Tesi: "Vaccine" – Grafiati

1

Piquart, François. "Les vaccins recombinants : données actuelles". Paris 5, 1989. http://www.theses.fr/1989PA05P110.

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2

Da, Silva Pissarra Joana. "Development of a multi-epitope peptide vaccine against human leishmaniases". Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTT013/document.

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La leishmaniose est une maladie tropicale négligée à transmission vectorielle qui est endémique dans 98 pays dont les plus pauvres. Vingt espèces de Leishmania sont capables d’établir une infection intracellulaire au sein des macrophages humains, provoquant différentes manifestations cliniques. Le développement d'un vaccin contre les leishmanioses est étayé par des preuves d'immunité naturelle contre l'infection, induite par une réponse à médiation cellulaire de type Th1 dominante associée à la production d'IFN-γ, d'IL-2 et de TNF-α par des cellules T polyfonctionnelles TCD4+ et TCD8+, conduisant à l'activation classique des macrophages entrainant la destruction des parasites. Induire une protection robuste et durable et déterminer les épitopes immunodominants responsables de la protection naturelle représente un véritable défi.Les protéines sécrétées sont des facteurs de virulence jouant un rôle important dans le cycle de vie des leishmanies et sont capables d’induire une protection durable chez le chien, un bon modèle pour l’infection humaine. Notre objectif est de développer, à partir du sécrétome de Leishmania, un vaccin de seconde génération reproductible et facile à produire à bas prix dans les zones d’endémie, avec des rendements de production rendant possible son utilisation à grande échelle.Les sécrétomes des six espèces les plus pathogènes de leishmanie (plus L. tarentolae) ont été analysés et comparées par spectrométrie de masse. Les antigènes candidats ont été recherchés dans l'ensemble des données disponibles (analyses protéomiques, littérature…). 52 antigènes candidats vaccin ont ainsi été sélectionnés, dont 28 avaient déjà été décrits et 24 sont nouveaux et découverts grâce à une approche de vaccinologie réverse.Une analyse de la prédiction de liaison des épitopes in silico HLA-I et –II a été réalisée sur tous les antigènes candidats vaccin, prenant ainsi en compte le polymorphisme HLA de la population mondiale. Pour sélectionner les meilleurs épitopes parmi des milliers d’épitopes potentiels, un script R automatisé a été développé en interne, selon des critères rationnels stricts. Ainsi, 50 épitopes de classe I et 24 épitopes de classe II ont été sélectionnés et synthétisés sous forme de peptides individuels. Des essais de toxicité in vitro ont montré l’absence de toxicité cellulaire de ces peptides.Les individus guéris par chimiothérapie généralement développent des réponses immunitaires protectrices à Leishmania. Des tests de stimulation des PBMC ont donc été réalisés avec des échantillons biologiques provenant de donneurs guéris de Tunisie et la production d'IFN-γ a été évaluée par ELISpot. De plus, il était important d'inclure dans l'étape de validation expérimentale des peptides des échantillons provenant d’individus naïfs, population cible à vacciner avec un vaccin prophylactique. Les résultats montrent que des peptides spécifiques de Leishmania induisent avec succès la production d'IFN-γ par les PBMC totaux provenant de donneurs guéris et par les lymphocytes T spécifiques amplifiés à partir du répertoire naïf.Globalement, la validation expérimentale des peptides réalisée exclusivement sur des échantillons humains nous fournira une base préclinique très solide pour développer un vaccin efficace capable de protéger les populations touchées par ces maladies. Elle constituera un moyen sûr et rentable de mieux sélectionner les candidats retenus pour le vaccin et d'éliminer ceux qui présentent un risque d'échec élevé au tout début du processus de développement du vaccin.Grâce à la combinaison de l'analyse protéomique et d'outils in silico, des candidats peptidiques prometteurs ont été rapidement identifiés pour le développement d'un vaccin. Le « pipeline » de développement préclinique du vaccin proposé fournit une sélection rapide de peptides immunogènes, offrant une approche puissante pour accélérer le déploiement d'un vaccin pan-spécifique efficace contre les leishmanioses
Leishmaniasis is a vector-borne neglected tropical disease endemic to 98 countries worldwide. Twenty Leishmania species are capable of establishing intracellular infection within human macrophages, causing different clinical presentations. Vaccine development against leishmaniases is supported by evidence of natural immunity against infection, mediated by a dominant cellular Th1 response and production of IFN-γ, IL-2 and TNF-α by polyfunctional TCD4+ and TCD8+ cells, ultimately leading to macrophage activation and parasite killing.Excreted-secreted proteins are important virulence factors present throughout Leishmania life stages and are able to induce durable protection in dogs, a good model for human infection. We aim to develop a second generation vaccine from the Leishmania secretome, with the potential for large scale dissemination in a cost-effective, reproducible approach.The secretome of six main pathogenic species (plus L. tarentolae) was analysed by Mass-Spectrometry and conserved candidate antigens were searched in the complete dataset. A total of 52 vaccine antigen candidates were selected, including 28 previously described vaccine candidates, and an additional 24 new candidates discovered through a reverse vaccinology approach.In silico HLA-I and –II epitope binding prediction analysis was performed on all selected vaccine antigens, with world coverage regarding HLA restriction. To select the best epitopes, an automated R script was developed in-house, according to strict rational criteria. From thousands of potential epitopes, the automated script, in combination with optimal IC50, homology to host and solubility properties, allowed us to select 50 class I and 24 class II epitopes, synthesized as individual peptides. In vitro toxicity assays showed these selected peptides are non-toxic to cells.The peptides’ immunogenicity was evaluated using immunoscreening assays with immune cells from human donors, allowing for the validation of in silico epitope predictions and selection, and the assessment of the peptide’s immunogenicity and prophylactic potential. Healed individuals, which had active infection and received treatment, possess Leishmania-specific memory responses and are resistant to reinfection, being considered the gold standard of protective immunity. On the other hand, the naive population is extremely important to include in the experimental validation step since it is the target population to vaccinate with a prophylactic vaccine. Importantly, a minimum specific T-cell precursor frequency is needed to induce long-lasting memory protective responses. Furthermore, there is also a positive correlation between immunodominant epitopes and a high frequency of specific T-cell precursors. Peptides able to induce Th1 and/or cytotoxic immune responses in both background are promising candidates for a vaccine formulation. Altogether,experimental validation exclusively in human samples will provide us a very strong base for a vaccine formulation and allow to accelerate translation to the field.Results show Leishmania-specific peptides successfully induce IFN-γ production by total PBMC from healed donors, and by specific T cells amplified from the naïve repertoire. Preliminary evidence exists for peptides which are immunogenic in both immune backgrounds (eight HLA-class I 9-mer peptides and five class II 15-mer peptides) which are, for now, the most promising candidates to advance for the multi-epitope peptide design.Through the combination of proteomic analysis and in silico tools, promising peptide candidates were swiftly identified and the secretome was further established as an optimal starting point for vaccine development. The proposed vaccine preclinical development pipeline delivered a rapid selection of immunogenic peptides, providing a powerful approach to fast-track the deployment of an effective pan-specific vaccine against Leishmaniases

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3

Gayet, Rémi. "Impact de la réponse IgA dans une nouvelle stratégie de vaccination muqueuse contre Salmonella et dans la régulation de la réponse adaptative". Thesis, Lyon, 2018. http://www.theses.fr/2018LYSES015/document.

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Les entérobactéries Salmonella sont divisées en plusieurs sérovars dont les quatre principaux Typhimurium, Enteritidis, Typhi et Paratyphi sont responsables soit de gastroentérites soit de fièvres typhoïdes, à raison de plus de 90 millions de cas et 400 000 décès par an. L’apparition de souches multi-résistantes nécessite la mise en place d’une vaccination prophylactique muqueuse. L’environnement intestinal est caractérisé par une balance entre tolérance immunitaire et réaction inflammatoire régulée par les immunoglobulines (Ig) A sécrétoires. Les IgA des sécrétions muqueuses sont dimériques, les IgA sériques sont monomérique et deux isotypes ont été décrits chez l’Homme: IgA1 et IgA2. Nous avons tout d’abord exploré les fonctions des différents isotypes et isoformes des IgA humaines. Nous avons pu noter un rôle anti-inflammatoire des IgA1 à l’inverse d’un rôle pro-inflammatoire des IgA2 et nous avons souligné un processus de régulation de l’expression des récepteurs aux IgA par les IgA elles-mêmes ainsi qu’un axe IgA/lymphocytes T CD8 cytotoxiques. Nous avons ensuite mis en place un vaccin multivalent composé des antigènes SseB et OmpC de Salmonella liés à des Ig sécrétoires. Cette étude a mis en évidence une solide réponse immunitaire humorale et cellulaire spécifique aux antigènes couplés à des IgA ou IgM après vaccination intra-nasale au niveau systémique et muqueux. Par ailleurs, de plus fortes réponses humorales et systémiques spécifiques ont été observées en couplant à la fois OmpC et SseB sur l’IgA. Ce travail de thèse ouvre de nouvelles perspectives pour la mise en place de vaccins muqueux multivalents et pourrait apporter des réponses quant au rôle des IgA
The enterobacteria Salmonella species are divided into several serovars such as Typhimurium, Enteritidis, Typhi and Paratyphi which are the major causative agents of either gastroenteritis or typhoid fever. They are responsible for more than 90 million cases and 400 000 deaths each year. The increase in multi-drug resistant strains requires the implementation of prophylactic mucosal vaccines. Besides, the intestinal environment is characterized by a balance between immune tolerance and inflammatory response tightly regulated by secretory immunoglobulins (Ig) A. Mucosal IgA are mainly dimeric, serum IgA monomeric and two IgA isotypes have been described in humans: IgA1 and IgA2. We firstly explored the functions of the different isotypes and isoforms of human IgA. We pointed out a pro-inflammatory role of IgA2 whereas IgA1 rather oriented the immunity towards an anti-inflammatory response. We have also highlighted both the regulation of IgA receptors expression by IgA and an IgA/CD8 cytotoxic T cells axis. We also designed a multivalent vaccine against Salmonella by coupling two antigens – SseB and OmpC – to secretory Ig. We pointed out solid specific humoral and cellular responses against both these antigens coupled to either IgA or IgM after intra-nasal immunization in mucosal but also systemic compartments. We have also demonstrated the possibility to preserve and increase the antigen immunogenicity with a multivalent vaccine. This thesis thus paves the way for new secretory Ig-vectorized mucosal vaccines. In addition, the immune response could be modulated through the chosen isotype or isoform and the differences in immune activation generated by structural changes in IgA could shed some light on their role in mucosal homeostasis

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4

Grubb, Kimberley L. "A genomic approach to the identification of novel malaria vaccine antigens /". Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=98715.

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As the number of drug-resistant malaria parasites continues to grow, pressure is increasing to find an effective, cross-protective, multi-valent malaria vaccine (32). Expression library immunisation is an un-biased screening technique that leads to the identification of novel, protective antigens that can be administered as components of a multivalent DNA vaccine (9, 50, 75, 86, 92). Here, a P. c. adami DS expression library has been evaluated as a malaria vaccine in mice, and several subpools of cross-protective plasmids have been identified. Upon vaccination with these plasmid subpools, mice demonstrate significantly lower mean cumulative parasitemia values than control vaccinated mice, when challenged with avirulent heterologous P. c. adami DK parasites. These cross-protective responses correlate with the induction of opsonizing antibodies against infected red blood cells and the production of IFN-gamma by T-cells. The determination of P. c. adami antigens capable of inducing strain-transcending immunity implies the identification of orthologues in the P. falciparum genome that may be applied as components of a human malaria vaccine.

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5

Atcheson, Erwan. "Prospects for enhancing malaria vaccine efficacy by combining pre-erythrocytic antigens". Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:6506c003-7065-4d48-b049-f5e9136443d5.

