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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 leishmaniosesLeishmaniasis 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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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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Thompson, Fiona Mary. "Malaria immunology and vaccine development." Thesis, University of Southampton, 2008. https://eprints.soton.ac.uk/67626/.
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This thesis describes work undertaken by the author at the University of Oxford. It begins by providing an introduction to malaria infection and pathophysiology, and a review of the latest attempts to produce an effective malaria vaccine. It goes on to describe the rationale behind the vaccines developed by the University of Oxford and others. A brief introduction to the process of planning and carrying out clinical trials of vaccines is then provided, and is followed by chapters describing two clinical trials, designed to test the safety, immunogenicity and then efficacy of candidate malaria vaccines. These trials were performed in Oxford, to examine two different vaccination approaches. The first intended to broaden the specificity of the vaccine induced immune response, by providing multiple antigens in one vaccine, aiming thereby to improve protection from malaria infection. The second regimen used a combination vaccine intending to induce both humoral and cellular immunity simultaneously, thereby providing enhanced efficacy against malaria infection. Neither approach was sufficient to provide protection from infection in the challenge studies described; however, some impact on the disease was detected in the second study. This is examined in detail. The laboratory work described studies background immune responses (both cellular and humoral) to vaccine antigens in a malaria exposed population, intended to support the inclusion of these antigens in the multi-antigen vaccine. The remaining chapters describe work in parasite life cycle modelling, undertaken to aid interpretation of results of these clinical trials, and finally an examination of the clinical course of malaria in the control volunteers who have taken part in the many challenge studies conducted in Oxford.
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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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Brune, Karl Dietrich. "Engineering modular platforms for rapid vaccine development." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:41d57165-6e7c-4ca7-8025-b5ec31794c8c.
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Vaccines have saved more lives than any other medical intervention. Recombinant vaccines provide unmatched safety profiles, but at the expense of reduced immunogenicity. Virus-like particles (VLPs) resemble viruses in size, shape and repetitive arrangement but are devoid of pathogenic genetic material and therefore safe. Poor immunogens can be rendered immunogenic by display on VLPs. Successfully decorating VLPs is still a major challenge. Genetic fusion or chemical modification is often time-consuming and can lead to misassembly or misfolding, which obstructs generation of the desired immune response. SpyCatcher is a genetically encodable protein, previously engineered to form a covalent isopeptide bond to its peptide-partner SpyTag. Presented in this thesis are SpyCatcher-VLPs, based on the fusion of SpyCatcher to the bacteriophage VLP AP205. SpyCatcher- VLPs can be conveniently conjugated with SpyTag fused antigens, simply by mixing. I demonstrate the modularity of this approach by covalently linking several complex, cysteine-rich malarial antigens to SpyCatcher-VLPs, such as the transmission-blocking antigen Pfs25 and the blood-stage antigen CIDR. A single administration of Pfs25-SpyTag conjugated to SpyCatcher-VLPs induced potent antibody generation against Pfs25, even in the absence of adjuvant. Anti-Pfs25 antibodies induced by this platform conveyed potent transmission-blocking activity in the mosquito vector. The thesis further demonstrates the feasibility of more complex Catcher-nanoparticle architectures. The previously engineered SnoopCatcher covalently reacts with SnoopTag peptide and is orthogonal to the SpyCatcher / SpyTag pair. IMX313 is an engineered chimera of the multimerization domain of chicken complement inhibitor C4-binding protein. This work describes fusion of SnoopCatcher and SpyCatcher to IMX313, which yields independently addressable Catcher-moieties on a single IMX313 nanoparticle. Display of two antigens on one particle may enable single-particle, multi-disease vaccines as well as multi-stage vaccines to tackle immune evasion of parasites. The platforms presented should accelerate and enhance vaccine development and may create opportunities for imaging and metabolic engineering.
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Flock, Margareta. "Development of a vaccine against strangles /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-500-3/.
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Poobalane, Saravanane. "Aeromonas hydrophila vaccine development using immunoproteomics." Thesis, University of Stirling, 2007. http://hdl.handle.net/1893/195.
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Aeromonas hydrophila is an opportunistic pathogen that causes a wide range of symptoms and diseases in fish. Development of a commercial vaccine has been problematic due to the heterogenicity between isolates of A. hydrophila. A new approach using immunoproteomics was used in this study to try to develop a vaccine that would protect against a wide range of A. hydrophila strains. The virulence of 14 isolates of A. hydrophila from different geographical regions was determined in common carp (Cyprinus carpio) indicating that 6 isolates were virulent, while 8 isolates were avirulent. Expression of cellular and extracellular products (ECP) of six of these isolates (4 virulent and 2 avirulent isolates) were examined following culture of the bacterium in vitro, in tryptic soy broth, and in vivo, in dialysis tubing placed within the peritoneal cavity of carp. Two types of molecular weight cut off tubes (25 and 100 kDa) were used for the implants. Whole cell (WC), outer membrane protein (OMP) and ECPs of the bacteria grown in vitro and in vivo were analysed by 1 dimensional sodium dodecyl sulphate-polyacrylamide gel electrophoresis (1D SDS-PAGE). Additionally, 2D SDS-PAGE was used to analyse WC preparations of A. hydrophila grown in vitro and in vivo. The production of unique proteins and up and down-regulation of protein expression were observed in all the preparations of bacteria grown in vitro and in vivo. Unique bands were seen in the 1D SDS-PAGE at 58 and 55 kDa for WC and OMP preparations, respectively, for all the isolates cultured in vivo. Bands of increased intensity were observed at 70, 55, 50 and 25 kDa with WC preparations for the virulent isolates cultured in vivo. Analysis of WC preparations by 2D SDS-PAGE indicated differences in the expression of spots between bacteria cultured in vitro and in vivo. A number of unique spots, mostly between 30 and 80 kDa with pI values ranging from 5.0-6.0 were observed in the bacteria grown in vivo. The protein profiles of different preparations (WC, OMP, ECP) of bacteria cultured in vitro and in vivo were screened by 1D Western blot using antibodies from carp artificially infected with different isolates of A. hydrophila to identify potential vaccine candidates. The WC preparations of A. hydrophila (T4 isolate) grown in vitro were also analysed by 2D Western blot. A 50 kDa protein of A. hydrophila was found to be the most immunogenic molecule in both WC and OMP of bacteria grown both in vitro and in vivo. The protection efficacy of this protein was determined in goldfish by vaccinating fish with electro-eluted 50 kDa protein then challenging the fish with A. hydrophila. Fish were also passively immunised with fish sera raised to the 50 kDa protein and then challenged. The relative percentage survival (RPS) was 67 % in the vaccination trial, while the results were inconclusive for the passive immunisation trial. The 50 kDa protein was confirmed to be the S-layer protein of A. hydrophila following identification using matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS). Recombinant S-layer protein was then produced and the cross-protection efficacy of this protein against six virulent isolates of A. hydrophila was confirmed in a large scale vaccination trial using carp. The RPS value for the 6 isolates of A. hydrophila ranged from between 56 and 87 %. The results of this project suggest that the immunogenic S-layer protein of A. hydrophila could be used as a common antigen to protect fish against infection by different isolates of this pathogenic bacterium.
