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  1. Article ; Online: Model-informed target product profiles of long-acting-injectables for use as seasonal malaria prevention.

    Burgert, Lydia / Reiker, Theresa / Golumbeanu, Monica / Möhrle, Jörg J / Penny, Melissa A

    PLOS global public health

    2022  Volume 2, Issue 3, Page(s) e0000211

    Abstract: Seasonal malaria chemoprevention (SMC) has proven highly efficacious in reducing malaria incidence. However, the continued success of SMC is threatened by the spread of resistance against one of its main preventive ingredients, Sulfadoxine-Pyrimethamine ( ...

    Abstract Seasonal malaria chemoprevention (SMC) has proven highly efficacious in reducing malaria incidence. However, the continued success of SMC is threatened by the spread of resistance against one of its main preventive ingredients, Sulfadoxine-Pyrimethamine (SP), operational challenges in delivery, and incomplete adherence to the regimens. Via a simulation study with an individual-based model of malaria dynamics, we provide quantitative evidence to assess long-acting injectables (LAIs) as potential alternatives to SMC. We explored the predicted impact of a range of novel preventive LAIs as a seasonal prevention tool in children aged three months to five years old during late-stage clinical trials and at implementation. LAIs were co-administered with a blood-stage clearing drug once at the beginning of the transmission season. We found the establishment of non-inferiority of LAIs to standard 3 or 4 rounds of SMC with SP-amodiaquine was challenging in clinical trial stages due to high intervention deployment coverage. However, our analysis of implementation settings where the achievable SMC coverage was much lower, show LAIs with fewer visits per season are potential suitable replacements to SMC. Suitability as a replacement with higher impact is possible if the duration of protection of LAIs covered the duration of the transmission season. Furthermore, optimising LAIs coverage and protective efficacy half-life via simulation analysis in settings with an SMC coverage of 60% revealed important trade-offs between protective efficacy decay and deployment coverage. Our analysis additionally highlights that for seasonal deployment for LAIs, it will be necessary to investigate the protective efficacy decay as early as possible during clinical development to ensure a well-informed candidate selection process.
    Language English
    Publishing date 2022-03-14
    Publishing country United States
    Document type Journal Article
    ISSN 2767-3375
    ISSN (online) 2767-3375
    DOI 10.1371/journal.pgph.0000211
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  2. Article ; Online: Mechanistic within-host models of the asexual Plasmodium falciparum infection: a review and analytical assessment.

    Camponovo, Flavia / Lee, Tamsin E / Russell, Jonathan R / Burgert, Lydia / Gerardin, Jaline / Penny, Melissa A

    Malaria journal

    2021  Volume 20, Issue 1, Page(s) 309

    Abstract: Background: Malaria blood-stage infection length and intensity are important drivers of disease and transmission; however, the underlying mechanisms of parasite growth and the host's immune response during infection remain largely unknown. Over the last ...

    Abstract Background: Malaria blood-stage infection length and intensity are important drivers of disease and transmission; however, the underlying mechanisms of parasite growth and the host's immune response during infection remain largely unknown. Over the last 30 years, several mechanistic mathematical models of malaria parasite within-host dynamics have been published and used in malaria transmission models.
    Methods: Mechanistic within-host models of parasite dynamics were identified through a review of published literature. For a subset of these, model code was reproduced and descriptive statistics compared between the models using fitted data. Through simulation and model analysis, key features of the models were compared, including assumptions on growth, immune response components, variant switching mechanisms, and inter-individual variability.
    Results: The assessed within-host malaria models generally replicate infection dynamics in malaria-naïve individuals. However, there are substantial differences between the model dynamics after disease onset, and models do not always reproduce late infection parasitaemia data used for calibration of the within host infections. Models have attempted to capture the considerable variability in parasite dynamics between individuals by including stochastic parasite multiplication rates; variant switching dynamics leading to immune escape; variable effects of the host immune responses; or via probabilistic events. For models that capture realistic length of infections, model representations of innate immunity explain early peaks in infection density that cause clinical symptoms, and model representations of antibody immune responses control the length of infection. Models differed in their assumptions concerning variant switching dynamics, reflecting uncertainty in the underlying mechanisms of variant switching revealed by recent clinical data during early infection. Overall, given the scarce availability of the biological evidence there is limited support for complex models.
    Conclusions: This study suggests that much of the inter-individual variability observed in clinical malaria infections has traditionally been attributed in models to random variability, rather than mechanistic disease dynamics. Thus, it is proposed that newly developed models should assume simple immune dynamics that minimally capture mechanistic understandings and avoid over-parameterization and large stochasticity which inaccurately represent unknown disease mechanisms.
    MeSH term(s) Computer Simulation ; Host-Parasite Interactions ; Humans ; Malaria, Falciparum/parasitology ; Parasitemia/parasitology ; Plasmodium falciparum/physiology
    Language English
    Publishing date 2021-07-10
    Publishing country England
    Document type Journal Article
    ISSN 1475-2875
    ISSN (online) 1475-2875
    DOI 10.1186/s12936-021-03813-z
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  3. Article ; Online: Emulator-based Bayesian optimization for efficient multi-objective calibration of an individual-based model of malaria.

