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Journal articleStopard 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: 1553-734XDuring 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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Journal articleHellewell J, Sherrard-Smith E, Ogoma S, et al., 2021,
Assessing the impact of low-technology emanators alongside long-lasting insecticidal nets to control malaria
, Philosophical Transactions of the Royal Society B: Biological Sciences, Vol: 376, Pages: 1-9, ISSN: 0962-8436Malaria control in sub-Saharan Africa relies on the widespread use of long-lasting insecticidal nets (LLINs) or the indoor residual spraying of insecticide. Disease transmission may be maintained even when these indoor interventions are universally used as some mosquitoes will bite in the early morning and evening when people are outside. As countries seek to eliminate malaria, they can target outdoor biting using new vector control tools such as spatial repellent emanators, which emit airborne insecticide to form a protective area around the user. Field data are used to incorporate a low-technology emanator into a mathematical model of malaria transmission to predict its public health impact across a range of scenarios. Targeting outdoor biting by repeatedly distributing emanators alongside LLINs increases the chance of elimination, but the additional benefit depends on the level of anthropophagy in the local mosquito population, emanator effectiveness and the pre-intervention proportion of mosquitoes biting outdoors. High proportions of pyrethroid-resistant mosquitoes diminish LLIN impact because of reduced mosquito mortality. When mosquitoes are highly anthropophagic, this reduced mortality leads to more outdoor biting and a reduced additional benefit of emanators, even if emanators are assumed to retain their effectiveness in the presence of pyrethroid resistance. Different target product profiles are examined, which show the extra epidemiological benefits of spatial repellents that induce mosquito mortality.
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Journal articleGuglielmo F, Sanou A, Churcher TS, et al., 2020,
Quantifying the individual variability in people’s exposure to mosquito bites in Burkina Faso
, Malaria Journal<jats:title>Abstract</jats:title> <jats:p><jats:bold>Background</jats:bold>The Cascades Region, Burkina Faso, has high malaria burden despite reported high insecticide treated bed net (ITN) use. Human and vector activities outside the hours when indoor interventions offer direct protection from infectious bites potentially increase exposure risk to bites from malaria-transmitting <jats:italic>Anopheles </jats:italic>mosquitoes. We investigate the degree of variation in human behaviour both between individuals and through time (season) to quantify how it impacts exposure to malaria vectors.<jats:bold>Methods</jats:bold>Patterns in human overnight activity (18:00-06:00) to quantify time spent using an ITN across 7 successive nights in two rural communities, Niakore (N = 24 participants) and Toma (71 participants), were observed in the dry and rainy seasons, between 2017-2018. Hourly human landing <jats:italic>Anopheles </jats:italic>mosquito catches were conducted in Niakore specifically, and Cascades Region generally, between 2016-2017. Data were statistically combined to estimate seasonal variation in time spent outdoors and <jats:italic>Anopheles </jats:italic>bites received per person per night (bpppn).<jats:bold>Results</jats:bold>Substantial variability in exposure to outdoor <jats:italic>Anopheles</jats:italic> bites was detected within and between communities and across seasons. In October, when <jats:italic>Anopheles </jats:italic>densities are highest, an individual’s risk of <jats:italic>Anopheles</jats:italic> bites ranged from 2.2 to 52.2 bpppn within the same week with variable risk dependent on hours spent indoors. Comparably higher outdoor human activity was observed in April and July but, due to lower <jats:italic>Anopheles </jats:italic>densities estimated bpppn were 0.2 – 4.7 bpppn, and 0.5 &nda
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Journal articleGuglielmo F, Sanou A, Churcher TS, et al., 2021,