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Beard, Jody. "Early development of a hookworm vaccine." Thesis, University of Nottingham, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.416306.
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Aguilar, Roberto III. "Development of A Testicular Cancer Vaccine." Cleveland State University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=csu1461270103.
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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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Maas, Alexander. "DIVA vaccine development against Actinobacillus pleuropneumoniae infection." [S.l.] : [s.n.], 2006. http://deposit.ddb.de/cgi-bin/dokserv?idn=983732574.
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Hota-Mitchell, Sheela. "Molecular approaches to vaccine development against schistosomiasis." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape17/PQDD_0004/NQ32311.pdf.
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Leung, Beatrice Pui See. "Development of a DNA vaccine against melioidosis." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0018/MQ55225.pdf.
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Leduc, Isabelle. "Strain typing and vaccine development for chancroid." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/NQ66163.pdf.
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Al, Yaghchi C. "Development of virus-infected cancer cell vaccine." Thesis, Queen Mary, University of London, 2016. http://qmro.qmul.ac.uk/xmlui/handle/123456789/18408.
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Oncolytic viruses can be genetically modified to limit their replication in normal cells rendering them a cancer specific treatment. In addition, they can induce a 'danger signal' in the form of pathogen- and damage-associated molecular patterns leading to anti-tumour immunity. Furthermore, they can be armed with various immunomodulatory molecules to further enhance anti-tumour immunity. In this project I aim to exploit these qualities to develop a translatable cancer vaccine. Virus-infected cancer cells were injected subcutaneously in a prime/boost regimen. Dying cancer cells will release the required danger signal leading to dendritic cell activation and cross-presentation of tumour associated antigens to T cells to elicit an anti-tumour immune response. Our results in the murine pancreatic cancer model showed that vaccination with virusinfected DT6606 cells induced tumour specific immunity capable of protecting vaccinated animals against re-challenge with tumour cells. The highest level of interferon gamma production, a surrogate marker of anti-tumour immunity, was achieved when animals were primed with adenovirus-infected cells. There was no significant difference between various boost groups. To enhance the safety of the proposed protocol a secondary treatment was introduced to arrest the proliferation of tumour cells prior to injection. Our results confirmed that secondary treatment with mitomycin does not affect the induction of tumour specific immunity and it does not affect the release of pathogen-associated molecular patterns in the form of viral proteins and DNA. To test our vaccination regimen in head and neck squamous cell carcinoma (HNSCC) we develop a clinically relevant mouse model using SCC7, B4B8 and LY2 cells to replicate various clinical scenarios including locally advancing disease and post excision locoregional recurrence. Vaccinating mice with HNSCC cells pre-infected with our recently developed tumour-targeted triple-deleted adenovirus (AdTD) resulted in a cell-specific antitumour immune response. In addition, it resulted in an increase in effector memory T-cells of both CD4+ and CD8+ phenotypes. Efficacy studies showed our vaccination can significantly slow down the growth rate of tumours in locally advancing disease. This led to increase survival of the vaccinated mice although it did not reach statistical significance. To further enhance the efficacy of our vaccination regimen, we aimed to increase T cell trafficking to the tumour site. CCL25 is a gut homing chemokine. Priming T cells in the presence of CCL25 will lead to upregulation of the surface expression of α4β7 integrin. The latter is a ligand of MAdCAM-1, a cell adhesion molecule highly expressed in the gut and pancreatic tumours. The α4β7/MAdCAM-1 interaction results in preferential homing of activated T cells to these organs. We hypothesised that vaccinating mice with pancreatic tumour cells pre-infected with a CCL25-armed adenovirus will lead to increased T cell trafficking to pancreatic tumours leading to enhanced efficacy. Although we achieved encouraging results in our pilot experiment, we did not detect any significant increase in α4β7 expression once we added a secondary treatment to the vaccination protocol. Similarly, efficacy experiments in the pancreatic cancer transgenic KPC mice did not show any difference in survival between AdTD-CCL25 and the control virus although both groups showed a trend towards increased survival compared to naïve mice. In conclusion, Virus-infected cancer cell vaccine is a potentially promising immunotherapeutic strategy that can be combined with traditional cancer therapies to increase survival of HNSCC and pancreatic cancer patients.
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Hussain, Muattaz Yassein. "Studies on development of a Leishmanial vaccine." Thesis, University of Strathclyde, 2017. http://digitool.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=29430.
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Leishmaniasis is a disease caused by infection with the obligate intracellular parasite of the genus Leishmania. Leishmaniasis is a public health problem; it is estimated that approximately 12-15 million people worldwide are infected. An estimated 1.5-2 million new cases occur each year, 350 million people are at risk of infection, and it causes 70000 deaths per year. Therefore, development of a vaccine to prevent infection is required. The overall aim of this study was to develop a vaccine to protect against Leishmania infection using live nonpathogenic L. tarentolae transfected with gamma glutamylcysteine synthetase (γGCS) from three different species (L. donovani, L. mexicana and L. major). Previous studies for expressing recombinant γGCS using E. coli as an expression system have shown that it was not possible to produce pure full-length recombinant γGCS protein. Therefore, in this project, using an expression vector that is phylogenically more like Leishmania. L. tarentolae has been used as an expression system for eukayotic recombinant proteins. Studies of the expression of L. donovani, L. mexicana and L. major γGCS recombinant proteins showed that parasites integrated with a green fluorescent protein γGCS-His gene gave stable expression of the fusion protein for six months without the requirement for antibiotics to maintain expression of the gene insert. Supplementing the culture medium with hydrogen peroxide (H2O2) increased proliferation of parasites in cell culture. The addition of a 12 μM of H2O2 supplement increased the number of the parasites in cell culture, which can conclude that expression of the GFP-γGCS-His recombinant protein has been increased. Expression of the recombinant GFP-γGCS-His protein produced full-length protein and truncated protein, but after isolation from an affinity column, it was impossible to produce pure full-length protein for all three transfected parasites. Therefore, this purification method failed to remove non-specific protein contamination. The live non-pathogenic lizard parasite, L. tarentolae, expressing elected Leishmania antigens has recently provided a promising new approach as a safe and effective live vaccine candidate to prevent Leishmaniasis. Here, this study evaluated the immunoprotective potential of a live vaccine against L. major infection in BALB/c mice, using L. tarentolae transfected with the GFP-γGCS-His sequence gene from one of three different species (L. donovani, L. major or L. mexicana) or a ‘triple vaccine’ using a 1:1:1 mixture of L. tarentolae transfected with the GFP-γGCS-His sequence gene of the three pathogenic species. Vaccination with transfected L. tarentolae with GFP-γGCS-His gene from L. donovani, L. major and L. mexicana (triple vaccine) induced significant parasite specific Th1 immune responses based on antibody titres and cytokine production in vitro in stimulated splenocytes and popliteal lymph nodes from immunised mice. Vaccination by subcutaneous injection with the triple vaccine caused the highest percentage reduction in parasite burdens compared to controls ± SE, was 94% ± 0.01 in L. major infected mice. Vaccination with L.t L. maj GFP-γGCS-His, L. mex GFP-γGCS-His and L. don GFP-γGCS-His parasites failed to give significant protection against L. major infection, but vaccination with L. t L. maj GFP-γGCSHis resulted in an 86% ± 0.01 suppression in parasite burden compared to controls. In conclusion, the results of this study indicate that vaccination with transfected L. tarentolae parasites against L. major infection enhanced the protective efficacy and that the triple vaccine is a potential vaccine candidate.