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Malaria causes almost half a million deaths each year. Existing interventions will almost certainly not be enough to tackle this enormous public health problem on their own. An effective vaccine is urgently needed. The leading malaria vaccine, RTS,S, confers suboptimal protective efficacy, and in addition targets only Plasmodium falciparum and not the other major species of human malaria, P. vivax. This thesis investigates the potential of combining pre-erythrocytic malaria vaccines as a means of enhancing protective efficacy. A novel mathematical model was developed which expresses probability of protection as a function of vaccine-induced humoural and cellular responses. The model predicts that combining partially effective vaccines should result in more than additive improvements in protective efficacy. This was supported by an experiment combining Rv21, a P. vivax circumsporozoite virus-like particle, with viral vectored P. vivax TRAP, the two leading pre-erythrocytic malaria vaccine antigens; this combination raised protective efficacy from 50% and 0%, respectively, to 100% sterile protection. It was also found that antigenic interference, a reduction in anti-CSP titres when Rv21 and PvTRAP are combined, occurred only in the presence of Matrix M adjuvant, and not when using alum, AddaVax or no adjuvant. With a view to creating a single-component multi-antigen vaccine, which would be more cost-effective than a multi-component vaccine, experiments were carried out to establish the virus-like particle Qβ as a platform capable of eliciting protective immunity via the display of short peptides derived from the CSP repeat region of both P. vivax and P. falciparum. For the first time, a tetramer peptide derived from the CSP repeat region of P. vivax VK210, AGDR, was shown capable of eliciting protective immunity alone. Finally, five novel linear B-cell epitopes were discovered, one from P. falciparum CSP, three from P. vivax TRAP and one from TRSP, each capable of conferring partial protection on mice. These epitopes were identified using novel screening methods, using sera from whole-protein vaccinated mice or by exploiting conservation within invasion protein sequences. Two of the protective epitopes, (NANP)6 and (ADGN long) were combined and found to enhance protective efficacy as predicted by the mathematical model. Thus this thesis lays the groundwork for the development of a single-component multi-epitope malaria vaccine with enhanced protective efficacy.

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6

Zaza, Amélie. "Développement de nouvelles approches thérapeutiques dans la lutte contre les infections à arénavius : vaccination et immunothérapie passive". Thesis, Lyon, 2018. http://www.theses.fr/2018LYSE1013.

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La famille des Arenaviridae comporte sept virus responsables de fièvres hémorragiques humaines. Ces virus représentent un risque naturel pour les populations vivant dans les zones endémiques, ou y séjournant comme les militaires français déployés. Ce risque peut également toucher des populations vivant en dehors des zones endémiques en raison du risque d'importation d'un patient infecté ou consécutivement à l'utilisation intentionnelle et malveillante de tels virus dans le cadre d'une attaque bioterroriste. Les fièvres hémorragiques humaines causées par les arénavirus sont relativement rares et les premiers symptômes, non spécifiques, sont souvent confondus avec ceux de maladies plus fréquentes dans ces régions, comme le paludisme ou les arboviroses. Par conséquent, le diagnostic clinique est souvent retardé, ce qui réduit l'efficacité du seul traitement étiologique actuellement préconisé, la ribavirine. Dans ce contexte, le développement de solutions prophylactiques similaires au vaccin Candid #1, protégeant contre l'arénavirus Junin, constituent une alternative intéressante. Dans le cadre du développement de candidats vaccins, la première stratégie utilisée dans ce travail a consisté à atténuer la pathogénicité du virus d'intérêt en ciblant une étape clé de la réplication des arénavirus. Nous avons choisi l'étape du bourgeonnement viral, dont l'acteur principal est la protéine Z. Une preuve de concept a été réalisée avec le virus de la chorioméningite lymphocytaire (LCMV). Pour cela, nous avons conçu un système de génétique inverse qui exprime un segment L viral où le gène de la protéine Z est remplacé par un gène d'intérêt. De manière surprenante, ce virus recombinant était capable de produire en culture cellulaire une progénie à un titre très faible sans l'apport en trans de la protéine Z. Nous avons identifié des domaines tardifs dans la séquence peptidique de la nucléoprotéine, motifs peptidiques permettant le détournement de la machinerie cellulaire impliquée dans la production d'exosomes et présents dans les protéines de matrices virales, comme la protéine Z des arénavirus. Nous avons observé que ces domaines pourraient partiellement compenser l'absence de la protéine Z. Des résultats similaires ont été obtenus avec deux autres arénavirus ayant une importance majeure en santé publique, les virus Lassa et Machupo, tous deux responsables de fièvres hémorragiques humaines. Cette suppression pourrait constituer une stratégie d'atténuation et semblerait prometteuse en vue du développement de candidats vaccins réplicatifs atténués. En effet, elle pourrait être utilisée sur plusieurs arénavirus responsables de pathologies humaines. Une approche complémentaire à cette stratégie vaccinale a été envisagée. Dans le but de développer un traitement d'urgence, utilisant des immunoglobulines équines hautement purifiées, les F(ab')2, selon la méthodologie de la société Fab'entech, deux études préliminaires ont été réalisées. La première a permis de vérifier la capcité des virus à se répliquer dans les cellules immunitaires circulantes de cheval. La seconde a permis l'évaluation du cahier des charges qualité de particules virales en vue de leur utilisation comme source d'antigène afin de produire les F(ab')2. Une seconde stratégie vaccinale a été envisagée, basée sur une modification du nombre de segments génomiques viraux. Des travaux précédents ont montré qu'un arénavirus à 3 segments, au lieu de 2, était viable et atténué, tout en pouvant exprimer 2 gènes d'intérêt supplémentaires. Cette stratégie a été utilisée sur le virus Machupo, responsable de fièvres hémorragiques en Bolivie. Ce virus recombinant devrait exprimer les glycoprotéiques tronquées des virus Chapare et Guanarito. Ce candidat vaccin a été caractérisé en culture cellulaire, et a induit une protection de 50% des animaux lors d'une administration en post-exposition [etc...]
The Arenaviridae family comprises seven viruses responsible for human hemorrhagic fevers. These viruses represent a natural threat to the local populations, healthcare workers and scientists, as well as to the French forces deployed in the regions where these viruses are endemic. This viral threat can also be intentional in case of a bioterrorist attack. Human hemorrhagic fevers caused by arenaviruses are relatively rare and the first symptoms, frequently non-specific, are often confused with more common diseases such as malaria. Therefore, their diagnosis is delayed, which reduces the efficacy of ribavirin, the only etiological treatment currently recommended. ln this context, the development of prophylactic treatments, such as the Candid #1 vaccine targeting the Junin arenavirus, are an interesting alternative. The first strategy developed in this work to produce a vaccine candidate relied on the attenuation of the virus of interest by targeting a key stage of its replication. We chose the egress step, in which the main actor is the Z protein. This work was conducted using the lymphocytic choriomeningitis virus (LCMV). We therefore designed a reverse genetic system, and replaced the Z gene by the fluorescent protein eGFP reporter gene. Surprisingly, during its cellular infection, a progeny was detected in absence of the Z protein trans-complementation although the titer remained very low. ln this infectious model, we further identified late motifs in the nucleoprotein genome, comparable to those known in the Z protein. These NP late motifs seemed to play an essential role in the compensation of the absence of the Z protein. Similar results were observed using two others arenaviruses of medical importance, the Lassa and Machupo viruses, responsible of human hemorrhagic fevers. The strong diminution of the resulting vaccine candidate replication suggests that this strategy would render safe enough BSL-4 viruses to be used as a multivalent vaccine platform in humans. A complementary approach has been studied in this work. ln order to develop an emergency treatment, based on the production of highly purified F(ab')2 equine immunoglobulins, according to the Fab'entech technology. Two preliminary studies were carried out. The first one consisted in the study of the replication of arenaviruses in circulating horse's white blood cells. The second tested the specifications of attenuated viral particles that could be used as an antigen source to produce the F(ab')2 under good manufacturing practices. Another vaccine strategy was developed using the previously described duplication of the LCMV S genomic small segment in order to produce a tri-segmented recombinant virus. This genetic modification, known to attenuate the LCMV virus pathogenicity, allows the expression of two genes of interest. This strategy has been applied onto the South American Machupo virus, responsible for hemorrhagic fevers in Bolivia. A recombinant Machupo virus was designed to express the truncated glycoproteins of the Chapare and Guanarito viruses, two other New World mammarenaviruses responsible of human hemorrhagic fevers. This vaccine candidate was characterized in cell culture, and showed a 50% post-exposure protective effect in the animal model used. Taken together this work led to the development of two vaccine strategies and to the identification of a promising source of antigens to be used to produce highly purified F(ab')2 polyclonal immunoglobulin, which is the first step to the development of an emergency treatment

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7

Pifferi, Carlo. "Design and synthesis of multivalent glycoconjugates for anti-cancer immunotherapy". Thesis, Université Grenoble Alpes (ComUE), 2017. http://www.theses.fr/2017GREAV060/document.

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Le cancer est l’une des principales causes de mort dans le pays développés ; bien que les opérations chirurgicales, la radiothérapie et la chimiothérapie représentent aujourd’hui les principales options de traitement des patients souffrants de tumeurs malignes, leurs effets secondaires sévères ont ouvert la voie au développement de l’immunothérapie antitumorale. A part l’immunothérapie passive, qui est basée sur les anticorps ou tout autre composant du système immunitaire synthétisés en dehors du corps dont la potentielle menace de réactions immunes a été prouvée, nous avons concentré nos efforts sur l’immunothérapie active, qui réside dans la stimulation du système immunitaire du patient pour éradiquer sélectivement les cellules malignes. L’identification d’antigènes carbohydrates associés aux tumeurs (TACAs), surexprimés à la surface des cellules cancéreuses, a permis le développement de vaccins spécifiques à cet antigène. Il est connu depuis plus de 40 ans que la majorité des cancers chez l’homme sont caractérisés par une glycosylation aberrante. Les cellules tumorales peuvent surexprimer des versions tronquées d’oligosaccharides, une séquence terminale inhabituelle ou une augmentation de la sialylation des glycolipides et des glycoprotéines de surface. Un oligosaccharide d’une glycoprotéine tronqué peut rendre une partie de la chaîne principale du peptide, d’habitude caché par le sucre, plus accessible au système immunitaire. Parmi les différents TACAs, nous avons concentré notre attention sur les antigènes Tn et Tf, qui peuvent être trouvés sur des glycoprotéines comme MUC-1, surexprimés sur plus de 90% des carcinomes du sein. Bien que la conception de ces immunomodulateurs repose toujours sur des règles empiriques, il est important de déclencher à la fois la réponse humorale et cellulaire, ainsi qu’un effet de mémoire. Ce défi peut être relevé en combinant, sur une seule molécule, l’antigène carbohydrate exprimés à la surface des tumeurs (épitope des cellules B), les peptides capables de stimuler les cellules CD4+ et CD8+ (épitopes des cellules T) et un adjuvant, pour recueillir tous les éléments du système immunitaire au niveau du site d’injection et renforcer l’absorption des antigènes. De précédentes études faites dans notre groupe de recherche ont publié pour la première fois la synthèse et l’évaluation immunologique d’un prototype de vaccin anticancéreux à quatre composant capable d’induire une réponse immunitaire de longue durée sur des modèles murins. Dans mon travail de thèse, nous avons voulu synthétiser des prototypes de vaccin anticancéreux basés sur les TACAs avec des propriétés immunologiques accrues. Notre stratégie de conception a été guidée par (i) l’importance d’une haute densité de carbohydrates pour promouvoir une capture d’antigène plus efficace et un traitement par les cellules présentatrices d’antigène, et (ii) l’expression hétérogène des TACAs au cours de la maladie et parmi différents patients. En respectant ces deux aspects, il sera possible de déclencher une réponse immunitaire plus forte et à plusieurs facettes
Cancer is one on the leading causes of death in developed countries; although surgical resection, direct irradiation and cytotoxic chemotherapy represent nowadays the main treatment options for patients suffering with malignancies, their severe side effects paved the way for the rise in popularity of antitumoral immunotherapy. Apart from passive immunotherapy, which is comprised of antibodies or other immune system components that are made outside of the body and has been shown to be associated to potentially life threatening immune reactions, we focused our efforts towards active immunotherapy, which purpose is stimulate the patient immune system to selectively eradicate malignant cells. The identification of tumor-associated carbohydrate antigens (TACAs) on the surface of cancer cells has allowed the development of antigen-specific vaccines. It has been known for over four decades that the majority of human cancers are characterized by aberrant glycosylation. Tumor cells may over-express truncated versions of oligosaccharides, unusual terminal oligosaccharide sequences, or increase sialylation of cell-surface glycolipids and O- and N-linked glycoproteins. A truncated oligosaccharide of a glycoprotein may render a part of the peptide backbone, which is normally shielded by the glycan, more accessible to the immune system. Among the assortment of TACAs we focussed our attention on Tn and TF-antigens, which can be found in membrane-bound glycoproteins like MUC-1, over-expressed in more than 90% of breast carcinomas. Although the design of such immuno-modulators still relies on empiric rules, it is noteworthy important to trigger both humoral and cellular responses, and a memory effect. This challenge can be achieved by combining, within a single molecule, carbohydrate antigen expressed on the surface of tumors (B-cell epitope), peptides capable to stimulate both CD4+ and CD8+ T-cells (T-cell epitopes) and an adjuvant, to gather immune system elements in the injection site and boost the antigen uptake. Previous studies of our research group reported for the first time the synthesis and immunological evaluation of a four-component anticancer vaccine prototype capable of inducing a long-lasting immune response in mice models. In my PhD work we aimed to synthesize TACA-based anticancer vaccine prototypes with improved immunological properties. The principles which guided our design strategies rely on (i) the importance of a high density of carbohydrate epitopes to promote a more effective antigen capture and processing by antigen-presenting cells, and (ii) the evidence of heterogenic expression patterns of TACAs during the course of the disease and among different individuals. Addressing these two aspects would provide a stronger and multifaceted immune response

