22 results found
de Jong RM, Meerstein-Kessel L, Da DF, et al., 2021, Monoclonal antibodies block transmission of genetically diverse Plasmodium falciparum strains to mosquitoes, npj Vaccines, Vol: 6, Pages: 1-9, ISSN: 2059-0105
Malaria parasite transmission to mosquitoes relies on the uptake of sexual stage parasites during a blood meal and subsequent formation of oocysts on the mosquito midgut wall. Transmission-blocking vaccines (TBVs) and monoclonal antibodies (mAbs) target sexual stage antigens to interrupt human-to-mosquito transmission and may form important tools for malaria elimination. Although most epitopes of these antigens are considered highly conserved, little is known about the impact of natural genetic diversity on the functional activity of transmission-blocking antibodies. Here we measured the efficacy of three mAbs against leading TBV candidates (Pfs48/45, Pfs25 and Pfs230) in transmission assays with parasites from naturally infected donors compared to their efficacy against the strain they were raised against (NF54). Transmission-reducing activity (TRA) was measured as reduction in mean oocyst intensity. mAb 45.1 (α-Pfs48/45) and mAb 4B7 (α-Pfs25) reduced transmission of field parasites from almost all donors with IC80 values similar to NF54. Sequencing of oocysts that survived high mAb concentrations did not suggest enrichment of escape genotypes. mAb 2A2 (α-Pfs230) only reduced transmission of parasites from a minority of the donors, suggesting that it targets a non-conserved epitope. Using six laboratory-adapted strains, we revealed that mutations in one Pfs230 domain correlate with mAb gamete surface binding and functional TRA. Our findings demonstrate that, despite the conserved nature of sexual stage antigens, minor sequence variation can significantly impact the efficacy of transmission-blocking mAbs. Since mAb 45.1 shows high potency against genetically diverse strains, our findings support its further clinical development and may inform Pfs48/45 vaccine design.
Challenger JD, Foo CY, Wu Y, et al., 2021, Modelling upper respiratory viral load dynamics of SARS-CoV-2
<jats:title>Abstract</jats:title><jats:p>Relationships between viral load, severity of illness, and transmissibility of virus, are fundamental to understanding pathogenesis and devising better therapeutic and prevention strategies for COVID-19. Here we present within-host modelling of viral load dynamics observed in the upper respiratory tract (URT), drawing upon 2172 serial measurements from 605 subjects, collected from 17 different studies. We developed a mechanistic model to describe viral load dynamics and host response, and contrast this with simpler mixed-effects regression analysis of peak viral load and its subsequent decline. We observed wide variation in URT viral load between individuals, over 5 orders of magnitude, at any given point in time since symptom onset. This variation was not explained by age, sex, or severity of illness, and these variables were not associated with the modelled early or late phases of immune-mediated control of viral load. We explored the application of the mechanistic model to identify measured immune responses associated with control of viral load. Neutralizing antibody correlated strongly with modelled immune-mediated control of viral load amongst subjects who produced neutralizing antibody. Our models can be used to identify host and viral factors which control URT viral load dynamics, informing future treatment and transmission blocking interventions.</jats:p>
Challenger J, Olivera Mesa D, Da DF, et 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.
Mumtaz 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: 1475-2875
BackgroundIn 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
Mousa 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: 1549-1277
Background: 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
Sherrard-Smith E, Hogan AB, Hamlet A, et al., 2020, The potential public health consequences of COVID-19 on malaria in Africa., Nature Medicine, Vol: 26, Pages: 1411-1416, ISSN: 1078-8956
The burden of malaria is heavily concentrated in sub-Saharan Africa (SSA) where cases and deaths associated with COVID-19 are rising1. In response, countries are implementing societal measures aimed at curtailing transmission of SARS-CoV-22,3. Despite these measures, the COVID-19 epidemic could still result in millions of deaths as local health facilities become overwhelmed4. Advances in malaria control this century have been largely due to distribution of long-lasting insecticidal nets (LLINs)5, with many SSA countries having planned campaigns for 2020. In the present study, we use COVID-19 and malaria transmission models to estimate the impact of disruption of malaria prevention activities and other core health services under four different COVID-19 epidemic scenarios. If activities are halted, the malaria burden in 2020 could be more than double that of 2019. In Nigeria alone, reducing case management for 6 months and delaying LLIN campaigns could result in 81,000 (44,000-119,000) additional deaths. Mitigating these negative impacts is achievable, and LLIN distributions in particular should be prioritized alongside access to antimalarial treatments to prevent substantial malaria epidemics.