Quantifying individual variability in exposure risk to mosquito bites in the Cascades region, Burkina Faso
, Malaria Journal, Vol: 20, Pages: 1-14, ISSN: 1475-2875BackgroundThe Cascades region, Burkina Faso, has a high malaria burden despite reported high insecticide-treated mosquito net (ITN) use. Human and vector activities outside the hours when indoor interventions offer direct protection from infectious bites potentially increase exposure risk to bites from malaria-transmitting Anopheles mosquitoes. This work investigated the degree of variation in human behaviour both between individuals and through time (season) to quantify how it impacts exposure to malaria vectors.MethodsPatterns in human overnight activity (18:00–06:00) to quantify time spent using an ITN across 7 successive nights in two rural communities, Niakore (N = 24 participants) and Toma (71 participants), were observed in the dry and rainy seasons, between 2017 and 2018. Hourly human landing Anopheles mosquito catches were conducted in Niakore specifically, and Cascades region generally, between 2016 and 2017. Data were statistically combined to estimate seasonal variation in time spent outdoors and Anopheles bites received per person per night (bpppn).ResultsSubstantial variability in exposure to outdoor Anopheles bites was detected within and between communities across seasons. In October, when Anopheles densities are highest, an individual’s risk of Anopheles bites ranged from 2.2 to 52.2 bites per person per night (bpppn) within the same week with variable risk dependent on hours spent indoors. Comparably higher outdoor human activity was observed in April and July but, due to lower Anopheles densities estimated, bpppn were 0.2–4.7 and 0.5–32.0, respectively. Males and people aged over 21 years were predicted to receive more bites in both sentinel villages.ConclusionThis work presents one of the first clear descriptions of the degree of heterogeneity in time spent outdoors between people and across the year. Appreciation of sociodemographic, cultural and entomological activities will help refine approaches to vector
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Journal articleMoser KA, Madebe RA, Aydemir O, et al., 2021,
Describing the current status of <i>Plasmodium falciparum</i> population structure and drug resistance within mainland Tanzania using molecular inversion probes
, MOLECULAR ECOLOGY, Vol: 30, Pages: 100-113, ISSN: 0962-1083- Author Web Link
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Journal articleWitmer K, Dahalan F, Delves M, et al., 2021,
Transmission of artemisinin-resistant malaria parasites to mosquitoes under antimalarial drug pressure
, Antimicrobial Agents and Chemotherapy, Vol: 65, Pages: 1-17, ISSN: 0066-4804Resistance to artemisinin-based combination therapy (ACT) in the Plasmodium falciparum parasite is threatening to reverse recent gains in reducing global deaths from malaria. Whilst resistance manifests as delayed parasite clearance in patients the phenotype can only spread geographically via the sexual stages and mosquito transmission. In addition to their asexual killing properties, artemisinin and its derivatives sterilise sexual male gametocytes. Whether resistant parasites overcome this sterilising effect has not, however, been fully tested. Here, we analysed P. falciparum clinical isolates from the Greater Mekong Subregion, each demonstrating delayed clinical clearance and known resistance-associated polymorphisms in Kelch13 (PfK13var). As well as demonstrating reduced asexual sensitivity to drug, certain PfK13var isolates demonstrated a marked reduction in sensitivity to artemisinin in an in vitro male gamete formation assay. Importantly, this same reduction in sensitivity was observed when the most resistant isolate was tested directly in mosquito feeds. These results indicate that, under artemisinin drug pressure, whilst sensitive parasites are blocked, resistant parasites continue transmission. This selective advantage for resistance transmission could favour acquisition of additional host-specificity or polymorphisms affecting partner drug sensitivity in mixed infections. Favoured resistance transmission under ACT coverage could have profound implications for the spread of multidrug resistant malaria beyond Southeast Asia.
