriguez-Manzano Jet al., 2023,

A dual paper-based nucleic acid extraction method from blood in under ten minutes for point-of-care diagnostics

, The Analyst, Vol: 148, Pages: 3036-3044, ISSN: 0003-2654

Nucleic acid extraction (NAE) plays a crucial role for diagnostic testing procedures. For decades, dried blood spots (DBS) have been used for serology, drug monitoring, and molecular studies. However, extracting nucleic acids from DBS remains a significant challenge, especially when attempting to implement these applications to the point-of-care (POC). To address this issue, we have developed a paper-based NAE method using cellulose filter papers (DBSFP) that operates without the need for electricity (at room temperature). Our method allows for NAE in less than 7 min, and it involves grade 3 filter paper pre-treated with 8% (v/v) igepal surfactant, 1 min washing step with 1× PBS, and 5 min incubation at room temperature in 1× TE buffer. The performance of the methodology was assessed with loop-mediated isothermal amplification (LAMP), targeting the human reference gene beta-actin and the kelch 13 gene from P. falciparum. The developed method was evaluated against FTA cards and magnetic bead-based purification, using time-to-positive (min) for comparative analysis. Furthermore, we optimised our approach to take advantage of the dual functionality of the paper-based extraction, allowing for elution (eluted disk) as well as direct placement of the disk in the LAMP reaction (in situ disk). This flexibility extends to eukaryotic cells, bacterial cells, and viral particles. We successfully validated the method for RNA/DNA detection and demonstrated its compatibility with whole blood stored in anticoagulants. Additionally, we studied the compatibility of DBSFP with colorimetric and lateral flow detection, showcasing its potential for POC applications. Across various tested matrices, targets, and experimental conditions, our results were comparable to those obtained using gold standard methods, highlighting the versatility of our methodology. In summary, this manuscript presents a cost-effective solution for NAE from DBS, enabling molecular testing in virtually

Journal article

Topazian HM, Schmit N, Gerard-Ursin I, Charles GD, Thompson H, Ghani AC, Winskill Pet al., 2023,

Modelling the relative cost-effectiveness of the RTS,S/AS01 malaria vaccine compared to investment in vector control or chemoprophylaxis

, VACCINE, Vol: 41, Pages: 3215-3223, ISSN: 0264-410X

Journal article

Malpartida Cardenas K, Moser N, Ansah F, Pennisi I, Ahu Prah D, Eva Amoah L, Awandare G, Hafalla JC, Cunnington A, Baum J, Rodriguez Manzano J, Georgiou Pet al., 2023,

Sensitive detection of asymptomatic and symptomatic malaria with seven novel parasite-specific LAMP assays and translation for use at point-of-care

, Microbiology Spectrum, Vol: 11, Pages: 1-12, ISSN: 2165-0497

Human malaria is a life-threatening parasitic disease with high impact in the sub-Saharan Africa region, where 95% of global cases occurred in 2021. While most malaria diagnostic tools are focused on Plasmodium falciparum, there is a current lack of testing non-P. falciparum cases, which may be underreported and, if undiagnosed or untreated, may lead to severe consequences. In this work, seven species-specific loop-mediated isothermal amplification (LAMP) assays were designed and evaluated against TaqMan quantitative PCR (qPCR), microscopy, and enzyme-linked immunosorbent assays (ELISAs). Their clinical performance was assessed with a cohort of 164 samples of symptomatic and asymptomatic patients from Ghana. All asymptomatic samples with a parasite load above 80 genomic DNA (gDNA) copies per μL of extracted sample were detected with the Plasmodium falciparum LAMP assay, reporting 95.6% (95% confidence interval [95% CI] of 89.9 to 98.5) sensitivity and 100% (95% CI of 87.2 to 100) specificity. This assay showed higher sensitivity than microscopy and ELISA, which were 52.7% (95% CI of 39.7 to 67%) and 67.3% (95% CI of 53.3 to 79.3%), respectively. Nine samples were positive for P. malariae, indicating coinfections with P. falciparum, which represented 5.5% of the tested population. No samples were detected as positive for P. vivax, P. ovale, P. knowlesi, or P. cynomolgi by any method. Furthermore, translation to the point-of-care was demonstrated with a subcohort of 18 samples tested locally in Ghana using our handheld lab-on-chip platform, Lacewing, showing comparable results to a conventional fluorescence-based instrument. The developed molecular diagnostic test could detect asymptomatic malaria cases, including submicroscopic parasitemia, and it has the potential to be used for point-of-care applications.

