ORCID Profile
0000-0002-5129-8180
Current Organisation
UNSW Sydney
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Publisher: Cold Spring Harbor Laboratory
Date: 02-05-2022
DOI: 10.1101/2022.04.28.22274398
Abstract: In malaria endemic regions, transmission of Plasmodium falciparum parasites is often seasonal with very low transmission during the dry season and high transmission in the wet season. Parasites survive the dry season within some in iduals who experience prolonged carriage of parasites and are thought to ‘seed’ infection in the next transmission season. We use a combination of mathematical simulations and data analysis to characterise dry season carriers and their role in the subsequent transmission season. Simulating the life-history of in iduals experiencing repeated exposure to infection predicts that dry season carriage is more likely in the oldest, most exposed and most immune in iduals. This hypothesis is supported by data from a longitudinal study in Mali that shows that carriers are significantly older, experience a higher biting rate at the beginning of the transmission season and develop clinical malaria later than non-carriers. Further, since the most exposed in iduals in a community are most likely to be dry season carriers, we show that this is predicted to enable a more than 2-fold faster spread of parasites into the mosquito population at the start of the subsequent wet season.
Publisher: Springer Science and Business Media LLC
Date: 19-11-2019
DOI: 10.1007/S00285-018-1310-2
Abstract: Plasmids are autonomously replicating genetic elements in bacteria. At cell ision, plasmids are distributed among the two daughter cells. This gene transfer from one generation to the next is called vertical gene transfer. We study the dynamics of a bacterial population carrying plasmids and are in particular interested in the long-time distribution of plasmids. Starting with a model for a bacterial population structured by the discrete number of plasmids, we proceed to the continuum limit in order to derive a continuous model. The model incorporates plasmid reproduction, ision and death of bacteria, and distribution of plasmids at cell ision. It is a hyperbolic integro-differential equation and a so-called growth-fragmentation-death model. As we are interested in the long-time distribution of plasmids we study the associated eigenproblem and show existence of eigensolutions. The stability of this solution is studied by analyzing the spectrum of the integro-differential operator given by the eigenproblem. By relating the spectrum with the spectrum of an integral operator we find a simple real dominating eigenvalue with a non-negative corresponding eigenfunction. Moreover, we describe an iterative method for the numerical construction of the eigenfunction.
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.JTBI.2022.111014
Abstract: Malaria is a mosquito-borne disease with a devastating global impact. Plasmodium vivax is a major cause of human malaria beyond sub-Saharan Africa. Relapsing infections, driven by a reservoir of liver-stage parasites known as hypnozoites, present unique challenges for the control of P. vivax malaria. Following indeterminate dormancy periods, hypnozoites may activate to trigger relapses. Clearance of the hypnozoite reservoir through drug treatment (radical cure) has been proposed as a potential tool for the elimination of P. vivax malaria. Here, we introduce a stochastic, within-host model to jointly characterise hypnozoite and infection dynamics for an in idual in a general transmission setting, allowing for radical cure. We begin by extending an existing activation-clearance model for a single hypnozoite, adapted to both short- and long-latency strains, to include drug treatment. We then embed this activation-clearance model in an epidemiological framework accounting for repeated mosquito inoculation and the administration of radical cure. By constructing an open network of infinite server queues, we derive analytic expressions for several quantities of epidemiological significance, including the size of the hypnozoite reservoir the relapse rate the relative contribution of relapses to the infection burden the distribution of multiple infections the cumulative number of recurrences over time, and the time to first recurrence following drug treatment. We derive from first principles the functional dependence between within-host and transmission parameters and patterns of blood- and liver-stage infection, whilst allowing for treatment under a mass drug administration regime. To yield population-level insights, our analytic within-host distributions can be embedded in multiscale models. Our work thus contributes to the epidemiological understanding of the effects of radical cure on P. vivax malaria.
