Thèse d'exercice : Médecine. Médecine générale : Paris 12 : 2007. / Titre provenant de l'écran-titre. 103 f. ill. Bibliogr. f. 94-103.

Despite the use of measles vaccine for over 30 years, measles continues to occur even in highly vaccinated populations. The goal set by the Pan American Health Organization to eliminate measles from the Americas has not been accomplished yet. Although live-measles attenuated vaccines have dramatically reduced the incidence of measles infection, relatively little is known about the immune response generated by vaccination. The principal objective of the work described in this thesis was to perform detailed analysis of cellular and humoral responses to primary measles vaccination in children from the developed and developing worlds. Studies involving Canadian children ranging in age from 12 months to 15 years of age demonstrated that cellular "memory" for measles antigens (lymphoproliferation) was induced in only 50--60% of vaccinees but that, in some children, this cellular response was more durable than anti measles antibody production. Phenotypic studies in these children demonstrated an evolution of early CD8+ T cell activation with later CD4+ T cell activation over a 5--8 week period after vaccination. Expression of CD30, a putative Th2 marker and the costimulatory molecule CTLA-4 on CD4+ and CD8+ T cells, was associated with a strong humoral response while increased production of IFN-gamma and IL-12 was associated with a strong LP response to vaccination. Similar, though less extensive, studies in Peru revealed that less than 25% of these developing world children mount detectable measles-specific LP responses after vaccination, despite having high antibody titers. Although there are many differences between the two study populations (e.g.: race, age at vaccination, vaccine strain), one especially striking difference was the relative "maturity" of T cells in Peruvian children (CD45RO expression) and the marked degree of PBMC activation at the time of vaccination in this setting.

Thesis (M.S.)--University of Michigan, 1991.

Toxoplasma gondii, protozoaire intracellulaire obligatoire, est l’agent responsable de la toxoplasmose, infection qui revêt un caractère sévère au cours de toxoplasmoses cérébrales ou congénitales en médecines humaine et vétérinaire. Aucun vaccin n’est actuellement disponible ; le développement de stratégies vaccinales efficaces est donc d’actualité. Le potentiel vaccinant de deux protéines de rhoptries de T. gondii, RON4 et ROP18, protéines injectées dans la cellule au site de l’invasion lors de l’étape d’attachement à la cellule, a été évalué dans deux stratégies vaccinales contre la toxoplasmose chronique chez la souris: vaccination ADN par voie intramusculaire et vaccination par voie nasale avec des protéines recombinantes. L’immunisation avec des plasmides optimisés exprimant RON4, la partie N-terminale ou la partie C-terminale de RON4 co-administrés avec un plasmide exprimant l’adjuvant GM-CSF ou l’immunisation par voie nasale avec une protéine recombinante RON4 associée à la toxine cholérique, induit des réponses systémiques humorale et cellulaire (mixte Th1/Th2) mais ne confère pas de protection. Dans nos conditions expérimentales RON4 n’est pas un candidat vaccin potentiel. Des stratégies pour augmenter son immunogénicité par voie nasale et pour orienter la réponse cellulaire vers un profil Th1 pourraient cependant être envisagées. L’immunisation avec des plasmides bicistroniques exprimant à la fois ROP18 sous forme sécrétée et le GM-CSF ou ROP18 cytosolique et le GM-CSF, induit des réponses humorales et cellulaires (Th1) similaires et ne confère pas de protection significative. La co-administration d’un plasmide exprimant l’IL-12 n’augmente pas les réponses immunes avant infection mais a néanmoins contribué à augmenter la réponse cellulaire après infection. L’immunisation par voie nasale avec une protéine recombinante ROP18 associée à la toxine cholérique, induit une réponse systémique humorale (Th1/Th2) et confère une protection significative (réduction de la charge parasitaire de 50%). La co-administration de l’adjuvant poly I:C augmente la réponse cellulaire mais n’a pas d’effet sur la protection. Nos résultats suggèrent que ROP18 est un candidat vaccin potentiel, des stratégies pour améliorer son effet protecteur sont à envisager. / Toxoplasma gondii, an obligate intracellular protozoan, is the etiologic agent of toxoplasmosis. This infection has severe consequences during cerebral or congenital toxoplasmosis both in human and veterinary medicines. No vaccine is currently available, so the design of efficient vaccine strategies is still a topical question. In this study, RON4 and ROP18, two rhoptry proteins of T. gondii which are discharged into the host cell at the invasion site, immediately following intimate contact with the host cell, were evaluated in two vaccine strategies against chronic infection in mice: DNA vaccination by the intramuscular route and recombinant protein vaccination by the nasal route. DNA immunization with optimized plasmids encoding full length RON4, or only the N-terminal, or the C-terminal part of RON4 plus a plasmid encoding the adjuvant GM-CSF or nasal immunization with a recombinant RON4 protein plus cholera toxin induced systemic humoral and cellular responses (mixed Th1/Th2) but failed to confer protection. Strategies intended to enhance the immunogenicity of RON4 by the nasal route and to enhance the Th1 immune response against RON4 could be more effective.DNA immunization with ROP18 expressed as a secreted or a cytosolic form by bicistronic vectors which encode both the antigen and the adjuvant GM-CSF induced similar humoral and cellular (Th1) responses but did not confer significant protection. Co-administration of a plasmid encoding the adjuvant IL-12 did not enhance the immune responses before challenge but was able to prime a cellular immune response that was boosted by the parasite infection. Nasal immunization with a recombinant ROP18 protein plus cholera toxin induced systemic humoral responses (mixed Th1/Th2) and conferred partial protection (50% brain cysts reduction). Co-administration of the adjuvant poly I:C enhanced the cellular response but did not potentiate the protection. Our data suggest that ROP18 is a potential vaccine candidate against toxoplasmosis. Strategies to improve the protective effect of ROP18 should be investigated.

