47 results found
Watson 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: 0737-4038
Substantial progress has been made globally to control malaria, however there is a growing need for innovative new tools to ensure continued progress. One approach is to harness genetic sequencing and accompanying methodological approaches as have been used in the control of other infectious diseases. However, to utilise these methodologies for malaria we first need to extend the methods to capture the complex interactions between parasites, human and vector hosts, and environment, which all impact the level of genetic diversity and relatedness of malaria parasites. We develop an individual-based transmission model to simulate malaria parasite genetics parameterised using estimated relationships between complexity of infection and age from 5 regions in Uganda and Kenya. We predict that cotransmission and superinfection contribute equally to within-host parasite genetic diversity at 11.5% PCR prevalence, above which superinfections dominate. Finally, we characterise the predictive power of six metrics of parasite genetics for detecting changes in transmission intensity, before grouping them in an ensemble statistical model. The model predicted malaria prevalence with a mean absolute error of 0.055. Different assumptions about the availability of sample metadata were considered, with the most accurate predictions of malaria prevalence made when the clinical status and age of sampled individuals is known. Parasite genetics may provide a novel surveillance tool for estimating the prevalence of malaria in areas in which prevalence surveys are not feasible. However, the findings presented here reinforce the need for patient metadata to be recorded and made available within all future attempts to use parasite genetics for surveillance.
Walker P, Cairns M, Slater H, et al., 2020, Modelling the incremental benefit of introducing malaria screening strategies to antenatal care in Africa, Nature Communications, Vol: 11, Pages: 1-12, ISSN: 2041-1723
Plasmodium falciparum in pregnancy is a major cause of adverse pregnancy outcomes. We combine performance estimates of standard rapid diagnostic tests (RDT) from trials of intermittent screening and treatment in pregnancy (ISTp) with modelling to assess whether screening at antenatal visits improves upon current intermittent preventative therapy with sulphadoxine-pyrimethamine (IPTp-SP). We estimate that RDTs in primigravidae at first antenatal visit are substantially more sensitive than in non-pregnant adults (OR = 17.2, 95% Cr.I. 13.8-21.6), and that sensitivity declines in subsequent visits and with gravidity, likely driven by declining susceptibility to placental infection. Monthly ISTp with standard RDTs, even with highly effective drugs, is not superior to monthly IPTp-SP. However, a hybrid strategy, recently adopted in Tanzania, combining testing and treatment at first visit with IPTp-SP may offer benefit, especially in areas with high-grade SP resistance. Screening and treatment in the first trimester, when IPTp-SP is contraindicated, could substantially improve pregnancy outcomes.
Sherrard-Smith E, Hogan A, Hamlet A, et 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.
Slater HC, Foy BD, Kobylinski K, et al., 2020, Ivermectin as a novel complementary malaria control tool to reduce incidence and prevalence: a modelling study, Lancet Infectious Diseases, Vol: 20, Pages: 498-508, ISSN: 1473-3099
BACKGROUND: Ivermectin is a potential new vector control tool to reduce malaria transmission. Mosquitoes feeding on a bloodmeal containing ivermectin have a reduced lifespan, meaning they are less likely to live long enough to complete sporogony and become infectious. We aimed to estimate the effect of ivermectin on malaria transmission in various scenarios of use. METHODS: We validated an existing population-level mathematical model of the effect of ivermectin mass drug administration (MDA) on the mosquito population and malaria transmission against two datasets: clinical data from a cluster- randomised trial done in Burkina Faso in 2015 wherein ivermectin was given to individuals taller than 90 cm and entomological data from a study of mosquito outcomes after ivermectin MDA for onchocerciasis or lymphatic filariasis in Burkina Faso, Senegal, and Liberia between 2008 and 