Publisher: Springer Science and Business Media LLC
Date: 28-04-2022
Publisher: Elsevier BV
Date: 07-2022
Publisher: Springer Science and Business Media LLC
Date: 28-07-2023
DOI: 10.1038/S41467-023-40204-1
Abstract: Multiple monoclonal antibodies have been shown to be effective for both prophylaxis and therapy for SARS-CoV-2 infection. Here we aggregate data from randomized controlled trials assessing the use of monoclonal antibodies (mAb) in preventing symptomatic SARS-CoV-2 infection. We use data on the in vivo concentration of mAb and the associated protection from COVID-19 over time to model the dose-response relationship of mAb for prophylaxis. We estimate that 50% protection from COVID-19 is achieved with a mAb concentration of 96-fold of the in vitro IC50 (95% CI: 32—285). This relationship provides a tool for predicting the prophylactic efficacy of new mAb and against SARS-CoV-2 variants. Finally, we compare the relationship between neutralization titer and protection from COVID-19 after either mAb treatment or vaccination. We find no significant difference between the 50% protective titer for mAb and vaccination, although s le sizes limited the power to detect a difference.
Publisher: Cold Spring Harbor Laboratory
Date: 20-05-2022
DOI: 10.1101/2022.05.18.22275180
Abstract: A key characteristic of Plasmodium vivax parasites is their ability to adopt a latent liver-stage form called hypnozoites, able to cause relapse of infection months or years after a primary infection. Relapses of infection through hypnozoite activation are a major contributor to blood-stage infections in P vivax endemic regions and are thought to be influenced by factors such as febrile infections, immunity, and transmission intensity. Some of these factors may cause temporary changes in hypnozoite activation over time, leading to ‘temporal heterogeneity’ in reactivation risk. In addition, variation in exposure to infection may be a longer-term characteristic of in iduals that leads to ‘population heterogeneity’ in hypnozoite activation. We analyze data on risk of P vivax in two previously published data sets from Papua New Guinea and the Thailand-Myanmar border region. Modeling different mechanisms of reactivation risk, we find strong evidence for population heterogeneity, with 30% of patients having almost 70% of all P vivax infections. Model fitting and data analysis indicates that in idual variation in relapse risk is a primary source of heterogeneity of P vivax risk of recurrences.
Publisher: Springer Science and Business Media LLC
Date: 25-08-2023
DOI: 10.1038/S41467-023-40974-8
Abstract: We report an analysis of the propensity of the antimalarial agent cabamiquine, a Plasmodium -specific eukaryotic elongation factor 2 inhibitor, to select for resistant Plasmodium falciparum parasites. Through in vitro studies of laboratory strains and clinical isolates, a humanized mouse model, and volunteer infection studies, we identified resistance-associated mutations at 11 amino acid positions. Of these, six (55%) were present in more than one infection model, indicating translatability across models. Mathematical modelling suggested that resistant mutants were likely pre-existent at the time of drug exposure across studies. Here, we estimated a wide range of frequencies of resistant mutants across the different infection models, much of which can be attributed to stochastic differences resulting from experimental design choices. Structural modelling implicates binding of cabamiquine to a shallow mRNA binding site adjacent to two of the most frequently identified resistance mutations.
Publisher: Cold Spring Harbor Laboratory
Date: 28-11-2022
DOI: 10.1101/2022.11.22.22282199
Abstract: Multiple monoclonal antibodies have been shown to be effective for both prophylaxis and therapy for SARS-CoV-2 infection. Here we aggregate data from randomized controlled trials assessing the use of monoclonal antibodies in preventing symptomatic SARS-CoV-2 infection. We use data on changes in the in vivo concentration of monoclonal antibodies, and the associated protection from COVID-19, over time to model the dose-response relationship of monoclonal antibodies for prophylaxis. We estimate that 50% protection from COVID-19 is achieved with a monoclonal antibody concentration of 54-fold of the in vitro IC50 (95% CI: 16 – 183). This relationship provides a quantitative tool allowing prediction of the prophylactic efficacy and duration of protection for new monoclonal antibodies administered at different doses and against different SARS-CoV-2 variants. Finally, we compare the relationship between neutralization titer and protection from COVID-19 after either monoclonal antibody treatment or vaccination. We find no evidence for a difference between the 50% protective titer for monoclonal antibodies and vaccination.
