197 research outputs found
Living on Three Time Scales:The Dynamics of Plasma Cell and Antibody Populations Illustrated for Hepatitis A Virus
No full textUnderstanding the mechanisms involved in long-term persistence of humoral immunity after natural infection or vaccination is challenging and crucial for further research in immunology, vaccine development as well as health policy. Long-lived plasma cells, which have recently been shown to reside in survival niches in the bone marrow, are instrumental in the process of immunity induction and persistence. We developed a mathematical model, assuming two antibody-secreting cell subpopulations (short- and long-lived plasma cells), to analyze the antibody kinetics after HAV-vaccination using data from two long-term follow-up studies. Model parameters were estimated through a hierarchical nonlinear mixed-effects model analysis. Long-term individual predictions were derived from the individual empirical parameters and were used to estimate the mean time to immunity waning. We show that three life spans are essential to explain the observed antibody kinetics: that of the antibodies (around one month), the short-lived plasma cells (several months) and the long-lived plasma cells (decades). Although our model is a simplified representation of the actual mechanisms that govern individual immune responses, the level of agreement between long-term individual predictions and observed kinetics is reassuringly close. The quantitative assessment of the time scales over which plasma cells and antibodies live and interact provides a basis for further quantitative research on immunology, with direct consequences for understanding the epidemiology of infectious diseases, and for timing serum sampling in clinical trials of vaccines.</p
Modelling the spread of hepatitis E virus in the pig production sector and evaluating stratégies to mitigate the risk of human exposure
No full textLe virus de l’hépatite E (HEV) est un agent zoonotique dont les porcs représentent le principal réservoir dans les pays industrialisés. Le présent projet de recherche a combiné études épidémiologiques, modélisation mathématique et sciences sociales pour proposer des leviers de réduction du risque d’exposition humaine au HEV par consommation de produits à base de porc. Deux essais expérimentaux et une étude en conditions naturelles ont mis en évidence le rôle majeur des co-infections immunomodulatrices dans la dynamique de l’infection par le HEV chez le porc, ces pathogènes intercurrents conduisant à une infection chronique par le HEV et à un risque augmenté de présence du virus dans le foie, le sang et les muscles des animaux abattus. Le développement d’un modèle intra-élevage, stochastique, individu-centré et multi-pathogènes, a permis de dégager des pistes de maîtrise à la fois zootechniques et sanitaires pour réduire la prévalence du virus en élevage. En complément, la conception d’un modèle inter-troupeaux a rendu possible l’analyse des facteurs de diffusion du virus dans un réseau d’élevages français. L’ensemble de ces mesures de gestion du HEV a été soumis à l’avis des organisations publiques et privées et des acteurs individuels de la filière porcine (éleveurs, conseillers, vétérinaires) par des approches de sciences humaines et sociales. Finalement, ce projet transversal et multi-disciplinaire a permis de définir des axes d’action tangibles et réalisables de gestion du HEV dans la filière porcine tout en apportant des contributions méthodologiques significatives en épidémiologie et en modélisation.Hepatitis E virus (HEV) is a zoonotic pathogen whose main reservoir in industrialised countries is pigs. This research project combined epidemiological studies, mathematical modelling and social sciences to propose levers for reducing the risk of human exposure to HEV through the consumption of pork products. Two experimental trials and one study under natural conditions highlighted the major role of immunomodulating co-infections on the dynamics of HEV infection in pigs, as these intercurrent pathogens led to chronic HEV infection and an increased risk of the virus in the liver, blood and muscles of slaughtered animals. The development of a within-herd, stochastic, individual-based and multi-pathogen model has made it possible to identify both zootechnical and sanitary control measures to reduce the prevalence of the virus on farms. In addition, the design of a between-herd model has enabled to analyse the factors responsible for the spread of the virus in a network of French farms. All these HEV control measures have been submitted for the opinion of public and private organisations and individual players in the pig sector (farmers, farming advisors, veterinarians) through social science approaches. Finally, this transversal and multidisciplinary project made it possible to define tangible and achievable lines of action for the management of HEV in the pig sector while making significant methodological contributions in epidemiology and modelling
Modélisation en épidémiologie vétérinaire: Développements méthodologiques et applications
No full textTransmission dynamics of African swine fever in wild boar populations in South Korea