Les anticorps sont des corrélats de protection pour différents vaccins qui sont sur le marché. Une meilleure connaissance des modes d’action des vaccins au cours de la primo-vaccination et des rappels sont nécessaires pour améliorer ceux déjà disponibles et ceux en cours de développement.En développant un pipeline d’analyse des données de cytométrie en masse, nous avons étudié l’hétérogénéité des cellules B de macaques et établi un atlas des cellules B dans diffèrent organes.Nous avons démontré que les cellules B du sang sont enrichies au cours du temps après la primo vaccination et/ou le rappel. Quand nous comparons la réponse humorale de 2 stratégies de vaccination, nous découvrons qu’à différence du rappel précoce (2 semaines après la primo-vaccination), le rappel classique (2 mois après la primo-vaccination) permet le développement des IgA, de la maturation d’affinité, des nAbs, d’ADCC et des cellules B spécifique du vaccin. Ces résultats montrent le rôle principal du décalage entre la primo vaccination et rappel. / The exact immunological event involved in the induction of long-term humoral memory induced by vaccines remain unknown. Antibody and B lymphocyte responses are dynamics and change progressively over time after a first antigen encounter. A second immunization perturbates this continuous evolution and modifies these cells and proteins tremendously. My goal was to characterize in depth vaccine-induced B cell response in the context of prime-boost immunizations because the optimal vaccine schedule is not precise enough and we lack a clear knowledge of the mechanisms behind this assumption. I utilize a model of non-human primates (NHP) immunized with Modified Vaccinia Ankara (MVA). I was interested in different events concerning the humoral immune response induced by MVA and used complementary tools to generate high throughput data, such as mass cytometry, and serology. It was developed tools to study macaque B cells longitudinally, including vaccine-specific B cells, using high-dimensional cytometry data (by developing a mass cytometry Ab panel and analytical tools). I mapped the phenotypic diversity of B cells across relevant tissues (blood, lymph nodes, spleen, and bone marrow), analyzed the Ab and B cell subsets dynamics over time and after one or two immunizations, and compared the Ab response after a short vs. a longer delay between prime and boost. Thus, these data point to a direct role for longer delay between prime and boost that allow better maturation of the humoral immune response, providing insights into how vaccine specific memory B cells may be enhanced to drive affinity maturation in new vaccine approaches.