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.JMB.2019.06.027
Abstract: Following ingestion, gastrointestinal pathogens compete against the gastrointestinal microbiota and overcome host immune defenses in order to cause infections. Besides employing direct killing mechanisms, the commensal microbiota occupies metabolic niches to outcompete invading pathogens. Salmonella enterica serovar Typhimurium (S. Typhimurium) uses several strategies to successfully colonize the gut and establish infection, of which an increasing number is based on phenotypic heterogeneity within the S. Typhimurium population. The utilization of myo-inositol (MI) and the production of colicin confer a selective advantage over the microbiota in terms of exploitative and interference competition, respectively. In this review, we summarize the genetic basis underlying bistability of MI catabolism and colicin production. As demonstrated by single-cell analyses, a stochastic switch in the expression of the genes responsible for colicin production and MI degradation constitutes the heterogeneity of the two phenotypes. Both genetic systems are tightly regulated to avoid their expression under non-appropriate conditions and possible detrimental effects on bacterial fitness. Moreover, evolutionary mechanisms underlying formation and stability of these phenotypes in S. Typhimurium are discussed. We propose that both MI catabolism and colicin production create a bet-hedging strategy, which provides an adaptive benefit for S. Typhimurium in the fluctuating environment of the mammalian gut.
Publisher: Cold Spring Harbor Laboratory
Date: 22-03-2022
DOI: 10.1101/2022.03.21.22272672
Abstract: A large number of studies have been carried out involving passive antibody administration for the treatment and prophylaxis of COVID-19 and have shown variable efficacy. However, the determinants of treatment effectiveness have not been identified. Here we aimed to aggregate all available data on randomised controlled trials of passive antibody treatment for COVID-19 to understand how the dose and timing affect treatment outcome. We analysed published studies of passive antibody treatment from inception to 7 January 2022 that were identified after searching various databases such as MEDLINE, Pubmed, ClinicalTrials.gov. We extracted data on treatment, dose, disease stage at treatment, and effectiveness for different clinical outcomes from these studies. To compare administered antibody levels between different treatments, we used data on in vitro neutralisation of pseudovirus to normalise the administered dose of antibody. We used a mixed-effects regression model to understand the relationship between disease stage at treatment and effectiveness. We used a logistic model to analyse the relationship between administered antibody dose (normalised to the mean convalescent titre) and outcome, and to predict efficacy of antibodies against different Omicron subvariants. We found that clinical stage at treatment was highly predictive of the effectiveness of both monoclonal antibodies and convalescent plasma therapy in preventing progression to subsequent stages (p .0001 and p=0.0089, respectively, chi-squared test). We also analysed the dose-response curve for passive antibody treatment of ambulant COVID-19 patients to prevent hospitalisation. Using this quantitative dose-response relationship, we predict that a number of existing monoclonal antibody treatment regimens should maintain clinical effectiveness in infection with currently circulating Omicron variants. Early administration of passive antibody therapy is crucial to achieving high efficacy in preventing clinical progression. A dose-response curve was derived for passive antibody therapy administered to ambulant symptomatic subjects to prevent hospitalisation. For many of the monoclonal antibody regimens analysed, the administered doses are estimated to be between 7 and fold higher than necessary to achieve 90% of the maximal efficacy against the ancestral (Wuhan-like) virus. This suggests that a number of current treatments should maintain high efficacy against Omicron subvariants despite reduction in in vitro neutralisation potency. This work provides a framework for the rational assessment of future passive antibody prophylaxis and treatment strategies for COVID-19. This work is supported by an Australian government Medical Research Future Fund awards GNT2002073 and MRF2005544 (to MPD, SJK), MRF2005760 (to MPD), an NHMRC program grant GNT1149990 (SJK and MPD), and the Victorian Government (SJK). SJK is supported by a NHMRC fellowship. DC, MPD, ZKM and EMW are supported by NHMRC Investigator grants and ZKM and EMW by an NHMRC Synergy grant (1189490). DSK is supported by a University of New South Wales fellowship. KLC is supported by PhD scholarships from Monash University, the Haematology Society of Australia and New