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8

Dunachie, Susanna Jane. "Malaria vaccines and microarrays : clinical and laboratory evaluation of two vaccine regimens". Thesis, Open University, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.446277.

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9

BOEHNER, CONSTANCE WILLIAMS. "FACTORS AFFECTING STD VACCINE ACCEPTANCE IN COLLEGE STUDENTS". University of Cincinnati / OhioLINK, 2002. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1014411621.

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10

Hughson, M. D. "Micro-scale vaccine bioprocessing of a Japanese Encephalitis Virus vaccine". Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1427445/.

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Japanese Encephalitis (JE) is the most common form of viral encephalitis in the world, caused by the Japanese Encephalitis virus (JEV), it is responsible for around 10,000 deaths a year whilst many more are left with long term neurological sequelae and disability. This work sought to use small-scale development techniques alongside high-throughput methodologies to explore and develop selected processing techniques. Formaldehyde inactivation of JEV was characterised and optimised through the use of Design of Experiments screening techniques where temperature, time and formaldehyde concentration were found to be key factors in antigen loss. Glycine and to a lesser extent sorbitol were found to have positive effects as stabilisers during inactivation at different stages of the process. Four anion exchange resins were screened at micro-scale, with the help of an ELISA method evaluated for high-throughput screening, for their potential to replace sucrose gradient purification as the principle purification step of the process. Although Q Sepharose FF was eventually chosen for scale-up studies, the transition of method and recovery rates from batch bind micro-plate studies to 1 mL column scale proved difficult. Yet it was observed that pre-treatment of feed with formaldehyde and glycine could increase JEV antigen recovery rates in flow-through mode chromatography, thought to be due to enhanced stability of the virus particles.

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11

Khan, Tila. "Tailored influenza virus vaccines for both the young and old: Vaccine Efficacy of Whole Inactivated Vaccines bearing Immunomodulatory Adjuvants or Multimeric peptides". Diss., Virginia Tech, 2012. http://hdl.handle.net/10919/77130.

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Influenza epidemics and pandemics remain a significant burden to world health and economy. Low efficacy of current inactivated influenza vaccines in the elderly and immunocompromized and the inability to protect against antigenically drifted or shifted strains of influenza virus are the two major problems in influenza vaccine research. To overcome these hurdles, we have utilized an in vitro cell culture vaccine platform, which results in whole inactivated influenza vaccine (WIV) bearing bioactive membrane-anchored immunomodulatory proteins such as cytokines on the virion surface, collectively known as CYT-IVACs (Cytokine bearing-Inactivated Vaccine). In addition, we tested whether a multimeric M2e peptide presented on WIV can serve to enhance immunogenicity and augment protective efficacy of whole virus vaccines. Our panel of cytokines includes IL-2, IL-4, IL-12, IL-23, and Flt3L as well as the multimeric M2e peptide, all fused to the membrane anchoring regions of influenza virus hemagglutinin protein and constitutively expressed in virus permissive MDCK cell line. Subsequent infection with influenza virus results in incorporation of fusion constructs directly into budding progeny virions that are harvested, purified and inactivated to generate distinct CYT-IVAC formulations. Following validation of immunomodulator incorporation, vaccines were tested for in vivo efficacy in either "young adult" or "aged" female Balb/c mice. Our results demonstrate that our CYT-IVAC~IL-12/HA and CYT-IVAC~IL-23/HA serve as potent mucosal adjuvants in young adult mice elicited significantly high levels of mucosal IgA antibodies and afford superior protection against lethal virus challenge. Our Flt3L/HA formulation was the most effective stimulator of systemic anti-viral antibody levels. In "aged" mice a single dose formulation of IL-12 bearing CYTIVAC was superior at affording protection against lethal homotypic virus challenge. Finally, administration of multimeric M2e molecule co-presented on WIV elicited prolonged antibody responses in "young adult mice" and provided cross-protection from challenge with the heterologous influenza A pandemic strain 2009 H1N1. In conclusion, the CYT-IVAC approach represents a novel tailored advancement to current WIV approaches that has the potential to elicit both potent mucosal and systemic immune responses in young and old.
Ph. D.

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12

Blignaut, Belinda. "Improved vaccines for foot-and-mouth disease control : evaluation of a chimera-derived FMD vaccine in relation to a current SAT type vaccine". Thesis, University of Pretoria, 2012. http://hdl.handle.net/2263/30806.

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Foot-and-mouth disease virus (FMDV), a member of the Picornaviridae, causes a highly contagious disease that affects cloven-hoofed animals and leads to production losses, especially in intensive farming systems. In sub-Saharan Africa, control of the disease is complicated by the extensive variability of the South African Territories (SAT) type viruses, which exist as distinct genetic and antigenic variants in different geographical regions. Improved control of FMD, therefore, requires vaccines to be custom-made to specific geographical areas. In this regard, a potentially powerful approach involves the engineering of chimeric FMDV of which the antigenic properties can be readily manipulated. Consequently, the aim of this study was essentially to evaluate a custom-engineered chimeric FMD vaccine in relation to a current SAT type vaccine. To enable the selection of vaccine strains that would provide the best vaccine match against emerging viruses, phylogenetic, genetic and antigenic analyses of SAT serotypes prevalent in sub-Saharan Africa was performed. The results indicated that although SAT1 and SAT2 viruses displayed similar genetic variation within each serotype, antigenic disparity, as measured by r1-values, was less pronounced for SAT1 viruses compared with SAT2 viruses. Consequently, the SAT1 virus KNP/196/91 was selected and a cross-serotype chimeric virus, vKNP/SAT2, was engineered by replacing the external capsid-encoding region (1B-1D/2A) of an infectious cDNA clone of the SAT2 vaccine strain, ZIM/7/83, with that of KNP/196/91. The population diversity of the cell-adapted chimeric virus and pig-adapted KNP/196/91 virus was investigated by means of pyrosequencing; the results of which indicated that the population diversity of the respective viruses was indeed comparable to each other. Subsequently, chemically inactivated vaccines were produced from intact 146S virion particles of both the chimeric and parental viruses and evaluated in a full potency test. Pigs vaccinated with the chimeric vaccine produced neutralising antibodies and showed protection against homologous FMDV challenge. Cumulatively, the data provide support that chimeric vaccines containing the external capsid of field isolates can be successfully produced and that they induce protective immune responses in FMD host species. The potential therefore exists to generate more effective newgeneration chemically inactivated-FMD vaccines that are custom-engineered and specifically produced for geographical areas.
Thesis (PhD)--University of Pretoria, 2012.
Microbiology and Plant Pathology
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Genard, Romain. "Rôle du facteur de transcription Nrf2 dans l'immunomodulation induit par les adjuvants vaccinaux". Thesis, Université Paris-Saclay (ComUE), 2015. http://www.theses.fr/2015SACLS230/document.

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Les adjuvants vaccinaux permettent d’augmenter la réponse immunitaire dirigée contre un antigène donné. Certains de ces adjuvants miment des signaux de danger, tels que des agonistes des récepteurs de l’immunité, les récepteurs Toll-like (TLR) ou les récepteurs NOD-like (NLR), et permettent une activation des cellules dendritiques (DC). Les DC sont essentielles dans la mise en place d’une réponse adaptative contre un antigène : elles acquièrent un phénotype mature, contrôlé par les voies des MAPK et NF-κB, permettant la présentation de l’antigène aux lymphocyte T et l’initiation d’une réponse spécifique. La voie Nrf2/Keap1, impliquée principalement dans la détoxication des xénobiotiques et le contrôle du stress oxydant, peut être activée en réponse à des agonistes des TLR tels que le LPS (agoniste TLR 4). Nous avons mis en évidence qu’un traitement par le R848 (agoniste TLR7/8) ou le MDP (agoniste NOD2) induit la transcription des gènes cibles de Nrf2 dans les DC murines. Nrf2 participe également à la production de cytokines inflammatoires en réponse au LPS et au R848 et jouet un rôle dans la prolifération lymphocytaire induite par les DC pré-traitées avec le MDP. Par ailleurs, Nrf2 contrôle la réponse anticorps spécifiques de l’antigène chez la souris. L’injection d’anatoxine tétanique induit une production d’anticorps plus élevé chez la souris déficiente nrf2 par rapport aux souris sauvages. Cette augmentation de la production d’anticorps est corrélée avec une augmentation du nombre de lymphocyte B dans la moelle osseuse et la rate
Vaccine adjuvants are able to boost immune response toward antigens when there are simultaneously injected. Some of these adjuvant mimic danger signals, such as Toll like receptors (TLR) agonists or NOD-like receptors agonists, required for dendritic cell (DC) activation. DC are essentiales for adaptative immune response against antigens : they acquire mature phenotype, controlled by MAPK and NF-kB signaling pathway, leading to antigen presentation and specific immune response. The Nrf2/keap1 signaling pathway, mainly involves in xenobiotics detoxication and oxidative stress control, can be activate by TLR agonists, such as LPS (TLR 4 agonist).We showed that R848 (TLR 7/8 agonist) and MDP (NOD2 agonist) could induce Nrf2’s target genes transcription in murines dendritic cells (BMDC). Nrf2 seems also to be part of inflammatory cytokines production in response to LPS or R848 and modulated T lymphocyte proliferation induced by MDP pre-treated BMDC. Moreover, Nrf2 appears to play a role in specific antibodies response against an antigen in mice. . In fact, Tetanus toxoid (TT) injection induces higher titer of antibodies anti-TT in nrf2-/- mice compared to nrf2+/+ mice. This increase is also correlated with more specific B lymphocytes in bone marrow and spleen after TT immunisation

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14

Rainczuk, Adam 1976. "Evaluation of DNA vaccine targeting strategies and expression library immunisation against lethal erythrocytic stage Malaria". Monash University, Dept. of Biochemistry and Molecular Biology, 2003. http://arrow.monash.edu.au/hdl/1959.1/5685.