Journal article

Hamilton F, Mitchell R, Constantinescu A, Hughes D, Cunnington A, Ghazal P, Timpson NJet al., 2023,

The effect of IL-6 signalling on severe malaria: a Mendelian randomisation analysis

, International Journal of Infectious Diseases, Vol: 129, Pages: 251-259, ISSN: 1201-9712

ObjectivesSevere malaria remains a deadly disease for many young children in low- and middle-income countries. Levels of interleukin (IL)-6 have been shown to identify cases of severe malaria and associate with severity, but it is unknown if this association is causal.MethodsA single nucleotide polymorphism (SNP; rs2228145) in the IL-6 receptor was chosen as a genetic variant that is known to alter IL-6 signaling. We tested this, then took this forward as an instrument to perform Mendelian randomization (MR) in MalariaGEN, a large cohort study of patients with severe malaria at 11 worldwide sites.ResultsIn MR analyses using rs2228145, we did not identify an effect of decreased IL-6 signaling on severe malaria (odds ratio 1.14, 95% confidence interval 0.56-2.34, P = 0.713). The estimates of the association with any severe malaria subphenotype were similarly null, although with some imprecision. Further analyses using other MR approaches had similar results.ConclusionThese analyses do not support a causal role for IL-6 signaling in the development of severe malaria. This result suggests IL-6 may not be causal for severe outcomes in malaria, and that therapeutic manipulation of IL-6 is unlikely to be a suitable treatment for severe malaria.

Journal article

Whittaker C, Hamlet A, Sherrard-Smith E, Winskill P, Cuomo-Dannenburg G, Walker PGT, Sinka M, Pironon S, Kumar A, Ghani A, Bhatt S, Churcher TSet al., 2023,

Seasonal dynamics of Anopheles stephensi and its implications for mosquito detection and emergent malaria control in the Horn of Africa

, Proceedings of the National Academy of Sciences of USA, Vol: 120, Pages: 1-9, ISSN: 0027-8424

Invasion of the malaria vector Anopheles stephensi across the Horn of Africa threatens control efforts across the continent, particularly in urban settings where the vector is able to proliferate. Malaria transmission is primarily determined by the abundance of dominant vectors, which often varies seasonally with rainfall. However, it remains unclear how An. stephensi abundance changes throughout the year, despite this being a crucial input to surveillance and control activities. We collate longitudinal catch data from across its endemic range to better understand the vector's seasonal dynamics and explore the implications of this seasonality for malaria surveillance and control across the Horn of Africa. Our analyses reveal pronounced variation in seasonal dynamics, the timing and nature of which are poorly predicted by rainfall patterns. Instead, they are associated with temperature and patterns of land use; frequently differing between rural and urban settings. Our results show that timing entomological surveys to coincide with rainy periods is unlikely to improve the likelihood of detecting An. stephensi. Integrating these results into a malaria transmission model, we show that timing indoor residual spraying campaigns to coincide with peak rainfall offers little improvement in reducing disease burden compared to starting in a random month. Our results suggest that unlike other malaria vectors in Africa, rainfall may be a poor guide to predicting the timing of peaks in An. stephensi-driven malaria transmission. This highlights the urgent need for longitudinal entomological monitoring of the vector in its new environments given recent invasion and potential spread across the continent.

Journal article

Unwin H, Sherrard-Smith E, Churcher T, Ghani Aet al., 2023,

Quantifying the direct and indirect protection provided by insecticide treated bed nets against malaria

, Nature Communications, Vol: 14, Pages: 1-12, ISSN: 2041-1723

Long lasting insecticidal nets (LLINs) provide both direct and indirect protection against malaria. As pyrethroid resistance evolves in mosquito vectors, it will be useful to understand how the specific benefits LLINs afford individuals and communities may be affected. Here we use modelling to show that there is no minimum LLIN usage needed for users and non-users to benefit from community protection. Modelling results also indicate that pyrethroid resistance in local mosquitoes will likely diminish the direct and indirect benefits from insecticides, leaving the barrier effects intact, but LLINs are still expected to provide enhanced benefit over untreated nets even at high levels of pyrethroid resistance.