Challenger J, Goncalves BP, Bradley J, et al., 2019, How delayed and non-adherent treatment contribute to onward transmission of malaria: a modelling study, BMJ Global Health, Vol: 4, ISSN: 2059-7908
IntroductionArtemether-lumefantrine (AL) is the most widely-recommended treatment for uncomplicatedPlasmodium falciparum malaria. Its efficacy has been extensively assessed in clinical trials. In routinehealthcare settings, however, its effectiveness can be diminished by delayed access to treatmentand poor adherence. As well as affecting clinical outcomes, these factors can lead to increasedtransmission, which is the focus of this study.MethodsWe extend a within-host model of Plasmodium falciparum to include gametocytes, the parasiteforms responsible for onward transmission. The model includes a pharmacokineticpharmacodynamic model of AL, calibrated against both immature and mature gametocytes usingindividual-level patient data, to estimate the impact that delayed access and imperfect adherence totreatment can have on onward transmission of the parasite to mosquitoes.ResultsUsing survey data from 7 African countries to determine the time taken to acquire antimalarialsfollowing fever increased our estimates of mean total infectivity of a malaria episode by up to 1.5-fold, compared to patients treated after 24 hours. Realistic adherence behaviour, based on datafrom a monitored cohort in Tanzania, increased the contribution to transmission by 2.2 to 2.4-fold,compared to a perfectly-adherent cohort. This was driven largely by increased rates of treatmentfailure leading to chronic infection, rather than prolonged gametocytaemia in patients who haveslower, but still successful, clearance of parasites after imperfect adherence to treatment. Ourmodel estimated that the mean infectivity of untreated infections was 29-51 times higher than thatof treated infections (assuming perfect drug adherence), underlining the importance of improvingtreatment coverage.ConclusionUsing mathematical modelling, we quantify how delayed treatment and non-adherent treatmentcan increase transmission compared to prompt effective treatment. We also highlight thattransmission from the large proporti
Challenger JD, Sagara I, Olivera D, et al., 2019, UNDERSTANDING THE PROCESSES GOVERNING THE POPULATION-LEVEL IMPACT OF A TRANSMISSION BLOCKING VACCINE AGAINST MALARIA IN FIELD TRIAL SETTINGS, 68th Annual Meeting of the American-Society-for-Tropical-Medicine-and-Hygiene (ASTMH), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 414-414, ISSN: 0002-9637
Mousa A, Challenger JD, Cunnington AJ, et al., 2019, THE EFFECT OF DELAYED TREATMENT ON PROGRESSION TO SEVERE PLASMODIUM FALCIPARUM MALARIA: A POOLED MULTICENTRE INDIVIDUAL-PATIENT ANALYSIS, 68th Annual Meeting of the American-Society-for-Tropical-Medicine-and-Hygiene (ASTMH), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 215-215, ISSN: 0002-9637
Mousa A, Challenger J, Ghani A, et al., 2018, THE BURDEN OF ANTIMALARIAL TREATMENT FAILURE IN AFRICA: EVIDENCE FROM HOUSEHOLD SURVEYS, 67th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTHM), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 549-549, ISSN: 0002-9637
Challenger J, Ghani A, Okell L, 2018, ASSESSING THE IMPACT OF IMPERFECT ADHERENCE TO ARTEMETHER-LUMEFANTRINE ON ONWARD TRANSMISSION OF THE <it>PLASMODIUM FALCIPARUM</it> PARASITE USING WITHIN-HOST MODELLING, 67th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTHM), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 341-341, ISSN: 0002-9637
Challenger J, Bruxvoort K, Ghani AC, et al., 2017, Assessing the impact of imperfect adherence to artemether-lumefantrine on malaria treatment outcomes using within-host modelling, Nature Communications, Vol: 8, ISSN: 2041-1723
Artemether-lumefantrine (AL) is the most widely-recommended treatment for uncomplicated Plasmodium falciparum malaria worldwide. Its safety and efficacy have been extensively demonstrated in clinical trials; however, its performance in routine health care settings, where adherence to drug treatment is unsupervised and therefore may be suboptimal, is less well characterised. Here we develop a within-host modelling framework for estimating the effects of sub-optimal adherence to AL treatment on clinical outcomes in malaria patients. Our model incorporates data on the human immune response to the parasite, and AL’s pharmacokinetic and pharmacodynamic properties. Utilising individual-level data of adherence to AL in 482 Tanzanian patients as input for our model predicted higher rates of treatment failure than were obtained when adherence was optimal (9% compared to 4%). Our model estimates that the impact of imperfect adherence was worst in children, highlighting the importance of advice to caregivers.
Parra-Rojas C, Challenger JD, Fanelli D, et al., 2016, Suppressing escape events in maps of the unit interval with demographic noise, Physical Review E, Vol: 94, ISSN: 1539-3755
We explore the properties of discrete-time stochastic processes with a bounded state space, whosedeterministic limit is given by a map of the unit interval. We nd that, in the mesoscopic descriptionof the system, the large jumps between successive iterates of the process can result in probabilityleaking out of the unit interval, despite the fact that the noise is multiplicative and vanishes at theboundaries. By including higher-order terms in the mesoscopic expansion, we are able to capturethe non-Gaussian nature of the noise distribution near the boundaries, but this does not precludethe possibility of a trajectory leaving the interval. We propose a number of prescriptions for treatingthese escape events, and we compare the results with those obtained for the metastable behavior ofthe microscopic model, where escape events are not possible. We nd that, rather than truncatingthe noise distribution, censoring this distribution to prevent escape events leads to results whichare more consistent with the microscopic model. The addition of higher moments to the noisedistribution does not increase the accuracy of the nal results, and it can be replaced by the simplerGaussian noise.