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15

Joseph, Karen T. "Vaccination in a Private Pediatric Practice". Digital Archive @ GSU, 2012. http://digitalarchive.gsu.edu/iph_theses/214.

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Background: Following the publication of Andrew Wakefield’s article claiming a link between Autism and the MMR vaccine in 1998, the U.K. and U.S. experienced a decline in vaccination rates. Combating the anti-vaccine messages highlighted by the media are the medical providers, who are consistently reported as an influential source of information for parental vaccine decision making. Despite efforts of the medical and public health community, some developed countries have seen a resurgence of vaccine preventable diseases. Purpose: This study seeks to examine parental vaccination concern in a private pediatric practice in metropolitan Atlanta. Methods: A questionnaire was created by the PI to assess parental vaccination concerns, including items to assess parental feelings toward the providers and nurses regarding preventative care. Data was analyzed in SPSS version 19.0. The study was approved by the IRB at Georgia State University. Results: A total of 283 participant responses were included in the sample. Overall vaccine adherence was 96.1% (272). However, a large minority of participants who were considered to have vaccine concerns were identified: 40.3% (114) of participants responded yes to at least one vaccine hesitation item. Conclusion: Vaccine adherence in a private pediatric practice remains high. However some parents continue to have vaccination concerns and may be at risk for deviating from the vaccine schedule. Using qualitative methods to obtain parental beliefs may provide a deeper understanding of parental decisions to aid in the development of public health education programs. The feasibility of collecting data at a private pediatric practice is discussed.

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16

Channing, Liezl. "Cost-effectiveness analysis of MVA85 vaccine: a new TB vaccine candidate". Master's thesis, University of Cape Town, 2013. http://hdl.handle.net/11427/9448.

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Includes bibliographical references.
Tuberculosis (TB) remains a major public health concern. The BCG vaccine is, currently, the only vaccine against TB and, although it provides some protection against disseminated forms of TB, its effectiveness in preventing primary infection and disease progression to pulmonary TB is highly varied. A number of potential new TB vaccine candidates have been identified and are, currently, undergoing clinical trials. One such candidate is MVA85A. This study aims to assess the potential cost-effectiveness of a new TB vaccine, the MVA85A vaccine. The study compares two TB vaccine strategies, from the perspective of the South African Government: i. BCG, given at birth, which is the current standard of care in South Africa; and ii BCG, given at birth, together with a booster vaccine (MVA85A) given at 4 months, which is the potential new strategy. The study employs Decision Analytical Modelling, through the use of a Markov model, to estimate the costs and outcomes of the two strategies. The cumulative costs and outcomes of each intervention are used to calculate the cost-effectiveness ratio (CER) (i.e. the cost per TB case averted and the cost per TB death averted) for each intervention. These two cost-effectiveness ratios are compared using an incremental cost-effectiveness ratio (ICER), which represents the additional cost per additional benefit received. The results of the cost-effectiveness analysis indicate that the MVA85A strategy is both more costly and more effective – there are fewer TB cases and deaths from TB – than BCG alone. The Government would need to spend an additional USD 1,105 for every additional TB case averted and USD 284,017 for every additional TB death averted. Given the disappointing results of the MVA85A vaccine clinical trial – showing an efficacy of only 17.3%, this study will predominantly contribute to establishing an efficacy threshold for future vaccines. Our research also contributes to the body of knowledge on economic evaluations involving new TB vaccines as - to the best of our knowledge - this is the first cost-effectiveness analysis conducted using trial data involving a novel TB vaccine and providing a direct comparison with BCG vaccination. Furthermore, it provides a standardized Markov model, which is relatively simple to adapt to local settings and, which could be used in the future, to estimate the potential cost-effectiveness of new TB vaccines in children between the ages of 0–10 years.

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17

Rummel, Ebba, e Klara Elverfors. "Föräldrars motiv för tveksamhet till vaccinationer av sina barn : En deskriptiv allmän litteraturstudie med utgångspunkt från kvalitativa studier". Thesis, Uppsala universitet, Institutionen för folkhälso- och vårdvetenskap, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-432468.

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Bakgrund: Vaccinationer räknas till sjukvårdens mest effektiva hälsoåtgärd och räddar cirka 1.5 miljoner liv årligen. Trots möjligheten att utnyttja vaccin väljer somliga att inte vaccineras. Detta fenomen kallas för vaccintveksamhet är ett av de tio största hoten mot den globala folkhälsan. Syfte: Syftet var att beskriva vilka motiv som leder till att föräldrar är tveksamma till att vaccinera sina barn. Metod: En allmän litteraturstudie med en deskriptiv design genomfördes. En litteratursökning utfördes i databaserna Cinal och Pubmed, vilket resulterade i elva kvalitativa studier som var relevanta för denna studies syfte. Travelbees omvårdnadsteori användes som teoretisk referensram. Resultat: Resultaten från artiklarna presenterades i 6 olika teman: oro gällande vaccinets säkerhet, misstro till myndigheter, påverkan av social miljö och normer, naturlig immunisering och sjukdomars allvarlighetsgrad och hälsosam livsstil. Föräldrar ifrågasatte vaccinets säkerhet och upplevde otillräcklig information från myndigheter. En del påverkades av samhällets normer. Somliga ansåg att en naturlig immunisering var att föredra och en del trodde att sjukdomarna var ofarliga. Vissa ansåg att en hälsosam livsstil gav ett tillräckligt skydd mot sjukdomarna. Slutsats: Föräldrarnas tveksamhet till att vaccinera sina barn grundas huvudsakligen i en ofullständig förståelse för vaccinets säkerhet och effektivitet. Många kände misstro till sjukvården och föredrog naturlig immunisering framför vaccinering. Den ofullständiga förståelsen bottnade i många fall i informationsbrist och resulterade i att föräldrar kände oro inför vaccin. Sjuksköterskan har en viktig roll i att inta god handlingsberedskap och att i vårdmötet säkerställa att föräldrarna ges förutsättningar att förstå nyttan och nödvändigheten med vaccin.
Background: Vaccine is one of the most effective tools to prevent diseases and saves around 1,5 million lives yearly. Despite access to vaccines, some individuals choose to not vaccinate. This phenomenon known as vaccine hesitancy, is one of the ten biggest threats to global public health. Purpose: The purpose of this study was to describe the motives behind parents’ hesitancy to vaccinate their children. Method: A litterature study with a descriptive design was performed. A literature search was conducted using Cinahl and PubMed databases, leading to eleven qualitative studies relevant to the purpose of this study. Travelbee's nursing theory was used as a theoretical model. Results: The results from all articles are presented in six themes: Concerns regarding the vaccine’s safety, Distrust of authorities, Impact of social environment and norms, Natural immunization and disease severity and Healthy lifestyle. Parents questioned the safety of the vaccine and experienced lack of information from authorities. Some were influenced by norms of the society. Multiple parents considered that a natural immunization was preferable to the actual diseases. Several believed that a healthy lifestyle would provide enough protection against the diseases. Conclusion: Parents hesitancy to vaccinate their children are mainly based on an incomplete understanding of the vaccine's safety and effectiveness. The incomplete understanding was due to a lack of information which led parents to worry about the vaccine. The nurse has an important role in taking good action readiness and to ensure that parents are given the conditions to understand the benefit and necessity of the vaccine.

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18

Qazi, Khaleda Rahman. "Heat shock proteins as vaccine adjuvants". Doctoral thesis, Stockholm : Department of Immunology, Wenner-Gren Institute, Stockholm University, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-441.

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19

Busch, Marc Gregory. "Evaluation of different SIV plasmid DNA vaccines : a model for HIV vaccine development /". For electronic version search Digital dissertations database. Restricted to UC campuses. Access is free to UC campus dissertations, 2004. http://uclibs.org/PID/11984.

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20

De, Cassan Simone. "Towards improved blood-stage malaria vaccines : characterising the underlying immunogenicity of vaccine adjuvants and vectors". Thesis, University of Oxford, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.711629.

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21

Haile, Melles. "Studies on new tuberculosis vaccine candidates in animal models /". Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-327-2/.

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22

Garcel, Aude. "Le vaccin antivariolique historique Lister : séquence génomique, diversité phénotypique et neuropathogénicité : perspectives vaccinales". Phd thesis, Grenoble 1, 2007. http://www.theses.fr/2007GRE10282.

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Jusqu’en 1980, date à laquelle la variole a été déclarée éradiquée suite à la pratique de la vaccination, elle a constitué un véritable fléau pour l’humanité. Le risque de réémergence du virus de la variole dans un contexte bioterroriste, compte-tenu des conditions de production, de la faible immunité de la population et des complications post-vaccinales liées aux vaccins historiques, rend le développement de nouveaux vaccins antivarioliques nécessaire. L’objectif du travail de thèse présenté dans ce mémoire est l’étude du vaccin antivariolique historique Lister dans un cadre de stratégie d’élaboration d’un nouveau vaccin issu de cette souche. La séquence génomique de ce vaccin est déterminée et décrite. Sa comparaison avec d’autres souches de virus de la vaccine met en évidence les singularités de la souche Lister. Par ailleurs, l’étude de la diversité de la population virale et sa caractérisation phénotypique et génétique devraient permettre d’éclairer le choix de la stratégie pour développer un nouveau vaccin dit de deuxième génération issu de cette souche : vaccin constitué d’un seul clone viral ou vaccin polyclonal. Enfin, l’étude de l’interaction du virus de la vaccine avec la barrière hémato-encéphalique montre une augmentation de sa perméabilité suite à l’infection des cellules endothéliales par le virus de la vaccine. De plus, des études in vivo mettent en évidence l’entrée et la réplication du virus dans le tissu cérébral, entraînant des atteintes cérébrales parfois mortelles. Ces perspectives permettent d’appréhender la neuropathogénicité du vaccin historique reliée aux encéphalites post-vaccinales, complications létales de la vaccination antivariolique
The smallpox constituted a real scourge for humanity until 1980, the year of the declaration of its eradication due to vaccination. The risk of variola virus reemerging as a biological weapon, considering manufacturing conditions, the low population immunity and historical vaccine post-vaccinal complications, make new smallpox vaccines development a necessity. In this paper, the historical Lister strain vaccine study is described as part of the elaboration strategy of a new vaccine coming from this strain. The genomic sequence of this vaccine is determined and described. Its comparison with other vaccinia virus strains underlines the Lister strain singularities. The viral population diversity study as well as the phenotypic and genetic characterization should highlight strategy choice for the development of a new second generation vaccine coming from the Lister strain : a clonal vaccine or a polyclonal one. Finally, the study of the vaccinia virus interaction with the blood-brain barrier demonstrates an increase in permeability due to vaccinia virus endothelial cells infection. Moreover, in vivo studies exhibit the viral entry and replication in the brain, sometimes responsible for critical cerebral reaches. These results suggest the first generation smallpox vaccine neuropathogenesis could have caused deadly post-vaccinal encephalitises, smallpox vaccination complications

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23

Garcel, Aude. "Le vaccin antivariolique historique Lister : séquence génomique, diversité phénotypique et neuropathogénicité : perspectives vaccinales". Phd thesis, Université Joseph Fourier (Grenoble), 2007. http://tel.archives-ouvertes.fr/tel-00198642.