Journal article

Thompson HA, Hogan AB, Walker PGT, Winskill P, Zongo I, Sagara I, Tinto H, Ouedraogo J-B, Dicko A, Chandramohan D, Greenwood B, Cairns M, Ghani ACet al., 2022,

Seasonal use case for the RTS,S/AS01 malaria vaccine: a mathematical modelling study

, The Lancet Global Health, Vol: 10, Pages: e1782-e1792, ISSN: 2214-109X

BACKGROUND: A 2021 clinical trial of seasonal RTS,S/AS01E (RTS,S) vaccination showed that vaccination was non-inferior to seasonal malaria chemoprevention (SMC) in preventing clinical malaria. The combination of these two interventions provided significant additional protection against clinical and severe malaria outcomes. Projections of the effect of this novel approach to RTS,S vaccination in seasonal transmission settings for extended timeframes and across a range of epidemiological settings are needed to inform policy recommendations. METHODS: We used a mathematical, individual-based model of malaria transmission that was fitted to data on the relationship between entomological inoculation rate and parasite prevalence, clinical disease, severe disease, and deaths from multiple sites across Africa. The model was validated with results from a phase 3b trial assessing the effect of SV-RTS,S in Mali and Burkina Faso. We developed three intervention efficacy models with varying degrees and durations of protection for our population-level modelling analysis to assess the potential effect of an RTS,S vaccination schedule based on age (doses were delivered to children aged 6 months, 7·5 months, and 9 months for the first three doses, and at 27 months of age for the fourth dose) or season (children aged 5-17 months at the time of first vaccination received the first three doses in the 3 months preceding the transmission season, with any subsequent doses up to five doses delivered annually) in seasonal transmission settings both in the absence and presence of SMC with sulfadoxine-pyrimethamine plus amodiaquine. This is modelled as a full therapeutic course delivered every month for four or five months of the peak in transmission season. Estimates of cases and deaths averted in a population of 100 000 children aged 0-5 years were calculated over a 15-year time period for a range of levels of malaria transmission intensity (Plasmodium falciparum parasite prevalence i

Journal article

Najer A, Blight J, Ducker CB, Gasbarri M, Brown JC, Che J, Hogset H, Saunders C, Ojansivu M, Lu Z, Lin Y, Yeow J, Rifaie Graham O, Potter M, Tonkin R, Penders J, Doutch JJ, Georgiadou A, Barriga HMG, Holme MN, Cunnington AJ, Bugeon L, Dallman MJ, Barclay WS, Stellacci F, Baum J, Stevens MMet al., 2022,

Potent virustatic polymer-lipid nanomimics block viral entry and inhibit malaria parasites in vivo

, ACS Central Science, Vol: 8, Pages: 1238-1257, ISSN: 2374-7943

Infectious diseases continue to pose a substantial burden on global populations, requiring innovative broad-spectrum prophylactic and treatment alternatives. Here, we have designed modular synthetic polymer nanoparticles that mimic functional components of host cell membranes, yielding multivalent nanomimics that act by directly binding to varied pathogens. Nanomimic blood circulation time was prolonged by reformulating polymer–lipid hybrids. Femtomolar concentrations of the polymer nanomimics were sufficient to inhibit herpes simplex virus type 2 (HSV-2) entry into epithelial cells, while higher doses were needed against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given their observed virustatic mode of action, the nanomimics were also tested with malaria parasite blood-stage merozoites, which lose their invasive capacity after a few minutes. Efficient inhibition of merozoite invasion of red blood cells was demonstrated both in vitro and in vivo using a preclinical rodent malaria model. We envision these nanomimics forming an adaptable platform for developing pathogen entry inhibitors and as immunomodulators, wherein nanomimic-inhibited pathogens can be secondarily targeted to sites of immune recognition.