2013. We extended the existing model to include a range of complementary malaria interventions (seasonal malaria chemoprevention and MDA with dihydroartemisinin-piperaquine) and to incorporate new data on higher doses of ivermectin with a longer mosquitocidal effect. We consider two ivermectin regimens: a single dose of 400 μg/kg (1 × 400 μg/kg) and three consecutive daily doses of 300 μg/kg per day (3 × 300 μg/kg). We simulated the effect of these two doses in a range of usage scenarios in different transmission settings (highly seasonal, seasonal, and perennial). We report percentage reductions in clinical incidence and slide prevalence. FINDINGS: We estimate that MDA with ivermectin will reduce prevalence and incidence and is most effective in areas with highly seasonal transmission. In a highly seasonal moderate transmission setting, three rounds of ivermectin only MDA at 3 × 300 μg/kg (rounds spaced 1 month apart) and 70% coverage is predicted to reduce clinical incidence by 71% and prevalence by 34%. We predict that adding ivermectin MDA to seasonal malaria ch
Mwesigwa J, Slater H, Bradley J, et al., 2019, FIELD PERFORMANCE OF THE HIGHLY-SENSITIVITY RAPID DIAGNOSTIC TEST IN A SETTING OF HIGHLY SEASONAL MALARIA TRANSMISSION, Publisher: OXFORD UNIV PRESS, Pages: S13-S13, ISSN: 0035-9203
Mwesigwa J, Slater H, Bradley J, et al., 2019, Field performance of the malaria highly sensitive rapid diagnostic test in a setting of varying malaria transmission, Malaria Journal, Vol: 18, Pages: 1-13, ISSN: 1475-2875
BackgroundThe Gambia has successfully reduced malaria transmission. The human reservoir of infection could further decrease if malaria-infected individuals could be identified by highly sensitive, field-based, diagnostic tools and then treated.MethodsA cross-sectional survey was done at the peak of the 2017 malaria season in 47 Gambian villages. From each village, 100 residents were randomly selected for finger-prick blood samples to detect Plasmodium falciparum infections using highly sensitive rapid diagnostic tests (HS-RDT) and PCR. The sensitivity and specificity of the HS-RDT were estimated (assuming PCR as the gold standard) across varying transmission intensities and in different age groups. A deterministic, age-structured, dynamic model of malaria transmission was used to estimate the impact of mass testing and treatment (MTAT) with HS-RDT in four different scenarios of malaria prevalence by PCR: 5, 15, 30, and 60%, and with seasonal transmission. The impact was compared both to MTAT with conventional RDT and mass drug administration (MDA).ResultsMalaria prevalence by HS-RDT was 15% (570/3798; 95% CI 13.9–16.1). The HS-RDT sensitivity and specificity were 38.4% (191/497, 95% CI 34.2–42.71) and 88.5% (2922/3301; 95% CI 87.4–89.6), respectively. Sensitivity was the highest (50.9%, 95% CI 43.3–58.5%) in high prevalence villages (20–50% by PCR). The model predicted that in very low transmission areas (≤ 5%), three monthly rounds of MTAT with HS-RDT, starting towards the end of the dry season and testing 65 or 85% of the population for 2 consecutive years, would avert 62 or 78% of malaria cases (over 2 years), respectively. The effect of the intervention would be lower in a moderate transmission setting. In all settings, MDA would be superior to MTAT with HS-RDT which would be superior to MTAT with conventional RDT.ConclusionThe HS-RDT’s field sensitivity was modest and varied by transmission intensity. In low to very
Watson O, Sumner K, Janko M, et al., 2019, False-negative malaria rapid diagnostic test results and their impact on community-based malaria surveys in sub- Saharan Africa, BMJ Global Health, Vol: 4, Pages: 1-9, ISSN: 2059-7908
Surveillance and diagnosis of Plasmodium falciparum malaria relies predominantly on rapid diagnostic tests (RDTs). However, false-negative RDT results are known to occur for a variety of reasons, including operator error, poor storage conditions, pfhrp2/3 gene deletions, poor performance of specific RDT brands and lots, and low-parasite-density infections. We used RDT and microscopy results from 85,000 children enrolled in Demographic Health Surveys and Malaria Indicator Surveys from 2009 to 2015 across 19 countries to explore the distribution of and risk factors for false-negative RDTs in Sub40 Saharan Africa, where malaria’s impact is greatest. We sought