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Abstract (sommario):

Jusqu'en 1980, date à laquelle la variole a été déclarée éradiquée suite à la pratique de la vaccination, elle a constitué un véritable fléau pour l'humanité. Le risque de réémergence du virus de la variole dans un contexte bioterroriste, compte-tenu des conditions de production, de la faible immunité de la population et des complications post-vaccinales liées aux vaccins historiques, rend le développement de nouveaux vaccins antivarioliques nécessaire.
L'objectif du travail de thèse présenté dans ce mémoire est l'étude du vaccin antivariolique historique Lister dans un cadre de stratégie d'élaboration d'un nouveau vaccin issu de cette souche.
La séquence génomique de ce vaccin est déterminée et décrite. Sa comparaison avec d'autres souches de virus de la vaccine met en évidence les singularités de la souche Lister.
Par ailleurs, l'étude de la diversité de la population virale et sa caractérisation phénotypique et génétique devraient permettre d'éclairer le choix de la stratégie pour développer un nouveau vaccin dit de deuxième génération issu de cette souche : vaccin constitué d'un seul clone viral ou vaccin polyclonal.
Enfin, l'étude de l'interaction du virus de la vaccine avec la barrière hémato-encéphalique montre une augmentation de sa perméabilité suite à l'infection des cellules endothéliales par le virus de la vaccine. De plus, des études in vivo mettent en évidence l'entrée et la réplication du virus dans le tissu cérébral, entraînant des atteintes cérébrales parfois mortelles. Ces perspectives permettent d'appréhender la neuropathogénicité du vaccin historique reliée aux encéphalites post-vaccinales, complications létales de la vaccination antivariolique.

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24

Dulal, Pawan. "Investigation of sugar-membrane vaccine stabilisation for improved vaccine thermostability and delivery". Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:db56c52c-a320-4cb6-88cc-cab8fbe3d92f.

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Vaccines and other biomolecules need to be maintained at specified storage temperatures from manufacture through to their end user. To satisfy this requirement an enormous network of fridges and freezers called the "cold chain" throughout the world must exist. This network may account for up to 80% of the total cost of vaccination and is susceptible to failure causing loss of vaccines. Stabilisation strategies for vaccines available in the literature have been limited to a few techniques for a few vaccines. To address this problem a novel, cost-efficient, and simple sugar-membrane technology has been developed. Sugar-membrane technology involves desiccation of biomolecules formulated in stabilising sugars in a fibrous matrix and has previously been demonstrated to thermostabilise live viral vectored vaccines exposed to extremes of temperature for prolonged periods of time. The thesis investigates the applicability of the technology in stabilising a wide range of vaccines. The data reported demonstrate the effectiveness of the technology in thermostabilising the vaccines irrespective of the intrinsic complexities and thermo-sensitivity of the initial product. In addition, the thesis also studies the applicability of the technology in thermostabilisation of vaccines of veterinary importance. An accelerated stability study of sugar-membrane thermostabilised veterinary vaccines also demonstrated that the data are superior to those reported previously for the corresponding vaccines. However, the nature of the current matrix is not suitable for translation to human medicine. This thesis therefore investigates a range of new potentially GMP-compatible fibrous matrices to identify alternative membranes for use clinically. The data indicate that an alternative hydrophobic membrane after physical or chemical surface modification could be considered as an alternative support matrix for the technology. Finally, to understand the reasons for outstanding thermostability delivered by the current membrane in more detail, the physical and chemical properties of the matrix were investigated. Results from this systematic study identified inherent properties of the matrix which could be linked to the superior thermostabilising property of the membrane. These findings will be used for further optimisation of the technology and development towards a more GMP compatible support matrix.

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25

Coston, Amber Dawn. "Cancer vaccine and therapy". Connect to resource, 2006. http://hdl.handle.net/1811/6557.

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Thesis (Honors)--Ohio State University, 2006.
Title from first page of PDF file. Document formatted into pages: contains 23 p.; also includes graphics. Includes bibliographical references (p. 21-23). Available online via Ohio State University's Knowledge Bank.

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26

Tsang, King Hei. "Vaccine supply chain optimisation". Thesis, Imperial College London, 2006. http://hdl.handle.net/10044/1/7545.

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LeÌtourneau, Sven C. "HIV-1 vaccine development". Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.442825.

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28

Pywell, Stephanie Mary. "Compensation for vaccine damage". Thesis, University of Hertfordshire, 2001. http://oro.open.ac.uk/43537/.

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Vaccination aims to prevent infectious disease, and is internationally acclaimed as a major contributor to public health. Although vaccines have many benefits, there are people who claim that they or their infant children have been injured, often permanently and severely, by the powerful biological agents introduced into their bodies by vaccination. The object of this thesis is to determine whether the law in England and Wales relating to vaccine damage is in need of reform. The answer to this question is determined by a moral and legal analysis of current vaccination policy and practice. The existing literature consists primarily of medical papers discussing the possibility of vaccine damage and legal discourses concerning compensation and consent to treatment. Detailed background information comes from in-depth semi-structured interviews with a consultant epidemiologist at the Public Health Laboratory Service and three organisers of Justice Awareness Basic Support (JABS), a vaccine information and support group. The main originality of the thesis is the information provided by approximately 360 responses to each of two surveys. Parents of pre-school children were surveyed about their experiences of, and views on, current vaccination policy and practice. Members of JABS who believe their children to be vaccine-damaged provided information about the vaccines which appear to have caused harm, as well as their experiences of, and views on, the legal routes to financial redress. The findings provide evidence of a dearth of reliable medical data about vaccine safety, and of some ethically unacceptable practices associated with infant vaccination. They also reveal that, theoretically and in the view of users, legal provision for the victims of vaccine damage in England and Wales is unsatisfactory. These factors combine to indicate that the law relating to compensation for vaccine damage is in need of reform. The thesis therefore concludes with suggestions for further research and some modifications to current law and policy. There should be a statutory scheme awarding compensatory, rather than token, payments to victims. Awards should be made subject to a generous test of causation, such as that which exists in respect of the US Vaccine Injury Compensation Program. Incentive payments to GPs should be discontinued, parents should be offered choices of vaccine, and vaccine promotional literature for healthcare workers and parents should present a balanced view of all available research. Above all, it is essential that these measures be supported by large-scale, independent medical research into the nature of possible links between vaccines and damage.

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Dicks, Matthew Douglas James. "Novel adenovirus vaccine vectors". Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:383aaf3d-284a-4bd7-877c-3270bd7c2e4f.

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Replication defective adenoviruses have emerged as promising vectors for delivery of vaccine antigens. The development of new vaccine vectors has recently focused on serotypes t, which the human population is less exposed in order to circumvent pre-existing anti vector immunity. This thesis describes the construction and optimisation of ChAdOX1, a new vector based on chimpanzee adenovirus Y2S, which has recently been manufactured to clinical grade for a Phase 1 human trial. Comparative immunogenicity studies between vectors of different serotype were performed in mice, with careful consideration of the infectious titer of vector preparations, since this parameter can confound studies based solely on viral particle estimation. Aft intramuscular administration, HAdV-S (Human adenovirus C) based vectors elicited superior transgene product specific T cell and antibody responses compared to a selection of chimpanzee adenovirus vectors (from Human adenovirus EJ including ChAdOX1. The construction of ChAdOXl in a bacterial artificial chromosome (BA C), enabled precise, and flexible modification of the genome by recombmation mediated genetic engineering. (recombmeering). Reverse genetics was performed to identify vector determinants of immunogenicity. Chimeric ChAdOXl vectors were created by replacement of native virus associated RNA (VA-RNA) and fiber sequences with the corresponding sequences from HAdV-5 Using these chimeric vectors, the importance of innate immunity and vector transduction in determining vector immunogenicity was investigated. Though the mechanisms responsible ultimately remain unclear, superior transgene product specific immune responses with HAdV-5 correlated with higher levels of transgene expression in vivo after vector administration. The current study has conclusively demonstrated that neither VA-RNA sequences, nor the fiber protein, are responsible for differences in immunogenicity between vectors, contrary to hypotheses based on previous studies.

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Ward, Scott Matthew. "Towards an HCV vaccine /". St. Lucia, Qld, 2001. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16402.pdf.

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Perna, Andrea. "Investigating Vaccine Hesitancy in Canada: A Quantitative and Qualitative Description of Vaccine Attitudes, Beliefs, and Perceptions of the Seasonal Influenza Vaccine". Thesis, Université d'Ottawa / University of Ottawa, 2016. http://hdl.handle.net/10393/34281.

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The overarching objective of this thesis was to investigate the phenomenon of vaccine hesitancy in Canada and examine relationships among vaccine beliefs, socio-demographic characteristics, and seasonal influenza immunization. Quantitative findings were derived from a national health risk perception survey administered to adults across Canada (N = 1,125). Respondents were asked to provide their level of agreement (1 = do not agree at all to 5 = agree completely) with 2 vaccine-related behaviour statements and 21 vaccine-related beliefs statements. A principal components analysis was performed to reduce the number of belief statements into meaningful components. Two components were retained and reflected negative beliefs about ‘vaccine safety’ and positive beliefs about ‘vaccine regulation and benefits’. Descriptive results presented in the first study indicated a heightened uncertainty about the long-term side effects of vaccination, particularly with respect to the purported link between the Measles-Mumps-Rubella vaccine and the development of autism, among survey respondents. Multivariate analyses identified differences in the endorsement of numerous vaccine beliefs according to age and educational attainment. Findings revealed that older respondents and respondents without a university education demonstrated more negative attitudes towards vaccination, whereas younger respondents and respondents with a university education demonstrated more positive vaccine attitudes, respectively. Finally, both components of vaccine beliefs were significant predictors of vaccine-related behaviours, including discussing information about vaccines with others and reported receipt of the seasonal influenza vaccine. The second study investigated interrelationships among components of vaccine beliefs, socio-demographic characteristics, and reported receipt of the seasonal influenza vaccine. A mediation analysis revealed that higher levels of agreement with the statement ‘I usually get the seasonal flu vaccine’ among older adults was associated with lower levels of agreement with negative beliefs about vaccine safety in conjunction with higher levels of agreement with positive beliefs about the regulation and benefits of vaccines, whereas the opposite was true for younger adults. Also, a significant moderation analysis revealed that among respondents with greater concern about vaccine safety, those with higher educational attainment reported lower levels of agreement with the statement ‘I usually get the seasonal flu vaccine’ compared to those with lower educational attainment. Recognizing the limitations of quantitative findings, a qualitative investigation was undertaken to provide more in-depth insight on the factors driving influenza immunization among healthy adults. A thematic analysis was performed on transcripts from 6 semi-structured focus group discussions with a total of 18 participants residing in Ottawa, Ontario. Findings identified 7 themes and 8 sub-themes related to contextual, vaccine specific, and individual determinants of vaccine hesitancy. Participants predominantly discussed themes related to individual determinants of vaccine hesitancy (perceived severity, susceptibility, and likelihood of contracting the influenza virus; personal interests; interactions with healthcare professionals). The perceived novelty, severity and effectiveness of the influenza vaccine, as well as a lack of information and discontent with communication by government health authorities and the media were also discussed. Overall, findings identified salient themes informing vaccine decision-making and behaviours among a sample of educated adults, which can inform subsequent studies investigating influenza immunization in a more representative sample of Canadian adults.

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Dimier, Julie. "Développement d'un vecteur virus de la vaccine, réplicatif et atténué, pour la vaccination antivariolique et pour la vaccination contre la fièvre hémorragique à virus Ebola". Phd thesis, Université de Grenoble, 2012. http://tel.archives-ouvertes.fr/tel-00870840.