Zealand and the Leukaemia Foundation. TT, HW and CB are members of the National COVID-19 Clinical Evidence Taskforce which is funded by the Australian Government Department of Health. We identified randomised controlled trials (RCTs) evaluating the effectiveness of SARS-CoV-2-specific neutralising monoclonal antibodies, hyperimmune immunoglobulin and convalescent plasma in the treatment of participants with a confirmed diagnosis of COVID-19 and in uninfected participants with or without potential exposure to SARS-CoV-2. The RCTs were identified from published searches conducted by the Cochrane Haematology living systematic review teams. A total of 37 randomised controlled trials (RCT) of passive antibody administration for COVID-19 were identified. This included 12 trials on monoclonal antibodies, 21 trials of convalescent plasma treatment, and 4 trials of hyperimmune globulin. These trials involved treatment of in iduals either prophylactically or at different stages of infection including post-exposure prophylaxis, symptomatic infection, and hospitalisation. The level of antibody administered ranged from a 250 ml volume of convalescent plasma through to 8 grams of monoclonal antibodies. Data for analysis was extracted from the original publications including dose and antibody levels of antibody administered, disease stage and timing of administration, primary outcome of study and whether they reported on our prespecified outcomes of interest, which include protection against symptomatic infection, hospitalisation, need for invasive mechanical ventilation (IMV) and death (all-cause mortality at 30 days). Our study included data across all 37 RCTs of passive antibody interventions for COVID-19 and aggregated the studies by the stage of infection at initiation of treatment. We found that prophylactic administration or treatment in earlier stages of infection had significantly higher effectiveness than later treatment. We also estimated the dose-response relationship between administered antibody dose and protection from progression from symptomatic ambulant COVID-19 to hospitalisation. We used this relationship to predict the efficacy of different monoclonal antibody treatment regimes against the Omicron subvariants BA.1, BA.2, and BA.4/5. We also used this dose-response relationship to estimate the maximal efficacy of monoclonal antibody therapy in the context of pre-existing endogenous neutralising antibodies. This work identifies that both prophylactic therapy and treatment in the early stages of symptomatic infection can achieve significant protection from infection or hospitalisation respectively. The dose-response relationship provides a quantitative means to predict the change in efficacy of different monoclonal antibodies against new variants and in semi-immune populations based on in vitro neutralisation data. We predict a number of existing monoclonal antibodies will be effective for preventing severe outcomes when administered early in BA.4/5 infections. It is likely that these therapies will provide little protection in in iduals with high levels of endogenous neutralising antibodies, such as healthy in iduals who have recently received a third dose of an mRNA vaccine.
Publisher: Springer Science and Business Media LLC
Date: 03-02-2023
DOI: 10.1186/S12936-023-04461-1
Abstract: In malaria endemic regions, transmission of Plasmodium falciparum parasites is often seasonal with very low transmission during the dry season and high transmission in the wet season. Parasites survive the dry season within some in iduals who experience prolonged carriage of parasites and are thought to ‘seed’ infection in the next transmission season. Dry season carriers and their role in the subsequent transmission season are characterized using a combination of mathematical simulations and data analysis of previously described data from a longitudinal study in Mali of in iduals aged 3 months–12 years (n = 579). Simulating the life-history of in iduals experiencing repeated exposure to infection predicts that dry season carriage is more likely in the oldest, most exposed and most immune in iduals. This hypothesis is supported by the data from Mali, which shows that carriers are significantly older, experience a higher biting rate at the beginning of the transmission season and develop clinical malaria later than non-carriers. Further, since the most exposed in iduals in a community are most likely to be dry season carriers, this is predicted to enable a more than twofold faster spread of parasites into the mosquito population at the start of the subsequent wet season. Carriage of malaria parasites over the months-long dry season in Mali is most likely in the older, more exposed and more immune children. These children may act as super-spreaders facilitating the fast spread of parasites at the beginning of the next transmission season.