to (i) identify spatial and demographic patterns of false-negative RDT (FN-RDT) results, defined as a negative RDT but positive gold-standard microscopy test, and (ii) estimate the percentage of infections missed within community-based malaria surveys due to FN-RDT results. Across all studies, 19.9% [95% CI: 19.0 – 20.9] of microscopy-positive subjects were negative by RDT. The distribution of FN-RDT results was spatially heterogeneous. The variance in FN-RDT results was best explained by the prevalence of malaria, with an increase in FN46 RDT results observed at lower transmission intensities, among younger subjects, and in urban areas. The observed proportion of FN-RDT results was not predicted by differences in RDT brand or lot performance alone. These findings characterise how the probability of detection by RDTs varies in different transmission settings and emphasize the need for careful interpretation of prevalence estimates based on surveys employing RDTs alone. Further studies are needed to characterise the cost-effectiveness of improved malaria diagnostics (e.g. PCR or highly sensitive RDTs) in community52 based surveys, especially in regions of low transmission intensity or high urbanicity.
Slater HC, Ross A, Felger I, et al., 2019, Author Correction: The temporal dynamics and infectiousness of subpatent Plasmodium falciparum infections in relation to parasite density, Nature Communications, Vol: 10, ISSN: 2041-1723
Correction to: Nature Communications https://doi.org/10.1038/s41467-019-09441-1; published online 29 March 2019
Watson OJ, Verity R, Ghani AC, et al., 2019, Impact of seasonal variations in Plasmodium falciparum malaria transmission on the surveillance of pfhrp2 gene deletions, eLife, Vol: 8, ISSN: 2050-084X
Ten countries have reported pfhrp2/pfhrp3 gene deletions since the first observation of pfhrp2-deleted parasites in 2012. In a previous study (Watson et al., 2017) we characterised the drivers selecting for pfhrp2/3 deletions, and mapped the regions in Africa with the greatest selection pressure. In February 2018, the World Health Organization issued guidance on investigating suspected false-negative rapid diagnostic tests (RDTs) due to pfhrp2/3 deletions. However, no guidance is provided regarding the timing of investigations. Failure to consider seasonal variation could cause premature decisions to switch to alternative RDTs. In response, we have extended our methods and predict that the prevalence of false-negative RDTs due to pfhrp2/3 deletions is highest when sampling from younger individuals during the beginning of the rainy season. We conclude by producing a map of the regions impacted by seasonal fluctuations in pfhrp2/3 deletions and a database identifying optimum sampling intervals to support malaria control programmes.
Foy BD, Alout H, Seaman JA, et al., 2019, Efficacy and risk of harms of repeat ivermectin mass drug administrations for control of malaria (RIMDAMAL): a cluster-randomised trial, LANCET, Vol: 393, Pages: 1517-1526, ISSN: 0140-6736
Slater H, Ross A, Felger I, et al., 2019, The temporal dynamics and infectiousness of subpatent Plasmodium falciparum infections in relation to parasite density, Nature Communications, Vol: 10, ISSN: 2041-1723
Malaria infections occurring below the limit of detection of standard diagnostics are common in all endemic settings. However, key questions remain surrounding their contribution to sustaining transmission and whether they need to be detected and targeted to achieve malaria elimination. In this study we analyse a range of malaria datasets to quantify the density, detectability, course of infection and infectiousness of subpatent infections. Asymptomatically infected individuals have lower parasite densities on average in low transmission settings compared to individuals in higher transmission settings. In cohort studies, subpatent infections are found to be predictive of future periods of patent infection and in membrane feeding studies, individuals infected with subpatent asexual parasite densities are found to be approximately a third as infectious to mosquitoes as individuals with patent (asexual parasite) infection. These results indicate that subpatent infections contribute to the infectious reservoir, may be long lasting, and require more sensitive diagnostics to detect them in lower transmission settings.