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Gebril, Ayman Mohamed. "Development of a mucosal vaccine delivery system." Thesis, University of Strathclyde, 2013. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=24878.
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Ramamoorthy, Sheela. "Approaches towards vaccine development against Neospora caninum." Diss., Virginia Tech, 2006. http://hdl.handle.net/10919/28054.
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Neospora caninum is an apicomplexan parasite that causes neuromuscular paralysis in dogs and abortions in cattle. N. caninum is responsible for losses of several million dollars to the dairy and beef industries in several parts of the world. The key players in the host immune response to N. caninum include CD4+ T cells, the Th1 cytokines IL-12, Interferon gamma and IgG2a isotype antibodies. There are currently no chemotherapeutic agents that are effective against adult cattle neosporosis. A commercially available, inactivated vaccine induces the undesirable Th2 type of immunity against N. caninum. Therefore, two approaches towards vaccine development against N. caninum that were designed to induce potent cell mediated immunity have been explored in this dissertation. The first approach consisted of the development of a bivalent recombinant vaccine for both brucellosis and neosporosis, while the second approach involved gamma irradiation of N. caninum tachyzoites for use as an attenuated vaccine against N. caninum.
Since N. caninum research has been conducted with several strains of mice and the different strains of mice vary in their susceptibility to infection with N. caninum, there is a need to develop a standard lab animal model for N. caninum. A gerbil and a C57BL/6 mouse model for N. caninum vaccine testing have been developed. It was found that the LD50 of N. caninum tachyzoites in gerbils was 9.3 x105 tachyzoites per gerbil delivered intra-peritoneally, (i.p) while for C57BL/6 mice the LD50 was 1.5 x107 tachyzoites per mouse delivered i.p. Vertical transmission rates in C57BL/6 mice infected with N. caninum tachyzoites during mid-gestation were determined and found to be in the range of 96-100%.
Putative protective antigens of N. caninum that included MIC1, MIC3, GRA2, GRA6 and SRS2 were expressed in B. abortus strain RB51 to create recombinant vaccine strains. C57BL/6 mice were vaccinated with either the recombinant strains or the irradiated tachyzoites. Antigen specific IgG2a and IgG1 responses and high levels of interferon gamma and IL-10 were induced by vaccination. Mice vaccinated with irradiated tachyzoites, RB51-MIC1 and RB51-GRA6 were completely protected against lethal challenge, while the mice vaccinated with RB51-SRS2, RB51-GRA2 and RB51-MIC3 were partially protected.
To determine the efficacy of the vaccines in preventing vertical transmission of N. caninum, mice were vaccinated and bred after administration of a booster dose four weeks after the primary vaccination. Antigen specific IgG1 and IgG2a and significant levels of IFN-ã and IL-10 were detected in vaccinated, pregnant mice. Pregnant mice were challenged with 5 x 106 N. caninum tachyzoites between days 11-13 of pregnancy. Brain tissue was collected from pups three weeks after birth and examined for the presence of N. caninum by a semi-nested PCR. Protection against vertical transmission elicited by the RB51-GRA6, RB51-MIC3, irradiated tachyzoite, RB51-GRA2, RB51-MIC1 and RB51-SRS2 vaccinated groups were 43%, 38%, 34%, 34%, 18%, and 7% respectively. Since not all the antigens that were highly protective against acute disease were not very effective in preventing vertical transmission, the role of the selected antigens in preventing acute disease and vertical transmission appear to differ. Only GRA6 was found to be effective in protecting against an acute lethal challenge as well as preventing vertical transmission 43% of the time.
In summary, two animal models for the testing of N. caninum vaccines were developed. N. caninum protective antigens were successfully expressed in B. abortus strain RB51. The irradiated tachyzoite and recombinant RB51-Neospora vaccines were highly effective in protecting against acute neosporosis and partially protective against vertical transmission. Therefore, both these approaches show great promise as practical and effective means to achieve the goal of successful prophylaxis against N. caninum induced abortions and reduce the chances of vertical transmission.Ph. D.
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Cash, Devin R. "DRUG AND VACCINE DEVELOPMENT FOR NEISSERIA GONORRHOEAEA." VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4093.
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Neisseria gonorrhoeae, the causative agent of the STI gonorrhea, is not preventable by vaccination and is rapidly developing resistance to antibiotics. One important strategy for gonococcal survival in the host is iron acquisition in the face of nutritional immunity. To overcome iron limitation, the gonococcus expresses TonB dependent transporters (TdTs), outer membrane proteins that facilitate nutrient acquisition. Of the TdTs, the transferrin (Tf), lactoferrin (Lf), and hemoglobin (Hb) receptors hijack iron directly from host proteins, and studies have already shown that the Tf receptor is essential for the initiation of human infection. Given that the TdTs are virulence factors, they are widely conserved across strains, and are not subject to antigenic variation, they are ideal targets for novel therapeutics and vaccine development. As such, studies exploring these proteins and their potential as vaccine candidates and antimicrobial targets are needed. In this study we report that loops of the Tf receptor protein TbpA are not strongly immunogenic, and the antibodies raised against them are incapable of inhibiting TbpA-Tf interactions on the gonococcal cell surface. We also report that the loop 3 helix motif of TbpA is a critical functional domain for Tf-binding and iron uptake; however, no single residue was identified that was essential for these functions. In addition, we report the development of a platform for the structure-function analysis of HpuA, a member of the poorly studied Hb receptor. We also present evidence that novel small molecules may be able to inhibit TbpA-Tf interaction, presenting the Tf receptor as a novel, species-specific antimicrobial target. Finally, we demonstrated that a novel drug, OSU-03012, has antimicrobial activity against the gonococcus through down-regulation of DnaK, a protein chaperone. These findings suggest that DnaK, a widely conserved protein, may be a universal target for antimicrobial development. These studies provide insight into the structure function relationship of TbpA, the drug potential of DnaK, and lay the framework for future investigations of the TdTs for use in a multi-antigen vaccine.