    Reiker, Theresa / Golumbeanu, Monica / Shattock, Andrew / Burgert, Lydia / Smith, Thomas A / Filippi, Sarah / Cameron, Ewan / Penny, Melissa A

    Nature communications

    2021  Volume 12, Issue 1, Page(s) 7212

    Abstract: Individual-based models have become important tools in the global battle against infectious diseases, yet model complexity can make calibration to biological and epidemiological data challenging. We propose using a Bayesian optimization framework ... ...

    Abstract Individual-based models have become important tools in the global battle against infectious diseases, yet model complexity can make calibration to biological and epidemiological data challenging. We propose using a Bayesian optimization framework employing Gaussian process or machine learning emulator functions to calibrate a complex malaria transmission simulator. We demonstrate our approach by optimizing over a high-dimensional parameter space with respect to a portfolio of multiple fitting objectives built from datasets capturing the natural history of malaria transmission and disease progression. Our approach quickly outperforms previous calibrations, yielding an improved final goodness of fit. Per-objective parameter importance and sensitivity diagnostics provided by our approach offer epidemiological insights and enhance trust in predictions through greater interpretability.
    MeSH term(s) Algorithms ; Bayes Theorem ; Calibration ; Communicable Diseases ; Computer Simulation ; Disease Progression ; Humans ; Machine Learning ; Malaria/epidemiology ; Malaria/transmission ; Models, Biological ; Normal Distribution ; Software
    Language English
    Publishing date 2021-12-10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-021-27486-z
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  4. Article ; Online: A pharmacokinetic-pharmacodynamic model for chemoprotective agents against malaria.

    Cherkaoui-Rbati, Mohammed H / Andenmatten, Nicole / Burgert, Lydia / Egbelowo, Oluwaseun F / Fendel, Rolf / Fornari, Chiara / Gabel, Michael / Ward, John / Möhrle, Jörg J / Gobeau, Nathalie

    CPT: pharmacometrics & systems pharmacology

    2022  Volume 12, Issue 1, Page(s) 50–61

    Abstract: Chemoprophylactics are a vital tool in the fight against malaria. They can be used to protect populations at risk, such as children younger than the age of 5 in areas of seasonal malaria transmission or pregnant women. Currently approved ... ...