No full textLa peste porcine africaine (PPA), causée par le virus PPA, est une maladie hémorragique très contagieuse chez les porcs, avec un taux de mortalité proche de 100 %. Depuis sa propagation depuis la Géorgie en 2007, le virus a atteint l'Europe de l'Est, de l'Ouest et l'Asie. La Corée du Sud a signalé son premier cas en 2019 près de la frontière nord-coréenne, suivi de cas chez les sangliers en octobre 2019. Malgré des efforts de contrôle incluant la recherche de carcasses, l'installation de clôtures et la réduction des populations, plus de 4 100 cas de sangliers infectés ont été signalés à travers le pays, menaçant l'industrie porcine.La plupart des études sur la PPA se sont concentrées sur l'Europe, limitant leur applicabilité au contexte coréen et compliquant la mise en œuvre de stratégies de contrôle efficaces. Les données de surveillance des sangliers en Corée offrent une occasion unique d'approfondir notre compréhension de l'épidémiologie de la PPA en Asie et de développer des stratégies de contrôle adaptées.Cette thèse visait à améliorer notre compréhension des dynamiques de la PPA chez les sangliers en Corée du Sud et à fournir des preuves pour des mesures de contrôle optimales. À travers une revue littérature, nous avons synthétisé les connaissances épidémiologiques sur la PPA dans le pays et identifié plusieurs lacunes, notamment dans la compréhension des dynamiques partiellement observées et des mesures de contrôle en lien avec l'écologie des sangliers et la topographie coréenne. Pour combler ces lacunes, nous avons appliqué des outils épidémiologiques quantitatifs basés sur des modèles statistiques et mécanistes à l'épidémie observée en D (2019-2022).La vitesse estimée du front de progression de la PPA variait selon les clusters spatio-temporels identifiés, allant de 0,15 à 0,99 km/semaine, montrant une association positive avec la densité des sangliers. L'efficacité des clôtures était inégale selon les zones. Un modèle mécaniste a montré qu'une cellule infectieuse favorable aux sangliers infecterait une cellule susceptible toutes les 2,38 semaines. Ce modèle a démontré l'association entre la densité des sangliers et la vitesse de propagation, estimant que les cellules favorables aux sangliers étaient cinq fois plus susceptibles et infectieuses que les autres. Environ un quart des cellules infectieuses ont été détectées, le front réel étant estimé 23 km en avance sur le front apparent. Cette disparité spatiale explique l'efficacité inégale des clôtures.Ces résultats éclairent la situation épidémiologique de la PPA en Corée du Sud, soulignant qu'une combinaison complexe de facteurs rend l'épidémie unique. Ces facteurs incluent les introductions virales cachées depuis un pays voisin, les translocations virales longues distances, les clôtures partiellement efficaces, et les montagnes catalysant la propagation de la PPA. Les clôtures étaient efficaces dans les zones où le front progressait lentement en raison de la faible densité des sangliers et où elles étaient largement espacées.À la lumière de ces conclusions, la PPA doit être considérée comme endémique en Corée. Les stratégies de contrôle doivent s'adapter à ce stade en confinant le virus dans les montagnes grâce à l'optimisation de l'environnement et des mesures de contrôle. Les efforts coordonnés doivent être dirigés par les autorités, qui doivent aussi protéger les porcs domestiques, réduisant le fardeau des agriculteurs. La recherche doit se concentrer sur le stade endémique, la dynamique des populations de sangliers et les facteurs de risque changeants. La gestion des maladies doit viser une surveillance optimisée. Alors que les autorités coréennes prévoient de retirer les clôtures, il est crucial d'explorer des stratégies de contrôle alternatives. Une évaluation des risques pour les exploitations agricoles doit être mise en œuvre. Enfin, la recherche doit développer des stratégies de gestion à long terme et des protocoles d'éradication pour la PPA.African swine fever (ASF), caused by the ASF virus, is a highly contagious haemorrhagic fever disease in swine with a case-fatality close to 100%. Since spreading from Georgia in 2007, the virus reached Eastern and Western Europe and further into Asia. South Korea reported its first ASF case in 2019 near North Korean border, followed by wild boar cases reported in October 2019. Despite extensive control efforts, including the active carcass searching, fencing, and depopulation, over 4,100 infected wild boar cases have been reported across the country, threatening the whole pig industry.Most ASF studies have focused on Europe, limiting their applicability to Korea and hindering the implementation of cost-effective control strategies. The ASF data in wild boar populations accumulated in Korea provides a unique setting to deepen our understanding of ASF epidemiology in Asia and an opportunity to develop more effective control strategies in this country.This thesis aimed to enhance our understanding of ASF dynamics in Korean wild boar populations and provide evidence for optimal control measures. Through a scoping review, we synthesized the epidemiological understanding of ASF in the country and identified several knowledge gaps, including understanding of the partially observed disease dynamics, and the implemented control measures related to wild boar ecology and Korean topography. To address some of these gaps, we applied quantitative epidemiological tools, based on statistical and mechanistic modelling, to the observed ASF epidemic in Korea (2019-2022).The estimated velocity of ASF wavefront varied by identified spatiotemporal clusters, ranging from 0.15 to 0.99 km/week, showing a potential positive association with wild boar densities. Fencing effectiveness was spatially heterogenous. A spatially-explicit mechanistic model showed that wild boar-favourable infectious cell would infect a wild boar-favourable susceptible cell every 2.38 week. This model demonstrated the positive association between wild boar density and velocity by estimating that wild boar-favourable cells were five times more susceptible and infectious than wild boar-unfavourable cells. Only about a quarter of infectious cells were eventually detected, resulting that the estimated true wavefront was 23 km ahead of the apparent one. This spatial discrepancy explained the identified spatially-heterogeneous effectiveness of the fences.These results shed new light on the ASF epidemiological situation in South Korea, highlighting that a complex combination of factors characterise the epidemic and make it unique. These factors include the continuous hidden viral introductions from neighbouring country, the occurrence of several long-distance viral translocations, partially-effective fencing strategies, and the presence of mountain ranges acting as catalyst for