Burrows J, Slater H, Macintyre F, et al., 2018, A discovery and development roadmap for new endectocidal transmission-blocking agents in malaria, Malaria Journal, Vol: 17, ISSN: 1475-2875
Reaching the overall goal of eliminating malaria requires halting disease transmission. One approach to blocking transmission is to prevent passage of the parasite to a mosquito, by preventing formation or transmission of gametocytes. An alternative approach, pioneered in the veterinary field, is to use endectocides, which are molecules that render vertebrate blood meals toxic for the mosquito vector, also killing the parasite. Field studies and modelling suggest that reducing the lifespan of the mosquito may significantly reduce transmission, given the lengthy maturation process of the parasite. To guide the development of new endectocides, or the reformulation of existing molecules, it is important to construct a framework of the required attributes, commonly called the target candidate profile. Here, using a combination of insights from current endectocides, mathematical models of the malaria transmission dynamics, and known impacts of vector control, a target candidate profile (TCP-6) and a regulatory strategy are proposed for a transmission reducing agent. The parameters chosen can be used to assess the potential of a new medicine, independent of whether it has classical endectocide activity, reduces the insect and parasite lifespan or any combination of all three, thereby constituting an ‘endectocidal transmission blocking’ paradigm.
Miglianico M, Eldering M, Slater H, et al., 2018, Repurposing isoxazoline veterinary drugs for control of vector-borne human diseases., Proceedings of the National Academy of Sciences, Vol: 115, Pages: E6920-E6926, ISSN: 0027-8424
Isoxazolines are oral insecticidal drugs currently licensed for ectoparasite control in companion animals. Here we propose their use in humans for the reduction of vector-borne disease incidence. Fluralaner and afoxolaner rapidly killed Anopheles, Aedes, and Culex mosquitoes and Phlebotomus sand flies after feeding on a drug-supplemented blood meal, with IC50 values ranging from 33 to 575 nM, and were fully active against strains with preexisting resistance to common insecticides. Based on allometric scaling of preclinical pharmacokinetics data, we predict that a single human median dose of 260 mg (IQR, 177-407 mg) for afoxolaner, or 410 mg (IQR, 278-648 mg) for fluralaner, could provide an insecticidal effect lasting 50-90 days against mosquitoes and Phlebotomus sand flies. Computational modeling showed that seasonal mass drug administration of such a single dose to a fraction of a regional population would dramatically reduce clinical cases of Zika and malaria in endemic settings. Isoxazolines therefore represent a promising new component of drug-based vector control.
Tadesse FG, Slater HC, Chali W, et al., 2018, The relative contribution of symptomatic and asymptomatic Plasmodium vivax and Plasmodium falciparum infections to the infectious reservoir in a low-endemic setting in Ethiopia, Clinical Infectious Diseases, Vol: 66, Pages: 1883-1891, ISSN: 1058-4838
Background: The majority of P. vivax and P. falciparum infections in low-endemic settings are asymptomatic. The relative contribution to the infectious reservoir of these infections, often of low-parasite-density, compared to clinical malaria cases, is currently unknown but important for malaria elimination strategies. Methods: We assessed infectivity of passively-recruited symptomatic malaria patients (n=41) and community-recruited asymptomatic individuals with microscopy- (n=41) and PCR-detected infections (n=82) using membrane feeding assays with Anopheles arabiensis mosquitoes in Adama, Ethiopia. Malaria incidence and prevalence data was used to estimate the contributions of these populations to the infectious reservoir. Results: Overall, 34.9% (29/83) of P. vivax and 15.1% (8/53) P. falciparum infected individuals infected ≥1 mosquitoes. Mosquito infection rates were strongly correlated with asexual parasite density for P. vivax (ρ = 0.63; P < .001) but not for P. falciparum (ρ = 0.06; P = .770). P. vivax symptomatic infections were more infectious to mosquitoes (infecting 46.5% of mosquitoes, 307/660) compared to asymptomatic microscopy-detected (infecting 12.0% of mosquitoes, 80/667; P = .005) and PCR-detected infections (infecting 0.8% of mosquitoes, 6/744; P < .001). Adjusting for population prevalence, symptomatic, asymptomatic microscopy- and PCR-detected infections were responsible for 8.0%, 76.2% and 15.8% of the infectious reservoir for P. vivax, respectively. For P. falciparum, mosquito infections were sparser and also predominantly from asymptomatic infections. Conclusions: In this low-endemic setting aiming for malaria elimination, asymptomatic infections are highly prevalent and responsible for the majority of onward mosquito infections. The early identification and treatment of asymptomatic infections might thus accelerate elimination efforts.
