Les enfants nés prématurément, et plus particulièrement les grands prématurés nés avant<p>31 semaines d’âge gestationnel, sont à haut risque de contracter des infections. La<p>vaccination peut prévenir certaines infections, dont la coqueluche qui est causée par la<p>bactérie Bordetella pertussis (Bp). Cependant, cette maladie infectieuse hautement<p>contagieuse est en recrudescence depuis plusieurs années malgré une bonne couverture<p>vaccinale. La morbidité et surtout la mortalité de la coqueluche affectent plus<p>particulièrement les jeunes enfants, incomplètement ou non encore vaccinés.<p>Il existe deux types de vaccins contre B. pertussis :les vaccins de première génération à<p>cellules entières et les vaccins acellulaires, plus récents. Suite à l’apparition d’effets<p>secondaires causés par le vaccin à cellules entières, les vaccins acellulaires, comprenant<p>seulement un certain nombre d’antigènes purifiés de B. pertussis, sont utilisés en Belgique<p>comme dans de nombreux autres pays industrialisés.<p>L’immunité protectrice contre B. pertussis fait appel tant à l’immunité cellulaire qu‘à<p>l’immunité humorale. De nombreuses études ont démontré une production d’anticorps<p>spécifiques aux antigènes de B. pertussis suite à l’administration des différents types de<p>vaccins. Par contre, peu d’entre elles ont analysé la réponse d’immunité cellulaire spécifique<p>caractérisée, entre autres, par une sécrétion d’Interféron-gamma (IFN-& / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

The adenylate cyclase toxin-hemolysin (CyaA) plays a key role in virulence of the whooping cough agent Bordetella pertussis. It translocates an AC enzyme into cytosol of CD11b+ phagocytes and subverts their bactericidal functions by unregulated conversion of ATP to cAMP. In parallel, CyaA permeabilizes cellular membrane by forming cation-selective pores. The goal of my diploma thesis was an analysis of the mechanism of interaction of the segment linking the invasive adenylate cyclase domain and the RTX hemolysin moiety of CyaA with target membrane. Our data show that the segment linking the AC to the hydrophobic domain of CyaA is directly involved in the interaction of the toxin with the membrane and controls the formation of small cationt-selective pores. Our results generate new knowledge that will be of relevance to the entire field of toxin biology and will enable the design of improved CyaA- based vaccines. Keywords: Bordetella pertussis, adenylate cyclase toxin, membrane translocation, pore- forming activity, black lipid bilayers, liposomes

L'évaluation médico-économique (EME) joue un rôle de plus en plus important dans le développement des recommandations cliniques et les décisions de prix et remboursement des produits de santé, notamment des vaccins. L'EME des vaccins fait l'objet de procédures et de recommandations méthodologiques spécifiques, distinctes des médicaments, dans de nombreux pays. Cette thèse illustre et répertorie les différentes questions méthodologiques concernant l'EME des programmes de vaccination sur la base de six études : estimation de la morbidité, mortalité et coûts liés aux infections à cytomégalovirus chez les receveurs de greffe d'organe solide ; description de l'état de santé subjectif et qualité de vie liée à la santé chez les femmes atteintes de candidose vulvovaginale récurrente (CVVR) ; revue critique des EME de la vaccination de rappel contre la coqueluche ; revue critique des EME de la vaccination contre le rotavirus ; analyse coût-efficacité de la vaccination antigrippale chez les personnes de 50 à 64 ans ; analyse coût-efficacité d'un vaccin antigrippal quadrivalent en Ontario. L'EME des programmes de vaccination nécessite de prédire l'effet d'un vaccin dans la vie réelle à partir d'essais cliniques, ce qui est particulièrement difficile pour plusieurs raisons : l'épidémiologie d'une infection peut varier dans le temps et l'espace, la réduction du risque d'infection après vaccination est différente de celle du risque de maladie, et la vaccination peut conduire à une augmentation ou diminution du risque chez les personnes non-vaccinées. De plus, la mesure et la valorisation des effets sur la qualité de vie soulèvent des questions méthodologiques et requièrent des choix normatifs liés aux faits que de nombreux vaccins ciblent les enfants, et que la réduction du risque peut améliorer la qualité de vie en dehors des périodes de maladie. Nous établissons finalement des recommandations pour les futures EME de programmes de vaccination, concernant la définition des stratégies à comparer, le choix de structure de modèle, l'estimation des paramètres cliniques et épidémiologiques, et la mesure et la valorisation de la qualité de vie et des coûts / Economic evaluation plays an increasingly important role in the development of clinical recommendations and pricing and reimbursement decisions for healthcare interventions, and particularly for vaccination. Specific processes and methodological recommendations have been developed for the economic evaluation of vaccines in many countries. This thesis identifies and illustrates different methodological questions about the economic evaluation of vaccination programs based on six studies: estimation of morbidity, mortality and costs associated with cytomegalovirus infections among receivers of solid organ transplant; description of subjective health state and quality of life among women with recurrent vulvovaginal candidosis; critical review of economic evaluations of pertussis booster vaccination; critical review of economic evaluations of rotavirus vaccination; cost-effectiveness analysis of influenza vaccination for people aged 50 to 64 years; cost-effectiveness analysis of a quadrivalent influenza vaccine in Ontario. The economic evaluation of vaccines requires predicting the effectiveness of vaccination based on clinical trial data, which is particularly difficult for several reasons: the epidemiology of an infection may vary over time and space, the effectiveness against infection may differ from effectiveness against disease, and vaccination may lead to an increase or decrease in the burden of disease among non-vaccinated persons. In addition, the measurement and valuation of effects of vaccination on quality of life raises methodological questions and requires normative choices related to the facts that many vaccines target children and that the reduction in risk may improve quality of life outside illness periods. We finally establish recommendations for future economic evaluations of vaccination programs, related to the definition of vaccination strategies to compare, the choice of model structure, the estimation of clinical and epidemiological parameters, and the measure and valuation of quality of life and costs