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Mughal, Muhammad Kashif. "Development of Pneumolysin as a vaccine candidate." Thesis, University of Glasgow, 2014. http://theses.gla.ac.uk/5151/.
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More than 90 serotypes of Streptococcus pneumoniae are responsible for causing a number of invasive and non-invasive diseases in humans. To combat this pathogen there are two types of vaccines available namely pneumococcal polysaccharide vaccine (PPV) and pneumococcal conjugate vaccine (PCV). Although these vaccines have reduced the incidence and prevalence of pneumococcal diseases yet these vaccines are unable to curb the disease and have some potential drawbacks. The problems associated with PPV is inability to mount appropriate immune response in young children (<2 years) of age and with PCV, disadvantages are serotype replacement and affordability. These disadvantages have shifted the focus of attention on developing vaccines that can provide serotype independent protection and is cost effective and can be used in developing and under-developing countries as well. Pneumolysin (PLY) is one of the members of cholesterol dependent cytolysin (CDC) family and is one of the key virulence factors of the bacterium. PLY has a wide variety of functions but the two most important functions are the ability to lyse the host cell by forming pores and activating the complement pathway. Studies have shown recombinant PLY to be a good vaccine candidate; however PLY is toxic and cannot be used as a vaccine. A number of toxoid versions have been made targeting residues responsible for toxin’s lytic activity and tested in-vivo models. ∆6 PLY is a toxoid made by deleting two amino acid residues and seems to be a potential candidate to be included in next generation pneumococcal vaccines. ∆6 PLY is immunogenic and act as an adjuvant as well, however ∆6 PLY causes the aggregation of red blood cells and therefore cannot be used in the vaccine. The present study is carried out to identify the residue/s responsible for causing this agglutination behaviour. A number of molecular biology techniques were used in this study for making mutants in different backgrounds and were tested for their lytic and agglutination activity. The study identified the single residue in domain 4 causing aggregation of the red blood cells. The agglutination negative mutant was then tested at different concentrations through a series of experiments including hemagglutination assays, fluorescence microscopy and fluorescence activated cell sorter (FACS). The study also highlighted some important regions of the toxins responsible for maintaining structure of the toxin. This new toxoid seems to have the potential to be used in future pneumococcal vaccines alone, in combination with other pneumococcal proteins and/or polysaccharides.
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Woodberry, Tonia. "Development of a mucosal HIV polytope vaccine /." [St. Lucia, Qld.], 2001. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16255.pdf.
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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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Hand, Nicholas. "Development of a Recombinant Attenuated Salmonella Cancer Vaccine." Thesis, The George Washington University, 2017. http://pqdtopen.proquest.com/#viewpdf?dispub=10635177.
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New treatments for neuroblastoma are desperately needed; high-risk neuroblastoma patients have a less than 50% five-year survival rate despite intensive treatment. The greatest impact on improving survival rates for cancer patients in recent years is the result of a number of immunotherapeutic approaches. A proportion of high-risk neuroblastoma patients undergo spontaneous regression, possibly mediated by the immune system, indicating the potential of immunotherapies targeting neuroblastoma-associated antigens. Recombinant attenuated Salmonella vaccines (RASV) are cost-effective and have shown efficacy against a number of pathogen-associated antigens and are easily adapted for use as cancer immunotherapies. Here we cloned survivin, a neuroblastoma tumor-associated antigen into RASV expression plasmids to develop 24 RASV candidate vaccines with an array of select phenotypes. While conventional recombinant attenuated Salmonella vaccines are permanently attenuated, the RASV used here are engineered with inducible in vivo attenuation and other delayed phenotypes shown to improve immune responses. Survivin expression did not impact the growth or stability of any of the RASV constructs. Six of the constructs were tested in vivo, the RASV survived in the gut lumen, and all RASV-immunized mice produced anti-Salmonella responses. Protein/adjuvant immunized mice produced humoral and cellular survivin specific immune responses; however two independent in vivo experiments showed that no survivin specific immune responses were induced in survivin-expressing RASV immunized mice. Based on the results, a number of improvements to the future development of the vaccine are suggested.
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Smith, Claire Mary. "Development of new vaccine strategies against Streptocarpus pneumoniae." Thesis, University of Leicester, 2005. http://hdl.handle.net/2381/30506.
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In this thesis I have shown that peptide mimotopes of both serotype 6B and 9V pneumococcal polysaccharide, following vaccination, can induce specific and anti-CPS antibodies and can protect mice against developing pneumococcal disease. This was achieved using previously described monoclonal antibodies (mAb) directed against the capsular polysaccharide of S. pneumoniae serotype 6B and 9V. These mAbs were shown to protect mice in passive immunisation experiments, and were then used to screen phage-displayed peptide libraries. In total four peptide mimics of serotype 9V pneumococcal polysaccharide and seven mimics of serotype 6B pneumococcal polysaccharide were identified. The peptides were conjugated to keyhole limpet haemocyanin (KLH) and were used to immunise mice. Two peptides, MP7 and MP13, were found significantly protect mice against a lethal challenge with S. pneumoniae and induce anti- capsule specific antibodies. This project showed that the poor immunogenicity of capsular polysaccharide could be improved using peptide mimics. Secondly, this thesis confronts the problem of high vaccine production costs by developing a transgenic plant capable of manufacturing pneumococcal polysaccharide. The four genes involved in type 3 pneumococcal capsular polysaccharide synthesis are closely linked on the bacterial chromosome, arranged within a single locus (cassette). I cloned a copy of the serotype 3 capsule synthase gene, cps3S, into a plant expression vector, which was transformed into tobacco plants by Agrobacterium-mediated gene transfer. After cultivating a second generation of transgenic plants, we have shown the stable integration of the cps3S gene and production of type 3 pneumococcal polysaccharide. This discovery aims to confront the high vaccine production costs associated with pneumococcal vaccines.