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Le virus Ebola, responsable d'une fièvre hémorragique virale létale et le virus de la variole, agent étiologique de la variole, sont des armes biologiques potentielles. Il n'existe pas de traitement ou de prophylaxie autorisés contre le virus Ebola, quelques candidats vaccins étant en cours de développement. Concernant la variole, des vaccins dits de première génération (virus de la vaccine) ont permis l'éradication de la maladie cependant ils sont à l'origine de complications post-vaccinales parfois sévères alors que des vaccins plus récents dits de troisième génération, non-réplicatifs, ont été développés pour leur innocuité mais restent faiblement immunogènes. Nous avons récemment développé plusieurs vecteurs viraux de type virus de la vaccine (VACV) par délétion d'un certain nombre de facteurs de virulence. Nous avons évalué leur innocuité, leur immunogénicité et leur efficacité en tant que candidats vaccins antivarioliques chez la souris puis utilisé l'un de ces vecteurs pour développer un candidat vaccin bivalent antivariolique et anti-virus Ebola. Ces virus de la vaccine délétés sont réplicatifs mais fortement atténués. Ils induisent une réponse en anticorps neutralisants spécifiques anti-vaccine similaire à celle induite par le vaccin antivariolique de première génération et induisent des réponses immunitaires cellulaires CD4+ et CD8+ spécifiques suffisantes pour protéger l'animal d'un challenge létal de cowpoxvirus en intranasal, simulant une infection par le virus de la variole. Le virus délété le plus immunogène et le plus sûr, nommé MVL, a été utilisé pour construire un vecteur viral codant pour la glycoprotéine du virus Ebola (EGP). Le gène entier d'EGP ou une forme chimérique d'EGP (fusion entre l'ectodomaine d'EGP et le domaine transmembranaire de la glycoprotéine B5 du VACV) ont été clonés dans le génome du vecteur viral. Ces deux vecteurs produisent des virus ayant incorporé EGP dans leur enveloppe. Ces deux candidats vaccins recombinants induisent de fortes réponses humorales spécifiques anti-EGP et anti-vaccine chez la souris immunocompétente. En conclusion, nous avons développé plusieurs candidats vaccins antivarioliques aussi immunogènes et efficaces que le vaccin historique et avec une atténuation similaire aux vaccins de troisième génération. L'un de ces candidats (MVL) a été utilisé comme vecteur viral pour exprimer la glycoprotéine hétérologue EGP, contre laquelle il induit une réponse immunitaire humorale forte

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Ishizuka, Andrew Scott. "Pre-clinical and clinical evaluation of the malaria vaccines RH5-VLP and PfSPZ vaccine". Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:521c5ef4-7d77-456f-910e-f1f207c80b8d.

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Despite progress through expanded use of bed nets and anti-malarial drugs, Plasmodium falciparum (Pf) malaria caused about 200 million cases and 500,000 deaths in 2015. An ideal vaccine would reduce the burden of disease and interrupt transmission. Despite decades of effort, there is no vaccine that can adequately address the global burden of malaria. This thesis focuses on two potential weaknesses in the parasite life-cycle. First, I investigate two vaccination strategies aimed at improving the antibody response to RH5, an essential and conserved protein for erythrocyte invasion. Due to instability of the resultant recombinant vaccine constructs, these efforts have required re-engineering of the vaccine platform, which remains an ongoing effort. Second, the immunogenicity and mechanism of protection of a live-attenuated whole sporozoite vaccine, PfSPZ Vaccine, was assessed. In a study that examined PfSPZ Vaccine at intravenous (IV) doses between 1.35 &tiles; 10⁵ to 4.5 &tiles; 10⁵ PfSPZ, I demonstrate that PfSPZ antibody responses correlated with durable sterile protection against controlled human malaria infection (CHMI). Surprisingly, the pre-vaccine frequency of Vγ9⁺Vδ2⁺ T cells, an innate T cell that recognizes conserved Plasmodium phosphoantigens, also correlated with durable sterile protection. Regarding the mechanism of protection, PfSPZ-specific antibodies as well as CD8 and CD4 T cells in the blood decreased substantially over time, yet sterile protection was maintained. In non-human primates, the CD8 T cell response in the liver at a memory time point was measured to be about 100-fold higher than found in the blood. Collectively, these data suggest that PfSPZ Vaccine confers durable protection in humans by long-lived, tissue-resident CD8 T cells. These findings were extended with a study using 9.0 x 10⁵ PfSPZ, wherein I demonstrate that T cell responses peaked immediately after the first vaccination with minimal T cell activation despite additional immunizations. This suggests that anti-PfSPZ immunity may be limiting the effectiveness of subsequent immunizations. Finally, I examined the T cell response to PfSPZ attenuated by chloroquine (termed PfSPZ-CVac). T cell responses were substantially higher than achieved with comparable PfSPZ Vaccine doses. Additionally, a significantly higher proportion of PfSPZ-specific CD4 T cells were polyfunctional, simultaneously expressing IFN-γ, IL-2, and TNF-α, in subjects that were protected from CHMI. In sum, these studies provide insight into the immunobiology of a protective immune response that may guide future malaria vaccine development efforts.

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McIntyre, Peter. "Measuring the public health impact of vaccines: disease burden, vaccine coverage, safety and effectiveness". Thesis, The University of Sydney, 2021. https://hdl.handle.net/2123/26251.

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This thesis has eight chapters describing inter-relationships between work in 66 papers published between 1999 and 2020 relevant to the over-arching topic of public health impact of vaccines: measurement of disease burden, vaccine coverage, safety and effectiveness Chapter 1 outlines the key data sources used: 1. routinely collected administrative data (disease notifications, ICD coded hospitalisations and mortality data) and 2. additional data sources the author had a key role in developing (National Serosurveillance. Paediatric Active Enhanced Surveillance (PAEDS). In chapter 4, development of analysis and reporting of data from the Australian Immunisation Register and in chapter 6 development of platforms for vaccine safety evaluation are described. In Chapter 5, how this work culminated in pilot initiatives to link data sources relevant to public health impact of vaccines in a birth cohort from New South Wales and Western Australia, with the aim of demonstrating the potential for an all-age national capacity, is outlined. Chapter 2 focuses on disease due to Bordetella pertussis and research under the headings of measuring prevalence and severity of pertussis, the effectiveness and impact of pertussis vaccines and clinical trials conducted to evaluate the immunogenicity and safety of acellular pertussis vaccine given within 4 days of birth. Chapter 3 focuses on disease due to Streptococcus pneumoniae and research measuring pneumococcal disease, effectiveness and impact of pneumococcal vaccines and a randomised trial comparing immune responses to pneumococcal conjugate and polysaccharide vaccines in the frail elderly. Chapter 7 includes studies of vaccine impact against Hepatitis B, varicella, meningococcal C disease, mumps and Q fever and Chapter 8 includes four major international reviews of vaccine programs and impact.

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Tarcha, Eric J. "Application of Immunoproteomics and Bioinformatics to coccidioidomycosis Vaccinology". University of Toledo Health Science Campus / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=mco1154441973.

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Siebert, Sarah. "Human Papillomavirus Vaccine Knowledge, Beliefs, Attitudes, and Barriers: A College-Based Intervention for Students to Increase Knowledge, Vaccine Intent, and Vaccine Uptake". Diss., North Dakota State University, 2018. https://hdl.handle.net/10365/27927.

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The purpose of this disquisition was to determine knowledge, beliefs, attitudes, and barriers of college-age students at North Dakota State University (NDSU) related to the human papillomavirus (HPV) and the vaccine used to prevent certain strains of the virus. HPV is the most common sexually transmitted infection in the United States, with the highest rates of infection occurring in the late teens to early twenties (CDC, 2015b). Therefore, there is a need to educate college age students about HPV and how to protect themselves from acquiring HPV. An intervention was designed to address the following clinical question: Will the provision of HPV education to college students, ages 18-26, increase HPV knowledge, vaccine intent, and the number of student HPV vaccinations within six months at NDSU? Project intervention consisted of two components: reaching out to NDSU students at the annual Sex Positivity Expo and members of two NDSU organizations, the Women's Activist Organization, and Violence Prevention Educators. Students were first instructed to take a pre-test to establish baseline HPV knowledge, beliefs, attitudes, and barriers. Following the pre-test, students were instructed to watch a short educational video about HPV and the HPV vaccine. Students then completed a similar post-test to assess if there were increases in basic HPV education, and changes in beliefs, attitudes, barriers, or intent to vaccinate. Results between pre-and post-survey data indicated an increase in both HPV knowledge and intent to vaccinate. An increase in vaccination rates was not noted, although of the 30 student participants, 70% had completed the HPV vaccine series prior to education. Questions addressing attitude indicated an increase in motivation to maintain a healthy lifestyle. Questions addressing belief indicated students believed they would be protected from the most cancer-causing strains of HPV. Fifty percent of students indicated they believed themselves at risk for acquiring HPV. Questions addressing barriers indicated the following were not barriers: healthcare coverage, work and school, and their provider offering them the chance to begin the HPV vaccine series. The only barrier identified with a slight increase in mean of 0.08 indicated the cost of the vaccine series to be a concern.

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Stubbe, Muriel. "Lymphocytes T CD4 et réponses vaccinales: du processus de différenciation à la mémoire immunologique". Doctoral thesis, Universite Libre de Bruxelles, 2007. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210593.

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Les lymphocytes T CD4 (LT CD4) jouent un rôle central dans la régulation des réponses immunitaires vis-à-vis des agents infectieux et des vaccins. Cependant, leur différenciation in vivo est encore mal comprise et les caractéristiques des LT CD4 capables de persister à long terme tout en assurant une réponse immunitaire protectrice sont mal définies. L’approfondissement de ces connaissances est indispensable pour le développement de nouveaux vaccins.

Pour approcher cette question, nous avons utilisé deux approches expérimentales. La première est un suivi de la différenciation des LT CD4 au cours de la réponse immune primaire chez des sujets vaccinés contre l’hépatite B ;la deuxième est la caractérisation phénotypique et fonctionnelle des LT CD4 mémoires antigène(Ag)-spécifiques pendant la phase d’état. Cette analyse a été réalisée au sein des LT CD4 spécifiques d’Ag vaccinaux, l’Ag de surface du virus de l’hépatite B (HBs) et la toxine tétanique (TT), ainsi que ceux spécifiques des Ag du cytomégalovirus (CMV). Les LT CD4 Ag-spécifiques ont été mis en évidence par cytométrie de flux après marquage intracytoplasmique du ligand du CD40 (CD40L) exprimé en réponse à une stimulation de courte durée par l’Ag. Des expériences basées sur la stimulation par la toxine du syndrome du choc toxique et le marquage du segment Vbeta2 du récepteur des LT ont démontré la bonne sensibilité et spécificité de cette méthode.

Le suivi de la réponse primaire chez 11 donneurs jusqu’à plus d’un an après immunisation par le vaccin anti-hépatite B a permis d’établir un modèle de différenciation des LT CD4 Ag-spécifiques in vivo chez l’homme. Nous avons mis en évidence des LT CD4 spécifiques d’un nombre limité de peptides immunodominants de la protéine HBs suggérant une réponse de type oligoclonale. Grâce à l’utilisation d’un cytomètre neuf couleurs, nous avons mené une analyse détaillée de l’hétérogénéité de la population mémoire HBs-spécifique. L’expression du CCR7 permet de distinguer des cellules de type mémoire centrale (LTCM, CCR7+) et effectrice (LTEM, CCR7-) se distinguant notamment par leur capacité à migrer vers les ganglions lymphatiques ainsi que par leurs propriétés fonctionnelles. Nous avons montré l’existence de ces deux sous-populations au sein des cellules HBs-spécifiques mais par opposition à leur définition initiale, ces LTCM sont capables de produire des cytokines effectrices. La proportion importante de LTCM exprimant le Ki67 témoigne d’une activité proliférative persistante in vivo et suggère la capacité de ces cellules à s’auto-renouveler et éventuellement à alimenter le pool des LTEM. La proportion importante de LTCM exprimant la chaîne alpha du récepteur à l’IL-7 (CD127) suggère que ces cellules sont sensibles aux signaux émanant de l’IL-7, une cytokine dont le rôle dans le maintien de la mémoire lymphocytaire T est connu. Compte tenu de la relevance potentielle de ces caractéristiques uniques pour le développement de vaccins et de l’accumulation de travaux montrant l’avantage sélectif des LTCM à conférer une immunité protectrice, nous avons focalisé la dernière partie de ces recherches sur cette sous-population. Une étude transversale des LTCM spécifiques de plusieurs types d’Ag (éliminés (HBs et TT) ou persistants (CMV)) a été menée. Nos résultats montrent une hétérogénéité, variable selon l’Ag, de la capacité de ces cellules à produire des cytokines effectrices et de leur phénotype de différenciation. Cette donnée nouvelle soulève la possibilité que les LTCM soient hétérogènes dans leur capacité à conférer une immunité protectrice. L’acquisition du marqueur KLRG1 par une fraction des LTCM s’associe à une capacité accrue à produire des cytokines effectrices et à une expression élevée du CD127. La possibilité que ces cellules soient particulièrement aptes à conférer une immunité protectrice et durable est discutée, tout comme les mécanismes menant à leur génération et l’intérêt de ces connaissances pour la conception de nouveaux vaccins.