Mes travaux de thèse ont pour but d’évaluer l’approche « épitope display » pour sa capacité d'induire les réponses cellulaires. Ad à capside modifiée par insertion de différents épitopes T issus de la ovalbumine ont étés produit. Après administration à des souris C57BL/6, j'ai mis en évidence l'induction de la réponse cellulaire dirigée contre les épitope insérés (grâce aux techniques ELISPOT, tétramères, ou bien en quantifiant la production d’IFNg par les splénocytes restimulés in vitro). J’ai démontré que ces réponses sont limités chez des souris préalablement immunisées avec Ad. Des manipulations en course ont pour but de confirmer ces résultats et d'évaluer la cinétique de ces réponses. Mon 2ème objectif est de comprendre les paramètres qui contrôlent l’immunogénicité des Ad présentant des épitopes. Ainsi, j’ai montré que l’ablation des interactions des Ad porteurs d’un épitope issu de l’ovalbumine avec les récepteurs/facteurs (intégrines, facteur X de la coagulation) impliqués dans l’entrée de l’Ad dans les cellules ne modifiait pas leur capacité à induire une réponse humorale contre l’ovalbumine. Ces résultats suggèrent que le processus d’infection virale n’est pas requis pour l’induction d’une réponse humorale par les Ad porteurs d’épitopes. / Recombinant adenoviruses (Ad) have recently been employed for a wide range of vaccination strategies. Unfortunately, highly prevalent pre-existing neutralizing antibodies (Abs), reduce their ability to trigger transgene expression. To avoid the step of gene transfer a new vaccination strategy has been proposed based on the use of Ad displaying epitopes inserted into their capsid proteins. Using an ovalbumin-derived B cell epitope, our group demonstrated that vaccination efficiency depends on both the site of peptide insertion and the host immune status towards Ad (Lanzi et al; 2011). The present work aims at (1) evaluating the potency of Ad displaying T-cell epitopes from ovalbumin to elicit cellular responses and (2) understanding the molecular bases controlling the efficacy of this vaccination strategy. 1) Ad displaying T-cell epitopes from ovalbumin were constructed, produced and characterized in vitro. First in vivo experiments in naive mice showed induction of cellular responses, assessed with techniques like ELISPOT, tetramer staining and in vitro splenocyte restimulation. Subsequent experiments showed that pre-exisitng anti-vector immunity is hampering the potent induction of anti-epitope cellular responses. Current work is aiming at confirming the obtained results as well as at evaluating the kinetics of cellular responses induced upon "epitope display" vaccination. 2)First, the influence of interactions of Ad (displaying OVA peptide) with their natural receptors was investigated. Different detargeted Ads were produced and characterized in vitro. Upon mice immunization these vectors led to unmodified anti-epitope humoral responses, suggesting that their efficacy does not depend on the ability to transduce cells. In parallel we sought to evaluate the impact of innate immunity on the outcome of anti-epitope adaptive immune responses. Upon immunization of WT and MyD88-/- mice with Ad displaying OVA epitope we observed that cellular responses induced in MyD88-/- mice are significantly diminished while humoral responses were not altered. These results remain to be confirmed but question the role of other innate immunity sensors in the immunogenicity of Ad-based vaccines. Altogether, our work is expected to provide the foundations for the development of Ad-based vaccines with minimized side effects and unaltered adjuvant properties.

Bakgrund: Vacciner har under många år varit en av de största bidragande faktorerna till en god folkhälsa. När många invånare vaccinerar sig skyddas fler mot smittsamma virussjukdomar i samhället. En tveksamhet till vacciner finns trots det hos många människor. Syfte: Syftet var att undersöka orsaker till vaccinationstveksamhet hos vuxna. Metod: En allmän litteraturstudie genomfördes för att besvara syftet. Tre databaser användes för informationssökning. Innehållet i artiklarna granskades med stöd av kategorisering av åsikter i en tabell. Resultat: Resultatet för litteraturstudien består av fyra kvantitativa artiklar, fem kvalitativa samt en med mixad metod. Fyra kategorier påvisades: brist på kunskap, oro, rädsla och brist på tillit, brist på stöd och attityder och kulturella aspekter. I resultatet framkom ett flertal anledningar till att individer erhöll en tveksamhet till vaccin däribland bristande kunskap och rädsla. Slutsats: Mer forskning krävs för att identifiera åtgärder som sjuksköterskan kan använda sig av i mötet med patienter som är tveksamma till vaccin. / Background: For many years, vaccines have been one of the major contributing factors to good public health. The fact that many people vaccinate provides protection against several viral diseases in society. Nevertheless, there are many people that have doubts about vaccines. Objective: The aim of the literature study was to investigate the causes of vaccination hesitancy with adults. Methods: A general literature study was conducted to answer the purpose. Three databases where used for information retrieval. The content of the articles was examined with the aid off categorization of opinions in a table. Results: The result of the literature study consists of four quantitative articles, five qualitative articles and one with a mixed method. The content of the articles was reviewed, and four categories were identified: lack of knowledge, concerns, fears and lack of trust, lack of support and attitudes and cultural aspects. In the results, there were a number of reasons why individuals hold a doubt towards vaccine, including lack of knowledge and fear. Conclusion: More research is needed to identify actions that the nurse can use when meeting patients with vaccine hesitancy.