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Clark, Douglas Alexander Stuart. "Haemonchus contortus and hookworms : parallels in vaccine development." Thesis, University of Glasgow, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.437717.
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Moynihan, Jennifer Susan. "The development of a synthetic hepatitis B vaccine." Thesis, Royal Veterinary College (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.392197.
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Mukhopadhyay, Tarit K. "Rapid vaccine development using a micro-scale platform." Thesis, University College London (University of London), 2008. http://discovery.ucl.ac.uk/1444233/.
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Vaccine research and development is becoming increasingly important because of the potential to create a blockbuster drug, such as Prevnar. However, the development pipeline continues to be a limiting factor in commercialising a vaccine. In this thesis a micro-scale platform is created to mimic the key features of a unit operation so that it is possible to calculate the impact of a commercial manufacturing process using this scaled down platform. Two model vaccines were applied to the micro-scale platform, a new Meningitis serogroup B vaccine based on the outer membrane vesicle proteins of Neisseria lactamica and the licensed UK Anthrax vaccine. To create the platform, cultures of Neisseria lactamica in microwells have been combined with statistical techniques such as Design of Experiments to increase biomass production by four fold and antigen yields by 165%. Microwell experiments were coupled with SELDI-TOF mass spectroscopy to enable a detailed insight into the changing vaccine composition with culture conditions. Microwell results here were scaled up to 2, 8 and 50 litre fermentations using dimensionless analysis based on the oxygen mass transfer co-efficient, kLa. The effects of pilot scale downstream processing were investigated using ultra scale down tools and models. It was possible to characterise product losses and the robustness of the process stream by conducting shear experiments. Furthermore, final product filter sterilisation was investigated using a microwell platform coupled with statistical analysis, particle sizing and DLVO theory. Through these studies it was possible to minimise aggregation and increase antigen transmission through the membrane from 35% to 78%. The platform was applied to cultures of Bacillus anthracis Sterne 34F2, the Anthrax vaccine strain. Microwells were used to mimic Thompson bottle cultures and ascertain the main factors which effect B. anthracis growth and antigen production. The cell density dependent signalling mechanism, known as quorum sensing was found to control growth and antigen production in B. anthracis and that a protein below 5kDa may be involved in the quorum sensing mechanism along with the auto inducer molecule, AI-2. Finally, transfer of B. anthracis vaccine production from static culture to a homogenous stirrer tank culture environment was investigated using a miniature bioreactor. It found that transfer was possible and that doing so reduced the culture time from 28 hours to just 14 hours, increasing production of PA and LF vaccine antigens by 25% and 78% respectively. Aeration of the culture showed that biomass production could be improved upon, but it had a detrimental effect on antigen expression.
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Vieira, Coutinho Abreu Gomes Iliano. "Molecular aspects of sand-fly-based vaccine development." Diss., Kansas State University, 2011. http://hdl.handle.net/2097/9224.
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Doctor of PhilosophyDepartment of Entomology
Marcelo Ramalho-Ortigao
The emergence and reemergence of vector-borne diseases pose significant threats to humans and other animals worldwide. Although vector control relies mostly on insecticides, the emergence of insecticide resistance urges for the development of new strategies to control the spread of such diseases. For sand fly-transmitted leishmaniasis, Transmission Blocking Vaccines (TBV) may constitute a feasible strategy to impair Leishmania transmission from infected to uninfected vertebrate hosts. Moreover, sand fly saliva-based vaccines represent an alternative or complementary approach as these vaccines protect different mammalian hosts against Leishmania. Based on the potential use of sand fly molecules as vaccines against leishmaniasis, we assessed the potential of Phlebotomus papatasi midgut secreted proteins as TBV candidates and the expression variability of sand fly salivary gland genes. Regarding the TBV approach, we took advantage of the RNA interference (RNAi) technique to evaluate the effects of knocking down P. papatasi midgut-specific genes on Leishmania major development within the sand fly midgut. Whereas peritrophin 1 (PpPer1) knock down led to increased Le. major load by 39%, knocking down chitinase 1 (PpChit1) reduced Le. major load in P. papatasi midguts by 63%. Thus, our data strongly suggest that PpChit1 constitutes a potential target for TBV approaches against Leishmania transmission in endemic areas. Concerning protective vaccines based on salivary gland secreted proteins, we searched for expression polymorphism in selected salivary gland genes in natural and colonized populations of P. papatasi. Significant differences in salivary gland gene expression were not only exhibited in P. papatasi specimens collected in different geographic habitats but also seasonal difference in gene expression was displayed by specimens belonging to the same population. As antigen dose is an important component of immune responses, different doses of salivary protein inoculated into host skin may interfere with vaccine protection. Thus, the efficacy of sand fly saliva-based vaccine upon exposure to different salivary protein doses must be evaluated before deployment in endemic areas. Our data also ruled out some biotic factors as responsible for fine-tuning the expression of such genes. Overall, this dissertation makes significant contribution to the development of sand fly-based vaccines against leishmaniasis.
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Ahmadi, Fard Ala. "Ebola hemorrhagic fever: outbreaks, modeling, and vaccine development." Kansas State University, 2016. http://hdl.handle.net/2097/32649.
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Master of ScienceDepartment of Biological & Agricultural Engineering
Caterina M. Scoglio
Lisa R. Wilken
Between the years 2014 and 2015, the world experienced a catastrophic outbreak of Ebola virus, which killed over 26,000 people. Several authorities and organizations actively participated in fighting the epidemic. Infectious disease modelers proved to be invaluable towards this goal. This report provides a background on the Ebola epidemic in West Africa and reviews the biological features of the Ebola virus. Moreover, this report applies a new model for Ebola propagation using data collected by the World Health Organization during the span of the outbreak. The model estimates the reproduction number and assesses the role of mitigation strategies in slowing down the progress of the disease. The report also concludes a review of recent advancements in vaccine production against Ebola.
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Duvenage, Lucian. "Beak and feather disease virus candidate vaccine development." Master's thesis, University of Cape Town, 2012. http://hdl.handle.net/11427/12785.