Doctorat en Sciences médicales
info:eu-repo/semantics/nonPublished

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Satti, Iman. "Immunogenicity of anti-leishmaniasis vaccines in man /". Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-779-7/.

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Le, Minh Quan. "Research on nanodelivery systems for nasal vaccine". Thesis, Lille 2, 2018. http://www.theses.fr/2018LIL2S020/document.

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L'administration nasale a un grand avantage pour stimuler l'immunité protectrice locale et systémique. Cependant, des systèmes d'administration et des adjuvants sont souvent nécessaires pour améliorer l'efficacité du vaccin intranasal. Nous avons appliqué la technologie des nanoparticules en tant que système universel de délivrance de vaccins contre la grippe dans le projet européen FP7 appelé UniVacFlu.Nous avons évalué différentes nanoparticules (NP) pour rechercher le meilleur nanovecteur. Pour cela, nous avons comparé 5 types de nanoparticules avec différentes charges de surface (anioniques ou cationiques) et diverses compositions internes comme vecteurs potentiels: des liposomes cationiques ou anioniques, des NP de PLGA cationique ou anionique (poly acide lactique co-glycolique) et une NP cationique composée de maltodextrine fonctionnalisée par un agent cationisant avec un coeur de lipides anioniques (NPL). Nous avons d'abord quantifié leur temps de résidence nasale après l'administration nasale chez la souris en utilisant l'imagerie in vivo et les NPL ont montré le plus long temps de résidence. L'endocytose in vitro sur des cellules muqueuses (cellules épithéliales des voies respiratoires, macrophages et cellules dendritiques) en utilisant des nanoparticules marquées a été réalisée par cytométrie de flux et microscopie confocale. Parmi les 5 nanoparticules, les NPL ont été majoritairement captées par 3 lignées cellulaires différentes représentatives d’un épithélium respiratoire et les mécanismes d'endocytose ont été caractérisés. Afin d’évaluer le meilleur vecteur en tant que véhicules, le chargement d'antigènes et la délivrance intracellulaire ont été évalués dans des cellules de la muqueuse des voies respiratoires (cellules épithéliales des voies aériennes, macrophages et cellules dendritiques) par cytométrie de flux. Nous montrons que les NPL sont les meilleurs candidats capables de délivrer la plus grande quantité de protéines dans les cellules. Pris ensemble, notre étude a révélé que parmi 5 nanoparticules, la NPL était le meilleur nanovecteur en termes de temps de résidence nasale, d'endocytose par les cellules et de délivrance de protéines dans l'épithélium des voies respiratoires. Les NPL ont donc été sélectionnées comme nanovecteurs pour le projet UniVac Flu.Les antigènes de la grippe CTA1-3M2e-DD et HA ont été formulés avec les NPL. Le CTA1-3M2e-DD est un antigène chimérique adjuvanté et ciblé. Il est composé de la sous-unité A1 de la toxine du choléra et un épitope conservé du virus grippal A (M2e), ainsi que le dimère de l'analogue synthétique de la protéine A de Staphylococcus aureus (DD) utilisé comme agent de ciblage des lyphocytes B. Pour améliorer l'effet antigénique, l’HA recombinant de H1N1 a été combinée avec CTA1-3M2e-DD. Ces formulations ont été évaluées chez la souris par le consortium UniVacFlu. Les résultats ont montré que CTA1-3M2e-DD et HA chargé dans les NPL formeraient un vaccin intranasal prometteur contre la grippe. Ce travail de thèse montre que les NPL sont des nanovecteurs d’intérêt pour le vaccin nasal
Nasal administration has great advantage for stimulating the immune system, such as stimulating local and systemic protective immunity. However, delivery systems and adjuvants are often necessary to improve the efficacy of the intranasal vaccine. We applied nanoparticle technology to deliver a universal influenza vaccine via the nasal route in a European FP7 project called UniVacFlu.We evaluated different nanoparticles to search the best nanocarrier for an intranasal vaccine. Here we compared 5 types of nanoparticles with different surface charges (anionic or cationic) and various inner compositions as potential vectors: cationic and anionic liposomes, cationic and anionic PLGA (Poly Lactic co-Glycolic Acid) nanoparticles and zwitterionic maltodextrin nanoparticles (cationic surface with an anionic lipid core: NPL). We first quantified their nasal residence time after nasal administration in mice using in vivo live imaging and NPL showed the longest residence time. In vitro endocytosis on mucosal cells (airway epithelial cells, macrophages and dendritic cells) using labeled nanoparticles were performed by flow cytometry and confocal microscopy. Among the 5 nanoparticles, NPL were taken up to the greatest extent by the 3 different cell lines and the endocytosis mechanisms of NPL were characterized. In order to compare different nanoparticles as vaccine carriers, antigen loading and cell delivery were evaluated. In this study, we compared the loading and delivery of labeling ovalbumin with airway mucosa cells (airway epithelial cells, macrophages and dendritic cells) by flow cytometry. Our data showed that NPL were the best candidate that can payload with highest amount of protein and eventually the most efficient cellular protein delivery capacity. Taken together, our study revealed that among 5 nanoparticles, NPL were the best nanocarrier that own longer nasal residence time, efficiently uptake and deliver protein into airway epithelium. NPL were then selected as nanocarrier for the UniVac Flu project.The flu antigens CTA1-3M2e-DD and HA were formulated with NPL. The CTA1-3M2e-DD is an adjuvanted antigen composed of the A1 subunit of cholera toxin and a conserved epitope of influenza A virus (M2e), as well as the dimer of the synthetic analogue of Staphylococcus aureus protein A (DD) used to target B cells. To improve antigenic effect, recombinant HA from H1N1 was combined with CTA1-3M2e-DD. These formulations were evaluated in mice by the UniVacFlu consortium. We observed that CTA1-3M2e-DD and HA loaded into NPL could be a promising universal intranasal influenza vaccine

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Adedokun, Amos. "Perceptions of Healthcare Workers Toward Influenza Vaccination". ScholarWorks, 2018. https://scholarworks.waldenu.edu/dissertations/4992.

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Even though influenza vaccinations were provided free to all healthcare workers in the United States, healthcare workers were not 100% compliant. The non-compliance with influenza vaccinations may expose their patients, their families, and the public at large to a high-risk source of influenza infection. This study's research questions included how registered nurses perceived influenza and influenza vaccination; registered nurses' self-reported incidents with influenza vaccination; and factors that contributed to registered nurses' non-compliance with influenza vaccination. Guided by the theory of reasoned action and the theory of planned behavior, the purpose of this qualitative study was to determine the factors that contributed to the non-compliance of registered nurses with receiving the influenza vaccination. Twenty participants from a healthcare facility in Florida were interviewed using an interview guide. Audio data was transcribed to text data; text data was coded and thematically analyzed by using ATLAS.ti software. Results revealed that 70% of registered nurses were afraid of influenza vaccination, while 80% of them saw influenza vaccination as ineffective; 90% of them had bad experiences or have seen colleagues/friends who have had bad experiences after influenza vaccination. In addition, 40% of registered nurses claimed that they already had good immunity, while 20% of them declined influenza vaccination because of personal choices. Research findings from this study may be utilized to bring positive social change to society at large. The findings may be utilized to enhance existing strategies or policies or even help formulate new policies and strategies that would address the concerns of HCWs, especially registered nurses.

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Cassan, Simone de. "Toward improved blood-stage malaria vaccines : characterising the underlying immunogenicity of vaccine adjuvants and vectors". Thesis, University of Oxford, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.560918.

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The vaccine field generally accepts that the induction of high-titre antibodies will be necessary to prevent the invasion of erythrocytes utilising vaccines targeting the blood-stage of malaria. Protein-in-adjuvant formulations are commonly used to achieve such responses. However, their clinical development can be limited by the reactogenicity of some of the most potent pre-clinical adjuvants and the cost and complexity of licensing new adjuvants for human use. Work in this thesis describes the comparative assessment of classical adjuvants such as alum to new pre-clinical adjuvants and adjuvants in clinical development for the induction of high and sustained antibody and T cells responses. These adjuvants induced a broad range of antibody responses when used in a three-shot protein-in-adjuvant regime using the model antigen ovalbumin and leading blood-stage malaria vaccine candidate antigens. Surprisingly, this range of antibody immunogenicity was greatly reduced and antibody responses were of a comparably high magnitude when a protein-in-adjuvant vaccine was used to boost antibody responses primed by an AdHuS vaccine recombinant for the same antigen. This adenovirus prime, protein boost regime also induced a more cytophilic antibody response and demonstrated improved efficacy of merozoite surface protein-l protein vaccines against a high-dose Plasmodium yoe/ii blood-stage challenge. Investigating the underlying differences between the vaccine platforms used suggests the improved boosting observed following an adenovirus prime is not due to differences in antigenic dose exposed to the immune system or extended immunisation intervals between adenovirus and protein vaccines, but rather appears to be inherent to the adenoviral vector, which induces more germinal centre cells and Tfollicular helper cells. Attempts to further enhance the immunogenicity of viral vectors through the direct addition of the adjuvants chloroquine and Adju-Phos" was not successful. 1.

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Bláha, BenjaminA F. "Platform processes for vaccine production : development of a universal influenza vaccine using Pichia pastoris". Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10047467/.

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Influenza virus remains a familiar threat to public health and continues to challenge the scientific community. Most challenging is responding to the evolutionary adaptability of influenza virus, which often hinders effective prevention or treatment. Furthermore, current production methods are logistically and technically inadequate to cope with pandemic surges, leaving a considerable number of individuals unprotected. Tandem Core Virus-Like Particles (VLPs), expressed in Pichia pastoris, offer an exciting proposition to create a platform process for a universal influenza vaccine. However, as with all novel concepts, characterisation of this technology was required and process methodologies were developed accordingly. Initially, critical process parameters, associated with production of novel VLP constructs, were identified. In doing so, a need for a robust, high-throughput miniaturised fermentation platform was recognised. To accommodate such an approach, a high-throughput, non-contact, automated, small-scale, scalable disruption tool was developed to extract VLPs from P. pastoris. Development and optimisation of this method led to matching and even outperforming High Pressure Homogenisation performance. Having developed the prerequisite tools for miniaturised upstream process development, the use of microtitre plates for studying heterologous protein expression was investigated. This proved to be challenging, predominantly due to reduced mass transfer capacity imposed by microtitre plates and the requirement of controlled methanol feeding. The use of pectin digest as an alternative indirect induction agent was studied. It was found that the use of this novel media resulted in the expression of heterologous protein, however, this effect was most likely a result of methanol liberation during digest preparation. Due to the requirements of a tightly controlled induction process, it was found that, microtitre plates provided an unsuitable platform for rapid upstream process development for methylotrophic yeast. As an alternative to microtitre plates, the effects of variance of previously identified critical process parameters were studied to a greater extent using miniaturised bioreactors, initially with a simplified, non-epitope-exposing, variant of Tandem Core VLP. Metabolic responses, such as final biomass concentration, required significantly different optimum operating conditions than product expression responses. It was also found that maximising expression of heterologous protein was not synonymous to maximising the production of VLPs. After characterising VLP expression in miniaturised bioreactors, these findings were translated to industrially relevant universal influenza vaccine production scenarios. This was accomplished by investigating the effects of scale-up and variation of epitope inserts that could be utilised as a universal influenza antigens. Following this, the scale-up of fermentation processes and was studied. It was found that mixed induction with glycerol feeding not only provided a better basis for scale-up but also resulted in higher product titres for more complex VLP constructs.