The design and development of “e-Vaccination” applications are not extensively researched within developing economies, in part because of the difficulty in gaining access to government officials and medical experts. Vaccination cards have been used to keep track of minors’ immunisation records in South Africa for over 30 years. The South African government is moving towards the use of electronic systems for the storage of such information. South Africa has a clearly defined electronic health strategy, which is to utilise information and communications technologies in healthcare to inter alia, engage in medical research, promote health education, monitoring of diseases and tracking public health. Supporting this strategy means digitising current paper-based systems. The result would be information that can be stored safely, backed up and analysed more easily than paper-based journals, documents and vaccination cards. The purpose of this research is to develop a better understanding of key stakeholders’ perceptions to the replacement of paper-based vaccination cards with an electronic system. This is important because digital records can be considered as a more effective method of storing vaccination data. This study is quantitative in nature and primary data in the form of Likert scale questionnaires were collected from 118 key stakeholders being nurses, doctors, parents and school administration staff. The Likert scale questionnaire data was analysed using the following statistical techniques: Cronbach Alpha Test, Chi-Square Test, Analysis of Variance Test and Principle Component Analysis. The analysis provided a deeper understanding of the key stakeholder’s perceptions to the use of e-Vaccination applications. e-Vaccination applications are affected by user friendliness of the application, the graphical design of the application, practicality of the application, user experience of the application as well as the usability of the application. The practical implications of this research on e-Vaccination applications is that designers, developers, policymakers and government have a deeper understanding of nurses, doctors, parents and school administration staff perceptions to the use of e-Vaccination. / School of Computing

Vaccinations are among the greatest accomplishments of public health. However, many parents are choosing not to vaccinate. The purpose of this study was to explore the association between social media influence and parents' decisions to vaccinate their children. The health belief model indicates that individuals' likelihood of engaging in a health-related behavior is determined by their perceptions of susceptibility, severity, benefits, and barriers. The research questions addressed whether there is an association between parents' perception of their children's disease susceptibility and their decisions about vaccination, and whether there is an association between exposure to messaging from social media and parents' decision to vaccinate. A quantitative, cross-sectional research design was used. The primary dependent variable was vaccination choices, and the primary independent variable was exposure to information about vaccination through social media. Data were gathered through a questionnaire administered to 269 White parents residing in Illinois with their own children between the ages of 0 and 18 years living with them. Binomial logistic regression showed that there was not a statistically significant relationship between parents' perception of disease susceptibility and vaccination choice or between parents' vaccination choice and exposure to online antivaccine advertisements. These study findings help in defining an overall picture of vaccine hesitancy in the United States. By focusing on the predictors of this behavior, it may be possible to implement interventions to combat the antivaccine movement with the goal of increasing vaccine compliance among parents.