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Includes bibliographical references.[Fix supervisors field.] Psittacine beak and feather disease, caused by a circovirus known as beak and feather disease virus (BFDV), is a threat to both wild and captive psittacine species. There is currently no vaccine against BFDV and safe and affordable vaccine candidates are needed to alleviate the disease burden caused by this virus. Production of the BFDV's major antigenic determinant, the capsid protein (CP), in the inexpensive and highly scalable plant expression system, could satisfy these requirements as a potential subunit vaccine. In this work, truncated CP (ÄN40 CP) was first expressed in E. coli to successfully generate anti-CP polyclonal antibodies. ÄN40 CP and full-length CP transient expression in tobacco (Nicotiana benthamiana) was optimised as fusions to elastin-like polypeptide (ELP). Fusion of CP or ÄN40 CP to ELPs of different lengths was shown to increase yield relative to unfused CP/ÄN40 CP. Free ELP and a GFP-ELP fusion could be purified by inverse transition cycling (ITC), using centrifugation and membrane filtration methods. A ÄN40 CP-ELP fusion expressed in plants could be partially purified and represents low-cost vaccine candidate against BFDV. A candidate DNA vaccine expressing ÄN40 CP was also evaluated for expression of the antigen in vitro and may prove useful in a prime-boost regimen together with one of the plant-produced vaccine candidates.
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Grieves, Jessica Louise. "Respiratory Syncytial Virus: Rodent Models and Vaccine Development." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1354147313.
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Coull, Jason J. "A molecular biology strategy for ectoparasite vaccine development." Thesis, University of Aberdeen, 1997. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU602286.
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De, Sai Lata. "Chemically Treated Malaria Parasites as a Multimodal System for Vaccine Development." Thesis, Griffith University, 2016. http://hdl.handle.net/10072/367793.
Full textAbstract:
Current measures to control malaria are becoming unreliable due to the emergence of parasite and vector resistance. Therefore, development of a safe and effective vaccine is essential for the eventual eradication of malaria. Challenges that have hindered malaria vaccine research include antigenic polymorphism, reproducing correlates of protection from preclinical to clinical studies and the paucity of challenge models to test vaccine efficacy. Altering the virulence of the whole parasite using genetic manipulation, irradiation or chemical treatment has been used as an alternative vaccine strategy to
address these challenges. A whole parasite vaccine should elicit a potent, protective immune response and overcome the limited efficacy observed in leading subunit vaccine candidates, such as RTS,S.
Previous publications from our laboratory have demonstrated that chemically attenuated blood-stage parasites persist in the blood at sub-patent levels. In the P. chabaudi rodent model, CD4+ T cells mediated protection upon homologous and heterologous challenge in an antibody-independent manner. However, in the P. yoelii model, protection was mediated in a cell- and antibody-dependent manner. Prior to testing this approach in humans, a pilot study was done in non-splenectomised Aotus nancymaae monkeys to investigate the persistence and immunogenicity of a single dose of chemically
attenuated ring-stage P. falciparum FVO parasites (CAPs). These CAPs induced proliferation of parasite-specific T cells; however, no parasite-specific IgG was detected. These experiments lay the groundwork for assessment of CAPs in humans as a potential vaccine against malaria.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
Institute for Glycomics
Science, Environment, Engineering and Technology
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Masterson, W. J. "Studies on the epitopes of the surface coat glycoprotein of a variant of Trypanosoma brucei brucei." Thesis, University of Cambridge, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.383834.
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Whyte, Paul. "Identification and characterisation of protective B cell epitopes on the fusion protein of respiratory syncytial virus." Thesis, University of Reading, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.241353.
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Beesley, Katrina M. "Expression of HBcAg fusion proteins in yeast and an investigation of their immunological properties." Thesis, Open University, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.292342.
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Okay, Sezer. "Development Of Recombinant Vaccines Composed Of Plpe And Omph From Pasteurella Multocida A:3." Phd thesis, METU, 2011. http://etd.lib.metu.edu.tr/upload/12613980/index.pdf.
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Pasteurella multocida serotype A:3 is a gram-negative bacterial pathogen which is one of the causative agents of shipping fever in cattle. In this study, ompH and two fragments of plpE gene (plpEN and plpEC) were cloned from the genomic DNA of P. multocida P-1062 (ATCC 15743, serotype A:3) and plpEN-ompH and plpEC-ompH fusions were constructed. In vitro expression of the genes was shown in HEK-293 cells. Later, full-length plpE gene was cloned and the recombinant proteins were expressed in E. coli and purified. Three DNA vaccine formulations, namely pCMV-ompH, pCMV-plpEN-ompH and pCMV-plpEC-ompH and five recombinant protein based vaccines, PlpEN-OmpH, PlpEC-OmpH, OmpH, PlpEC and PlpE were generated. Recombinant proteins were formulated with at least one of the adjuvants: alum, CpG, alum-CpG, oil based and oil based-CpG. BALB/c mice were immunized with these vaccine formulations and their sera were used for the evaluation of antibody and serum IFN-&gammatiters. Protective capacities of the vaccines were also evaluated via challenge of mice with 10 LD50 of P. multocida A:3. DNA vaccines induced immune responses, but did not provide protection. All protein vaccine formulations increased antibody levels and CpG containing formulations enhanced serum IFN-&gamma
titers. 100 µ
g of PlpEC-OmpH protein adsorbed on alum adjuvant conferred 40% protection while no protection was obtained with PlpEN-OmpH. Next, the effects of CpG, or its alum and oil based combinations as adjuvants were investigated on PlpEC-OmpH mediated protection. The vaccine formulation composed of PlpEC-OmpH and oil based-CpG adjuvant conferred 100% protection. Finally, the mice were vaccinated with recombinant OmpH, PlpEC and PlpE formulated with oil based-CpG adjuvant. OmpH, PlpEC and PlpE formulations provided 50%, 60% and 100% protection, respectively. These findings implicated that recombinant PlpE and PlpEC-OmpH fusion proteins when formulated with oil based-CpG adjuvant are potent acellular vaccine formulation candidates against shipping fever.
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Selke, Martin. "Development of a DIVA vaccine against Salmonella Typhimurium infection." [S.l.] : [s.n.], 2006. http://deposit.ddb.de/cgi-bin/dokserv?idn=983732760.
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Huijbers, Elisabeth J. M. "Development of a Cancer Vaccine Targeting Tumor Blood Vessels." Doctoral thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-170887.