ASF spread. Fencing was effective in areas where the wavefront progressed slowly due to low wild boar density and where fences were widely spaced.Given these findings, ASF should be considered endemic in South Korea. Control strategies for wild boar need to be updated to endemic stage by containing the virus within mountain ranges through leveraging the environment and control measures. Coordinated efforts for wild boar should be organized and led by authorities, who should take responsibility for protecting domestic pigs, reducing the burden of farmers. Research should focus on better understanding this endemic situation, including wild boar population dynamics and changing risk factors. Research on disease management should shift towards designing surveillance optimized for the endemic stage. As Korean authorities plan to remove fences, it needs to explore alternative control strategies. Farm-level risk assessment of spillover from wild boar should be implemented. Ultimately, research should aim to identify feasible long-term management strategies for successful eradication protocols for ASF
Coupling between agents, environments, and levels of organization in mechanistic models in epidemiology : application to the modelling of infectious diseases in pig farming systems
No full textLa modélisation épidémiologique s’est révélée être un outil essentiel dans la gestion de crises sanitaires. La compréhension, l’anticipation et la maîtrise des maladies sont des enjeux majeurs de santé publique et vétérinaire, et nécessite une représentation détaillée des processus impliqués. L’organisation spatio-temporelle de la population hôte est l’un des facteurs impactant la dynamique d’infection et les mesures de gestion, mais reste néanmoins difficile à représenter de manière explicite dans les modèles épidémiologiques. Les méthodologies informatiques d’intelligence artificielle (systèmes multi-agents) permettent de développer des solutions pour représenter explicitement les systèmes complexes fortement structurés dans les modèles épidémiologiques mécanistes. L’objectif de cette thèse est de proposer une solution générique, flexible et modulaire, basée sur des méthodologies d’intelligence artificielle, pour répondre à ces besoins. Nous avons développé un design pattern organisationnel multi agent multi-niveau pour représenter le couplage entre les agents, les environnements et les niveaux d’organisation. Le pattern a été implémenté dans le framework EMULSION et appliqué pour modéliser, de façon explicite et à une granularité fine, la propagation d’un virus influenza porcin et du virus du syndrome dysgénésique et respiratoire du porc dans des élevages pratiquant une conduite en bande. Ces modèles ont permis de confirmer le rôle déterminant joué par la structure d’élevage et la conduite mise en place, et d’identifier des mécanismes clefs de transmission. Le design pattern et ses applications ouvrent de nouvelles perspectives dans les SMA et en modélisation.Epidemiological modelling has proven to be an essential tool for health crises. Understanding, anticipating and controlling diseases are major public health and veterinary medicine challenges, and need a detailed representation of the processes involved. The spatio-temporal organization of the host population is one of the factors influencing infection dynamics and control measures, but remains difficult to represent explicitly in epidemiological modelling. Artificial intelligence computing methodologies (agent-based system) make it possible to develop solutions for explicitly representing highly structured complex systems in mechanistic epidemiological models. This PhD thesis aims to propose a generic, flexible and modular solution, based on artificial intelligence, to address these challenges. We have developed a multi-level agent-based organizational design pattern for representing the coupling between agents, environments, and organizational levels. The pattern has been implemented into the EMULSION framework and applied to model, explicitly with fine granularity, the spread of a swine influenza virus and of the porcine reproductive and respiratory syndrome virus in farms practising batch management. These models confirmed the significant role played by farm management, and identified the key elements of transmission. The design pattern and its applications open up new perspectives for multi level agent-based systems and modelling
Modélisation de la dynamique d infection par le circovirus porcin de type 2 (PCV-2) dans un élevage de type naisseur-engraisseur
No full textUn modèle stochastique individu-centré représentant la dynamique de population au sein d un élevage de production porcine a été développé, puis couplé avec un modèle épidémiologique spécifique au circovirus porcin de type 2 (PCV-2), agent étiologique de la maladie de l amaigrissement du porcelet (MAP). Un effort particulier a été porté sur l estimation des paramètres du modèle épidémiologique pour laquelle deux essais expérimentaux de transmission du virus ont été mis en place. Le modèle résultant a permis de tester l impact de différentes stratégies de conduite et mesures de prophylaxie sur la dynamique d infection, identifiée comme facteur de risque majeur du développement de la maladie.A stochastic individual-based model has been developed to represent the population dynamics within a pig production herd and coupled with a PCV-2 specific epidemiological model. Two experimental transmission studies were carried out to estimate accurately the main parameters of the epidemiological model. The resulting model has been used to evaluate the influence of husbandry and control measures on PCV-2 within herd infection dynamics, previously identified as a major risk factor for post-weaning multisystemic wasting syndrome.RENNES1-BU Sciences Philo (352382102) / SudocSudocFranceF
Maternally Derived Immunity Extends Swine Influenza A Virus Persistence within Farrow-to-Finish Pig Farms: Insights from a Stochastic Event-Driven Metapopulation Model.