    Abstract Chemoprophylactics are a vital tool in the fight against malaria. They can be used to protect populations at risk, such as children younger than the age of 5 in areas of seasonal malaria transmission or pregnant women. Currently approved chemoprophylactics all present challenges. There are either concerns about unacceptable adverse effects such as neuropsychiatric sequalae (mefloquine), risks of hemolysis in patients with G6PD deficiency (8-aminoquinolines such as tafenoquine), or cost and daily dosing (atovaquone-proguanil). Therefore, there is a need to develop new chemoprophylactic agents to provide more affordable therapies with better compliance through improving properties such as pharmacokinetics to allow weekly, preferably monthly, dosing. Here we present a pharmacokinetic-pharmacodynamic (PKPD) model constructed using DSM265 (a dihydroorotate dehydrogenase inhibitor with activity against the liver schizonts of malaria, therefore, a prophylaxis candidate). The PKPD model mimics the parasite lifecycle by describing parasite dynamics and drug activity during the liver and blood stages. A major challenge is the estimation of model parameters, as only blood-stage parasites can be observed once they have reached a threshold. By combining qualitative and quantitative knowledge about the parasite from various sources, it has been shown that it is possible to infer information about liver-stage growth and its initial infection level. Furthermore, by integrating clinical data, the killing effect of the drug on liver- and blood-stage parasites can be included in the PKPD model, and a clinical outcome can be predicted. Despite multiple challenges, the presented model has the potential to help translation from preclinical to late development for new chemoprophylactic candidates.
    MeSH term(s) Child ; Humans ; Female ; Pregnancy ; Antimalarials/pharmacology ; Antimalarials/therapeutic use ; Malaria/drug therapy ; Malaria/prevention & control ; Glucosephosphate Dehydrogenase Deficiency/chemically induced ; Glucosephosphate Dehydrogenase Deficiency/drug therapy ; Enzyme Inhibitors ; Liver
    Chemical Substances Antimalarials ; Enzyme Inhibitors
    Language English
    Publishing date 2022-11-22
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2697010-7
    ISSN 2163-8306 ; 2163-8306
    ISSN (online) 2163-8306
    ISSN 2163-8306
    DOI 10.1002/psp4.12875
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  5. Article ; Online: Ensemble modeling highlights importance of understanding parasite-host behavior in preclinical antimalarial drug development.

    Burgert, Lydia / Rottmann, Matthias / Wittlin, Sergio / Gobeau, Nathalie / Krause, Andreas / Dingemanse, Jasper / Möhrle, Jörg J / Penny, Melissa A

    Scientific reports

    2020  Volume 10, Issue 1, Page(s) 4410

    Abstract: Emerging drug resistance and high-attrition rates in early and late stage drug development necessitate accelerated development of antimalarial compounds. However, systematic and meaningful translation of drug efficacy and host-parasite dynamics between ... ...

    Abstract Emerging drug resistance and high-attrition rates in early and late stage drug development necessitate accelerated development of antimalarial compounds. However, systematic and meaningful translation of drug efficacy and host-parasite dynamics between preclinical testing stages is missing. We developed an ensemble of mathematical within-host parasite growth and antimalarial action models, fitted to extensive data from four antimalarials with different modes of action, to assess host-parasite interactions in two preclinical drug testing systems of murine parasite P. berghei in mice, and human parasite P. falciparum in immune-deficient mice. We find properties of the host-parasite system, namely resource availability, parasite maturation and virulence, drive P. berghei dynamics and drug efficacy, whereas experimental constraints primarily influence P. falciparum infection and drug efficacy. Furthermore, uninvestigated parasite behavior such as dormancy influences parasite recrudescence following non-curative treatment and requires further investigation. Taken together, host-parasite interactions should be considered for meaningful translation of pharmacodynamic properties between murine systems and for predicting human efficacious treatment.
    MeSH term(s) Animals ; Antiprotozoal Agents/chemistry ; Antiprotozoal Agents/pharmacology ; Antiprotozoal Agents/therapeutic use ; Disease Models, Animal ; Drug Development ; Drug Resistance/drug effects ; Host-Parasite Interactions ; Humans ; Malaria, Falciparum/drug therapy ; Malaria, Falciparum/parasitology ; Mice ; Mice, SCID ; Models, Theoretical ; Plasmodium berghei/drug effects ; Plasmodium berghei/physiology ; Plasmodium falciparum/drug effects ; Plasmodium falciparum/physiology
    Chemical Substances Antiprotozoal Agents
    Language English
    Publishing date 2020-03-10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-020-61304-8
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  6. Article ; Online: Parasite-Host Dynamics throughout Antimalarial Drug Development Stages Complicate the Translation of Parasite Clearance.

    Burgert, Lydia / Zaloumis, Sophie / Dini, Saber / Marquart, Louise / Cao, Pengxing / Cherkaoui, Mohammed / Gobeau, Nathalie / McCarthy, James / Simpson, Julie A / Möhrle, Jörg J / Penny, Melissa A

    Antimicrobial agents and chemotherapy

    2021  Volume 65, Issue 4

    Abstract: Ensuring continued success against malaria depends on a pipeline of new antimalarials. Antimalarial drug development utilizes preclinical murine and experimental human malaria infection studies to evaluate drug efficacy. A sequential approach is ... ...