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A treatment strategy for cancer is the suppression of tumor growth by directing an immune response to the tumor vessels, which will destroy the tissue. In this thesis we describe the development of a vaccine that targets antigens expressed around angiogenic vasculature in most solid tumors. These antigens are alternative spliced extra domains of glycoproteins present in the extracellular matrix; e.g. the extra domain-B (ED-B) and extra domain-A (ED-A) of fibronectin and the C-domain of tenascin-C (TNCC). We show that it is possible to break self-tolerance and induce a strong antibody response against ED-B by vaccination. Furthermore, tumor growth was inhibited and the changes observed in the tumor tissue were consistent with an attack of the tumor vasculature by the immune system. For clinical development of therapeutic vaccines, targeting self-molecules like ED-B, a potent but non-toxic biodegradable adjuvant is required. The squalene-based Montanide ISA 720 (M720) in combination with CpG DNA fulfilled these requirements and induced an equally strong anti-self immune response as the preclinical golden standard Freund’s adjuvant. We have further characterized the immune response against ED-B generated with the adjuvant M720/GpG. The ED-B vaccine also inhibited tumor growth in a therapeutic setting in a transgenic mouse model of pancreatic insulinoma in which tumorigenesis was already initiated. Furthermore, antibodies against ED-A and TNCC could be induced in mice and rabbits. We analyzed the expression of ED-A in breast tumors of transgenic MMTV-PyMT mice, a metastatic breast cancer model, with the aim to use this model to study the effect of an ED-A vaccine on metastasis. We also detected ED-B in canine mammary tumor tissue. Therefore vascular antigens might also represent potential therapeutic targets in dogs. All together our preclinical data demonstrate that a vaccine targeting tumor blood vessels is a promising new approach for cancer treatment.
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Guan, Xin. "Development of DNA vaccine-based anti-tumor immunotherapeutic system." 京都大学 (Kyoto University), 2010. http://hdl.handle.net/2433/120528.
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Stell, Anneliese Jane. "Development of a DNA vaccine for canine malignant melanoma." Thesis, Royal Veterinary College (University of London), 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.502377.
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Brown, Alan Peter. "Necator americanus characterisation of secreted proteinases and vaccine development." Thesis, Nottingham Trent University, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.314108.
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Naylor, Clive John. "Studies on avian pneumoviruses including development of a vaccine." Thesis, University of Liverpool, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.385304.
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Hacking, G. N. V. "Novel approaches towards the development of an HIV vaccine." Thesis, University of Cambridge, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.308246.
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Suzuki, Saori. "Basic research for the development of hepatitis C vaccine." 京都大学 (Kyoto University), 2016. http://hdl.handle.net/2433/215372.
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Contents of the present thesis were published in the following articles. 1. Suzuki S, Mori K, Higashino A, Iwasaki Y, Yasutomi Y, Maki N, Akari H. 2016. Persistent replication of a hepatitis C virus genotype 1b-based chimeric clone carrying E1, E2 and p6 regions from GB virus B in a New World monkey. Microbiol Immunol 60:26-34. Copyright © 1999-2016 John Wiley & Sons, Inc.2. Yoshida T, Suzuki S, Iwasaki Y, Kaneko A, Saito A, Enomoto Y, Higashino A, Watanabe A, Suzuki J, Inoue K, Kuroda T, Takada M, Ito R, Ito M, Akari H. 2013. Efficient in vivo depletion of CD8+ T lymphocytes in common marmosets by novel CD8 monoclonal antibody administration. Immunol Lett 154:12-17.Copyright © 2013 Elsevier B. V.Kyoto University (京都大学)
0048
新制・課程博士
博士(理学)
甲第19546号
理博第4206号
新制||理||1604(附属図書館)
32582
京都大学大学院理学研究科生物科学専攻
(主査)教授 明里 宏文, 教授 岡本 宗裕, 教授 中村 克樹
学位規則第4条第1項該当
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Ramirez, Paredes J. G. "The fish pathogen Francisella orientalis : characterisation and vaccine development." Thesis, University of Stirling, 2015. http://hdl.handle.net/1893/21822.
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Piscine francisellosis in an infectious emerging bacterial disease that affects several marine and fresh water fish species worldwide, including farmed salmon, wild and farmed cod, farmed tilapia and several ornamental species, for which no commercial treatment or vaccine exists. During 2011 and the first semester of 2012, chronic episodes of moderate to high levels of mortality with nonspecific clinical signs, and widespread multifocal white nodules as the most consistent gross pathological lesion were experienced by farmed tilapia fingerlings at two different locations in Northern Europe. In this study such outbreaks of granulomatous disease were diagnosed as francisellosis with a genus-specific PCR, and 10 new isolates of the bacterium including the one named STIR-GUS-F2f7, were recovered on a new selective “cysteine blood-tilapia” agar and cysteine heart agar with bovine haemoglobin. Ultrastructural observations of the pathogen in Nile tilapia (O. niloticus) tissues suggested the secretion of outer membrane vesicles (OMVs) by the bacterial cells during infection in these fish. This represented the first documented report of isolation of pathogenic Francisella strains from tilapia in Europe. The phenotypic characterisation indicated that isolates recovered were able to metabolise dextrin, N-acetyl-D glucosamine, D-fructose, α-D-glucose, D-mannose, methyl pyruvate, acetic acid, α-keto butyric acid, L-alaninamide, L-alanine, L-alanylglycine, L-asparagine, L-glutamic acid, L-proline, L-serine, L-threonine, inosine, uridine, glycerol, D L-α-glycerol phosphate, glucose-1-phosphate and glucose-6-phosphate. The predominant structural fatty acids of the isolates were 24:1 (20.3%), 18:1n-9 (16.9%), 24:0 (13.1%) 14:0 (10.9%), 22:0 (7.8%), 16:0 (7.6%) and 18:0 (5.5%). Anti-microbial resistance analyses indicated that STIR-GUS-F2f7 was susceptible to neomycin, novobiocin, amikacin, ciprofloxacin, imipenem, gatifloxacin, meropenem, tobramycin, nitrofurantoin, and levofloxacin using the quantitative broth micro-dilution method, while the qualitative disc diffusion method indicated susceptibility to enrofloxacin, kanamycin, gentamicin, tetracycline, oxytetracycline, florfenicol, oxolinic acid and streptomycin. The use of the following housekeeping genes: mdh, dnaA, mutS, 16SrRNA-ITS-23SrRNA, prfB putA rpoA, rpoB and tpiA indicated 100% similarity with other isolates belonging to the subspecies F. noatunensis orientalis (Fno). Koch’s postulates were successfully fulfilled by establishing an intraperitoneal injection (IP) challenge model with STIR-GUS-F2f7 in Nile tilapia. Moreover, the challenge model was used to investigate the susceptibility of 3 genetic groups of tilapia to STIR-GUS-F2f7. The lowest amount of bacteria required to cause mortality was 12 CFU/ml and this was seen as early as only 24 hours post infection in the red Nile tilapia and in the wild type after 26 days, no mortalities were seen in the species O. mossambicus with this dose. The mortality in red O. niloticus was significantly higher than that of the other two tilapia groups when 12 and 120 CFU/fish were injected. It was also observed that when a dose of 1200 CFU/ml was used, the mortality in O. niloticus wild type was significantly lower than that of the other two tilapia groups and no differences were seen among the 3 groups when the highest dose (1.2 x105 CFU/fish) was used. The median lethal dose (LD50) of O. niloticus wild type was the most stable during the experiment (values around 104 CFU/ml) and the highest of the three groups after day 25 post infection. At the end of the experiment (day 45) the LD50 was 30 CFU/ml in the red Nile tilapia, 2.3x104 CFU/ml for the wild type and 3.3x102 CFU/ml for O. mossambicus. This pattern, where the LD50 of the red tilapia was lower than that of the other two groups, was observed during the whole experiment. The outcomes of these experiments suggested that the red Nile tilapia family appeared to be the most susceptible while the wild type Nile tilapia family the most resistant. The complete genome of STIR-GUS-F2f7 was sequenced using next generation sequencing (NGS) Illumina Hi-Seq platform™, and the annotation of the assembled genome predicted 1970 protein coding sequences and 63 non-coding rRNA sequences distributed in 328 sub-systems. The taxonomy of the species Francisella noatunensis was revised using genomic-derived parameters form STIR-GUS-F2f7 and other strains in combination with a polyphasic approach that included ecologic, chemotaxonomic and phenotypic analyses. The results indicated that STIR-GUS-F2f7 and all the other strains from warm water fish represent a new bacterial species for which the name Francisella orientalis was assigned. Moreover the description of F. noatunensis was emended and the creation of a new subspecies within this taxon i.e. Francisella noatunensis subsp. chilense was proposed. The results of this study led to the development of a highly efficacious vaccine to protect tilapia against francisellosis.