Adenylate cyclase (CyaA, ACT) toxin is one of the major virulence factors of Bordetella pertussis. Although CyaA binds to many types of membranes, it is assumed that the integrin CD11b/CD18 is its receptor which is expressed on the surface of myeloid cells. CyaA belongs to the family of RTX toxin-hemolysins. CyaA acts on the host cells by two independent activities. One of them is the conversion of ATP to cyclic AMP, which is catalyzed by adenylate cyclase (AC) domain after its translocation into the cytosol of the host cell, which leads to the entry of calcium cations into the host cell. Translocation is probably initiated by interaction of CyaA monomer with the target membrane. The second activity is the formation of CyaA channel selective for cations, which probably causes colloid osmotic lysis of target cells. The channel forming activity is provided by RTX hemolysin domain which most probably forms oligomers, although it was found that CyaA as a monomer causes leakage of potassium cations from the host cell. It is also not clear whether the oligomerization of CyaA would occur in solution, or after interaction with the host membrane. The aim of this study was to examine the flow of sodium ions on the membrane of murine macrophages J774A.1, which express integrin CD11b/CD18 on their surface....

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Adenylate cyclase toxin (CyaA) produced by the causative agent of whooping cough Bordetella pertussis, is a key virulence factor important for colonization of the host. CyaA targets preferentially myeloid phagocytes expressing CD11b/CD18 integrin. By elevating cytosolic cAMP in the host cells, CyaA interferes with their phagocytic, chemotactic and oxidative burst capacities. Furthermore, CyaA modulates the secretion of cytokines and the maturation state in LPS-stimulated dendritic cells (DC) by affecting the expression of costimulatory molecules. In this study, we investigated the effects of CyaA on the capacity of murine bone-marrow DC to prime CD4+ and CD8+ T cells in response to ovalbumin epitopes delivered by the CyaA-AC- toxoid, as a model antigen. Further, we examined the possible impact of CyaA on the antigen uptake and processing for MHC class I and II-restricted presentation by DC, as we previously observed a decreased T cell stimulatory capacity of CyaA-treated DC in response to soluble ovalbumin. We found out that the high levels of cAMP generated by CyaA in LPS-stimulated DC account for the decreased presentation of ovalbumin epitopes carried by CyaA-AC- toxoid on MHC class I and II molecules, thereby impairing the CD8+ and CD4+ T cell responses. Whereas CyaA did not influence the...

The invention of the vaccine has been one of the greatest public health triumphs of the modern world. Each new vaccine has saved thousands - even millions - of lives worldwide, but this success has been fraught with controversy over the safety and even the effectiveness of vaccines. Vaccines have not always had a spotless safety record, but today’s vaccines are incredibly safe and continue to protect millions of people against diseases that have significantly declined or nearly disappeared from the developing world. It is this very success that has led many people to forget, or never discover, what those diseases are and how destructive they can be. This report tells the story of several families whose lives were deeply affected by vaccine-preventable diseases, accompanied with images that help tell their story. Following these stories is a broader discussion of the issues related to vaccines, the misunderstandings and misinformation that often circulate about them, a brief mention of their safety and efficacy, and a general discussion of many of the diseases they can prevent. / text

The Gram-negative aerobic coccobacillus Bordetella pertussis is one of the few exclusively human pathogens and the main causative agent of the respiratory infectious disease called pertussis, or whooping cough. Despite global vaccination programs, pertussis remains an important public-health burden and still accounts for over 100,000 infant deaths and over a dozen of millions of whooping cough cases every year. Substantial effort is devoted to studies on the mechanisms of action of virulence factors of B. pertussis, but the biology of interactions of B. pertussis with its human host remains largely underexplored. Evolution, genetics and adaptation of B. pertussis to the complex environment of human nasopharynx and the mechanisms enabling B. pertussis to overcome host innate and adaptive mucosal immune defenses, remain poorly understood. In such situations, unbiased exploratory omics approaches represent valuable tools for uncovering of unknown aspects of host-pathogen interactions and open the path to detailed analysis of virulence-underlying processes by mechanistic studies. In this thesis, I am presenting the results of three omics projects on B. pertussis biology that involved high-throughput proteomics. In the inital phosphoprotemics project, we analyzed the kinase signaling pathways hijacked...