Smit MR, Ochomo EO, Aljayyoussi G, et al., 2018, Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial, Lancet Infectious Diseases, Vol: 18, Pages: 615-626, ISSN: 1473-3099
BACKGROUND: Ivermectin is being considered for mass drug administration for malaria due to its ability to kill mosquitoes feeding on recently treated individuals. However, standard, single doses of 150-200 μg/kg used for onchocerciasis and lymphatic filariasis have a short-lived mosquitocidal effect (<7 days). Because ivermectin is well tolerated up to 2000 μg/kg, we aimed to establish the safety, tolerability, and mosquitocidal efficacy of 3 day courses of high-dose ivermectin, co-administered with a standard malaria treatment. METHODS: We did a randomised, double-blind, placebo-controlled, superiority trial at the Jaramogi Oginga Odinga Teaching and Referral Hospital (Kisumu, Kenya). Adults (aged 18-50 years) were eligible if they had confirmed symptomatic uncomplicated Plasmodium falciparum malaria and agreed to the follow-up schedule. Participants were randomly assigned (1:1:1) using sealed envelopes, stratified by sex and body-mass index (men: <21 vs ≥21 kg/m2; women: <23 vs ≥23 kg/m2), with permuted blocks of three, to receive 3 days of ivermectin 300 μg/kg per day, ivermectin 600 μg/kg per day, or placebo, all co-administered with 3 days of dihydroartemisinin-piperaquine. Blood of patients taken on post-treatment days 0, 2 + 4 h, 7, 10, 14, 21, and 28 was fed to laboratory-reared Anopheles gambiae sensu stricto mosquitoes, and mosquito survival was assessed daily for 28 days after feeding. The primary outcome was 14-day cumulative mortality of mosquitoes fed 7 days after ivermectin treatment (from participants who received at least one dose of study medication). The study is registered with ClinicalTrials.gov, number NCT02511353. FINDINGS: Between July 20, 2015, and May 7, 2016, 741 adults with malaria were assessed for eligibility, of whom 141 were randomly assigned to receive ivermectin 600 μg/kg per day (n=47), ivermectin 300 μg/kg per day (n=48), or placebo (n=46). 128 patients (91%) attended the primary outcome visit 7 da
Chaccour CJ, Ngha'bi K, Abizanda G, et al., 2018, Targeting cattle for malaria elimination: marked reduction of Anopheles arabiensis survival for over six months using a slow-release ivermectin implant formulation, Parasites & Vectors, Vol: 11, Pages: 287-287, ISSN: 1756-3305
BACKGROUND: Mosquitoes that feed on animals can survive and mediate residual transmission of malaria even after most humans have been protected with insecticidal bednets or indoor residual sprays. Ivermectin is a widely-used drug for treating parasites of humans and animals that is also insecticidal, killing mosquitoes that feed on treated subjects. Mass administration of ivermectin to livestock could be particularly useful for tackling residual malaria transmission by zoophagic vectors that evade human-centred approaches. Ivermectin comes from a different chemical class to active ingredients currently used to treat bednets or spray houses, so it also has potential for mitigating against emergence of insecticide resistance. However, the duration of insecticidal activity obtained with ivermectin is critical to its effectiveness and affordability. RESULTS: A slow-release formulation for ivermectin was implanted into cattle, causing 40 weeks of increased mortality among Anopheles arabiensis that fed on them. For this zoophagic vector of residual malaria transmission across much of Africa, the proportion surviving three days after feeding (typical mean duration of a gonotrophic cycle in field populations) was approximately halved for 25 weeks. CONCLUSIONS: This implantable ivermectin formulation delivers stable and sustained insecticidal activity for approximately 6 months. Residual malaria transmission by zoophagic vectors could be suppressed by targeting livestock with this long-lasting formulation, which would be impractical or unacceptable for mass treatment of human populations.