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Journal articleKitojo C, Chacky F, Kigadye ES, et al., 2020,
Evaluation of a single screen and treat strategy to detect asymptomatic malaria among pregnant women from selected health facilities in Lindi region, Tanzania
, Malaria Journal, Vol: 19, Pages: 1-8, ISSN: 1475-2875BackgroundIn areas of high transmission, malaria in pregnancy (MiP) primarily causes asymptomatic infections; these infections nonetheless increase the risk of adverse maternal and fetal outcomes. In 2014, Tanzania initiated a single screening and treatment (SST) strategy for all pregnant women at their first antenatal care (ANC) visit using malaria rapid diagnostic tests (RDT) for surveillance purposes. However, there is paucity of data on the effectiveness of SST in the prevention of MiP. The objective of this study was to estimate the number of asymptomatic infections among pregnant women detected by SST, which would have been missed in the absence of the policy.MethodsData from pregnant women attending their first ANC visits between October 2017 and June 2018, including gestational age, history of fever, and RDT results, were abstracted from ANC registers in eight health centres in two randomly selected districts, Kilwa and Lindi, in Lindi Region. The proportion of symptomatic (with history of fever in the past 48 h) and asymptomatic pregnant women with positive RDTs were calculated and stratified by trimester (first, second and third). The study areas were categorized as low transmission with prevalence < 10% or moderate/high with ≥ 10%.ResultsOver the study period, 1,845 women attended their first ANC visits; 22.1% were in the first trimester (< 12 weeks gestation age). Overall 15.0% of the women had positive RDTs, and there was a trend towards higher malaria prevalence in the first (15.9%) and second (15.2%) trimesters, compared to the third (7.1%), although the differences were not statistically significant (p = 0.07). In total, 6.9% of women reported fever within the past 48 h and, of these, 96.1% were RDT positive. For every 100 pregnant women in the moderate/high and low transmission areas, SST identified 60 and 26 pregnant women, respectively, with asymptomatic infections that would have otherwise
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Journal articleMumtaz R, Okell LC, Challenger J, 2020,
Asymptomatic recrudescence after artemether-lumefantrine treatment for uncomplicated falciparum malaria: a systematic review and meta-analysis
, Malaria Journal, Vol: 19, ISSN: 1475-2875BackgroundIn clinical trials of therapy for uncomplicated Plasmodium falciparum, there are usually some patients who fail treatment even in the absence of drug resistance. Treatment failures, which can be due to recrudescence or re-infection, are categorized as ‘clinical’ or ‘parasitological’ failures, the former indicating that symptoms have returned. Asymptomatic recrudescence has public health implications for continued malaria transmission and may be important for the spread of drug-resistant malaria. As the number of recrudescences in an individual trial is often low, it is difficult to assess how commonplace asymptomatic recrudescence is, and with what factors it is associated.MethodsA systematic literature review was carried out on clinical trials of artemether-lumefantrine (AL) in patients seeking treatment for symptomatic uncomplicated falciparum malaria, and information on symptoms during treatment failure was recorded. Only treatment failures examined by polymerase chain reaction (PCR) were included, so as to exclude re-infections. A multivariable Bayesian regression model was used to explore factors potentially explaining the proportion of recrudescent infections which are symptomatic across the trials included in the study.ResultsAcross 60 published trials, including 9137 malaria patients, 37.8% [95% CIs (26.6–49.4%)] of recrudescences were symptomatic. A positive association was found between transmission intensity and the observed proportion of recrudescences that were asymptomatic. Symptoms were more likely to return in trials that only enrolled children aged < 72 months [odds ratio = 1.62, 95% CIs (1.01, 2.59)]. However, 84 studies had to be excluded from this analysis, as recrudescences were not specified as symptomatic or asymptomatic.ConclusionsAL, the most widely used treatment for uncomplicated P. falciparum in Africa, remains a highly efficacious drug in most endemic countries. Howev
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Journal articleHogan A, Winskill P, Ghani A, 2020,
Estimated impact of RTS,S/AS01 malaria vaccine allocation strategies in sub-Saharan Africa: a modelling study
, PLoS Medicine, Vol: 17, Pages: 1-19, ISSN: 1549-1277Background: The RTS,S/AS01 vaccine against P. falciparum malaria infection completed phase 3 trials in 2014, and demonstrated efficacy against clinical malaria of approximately 36% over 4 years for a 4-dose schedule in children aged 5–17 months. Pilot vaccine implementation has recently begun in three African countries. If the pilots demonstrate both a positive health impact and resolve remaining safety concerns, wider roll-out could be recommended from 2021 onwards. Vaccine demand may however outstrip initial supply. We sought to identify where vaccine introduction should be prioritised to maximise public health impact under a range of supply constraints using mathematical modelling. Methods and Findings: Using a mathematical model of P. falciparum malaria transmission and RTS,S vaccine impact, we estimated the clinical cases and deaths averted in children