Challenger JD, Burioni R, Fanelli D, 2015, Turing-like instabilities from a limit cycle., Physical Review E, Vol: 92, ISSN: 1539-3755
The Turing instability is a paradigmatic route to pattern formation in reaction-diffusion systems. Following a diffusion-driven instability, homogeneous fixed points can become unstable when subject to external perturbation. As a consequence, the system evolves towards a stationary, nonhomogeneous attractor. Stable patterns can be also obtained via oscillation quenching of an initially synchronous state of diffusively coupled oscillators. In the literature this is known as the oscillation death phenomenon. Here, we show that oscillation death is nothing but a Turing instability for the first return map of the system in its synchronous periodic state. In particular, we obtain a set of approximated closed conditions for identifying the domain in the parameter space that yields the instability. This is a natural generalization of the original Turing relations, to the case where the homogeneous solution of the examined system is a periodic function of time. The obtained framework applies to systems embedded in continuum space, as well as those defined on a networklike support. The predictive ability of the theory is tested numerically, using different reaction schemes.
Parra-Rojas C, Challenger JD, Fanelli D, et al., 2014, Intrinsic noise and two-dimensional maps: Quasicycles, quasiperiodicity, and chaos, PHYSICAL REVIEW E, Vol: 90, ISSN: 1539-3755
Asllani M, Challenger JD, Pavone FS, et al., 2014, The theory of pattern formation on directed networks, Nature Communications, Vol: 5, ISSN: 2041-1723
Dynamical processes on networks have generated widespread interest in recent years. The theory of pattern formation in reaction-diffusion systems defined on symmetric networks has often been investigated, due to its applications in a wide range of disciplines. Here we extend the theory to the case of directed networks, which are found in a number of different fields, such as neuroscience, computer networks and traffic systems. Owing to the structure of the network Laplacian, the dispersion relation has both real and imaginary parts, at variance with the case for a symmetric, undirected network. The homogeneous fixed point can become unstable due to the topology of the network, resulting in a new class of instabilities, which cannot be induced on undirected graphs. Results from a linear stability analysis allow the instability region to be analytically traced. Numerical simulations show travelling waves, or quasi-stationary patterns, depending on the characteristics of the underlying graph.
Challenger JD, Fanelli D, McKane AJ, 2014, The Theory of Individual Based Discrete-Time Processes, JOURNAL OF STATISTICAL PHYSICS, Vol: 156, Pages: 131-155, ISSN: 0022-4715
Challenger JD, Fanelli D, McKane AJ, 2013, Intrinsic noise and discrete-time processes, PHYSICAL REVIEW E, Vol: 88, ISSN: 1539-3755
Challenger JD, McKane AJ, 2013, Synchronization of stochastic oscillators in biochemical systems, PHYSICAL REVIEW E, Vol: 88, ISSN: 1539-3755
Challenger JD, McKane AJ, Pahle J, 2012, Multi-compartment linear noise approximation, JOURNAL OF STATISTICAL MECHANICS-THEORY AND EXPERIMENT, ISSN: 1742-5468
Pahle J, Challenger JD, Mendes P, et al., 2012, Biochemical fluctuations, optimisation and the linear noise approximation, BMC Systems Biology, Vol: 6, Pages: 1-13, ISSN: 1752-0509
BackgroundStochastic fluctuations in molecular numbers have been in many cases shown to be crucial for the understanding of biochemical systems. However, the systematic study of these fluctuations is severely hindered by the high computational demand of stochastic simulation algorithms. This is particularly problematic when, as is often the case, some or many model parameters are not well known. Here, we propose a solution to this problem, namely a combination of the linear noise approximation with optimisation methods. The linear noise approximation is used to efficiently estimate the covariances of particle numbers in the system. Combining it with optimisation methods in a closed-loop to find extrema of covariances within a possibly high-dimensional parameter space allows us to answer various questions. Examples are, what is the lowest amplitude of stochastic fluctuations possible within given parameter ranges? Or, which specific changes of parameter values lead to the increase of the correlation between certain chemical species? Unlike stochastic simulation methods, this has no requirement for small numbers of molecules and thus can be applied to cases where stochastic simulation is prohibitive.ResultsWe implemented our strategy in the software COPASI and show its applicability on two different models of mitogen-activated kinases (MAPK) signalling -- one generic model of extracellular signal-regulated kinases (ERK) and one model of signalling via p38 MAPK. Using our method we were able to quickly find local maxima of covariances between particle numbers in the ERK model depending on the activities of phospho-MKKK and its corresponding phosphatase. With the p38 MAPK model our method was able to efficiently find conditions under which the coefficient of variation of the output of the signalling system, namely the particle number of Hsp27, could be minimised. We also investigated correlations between the two parallel signalling branches (MKK3 and MKK6) in this model
Mumtaz R, Okell LC, Challenger JD, 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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