Report

Topazian H, Schmit N, Gerard-Ursin I, Charles G, Thompson H, Ghani A, Winskill Pet al., 2022,

Modelling the relative cost-effectiveness Of The Rts,S vaccine compared to other recommended malaria interventions

Journal article

Sherrard-Smith E, Ngufor C, Sanou A, Guelbeogo M, NGuessan R, Elobolobo E, Saute F, Varela K, Chaccour C, Zulliger R, Wagman J, Robertson ML, Rowland M, Donnelly M, Gonahasa S, Staedke S, Kolaczinski J, Churcher Tet al., 2022,

Inferring the epidemiological benefit of indoor vector control interventions against malaria from mosquito data

, Nature Communications, Vol: 13, ISSN: 2041-1723

The cause of malaria transmission has been known for over a century but it is still unclear whether entomological measures are sufficiently reliable to inform policy decisions in human health. Decision-making on the effectiveness of new insecticide-treated nets (ITNs) and the indoor residual spraying of insecticide (IRS) have been based on epidemiological data, typically collected in cluster-randomised control trials. The number of these trials that can be conducted is limited. Here we use a systematic review to highlight that efficacy estimates of the same intervention may vary substantially between trials. Analyses indicate that mosquito data collected in experimental hut trials can be used to parameterize mechanistic models for Plasmodium falciparum malaria and reliably predict the epidemiological efficacy of quick-acting, neuro-acting ITNs and IRS. Results suggest that for certain types of ITNs and IRS using this framework instead of clinical endpoints could support policy and expedite the widespread use of novel technologies.

Journal article

Whittaker C, Winskill P, Sinka M, Pironon S, Massey C, Weiss DJ, Nguyen M, Gething PW, Kumar A, Ghani A, Bhatt Set al., 2022,

A novel statistical framework for exploring the population dynamics and seasonality of mosquito populations

, Proceedings of the Royal Society B: Biological Sciences, Vol: 289, Pages: 1-10, ISSN: 0962-8452

Understanding the temporal dynamics of mosquito populations underlying vector-borne disease transmission is key to optimizing control strategies. Many questions remain surrounding the drivers of these dynamics and how they vary between species—questions rarely answerable from individual entomological studies (that typically focus on a single location or species). We develop a novel statistical framework enabling identification and classification of time series with similar temporal properties, and use this framework to systematically explore variation in population dynamics and seasonality in anopheline mosquito time series catch data spanning seven species, 40 years and 117 locations across mainland India. Our analyses reveal pronounced variation in dynamics across locations and between species in the extent of seasonality and timing of seasonal peaks. However, we show that these diverse dynamics can be clustered into four ‘dynamical archetypes’, each characterized by distinct temporal properties and associated with a largely unique set of environmental factors. Our results highlight that a range of environmental factors including rainfall, temperature, proximity to static water bodies and patterns of land use (particularly urbanicity) shape the dynamics and seasonality of mosquito populations, and provide a generically applicable framework to better identify and understand patterns of seasonal variation in vectors relevant to public health.

Journal article

Green N, Agossa F, Yovogan B, Oxborough R, Kitau J, Müller P, Constant E, Rowland M, Tchacaya EFS, Benjamin KG, Churcher TS, Betancourt M, Sherrard-Smith Eet al., 2022,

An evidence synthesis approach for combining different data sources illustrated using entomological efficacy of insecticides for indoor residual spraying

, PLoS One, Vol: 17, Pages: e0263446-e0263446, ISSN: 1932-6203

BackgroundProspective malaria public health interventions are initially tested for entomological impact using standardised experimental hut trials. In some cases, data are collated as aggregated counts of potential outcomes from mosquito feeding attempts given the presence of an insecticidal intervention. Comprehensive data i.e. full breakdowns of probable outcomes of mosquito feeding attempts, are more rarely available. Bayesian evidence synthesis is a framework that explicitly combines data sources to enable the joint estimation of parameters and their uncertainties. The aggregated and comprehensive data can be combined using an evidence synthesis approach to enhance our inference about the potential impact of vector control products across different settings over time.MethodsAggregated and comprehensive data from a meta-analysis of the impact of Pirimiphos-methyl, an indoor residual spray (IRS) product active ingredient, used on wall surfaces to kill mosquitoes and reduce malaria transmission, were analysed using a series of statistical models to understand the benefits and limitations of each.ResultsMany more data are available in aggregated format (N = 23 datasets, 4 studies) relative to comprehensive format (N = 2 datasets, 1 study). The evidence synthesis model had the smallest uncertainty at predicting the probability of mosquitoes dying or surviving and blood-feeding. Generating odds ratios from the correlated Bernoulli random sample indicates that when mortality and blood-feeding are positively correlated, as exhibited in our data, the number of successfully fed mosquitoes will be under-estimated. Analysis of either dataset alone is problematic because aggregated data require an assumption of independence and there are few and variable data in the comprehensive format.ConclusionsWe developed an approach to combine sources from trials to maximise the inference that can be made from such data and that is applicable to other systems. Bayesian evidence synthes