Slater H, Li R, Walker P, et al., 2018, MODELLING THE IMPACT OF AN ULTRA-SENSITIVE <it>PLASMODIUM FALCIPARUM</it> RAPID DIAGNOSTIC TEST (U-RDT): DETECTING ASYMPTOMATIC INFECTIONS AND THE POTENTIAL FOR OVERTREATMENT, 67th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTHM), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 540-541, ISSN: 0002-9637
Li R, Ghani A, Walker P, et al., 2018, MODELING HRP2 DYNAMICS AND THE IMPLICATIONS FOR A NEW ULTRA-SENSITIVE RAPID DIAGNOSTIC TEST (U-RDT), 67th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTHM), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 539-539, ISSN: 0002-9637
Winskill P, Slater H, Griffin J, et al., 2017, The US President's Malaria Initiative, Plasmodium falciparum transmission and mortality: A modelling study, PLoS Medicine, Vol: 14, ISSN: 1549-1277
BackgroundAlthough significant progress has been made in reducing malaria transmission globally inrecent years, a large number of people remain at risk and hence the gains made are fragile.Funding lags well behind amounts needed to protect all those at risk and ongoing contributionsfrom major donors, such as the President’s Malaria Initiative (PMI), are vital to maintainprogress and pursue further reductions in burden. We use a mathematical modellingapproach to estimate the impact of PMI investments to date in reducing malaria burden andto explore the potential negative impact on malaria burden should a proposed 44% reductionin PMI funding occur.Methods and findingsWe combined an established mathematical model of Plasmodium falciparum transmissiondynamics with epidemiological, intervention, and PMI-financing data to estimate the contributionPMI has made to malaria control via funding for long-lasting insecticide treated nets(LLINs), indoor residual spraying (IRS), and artemisinin combination therapies (ACTs). Weestimate that PMI has prevented 185 million (95% CrI: 138 million, 230 million) malariacases and saved 940,049 (95% CrI: 545,228, 1.4 million) lives since 2005. If funding is maintained,PMI-funded interventions are estimated to avert a further 162 million cases (95%CrI: 116 million, 194 million) cases, saving a further 692,589 (95% CrI: 392,694, 955,653)lives between 2017 and 2020. With an estimate of US$94 (95% CrI: US$51, US$166) perDisability Adjusted Life Year (DALY) averted, PMI-funded interventions are highly costeffective.We also demonstrate the further impact of this investment by reducing caseloadson health systems. If a 44% reduction in PMI funding were to occur, we predict that this lossof direct aid could result in an additional 67 million (95% CrI: 49 million, 82 million) cases and290,649 deaths (95% CrI: 167,208, 395,263) deaths between 2017 and 2020. We have notmodelled indirect impacts of PMI funding (such as health systems strengthening
Hamainza B, Mudenda M, Miller J, et al., 2017, ZAMBIA'S NATIONAL STRATEGY TO MOVE FROM ACCELERATED BURDEN REDUCTION TO MALARIA ELIMINATION BY 2020, 65th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 486-486, ISSN: 0002-9637
Drakeley C, Noor AM, Achee NL, et al., 2017, malERA: An updated research agenda for characterising the reservoir and measuring transmission in malaria elimination and eradication, PLOS MEDICINE, Vol: 14, ISSN: 1549-1277
Watson O, Slater HC, Verity R, et al., 2017, Modelling the drivers of the spread of Plasmodium falciparum hrp2 gene deletions in sub-Saharan Africa, eLife, Vol: 6, ISSN: 2050-084X
Rapid diagnostic tests (RDTs) have transformed malaria diagnosis. The most prevalent P. falciparum RDTs detect histidine-rich protein 2 (PfHRP2). However, pfhrp2 gene deletions yielding false-negative RDTs, first reported in South America in 2010, have been confirmed in Africa and Asia. We developed a mathematical model to explore the potential for RDT-led diagnosis to drive selection of pfhrp2-deleted parasites. Low malaria prevalence and high frequencies of people seeking treatment resulted in the greatest selection pressure. Calibrating our model against confirmed pfhrp2-deletions in the Democratic Republic of Congo, we estimate a starting frequency of 6% pfhrp2-deletion prior to RDT introduction. Furthermore, the patterns observed necessitate a degree of selection driven by the introduction of PfHRP2-based RDT-guided treatment. Combining this with parasite prevalence and treatment coverage estimates, we map the model-predicted spread of pfhrp2-deletion, and identify the geographic regions in which surveillance for pfhrp2-deletion should be prioritised.