No full textSwine Influenza A Viruses (swIAVs) have been shown to persist in farrow-to-finish pig herds with repeated outbreaks in successive batches, increasing the risk for respiratory disorders in affected animals and being a threat for public health. Although the general routes of swIAV transmission (i.e. direct contact and exposure to aerosols) were clearly identified, the transmission process between batches is still not fully understood. Maternally derived antibodies (MDAs) were stressed as a possible factor favoring within-herd swIAV persistence. However, the relationship between MDAs and the global spread among the different subpopulations in the herds is still lacking. The aim of this study was therefore to understand the mechanisms induced by MDAs in relation with swIAV spread and persistence in farrow-to-finish pig herds. A metapopulation model has been developed representing the population dynamics considering two subpopulations-breeding sows and growing pigs-managed according to batch-rearing system. This model was coupled with a swIAV-specific epidemiological model, accounting for partial passive immunity protection in neonatal piglets and an immunity boost in re-infected animals. Airborne transmission was included by a between-room transmission rate related to the current prevalence of shedding pigs. Maternally derived partial immunity in piglets was found to extend the duration of the epidemics within their batch, allowing for efficient between-batch transmission and resulting in longer swIAV persistence at the herd level. These results should be taken into account in the design of control programmes for the spread and persistence of swIAV in swine herds
Control of endemic swine flu persistence in farrow-to-finish pig farms: a stochastic metapopulation modeling assessment
No full textAbstract Swine influenza viruses (swIAVs) are known to persist endemically in farrow-to-finish pig farms, leading to repeated swine flu outbreaks in successive batches of pigs at a similar age (mostly around 8 weeks of age). This persistence in European swine herds involves swIAVs from European lineages including H1avN1, H1huN2, H3N2, the 2009 H1N1 pandemic virus and their reassortants. The specific population dynamics of farrow-to-finish pig farms, the immune status of the animals at infection-time, the co-circulation of distinct subtypes leading to consecutive or concomitant infections have been evidenced as factors favouring swIAV persistence within herds. We developed a stochastic metapopulation model representing the co-circulation of two distinct swIAVs within a typical farrow-to-finish pig herd to evaluate the risk of reassortant viruses generation due to co-infection events. Control strategies related to herd management and/or vaccination schemes (batch-to-batch or mass vaccination of the sow herd and vaccination of growing pigs) were implemented to assess their relative efficacy regarding viral persistence. The overall probability of a co-infection event for France, possibly leading to reassortment, was evaluated to 16.8%. The export of consecutive piglets batches was identified as the most efficient measure facilitating swIAV infection fade-out. Although some vaccination schemes (batch-to-batch vaccination) had a beneficial effect in breeding sows by reducing the persistence of swIAVs within this subpopulation, none of vaccination strategies achieved swIAVs fade-out within the entire farrow-to-finish pig herd
Organization as a Multi-level Design Pattern for Agent-based Simulation of Complex Systems
No full textInternational audienceThis paper describes a generic design pattern to introduce organizational mechanisms into multi-level agent-based simulation architectures, to help the modelling of highly structured complex systems. This pattern makes it possible to specify how to couple any three levels of agents in a multi-level simulation architecture, through their relationships to environments, taking into account organizational constraints. As a proof of concept, we applied this pattern to the fine-grained modelling of batch management in pig farms, and illustrate how the pattern can be instantiated and composed at several agent levels to accurately handle a complex organization in time and space. We thus demonstrate the benefits of combining organizational concepts and multi-level patterns to represent and simulate complex dynamic systems
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