aged 0–5 years in sub-Saharan Africa under two scenarios for vaccine coverage (100% and realistic) and two scenarios for other interventions (current coverage and WHO Global Technical Strategy targets). We used a prioritisation algorithm to identify potential allocative efficiency gains fromprioritising vaccine allocation among countries or administrative units to maximise cases or deaths averted. If malaria burden at introduction is similar to current levels, assuming realistic vaccine coverage and country-level prioritisation in areas with parasite prevalence >10%, we estimate 4.3 million (95% credible interval, CrI 2.8–6.8 million) malaria cases and 22,000 (95% CrI 11,000–35,000) deaths in children younger than 5 years could be averted annually at a dose constraint of 30 million. This decreases to 3.0 million (95% CrI 2.0–4.7 million) cases and14,000 (95% CrI 7,000–23,000) deaths at a dose constraint of 20 million,and increases to 6.6 million (95% CrI 4.2–10.8 million) cases and38,000 (95% CrI 18
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Journal articleThompson H, Hogan A, Walker P, et al., 2020,
Modelling the roles of antibody titre and avidity in protection from Plasmodium falciparum malaria infection following RTS,S/AS01 vaccination
, Vaccine, Vol: 38, Pages: 7498-7507, ISSN: 0264-410XAnti-circumsporozoite antibody titres have been established as an essential indicator for evaluating the immunogenicity and protective capacity of the RTS,S/AS01 malaria vaccine. However, a new delayed-fractional dose regime of the vaccine was recently shown to increase vaccine efficacy, from 62.5% (95% CI 29.4–80.1%) under the original dosing schedule to 86.7% (95% CI, 66.8–94.6%) without a corresponding increase in antibody titres. Here we reanalyse the antibody data from this challenge trial to determine whether IgG avidity may help to explain efficacy better than IgG titre alone by adapting a within-host mathematical model of sporozoite inoculation. We demonstrate that a model incorporating titre and avidity provides a substantially better fit to the data than titre alone. These results also suggest that in individuals with a high antibody titre response that also show high avidity (both metrics in the top tercile of observed values) delayed-fractional vaccination provided near perfect protection upon first challenge (98.2% [95% Credible Interval 91.6–99.7%]). This finding suggests that the quality of the vaccine induced antibody response is likely to be an important determinant in the development of highly efficacious pre-erythrocytic vaccines against malaria.
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Journal articleMousa A, Al-Taiar A, Anstey NM, et al., 2020,
The impact of delayed treatment of uncomplicated P. falciparum malaria on progression to severe malaria: a systematic review and a pooled multicentre individual-patient meta-analysis
, PLoS Medicine, Vol: 17, Pages: 1-28, ISSN: 1549-1277Background: Delay in receiving treatment for uncomplicated malaria is often reported to increase the risk of developing severe malaria, but access to treatment remains low in most high-burden areas. Understanding the contribution of treatment delay on progression to severe disease is critical to determine how quickly patients need to receive treatment and to quantify the impact of widely implemented treatment interventions, such as “test-and-treat” policies administered by community health workers. We conducted a pooled individual-participant meta-analysis to estimate the association between treatment delay and presenting with severe malaria.Methods and Findings: A search using Ovid MEDLINE and Embase was initially conducted to identify studies on severe P. falciparum malaria which included information on treatment delay, such as fever duration 12(inceptions to 22nd September 2017). Studies identified included five case-control and eight other observational clinical studies of severe and uncomplicated malaria cases. Risk of bias was assessed using the Newcastle–Ottawa scale and all studies were ranked as “Good”, scoring ≥7/10. Individual-patient data were pooled from thirteen studies of 3,989(94.1% aged <15 years)severe malaria patients and 5,780(79.6% aged <15 years)uncomplicated malaria cases in Benin, Malaysia, Mozambique, Tanzania, The Gambia, Uganda, Yemen and Zambia. Definitions of severe malaria were standardised across studies to compare treatment delay in patients with uncomplicated malaria and different severe malaria phenotypes using age-adjusted mixed-effects regression. The odds of any severe malaria phenotype were significantly higher in children with longer delays between initial symptoms and arrival at the health facility (OR=1.33, 95%CI:1.07-1.64 for a delay of >24 hours vs. ≤24 hours;p=0.009). Reported illness duration was a strong predictor of presenting with severe malarial anaemia (SMA) in children
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Journal articleDjaafara BA, Whittaker C, Watson OJ, et al., 2020,
Quantifying the dynamics of COVID-19 burden and impact of interventions in Java, Indonesia