Publisher: American Institute of Mathematical Sciences (AIMS)
Date: 2017
Publisher: Springer Science and Business Media LLC
Date: 06-09-2023
Publisher: Public Library of Science (PLoS)
Date: 19-12-2022
DOI: 10.1371/JOURNAL.PNTD.0010990
Abstract: A key characteristic of Plasmodium vivax parasites is their ability to adopt a latent liver-stage form called hypnozoites, able to cause relapse of infection months or years after a primary infection. Relapses of infection through hypnozoite activation are a major contributor to blood-stage infections in P vivax endemic regions and are thought to be influenced by factors such as febrile infections which may cause temporary changes in hypnozoite activation leading to ‘temporal heterogeneity’ in reactivation risk. In addition, immunity and variation in exposure to infection may be longer-term characteristics of in iduals that lead to ‘population heterogeneity’ in hypnozoite activation. We analyze data on risk of P vivax in two previously published data sets from Papua New Guinea and the Thailand-Myanmar border region. Modeling different mechanisms of reactivation risk, we find strong evidence for population heterogeneity, with 30% of patients having almost 70% of all P vivax infections. Model fitting and data analysis indicates that in idual variation in relapse risk is a primary source of heterogeneity of P vivax risk of recurrences. Trial Registration: ClinicalTrials.gov NCT01640574 , NCT01074905 , NCT02143934 .
Publisher: Cold Spring Harbor Laboratory
Date: 19-06-2023
DOI: 10.1101/2023.06.18.23291566
Abstract: Surrogates of antiviral efficacy are needed for COVID-19. We investigated the relationship between the virological effect of treatment and clinical efficacy as measured by progression to severe disease in unvaccinated outpatients treated for mild to moderate COVID-19. We searched PubMed, Scopus and medRxiv from inception to 27 th September 2022, for randomised controlled trials (RCTs) which tested potential treatments for COVID-19 in non-hospitalized patients. We included studies that reported both clinical and virological outcomes. Clinical outcomes were the rate of disease progression (generally hospitalization or death within 28 days of commencing treatment) and virological outcomes were viral load (viral RNA copies in upper respiratory tract swabs) within the first 7 days of treatment. Studies were excluded if they did not report on the outcome of a primary randomised controlled trial, or if results were reported in a more complete form in another publication. Risk of Bias assessment was performed using the RoB 2.0 tool. We used generalised linear models with random effects to assess the association between outcomes and account for study heterogeneity. We identified 1372 unique studies of which 14 (with a total of 9257 participants) met inclusion criteria. Larger virological treatment effects at both day 3 and day 5 were associated with decreased odds of progression to hospitalisation or death in unvaccinated ambulatory subjects. The odds ratio (OR) for each extra two-fold reduction in viral load in treated compared to control subjects was 0.54 on both days 3 and 5 post treatment (day 3 95% CI 0.38 to 0.74, day 5 95%CI 0.41 to 0.72). There was no relationship between the odds of hospitalisation or death and virological treatment effect at day 7 (OR 0.91, 95%CI 0.74 to 1.13). This review provides evidence that treatment-induced acceleration of viral clearance within the first 5 days after treatment is a surrogate of clinical efficacy to prevent hospitalisation with COVID-19. Limitations included the aggregation of studies with differing designs, and evidence of risk of bias in some virological outcomes. These findings support the use of viral clearance as an early phase clinical trial endpoint of therapeutic efficacy. The authors were supported by the Australian Government Department of Health, Medical Research Future Fund, National Health and Medical Research Council and the University of New South Wales.
Publisher: American Society for Microbiology
Date: 25-08-2020
Abstract: Bacteria are excellent model organisms to study mechanisms of social evolution. The production of public goods, e.g., toxin release by cell lysis in clonal bacterial populations, is a frequently studied ex le of cooperative behavior. Here, we analyze evolutionary stabilization of toxin release by the enteric pathogen Salmonella . The release of colicin Ib (ColIb), which is used by Salmonella to gain an edge against competing microbiota following infection, is coupled to bacterial lysis mediated by temperate phages. Here, we show that phage-dependent lysis and subsequent release of colicin and phage particles occurs only in part of the ColIb-expressing Salmonella population. This phenotypic heterogeneity in lysis, which represents an essential step in the temperate phage life cycle, has evolved as a bet-hedging strategy under fluctuating environments such as the gastrointestinal tract. Our findings suggest that prophages can thereby evolutionarily stabilize costly toxin release in bacterial populations.
No related grants have been discovered for Eva Maria Stadler.