In 1911, the Uruguayan Parliament approved a law of mandatory smallpox vaccination. It was a controversial measure that generated a strong anti-vaccination campaign, led by the naturist movement. Embracing a transcendental understanding of nature, they saw vaccines and surgeries as a threat to the natural balance between body and soul. In this dissertation, I study how Uruguayan naturists positioned themselves as a secular alternative to science that combined reason and spirituality, and I show how they had a documented impact on the local political and scientific culture. By focusing on a country with a distinct anti-clerical tradition, I bring to the fore how apparently contradictory phenomena like secularity and spirituality overlap. The spirituality imbricated in their idea of nature, I conclude, resulted in conservative political gestures, even within progressive movements. Among many other things, they embraced a language of purity and sacredness around the body, both human and animal, that led them to the opposition to vaccinations, surgeries and meat consumption, which they regarded as violent moral transgressions. The influence of naturism in the country has not yet been sufficiently considered, and my research presents a first approach to a central aspect of the intellectual life of the period. Besides being a popular movement, it influenced key political, scientific and cultural figures, who, in turn, shaped laws, scientific policies and the elite’s understanding of science and its possibilities. To demonstrate this, through a cultural studies perspective, and in dialogue with science and technology studies and medical humanities, I do close-readings of an unexplored archive of naturist and theosophist periodicals, pamphlets and books published in the first two decades of the 20th century. I also study more well-known anarchist publications and philosophical works by prestigious medical doctors, such as Mateo Legnani (1884-1964), and Carlos Santín Rossi (1884-1936), both close to naturism, focusing on how they also represent an alternative body of knowledge where scientific thought and spirituality coalesce. I conclude by studying essays by the Spanish-Paraguayan writer Rafael Barrett (1876-1910), who debated with the Uruguayan naturists and wrote illuminating pieces on the issue. To this end, I structure the dissertation in three chapters. In the first one, I discuss the political impact of naturism and argue that the movement’s opposition to the 1911 law of compulsory smallpox vaccination highlighted the Government's tendency to subordinate individual freedoms, a fundamental principle of the newly formed liberal state, to what they saw as the common good, which contradicted the Government’s modernizing discourse and agenda. Moreover, naturists formulated some well-founded systematic critiques of the political values imbricated in academic medicine. By pointing this out, I challenge the opposition between them and university trained physicians, the latter historically represented as defenders of science and reason, and the former as religious fanatics. Indeed, the public health paradigm adopted by medical authorities appealed to nature in a very similar way than naturists did. Several renowned medical doctors, some of them parliamentary representatives, without openly identifying themselves as such made direct references to naturists’ precepts in their books and in public documents, including law bills. The second chapter revolves around the vision of science developed by naturism and its political and epistemological implications; there, I argue that while naturists amplified the metaphysical elements present in the history of medicine, from vitalism to Neo-Hippocratism and romanticism, such spiritual views remained compatible with the anticlericalism that characterized the Uruguayan society. I study two iterations of the movement that represent different understandings of science and that reveal specific political and philosophical tensions present in Uruguayan society. One of them, led by Antonio Valeta (1882-1945), proposed an accessible version of science, highlighting the autonomy of the individual. He appealed to values of freedom and personal effort that were part of the liberal imaginary and came into tension with the centrality of the state and its reformist agenda. The second one was developed by Fernando Carbonell (1880-1947), a member of the Theosophical Society and other esoteric groups. His vision was informed by a sophisticated system of beliefs, composed of mystical and conceptually dense metaphysical, ethical and aesthetic teachings that led to valid epistemological criticisms to the model of laboratory science that was being embraced by the authorities. In the third and final chapter, elaborating on the fact that naturists and other groups across the political spectrum mobilized a secular spirituality inherent to the idea of nature, I posit that this led to conservative political positions, even within progressive movements and individuals that were attracted to naturist precepts. Indeed, naturism explicitly opposed actions that could be considered revolutionary in favor of a gradual evolutionism, appealing to the same principle of non-violence embraced in their vegetarianism. In turn, they elevated the philosophical and metaphysical purity of the defense of the life of all beings above the actual living conditions of people and human suffering, romanticizing poverty and illiteracy as states closer to nature. To conclude, my dissertation brings attention to the diversity of belief systems and values still at stake in the present-day scientific landscape. Current iterations of naturism, as illustrated by the anti-vaccination movement both in Uruguay and internationally, resort to claims and arguments eerily similar to those developed more than 100 years ago in Montevideo and other parts of the world. Now, as they did in the past, activists advocate for individual freedom and against the intervention of foreign substances that alter the natural balance of their bodies. Moreover, within the context of the coronavirus pandemic, scientific discussions are taking over the public sphere in an unprecedented way, echoing past dynamics where public figures denounced scientists as biased and despotic elitists who wanted to subject the people to their arbitrary regulations.