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Danet, Nicolas. "Molecular characterisation of the recombinant Vesicular Stomatitis Virus- ZEBOV-GP virus, prototype vaccine against Ebola virus". Thesis, Lyon, 2019. http://www.theses.fr/2019LYSE1009/document.

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Ebolavirus (EBOV) est un filovirus responsable de fièvres hémorragiques virales sévères chez l’humain, qui peuvent être létales dans 90% des cas. L’actuelle épidémie en République Démocratique du Congo et l’ampleur démesurée de l'épidémie de 2014-2016 en Afrique de l’Ouest, qui a causé la mort de plus de 11 000 personnes, ont poussé les agences sanitaires internationales à tester plusieurs approches thérapeutiques afin d’essayer d’endiguer rapidement la propagation virale et de limiter la mortalité liée au virus lors de futures épidémies. Parmi toutes les stratégies testées, le virus recombinant réplicatif rVSV-ZEBOV qui exprime la glycoprotéine de surface d’EBOV, semble offrir la meilleur protection, aussi bien en modèle animaliers que sur le terrain. Avant d’être testé chez l’humain, de nombreuses études ont permis de mettre en évidence l’efficacité et l’innocuité de ce vaccin prototype. Pourtant et malgré le fait que de nombreuses études ont démontré l’importance et le rôle de la glycoprotéine GP dans l’efficacité des vaccins contre ce virus, aucune étude n’a encore été réalisé sur la nature des glycoprotéines virales synthétisées par le gène GP d’EBOV inséré dans le génome du virus VSV. Ainsi, les caractérisations moléculaires des protéines virales produites lors de l’infection par le virus rVSV-GP décrites dans ces travaux de thèse offrent de nouvelles perspectives pour comprendre le succès de ce vaccin mais aussi l’origine virales dans les effets secondaires sévères observés lors de la vaccination, et pourront aider à développer un vaccin plus sûr, qui n’est actuellement pas utilisable chez les personnes immunodéprimées
The filovirus Ebolavirus (EBOV) is the causative agent of severe viral hemorrhagic fevers in humans that can be lethal in 90% of cases. The current outbreak in the Democratic Republic of Congo and the extraordinary scale of the 2014-2016 outbreak in West Africa, that caused the death of more than 11 000 disease victims, lead the international public health agencies to test several therapeutic approach to limit viral spreading and mortality. Amongst those, the recombinant replication-competent rVSV-ZEBOV virus, that expressed EBOV GP glycoprotein, appears to offer the best protection in animal models and outbreak settings. While its effectiveness and safety have been widely investigated before human trials and despite numerous studies that showed the importance the nature of the glycoproteins which are produced during the infection from the EBOV GP gene that has been inserted in VSV genome are unknown. In this respect, the molecular characterisations of the viral glycoproteins synthesised during rVSV-GP presented in this thesis, offer new insights with which to understand the success of the rVSV-GP vaccine but also the potential viral origins of the severe adverse side effects observed during vaccination and could help in developing a safer vaccine, which currently cannot be used in an immunocompromised population

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44

Le, Duc Hong. "Bacterial spores as vaccine vehicles". Thesis, Royal Holloway, University of London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.405585.

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45

Mulholland, Wiliam James. "Targeted epidermal DNA vaccine delivery". Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.433351.

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46

Carson, Connor. "Vaccine trials against canine leishmaniasis". Thesis, University of Warwick, 2010. http://wrap.warwick.ac.uk/3637/.

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Zoonotic visceral leishmaniasis (ZVL) is a fatal disease caused by the sandfly-borne intracellular protozoan parasite Leishmania infantum, and vaccine development in the reservoir host (the domestic dog) is a current research priority. The aims of this study were (1) to conduct safety and immunogenicity trials of two candidate vaccines in dogs, and (2) to compare and demonstrate the utility of immunological and molecular tools for measurement of vaccine efficacy in naturally exposed dogs. DNA/ modified vaccinia virus Ankara (MVA) prime/boost canine vaccines expressing the Leishmania proteins TRYP and LACK were safe, and elicited a type-1 cytokine response, in vivo delayed-type hypersensitivity and IgG2 class responses, consistent with superior protective immunogenicity of TRYP over LACK. However, inconsistent associations were found between progressive disease in infected dogs and IgG class levels, prompting caution in use of the latter as a proxy for protective immunogenicity. Specific serological responses in vaccinated dogs did not cross-react with an unrelated diagnostic antigen rK39, and responses to crude parasite antigen (CLA) were minimal, enabling serological detection of infection incidence in vaccinated dogs. Particularly in early stage infection, CLA ELISA was more sensitive than rK39 ELISA and an rK39-based rapid diagnostic test, though rK39 serology was sensitive for diagnosis of symptomatic clinical cases. A commercially available PCR kit incorporating a rapid oligochromatographic detection step was tested for the first time in dogs, and proved highly sensitive for detection of ZVL infection in bone marrow, comparable to existing nested PCR methods. Molecular methods were investigated as proxy measures to replace labour-intensive xenodiagnosis for detection of the infectiousness of dogs to biting sand flies. Conventional and real-time PCR of tissues from naturally infected dogs were sensitive tests to identify infectiousness, but showed low to moderate specificity. Recommendations are made to improve the application of molecular methods as proxy measures of infectiousness and hence vaccine efficacy.

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47

Hanes, Justin Scott. "Polymer microspheres for vaccine delivery". Thesis, Massachusetts Institute of Technology, 1996. http://hdl.handle.net/1721.1/10153.

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48

Redmond, Diane L. "Towards a Haemonchus contortus vaccine". Thesis, University of Edinburgh, 2003. http://hdl.handle.net/1842/12845.

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49

Luo, Honglin. "Experimental DNA vaccine against filariasis". Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5547.

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Filarial infections are major causes of morbidity in the tropics and sub-tropics, afflicting over 150 million people in about 80 countries, causing debilitating symptoms such as elephantiasis (lymphatic filariasis), dermatitis and blindness (onchocerciasis or river blindness). Current control of lymphatic filariais relies on mass drug treatment with diethylcarbamazine（DEC) and albendazole while ivermectin is used against onchocerciasis. Repeat treatment is frequently required and this highlights the possibility of development of drug resistance. In addition, risk of adverse reactions following treatment excludes some patients from control programmes. Such circumstances urgently call for the development of complementary control measures such as vaccination. DNA vaccines are novel type of subunit vaccine in which production of the immunizing antigen is induced in host cells after introduction of a plasmid or recombinant viral vector containing the gene that encodes the antigen. DNA vaccines are relatively simple and cheap to produce and their stability makes them particularly suitable for use in remote regions that lack the cold-chain storage facilities required of conventional vaccines. Filarial nematodes are tissue-dwelling parasites that survive for many years in immunocompetent hosts. It is proposed that this longevity is, in part, due to the capacity of the parasites to modulate potentially lethal Th2 responses of their hosts. Consequently, the efficiency of a filarial vaccine may depend on how well it circumvents filarial-driven immunosuppression. To test this hypothesis, a series of DNA vaccines were developed and tested in the Litomosoides sigmodontis-mouse model of filarial infections. The L. sigmodontis Abundant Larval Transcript-1 (Ls-ALT) and Cysteine Protease Inhibitor (Ls-CPI) genes were cloned and genetically engineered to ablate their immunomodulatory properties by deleting the acid domain and by site mutation, respectively. In addition, the L. sigmodontis Venom Allergen Homologue (Ls-VAH) and Thioredoxin Peroxidase (Ls-TPX) were used in their native forms as vaccine targets. To improve immunisation and antigen processing by the host, these parasite genes were fused to a DNA sequence encoding an antibody that specifically binds dendritic cell surface protein (αDEC205 single chain Fv). DNA plasmids carrying mutated forms and/or anti-DEC205 were then co-administered with plasmids encoding the Th2 promoting cytokine IL4, and/or antigen-presenting cell activating MIP1α and Flt3L. Mice immunized with mutated forms (ADDALT and CPImu) of parasite antigens produced more specific antibody post-challenge and showed strongly increased lymphocyte stimulation above controls immunized with the native form. The immune response was further enhanced when plasmids encoding IL4, MIP1α, Flt3L and anti-DEC-205 forms were co-administered, resulting in production of a Th2/IgG1 phenotype. Significant reduction of worm burden (82.3%) was achieved by a cocktail vaccination which combined the ADDALT and CPImu candidates. Mice immunized with Ls-VAH and Ls-TPX DNA carried by αDEC205 elicited Th2-biased responses with up-regulated IgG1 and IgE antibodies as well as enhanced IL5, IL4, and IL13 and diminished IFNγ production compared to controls. The immune responses were further driven towards the Th2/IgG1 phenotype when Ls-VAH and Ls-TPX were injected with plasmids encoding ADDALT and CPImu and with the adjuvants Flt3L, MIP1α and IL4. This resulted in reduction in worm burden of 55.7% (cocktail vaccine containing Ls-VAH) and 41.6% (cocktail vaccine containing Ls-TPX) respectively in vaccinated animals.

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50

O'Connor, Daniel. "Genetics determinants of vaccine responses". Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:6e529d46-4a1a-423e-87e1-eaee8977791d.

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Vaccines have had a profound influence on human health with no other health intervention rivalling their impact on the morbidity and mortality associated with infectious disease. However, the magnitude and persistence of vaccine immunity varies considerably between individuals, a phenomenon that is not well understood. Recent studies have used contemporary technologies to correlate variations in the genome and transcriptome to complex phenotypic traits, and these approaches have started to provide fresh insight into the intrinsic factors determining the generation and persistence of vaccine-induced immunity. This thesis aimed to describe the relationship between genomic and transcriptomic variations, and the immunogenicity of childhood immunisations. Candidate gene and genome-wide genotyping was conducted to evaluate the influence of genetic variants on vaccine-induced immunity following childhood immunisation. Furthermore, contemporary methodologies were used to assess non-coding and coding gene transcript profiles following vaccination, to further dissect the molecular systems involved in vaccine responses. Key findings from this thesis include the description of the first genome-wide association studies into the persistence of immunity to three routine childhood immunisations: capsular group C meningococcal (MenC) conjugate vaccine, Haemophilus influenzae type b (Hib) conjugate vaccine and tetanus toxoid (TT) vaccine. Genome-wide genotyping was completed on over 2000 participants, with an additional 1000 participants genotyped at selected genetic markers. Genome-wide significant associations (p<5×10⁻⁸) were described between single- nucleotide polymorphisms (SNPs) in two genes, CNTN6 and ENKUR, and the persistence of serological immunity to MenC following immunisation of children 6-15 years of age. In addition, genome-wide significant associations were described between SNPs within an intergenic region of chromosome 10 and the persistence of TT-specific IgG concentrations following childhood immunisations. Furthermore, a number of variants in loci with putative involvement in the immune system such as FOXP1, the human leukocyte antigen locus and the lambda light chain immunoglobulin locus, were shown to have suggestive associations (p<1×10⁻⁵) with the persistence of vaccine-induced serological immunity. The fundamental challenge will be to describe functional mechanisms associated with these findings, and to translate these into innovative and pragmatic strategies to develop new and more effective vaccines.

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Tesi sul tema "Vaccine"

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