Brady OJ, Slater HC, Pemberton-Ross P, et al., 2017, Role of mass drug administration in elimination of Plasmodium falciparum malaria: a consensus modelling study, The Lancet Global Health, Vol: 5, Pages: E680-E687, ISSN: 2214-109X
BackgroundMass drug administration for elimination of Plasmodium falciparum malaria is recommended by WHO in some settings. We used consensus modelling to understand how to optimise the effects of mass drug administration in areas with low malaria transmission.MethodsWe collaborated with researchers doing field trials to establish a standard intervention scenario and standard transmission setting, and we input these parameters into four previously published models. We then varied the number of rounds of mass drug administration, coverage, duration, timing, importation of infection, and pre-administration transmission levels. The outcome of interest was the percentage reduction in annual mean prevalence of P falciparum parasite rate as measured by PCR in the third year after the final round of mass drug administration.FindingsThe models predicted differing magnitude of the effects of mass drug administration, but consensus answers were reached for several factors. Mass drug administration was predicted to reduce transmission over a longer timescale than accounted for by the prophylactic effect alone. Percentage reduction in transmission was predicted to be higher and last longer at lower baseline transmission levels. Reduction in transmission resulting from mass drug administration was predicted to be temporary, and in the absence of scale-up of other interventions, such as vector control, transmission would return to pre-administration levels. The proportion of the population treated in a year was a key determinant of simulated effectiveness, irrespective of whether people are treated through high coverage in a single round or new individuals are reached by implementation of several rounds. Mass drug administration was predicted to be more effective if continued over 2 years rather than 1 year, and if done at the time of year when transmission is lowest.InterpretationMass drug administration has the potential to reduce transmission for a limited time, but is not an
Sherrard-Smith E, Churcher TS, Upton LM, et 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
Winskill P, Slater HC, Griffin JT, et al., 2017, THE IMPORTANCE OF US FOREIGN AID FOR GLOBAL MALARIA CONTROL AND ELIMINATION, 66th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 217-217, ISSN: 0002-9637
Dighe A, Ghani A, Slater H, 2017, MODELLING THE POTENTIAL OF IVERMECTIN TREATED CATTLE AS A NOVEL MALARIA VECTOR CONTROL TOOL: IMPLICATIONS OF KILLING ZOOPHILIC MOSQUITOES, 66th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 331-331, ISSN: 0002-9637
Bellinger AM, Jafari M, Grant TM, et al., 2016, Oral, ultra-long-lasting drug delivery: Application toward malaria elimination goals., Science Translational Medicine, Vol: 8, Pages: 365ra157-365ra157, ISSN: 1946-6234