Journal article

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

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

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

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

Journal article

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

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

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

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

Journal article

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

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

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

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

Journal article

Unwin H, Mwandigha L, Winskill P, Ghani A, Hogan Aet al., 2021,

Analysis of the potential for a malaria vaccine to reduce gaps in malaria intervention coverage

, Malaria Journal, Vol: 20, Pages: 1-11, ISSN: 1475-2875

BackgroundThe RTS,S/AS01 malaria vaccine is currently being evaluated in a cluster-randomized pilot implementation programme in three African countries. This study seeks to identify whether vaccination could reach additional children who are at risk from malaria but do not currently have access to, or use, core malaria interventions.MethodsUsing data from household surveys, the overlap between malaria intervention coverage and childhood vaccination (diphtheria-tetanus-pertussis dose 3, DTP3) uptake in 20 African countries with at least one first administrative level unit with Plasmodium falciparum parasite prevalence greater than 10% was calculated. Multilevel logistic regression was used to explore patterns of overlap by demographic and socioeconomic variables. The public health impact of delivering RTS,S/AS01 to those children who do not use an insecticide-treated net (ITN), but who received the DTP3 vaccine, was also estimated.ResultsUptake of DTP3 was higher than malaria intervention coverage in most countries. Overall, 34% of children did not use ITNs and received DTP3, while 35% of children used ITNs and received DTP3, although this breakdown varied by country. It was estimated that there are 33 million children in these 20 countries who do not use an ITN. Of these, 23 million (70%) received the DTP3 vaccine. Vaccinating those 23 million children who receive DTP3 but do not use an ITN could avert up to an estimated 9.7 million (range 8.5–10.8 million) clinical malaria cases each year, assuming all children who receive DTP3 are administered all four RTS,S doses. An additional 10.8 million (9.5–12.0 million) cases could be averted by vaccinating those 24 million children who receive the DTP3 vaccine and use an ITN. Children who had access to or used an ITN were 9–13% more likely to reside in rural areas compared to those who had neither intervention regardless of vaccination status. Mothers’ education status was a strong predictor of inte

Journal article

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

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

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

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

Journal article

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

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

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

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

Journal article

Morris AL, Ghani A, Ferguson N, 2021,

Fine-scale estimation of key life-history parameters of malaria vectors: implications for next-generation vector control technologies

, Parasites and Vectors, Vol: 14, Pages: 1-12, ISSN: 1756-3305

BackgroundMosquito control has the potential to significantly reduce malaria burden on a region, but to influence public health policy must also show cost-effectiveness. Gaps in our knowledge of mosquito population dynamics mean that mathematical modelling of vector control interventions have typically made simplifying assumptions about key aspects of mosquito ecology. Often, these assumptions can distort the predicted efficacy of vector control, particularly next-generation tools such as gene drive, which are highly sensitive to local mosquito dynamics.MethodsWe developed a discrete-time stochastic mathematical model of mosquito population dynamics to explore the fine-scale behaviour of egg-laying and larval density dependence on parameter estimation. The model was fitted to longitudinal mosquito population count data using particle Markov chain Monte Carlo methods.ResultsBy modelling fine-scale behaviour of egg-laying under varying density dependence scenarios we refine our life history parameter estimates, and in particular we see how model assumptions affect population growth rate (Rm), a crucial determinate of vector control efficacy.ConclusionsSubsequent application of these new parameter estimates to gene drive models show how the understanding and implementation of fine-scale processes, when deriving parameter estimates, may have a profound influence on successful vector control. The consequences of this may be of crucial interest when devising future public health policy.

Journal article

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

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

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

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

Journal article

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

Localized release of matrix metallopeptidase 8 in fatal cerebral malaria

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

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

Journal article

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

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

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

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

Journal article

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

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

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

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

Journal article

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

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

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

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

Journal article

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

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

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

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

Journal article

Stopard IJ, Churcher TS, Lambert B, 2021,

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

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

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

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