<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>As in many countries, quantifying COVID-19 spread in Indonesia remains challenging due to testing limitations. In Java, non-pharmaceutical interventions (NPIs) were implemented throughout 2020. However, as a vaccination campaign launches, cases and deaths are rising across the island.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We used modelling to explore the extent to which data on burials in Jakarta using strict COVID-19 protocols (C19P) provide additional insight into the transmissibility of the disease, epidemic trajectory, and the impact of NPIs. We assess how implementation of NPIs in early 2021 will shape the epidemic during the period of likely vaccine roll-out.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>C19P burial data in Jakarta suggest a death toll approximately 3.3 times higher than reported. Transmission estimates using these data suggest earlier, larger, and more sustained impact of NPIs. Measures to reduce sub-national spread, particularly during Ramadan, substantially mitigated spread to more vulnerable rural areas. Given current trajectory, daily cases and deaths are likely to increase in most regions as the vaccine is rolled-out. Transmission may peak in early 2021 in Jakarta if current levels of control are maintained. However, relaxation of control measures is likely to lead to a subsequent resurgence in the absence of an effective vaccination campaign.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Syndromic measures of mortality provide a more complete picture of COVID-19 severity upon which to base decision-making. The high potential impact of the vaccine in Java is attributable to reductions in transmission to date and dependent on these be
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Journal articleWatson O, Okell L, Hellewell J, et al., 2020,
Evaluating the performance of malaria genetics for inferring changes in transmission intensity using transmission modelling
, Molecular Biology and Evolution, Vol: 38, Pages: 274-289, ISSN: 0737-4038Substantial progress has been made globally to control malaria, however there is a growing need for innovative new tools to ensure continued progress. One approach is to harness genetic sequencing and accompanying methodological approaches as have been used in the control of other infectious diseases. However, to utilise these methodologies for malaria we first need to extend the methods to capture the complex interactions between parasites, human and vector hosts, and environment, which all impact the level of genetic diversity and relatedness of malaria parasites. We develop an individual-based transmission model to simulate malaria parasite genetics parameterised using estimated relationships between complexity of infection and age from 5 regions in Uganda and Kenya. We predict that cotransmission and superinfection contribute equally to within-host parasite genetic diversity at 11.5% PCR prevalence, above which superinfections dominate. Finally, we characterise the predictive power of six metrics of parasite genetics for detecting changes in transmission intensity, before grouping them in an ensemble statistical model. The model predicted malaria prevalence with a mean absolute error of 0.055. Different assumptions about the availability of sample metadata were considered, with the most accurate predictions of malaria prevalence made when the clinical status and age of sampled individuals is known. Parasite genetics may provide a novel surveillance tool for estimating the prevalence of malaria in areas in which prevalence surveys are not feasible. However, the findings presented here reinforce the need for patient metadata to be recorded and made available within all future attempts to use parasite genetics for surveillance.
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Journal articleHogan A, Jewell B, Sherrard-Smith E, et 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: 2214-109XBackground: 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
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Journal articleMumtaz R, Okell LC, Challenger JD, 2020,
How often do symptoms return after unsuccessful drug treatment for malaria? A systematic review and meta-analysis
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>In clinical trials of therapies for uncomplicated <jats:italic>Plasmodium falciparum</jats:italic>, there are usually some patients who fail treatment even in the absence of drug resistance. Treatment failures are categorised as ‘clinical’ or ‘parasitological’ failures, the latter indicating that recrudescence of the infection has occurred without inducing the return of symptoms. Asymptomatic treatment failure has public health implications for continued malaria transmission and may be important for the spread of drug-resistant malaria. As the number of treatment failures in an individual trial is often low, it is difficult to assess how commonplace asymptomatic treatment failure is, and with what factors it is associated.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>A systematic literature review was carried out on clinical trials of artemether-lumefantrine (AL) in patients seeking treatment for symptomatic uncomplicated falciparum malaria, and information on symptoms during treatment failure was recorded. Only treatment failures examined by polymerase chain reaction (PCR) were included, so as to exclude reinfections. Using a multivariable Bayesian regression model, we explored factors potentially explaining the proportion of recrudescent infections which are symptomatic across the trials included in our study.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Across 60 published trials including 9137 malaria patients we found that 40.8% (95% CIs [35.9-45.8%]) of late treatment failures were symptomatic. We found a positive association between transmission intensity and the observed proportion of treatment failures that were asymptomatic. We also found that symptoms were more likely to return in t
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