Efforts at elimination of scourges, such as malaria, are limited by the logistic challenges of reaching large rural populations and ensuring patient adherence to adequate pharmacologic treatment. We have developed an oral, ultra-long-acting capsule that dissolves in the stomach and deploys a star-shaped dosage form that releases drug while assuming a geometry that prevents passage through the pylorus yet allows passage of food, enabling prolonged gastric residence. This gastric-resident, drug delivery dosage form releases small-molecule drugs for days to weeks and potentially longer. Upon dissolution of the macrostructure, the components can safely pass through the gastrointestinal tract. Clinical, radiographic, and endoscopic evaluation of a swine large-animal model that received these dosage forms showed no evidence of gastrointestinal obstruction or mucosal injury. We generated long-acting formulations for controlled release of ivermectin, a drug that targets malaria-transmitting mosquitoes, in the gastric environment and incorporated these into our dosage form, which then delivered a sustained therapeutic dose of ivermectin for up to 14 days in our swine model. Further, by using mathematical models of malaria transmission that incorporate the lethal effect of ivermectin against malaria-transmitting mosquitoes, we demonstrated that this system will boost the efficacy of mass drug administration toward malaria elimination goals. Encapsulated, gastric-resident dosage forms for ultra-long-acting drug delivery have the potential to revolutionize treatment options for malaria and other diseases that affect large populations around the globe for which treatment adherence is essential for efficacy.
Parr JB, Verity R, Doctor SM, et al., 2016, Pfhrp2-deleted Plasmodium falciparum parasites in the Democratic Republic of the Congo: a national cross-sectional survey, Journal of Infectious Diseases, Vol: 216, Pages: 36-44, ISSN: 0022-1899
Background.Rapid diagnostic tests (RDTs) account for more than two-thirds of malaria diagnoses in Africa. Deletions of the Plasmodium falciparum hrp2 (pfhrp2) gene cause false-negative RDT results and have never been investigated on a national level. Spread of pfhrp2-deleted P. falciparum mutants, resistant to detection by HRP2-based RDTs, would represent a serious threat to malaria elimination efforts.Methods.Using a nationally representative cross-sectional study of 7,137 children under five years of age from the Democratic Republic of Congo (DRC), we tested 783 subjects with RDT-/PCR+ results using PCR assays to detect and confirm deletions of the pfhrp2 gene. Spatial and population genetic analyses were employed to examine the distribution and evolution of these parasites.Results.We identified 149 pfhrp2-deleted parasites, representing 6.4% of all P. falciparum infections country-wide (95% confidence interval 5.1–8.0%). Bayesian spatial analyses identified statistically significant clustering of pfhrp2 deletions near Kinshasa and Kivu. Population genetic analysis revealed significant genetic differentiation between wild-type and pfhrp2-deleted parasite populations (GST = .046, p ≤ .00001).Conclusions.Pfhrp2-deleted P. falciparum is a common cause of RDT-/PCR+ malaria among asymptomatic children in the DRC and appears to be clustered within select communities. Surveillance for these deletions is needed, and alternatives to HRP2-specific RDTs may be necessary.
Slater HC, Okell LC, Ghani AC, 2016, Mathematical Modelling to Guide Drug Development for Malaria Elimination, Trends in Parasitology, Vol: 33, Pages: 175-184, ISSN: 1471-5007
Mathematical models of the dynamics of a drug within the host are now frequently used to guide drug development. These generally focus on assessing the efficacy and duration of response to guide patient therapy. Increasingly, antimalarial drugs are used at the population level, to clear infections, provide chemoprevention, and to reduce onward transmission of infection. However, there is less clarity on the extent to which different drug properties are important for these different uses. In addition, the emergence of drug resistance poses new threats to longer-term use and highlights the need for rational drug development. Here, we argue that integrating within-host pharmacokinetic and pharmacodynamic (PK/PD) models with mathematical models for the population-level transmission of malaria is key to guiding optimal drug design to aid malaria elimination.
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