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Burnett, Mary Susan. "Development of a live vaccine for human immunodeficiency virus /." Digital version accessible at:, 1997. http://wwwlib.umi.com/cr/utexas/main.
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Chen, Mei-Jane, and 陳美臻. "Development of anti-gastrin vaccine." Thesis, 2003. http://ndltd.ncl.edu.tw/handle/53093197054921760488.
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碩士國立陽明大學
生物化學研究所
91
Abstract Gastrin, produced by G cells in the gastric antrum, has been identified as the circulation hormone responsible for stimulation of acid secretion from the parietal cell. It also has an important trophic of growth —promoting influence on the gastric mucosa. Recent studies showed that excessive secretion of gastrin promotes the growth of some gastrointestinal cancers, as well as non-gastrointenstinal cancers, including pancreatic carcinoma, small cell lung cancer, and renal tumors. Peptic ulcers caused by increased stomach acid which is also dependent on gastrin. In this study, we propose to develop immunogens which can induce anti-gastrin antibody and neutralize overexpressed gastrin, and hopefully they could be used as safe and efficient therapy vaccine. Toward this end, we used Linear-Array Epitope (LAE) techniques to construct DNA fragments encoding multicopies of gastrin epitopes, followed by subcloning it into a protein expression vector. The immunogen is a fusion protein containing the receptor binding domain of Pseudomonas aeruginosa exotoxin A and multicopies of gastrin epitopes. Immunizing with the immunogens in rabbits could induce the anti-gastrin antibodies responses. On AR42J cells, through the detection of the suppression of ICER gene expression, we identify anti-gastrin antibody could inhibit the interaction between gastrin and gastrin receptor. In conclusion, anti-gastrin antibodies induced by gastrin immunogens could effectively neutralize gastrin activity in vitro and their therapeutic effects in vivo are under investigation now. The study also may pave the way to the development of anti-gastrin vaccine for gastrin dependent diseases.
49
Wang, Kuan-Kai, and 王冠凱. "Development of PEDV subunit vaccine." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/49526957823552356772.
Full textAbstract:
碩士國立屏東科技大學
動物疫苗科技研究所
103
Porcine epidemic diarrhea (PED) is caused by porcine epidemic diarrhea virus (PEDV). It would infect all age of swines, and be characterized by severe diarrhea, vomiting, and dehydration. PED was first reported in England in 1971 and the virus was first identified in Belgium. The virus belongs to the genus Alphacoronavirus, family Coronaviridae. It`s genome is single-stranded, positive-sense RNA which is contain 28 kb in length. The genome can translate four structure proteins, i.e. spike protein (S, 180-220kDa), membrane protein (M, 27-32kDa), envelope protein (E, 7kDa), and nucleocapsid protein (N, 55-58kDa). The spike protein plays the important role in receptor binding activity and elicts neutralizating antibody. And there are some studies prove evidences that spike protein contain neutralizating epitopes. In addition, Brevibacillus choshinensis expression system was use to produce recombinant protein in recent year. It is the gram-postive bacteria. Because the expression vector contains signal peptide, it can produce the recombinant protein in secreted form, and then we can harvest the protein without lysis bacteria and minimize lipopolysaccharide (LPS). B. choshinensis expression system has the ability to form a disulfide bond, which led the protein`s conformation close to native form. In this study, we used B. choshinensis expression system to produce PEDV spike protein to develop subunit vaccine, and through the result of SDS and western blot the protein could be produced by gram-positive bacterial expression system . We immunize the mice and harvest the serum to dectet the immune response by ELISA and neutralizating test.
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Chen, Shin-Han, and 陳信翰. "Development of PRRS subunit vaccine." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/33765741338798050188.
Full textAbstract:
碩士國立屏東科技大學
動物疫苗科技研究所
103
Porcine reproductive and respiratory syndrome virus (PRRSV) is the most economically significant disease of swine worldwide. Typical immunological features in PRRSV-infected pigs are delayed onset and low level of neutralizing antibodies and a weak cell-mediated immune response. The disease mainly causes premature delivery, miscarriage, stillbirth, mummified fetuses, severe pneumonia, edema and conjunctivitis in pigs. PRRSV belongs to the family Arteriviridae in the order Nidovirales, a family of positive-sense, single stranded linear RNA viruses. The genome is about 15 kb in length which contains nine ORFs. Several other factors such as animal age and bacterial co-infection can influence virus replication and clinical signs. Clostridium perfringens is a major pathogen of humans and livestock. Clostridium perfringens enterotoxin (CPE) causes the symptoms associated with several common gastrointestinal diseases. It's found that subcutaneous immunization of mice with the CPE fusion protein activated antigen-specific mucosal and systemic immune responses. M and GP5 proteins are essential for the neutralizing antibody, so we constructed a M -GP5 -CPE fusion proteins in prokaryotic expression system. The molecular weight and antigenicity were confirmed by SDS-PAGE and Western blot. Then, the subunit vaccine efficacy will be revealed by animal testing with intranasally immunized. Moreover, the immunoassay were tested by ELISA and determination of cytokine and neutralizing antibodies testing.