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Obwohl in den vergangenen Jahrzehnten große Fortschritte in der Entwicklung von Vakzinen gemacht worden sind, gibt es noch immer gefährliche Infektionskrankheiten gegen die es noch keine Impfstoffe gibt. Impfvektoren, die auf dem vesikulären Stomatitis-Virus (VSV) basieren haben in Tierversuchen schon vielversprechende Ergebnisse erzielt.Der Neurotropismus von VSV macht eine klinische Anwendung im Menschen aus Sicherheitsgründen aber äußerst schwierig. Durch Pseudotypisieren von VSV mit dem Glykoprotein des lymphozytären Choriomeningitis-Virus (VSV-GP) behält der Vektor seine Replikationsfähigkeit und verliert seinen Neurotropismus. So bleiben im Mausversuch selbst nach intrakranieller Applikation von VSV-GP die Tiere völlig gesund, während VSV injizierte Tiere an Neurotoxizität sterben.In dieser Arbeit wurde das Potential von VSV-GP als neuartiger Vakzinevektor im direkten Vergleich mit VSV bestimmt. Dazu wurde Ovalbumin (OVA) als Modellantigen verwendet.In Mäusen induzierten VSV und VSV-GP vergleichbare humorale und zelluläre OVA-spezifische Immunantworten nach einer einzigen Immunisierung. Eine zweite Dosis war jedoch nur mit VSV-GP-OVA effizient, da anders als VSV-OVA, VSV-GP-OVA keine vektorspezifischen neutralisierenden Antikörper induziert. Die von VSV-GP-OVA induzierte OVA-spezifische CTL Antwort, war mindestens so immunogen wie die von einem adenoviralen “state of the art” Vektor ausgelöste. Wie der adenovirale Vektor, vermittelte die prophylaktische Immunisierung mit VSV-GP-OVA einen kompletten Schutz im Listeria monocytogenes Infektionsmodell.Zusammenfassend kann man sagen, dass VSV-GP durch all seine Eigenschaften eine neue, äußerst potente virale Vektorplattform darstellt, auf der Impfstoffe gegen ein breites Spektrum an Erregern basieren könnten., Although there has been great progress in treatment and prevention of infectious diseases in the past years, effective vaccines against some of the most serious infections, are urgently needed. The vesicular stomatitis virus (VSV) has proven to be a potent viral vector vaccine candidate.However, translation of these promising studies into clinical application has so far been limited by VSV’s neurotropism. VSV pseudotyped with the glycoprotein GP of the lymphocytic choriomeningitis virus (VSV-GP) has completely lost neurotropism and is perfectly safe in mouse models, while maintaining replication fitness.Here, the potential of VSV-GP as a vaccine vector was analyzed with ovalbumin (OVA) as a model antigen. VSV-GP-OVA was directly compared to the VSV encoding OVA (VSV-OVA). In mice, VSV-OVA and VSV-GP-OVA induced equal levels of OVA-specific humoral and cellular immune responses upon a single immunization. However, boosting with the same vector was only possible for VSV-GP-OVA, as this vector did not induce vector specific humoral immunity, even after multiple applications. In contrast, neutralizing antibodies limited the immunogenicity of the VSV-OVA boost. In addition, OVA specific CTL responses induced by VSV-GP-OVA were at least as potent as those observed for a gold-standard adenoviral vector. Prophylactic vaccination with VSV-GP-OVA was highly efficient and completely protected mice in a Listeria monocytogenes challenge model.Taken together, VSV-GP can serve as a platform technology for the development of novel vaccines against a broad spectrum of diseases., by Reinhard Tober, Abweichender Titel laut Übersetzung der Verfasserin/des Verfassers, Innsbruck, Med. Univ., Diss., 2014

Background: Vesicular stomatitis virus (VSV) is a potent candidate vaccine vector for various viral diseases (e.g. HIV, HCV, RSV). The biggest limitation of VSV, however, is its neurotoxicity, which limits application in humans. The second drawback is that VSV induces neutralizing antibodies rapidly and is thus ineffective as a vaccine vector upon repeated applications. Our group has recently shown that VSV pseudotyped with the glycoprotein (GP) of the lymphocytic choriomeningitis virus (LCMV), VSV-GP, is not neurotoxic. The aim of this project was to evaluate the potential of VSV-GP as a vaccine vector. Methods: For this purpose, we used Ovalbumin (OVA) as a model antigen and analyzed immunogenicity of GP-pseudotyped and wildtype VSV containing OVA (VSV-GP-OVA and VSV-OVA) in vitro and in vivo in mouse models. Results: We showed that both vectors infected murine bone marrow-derived dendritic cells (bmDCs) in vitro. These bmDCs were able to activate OVA specific CD8+ and CD4+ T cells. Immunization experiments in mice revealed that both VSV-OVA and VSV-GP-OVA induced functional OVA-specific cytotoxic T cells (CTLs) after a single immunization. In addition, with both viruses, mice generated antibodies against OVA. However, boosting with the same virus was only possible for the GP-pseudotyped virus but not for wild type VSV. The efficacy of repeated immunization with VSV-OVA was most likely limited by high levels of neutralizing antibodies, which we detected after the first immunization. In contrast, no neutralizing antibodies against VSV-GP were induced even after boosting. Conclusion: Taken together, we showed that the non-neurotoxic VSV-GP is able to induce specific T cell and B cell responses against the model antigen OVA to the same level as the wild type VSV vector. However, in contrast to wild type VSV, VSV-GP-OVA boosted the immune response upon repeated applications. Thus, VSV-GP is a promising novel vaccine vector.