    Abstract Ensuring continued success against malaria depends on a pipeline of new antimalarials. Antimalarial drug development utilizes preclinical murine and experimental human malaria infection studies to evaluate drug efficacy. A sequential approach is typically adapted, with results from each stage informing the design of the next stage of development. The validity of this approach depends on confidence that results from murine malarial studies predict the outcome of clinical trials in humans. Parasite clearance rates following treatment are key parameters of drug efficacy. To investigate the validity of forward predictions, we developed a suite of mathematical models to capture parasite growth and drug clearance along the drug development pathway and estimated parasite clearance rates. When comparing the three infection experiments, we identified different relationships of parasite clearance with dose and different maximum parasite clearance rates. In
    MeSH term(s) Animals ; Antimalarials/pharmacology ; Antimalarials/therapeutic use ; Malaria, Falciparum/drug therapy ; Mice ; Mice, SCID ; Parasites ; Plasmodium berghei ; Plasmodium falciparum
    Chemical Substances Antimalarials
    Language English
    Publishing date 2021-03-18
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 217602-6
    ISSN 1098-6596 ; 0066-4804
    ISSN (online) 1098-6596
    ISSN 0066-4804
    DOI 10.1128/AAC.01539-20
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  7. Article ; Online: Kinesin family member 6 (kif6) is necessary for spine development in zebrafish.

    Buchan, Jillian G / Gray, Ryan S / Gansner, John M / Alvarado, David M / Burgert, Lydia / Gitlin, Jonathan D / Gurnett, Christina A / Goldsmith, Matthew I

    Developmental dynamics : an official publication of the American Association of Anatomists

    2014  Volume 243, Issue 12, Page(s) 1646–1657

    Abstract: Background: Idiopathic scoliosis is a form of spinal deformity that affects 2-3% of children and results in curvature of the spine without structural defects of the vertebral units. The pathogenesis of idiopathic scoliosis remains poorly understood, in ... ...

    Abstract Background: Idiopathic scoliosis is a form of spinal deformity that affects 2-3% of children and results in curvature of the spine without structural defects of the vertebral units. The pathogenesis of idiopathic scoliosis remains poorly understood, in part due to the lack of a relevant animal model.
    Results: We performed a forward mutagenesis screen in zebrafish to identify new models for idiopathic scoliosis. We isolated a recessive zebrafish mutant, called skolios, which develops isolated spinal curvature that arises independent of vertebral malformations. Using meiotic mapping and whole genome sequencing, we identified a nonsense mutation in kinesin family member 6 (kif6(gw326) ) unique to skolios mutants. Three additional kif6 frameshift alleles (gw327, gw328, gw329) were generated with transcription activator-like effector nucleases (TALENs). Zebrafish homozygous or compound heterozygous for kif6 frameshift mutations developed a scoliosis phenotype indistinguishable from skolios mutants, confirming that skolios is caused by the loss of kif6. Although kif6 may play a role in cilia, no evidence for cilia dysfunction was seen in kif6(gw326) mutants.
    Conclusions: Overall, these findings demonstrate a novel role for kif6 in spinal development and identify a new candidate gene for human idiopathic scoliosis.
    MeSH term(s) Animals ; Codon, Nonsense ; Disease Models, Animal ; Frameshift Mutation ; Humans ; Kinesin/genetics ; Kinesin/metabolism ; Phenotype ; Scoliosis/embryology ; Scoliosis/genetics ; Spine/embryology ; Zebrafish/embryology ; Zebrafish/genetics ; Zebrafish Proteins/genetics ; Zebrafish Proteins/metabolism
    Chemical Substances Codon, Nonsense ; Zebrafish Proteins ; Kinesin (EC 3.6.4.4)
    Language English
    Publishing date 2014-10-20
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1102541-4
    ISSN 1097-0177 ; 1058-8388
    ISSN (online) 1097-0177
    ISSN 1058-8388
    DOI 10.1002/dvdy.24208
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