Publikationsserver der Universitätsbibliothek Marburg

Titel:Measles virus as vaccine platform against highly pathogenic emerging viruses
Autor:Fiedler, Anna Helena
Weitere Beteiligte: Becker, Stephan (Prof. Dr.)
Veröffentlicht:2017
URI:https://archiv.ub.uni-marburg.de/diss/z2017/0310
DOI: https://doi.org/10.17192/z2017.0310
URN: urn:nbn:de:hebis:04-z2017-03109
DDC:610 Medizin, Gesundheit
Titel(trans.):Masernviren als Impfstoffplattform gegen hochpathogene neu auftretende Viren
Publikationsdatum:2017-05-31
Lizenz:https://creativecommons.org/licenses/by-nc-sa/4.0

Dokument

Schlagwörter:
Respiratory Syndrom, Impfstoffe, Coronavirus, Middle East, Virologie, Institut für Virologie, Masernviren ,

Summary:
Highly pathogenic viruses are a significant global danger since they can be spread by worldwide travel and trade almost without restriction. One particular threat comes from emerging infections, for which no adequate treatment options currently exist. To guard against local or global outbreaks of these viruses, the development of protective vaccines at an early stage is therefore a desirable form of intervention. Vector-based vaccine platforms, such as that of replication-competent recombinant measles virus (rMV), constitute good prospective vaccine candidates, since they have the potential to allow for an easy exchange of antigen-encoding genes, thereby enabling rapid vaccine production after standardisation. To assess their suitability as a potential vaccine platform against highly infectious viral pathogens, rMVs were generated as part of the practical element of this thesis. These encoded for antigens of the following emerging pathogens: Middle East respiratory syndrome coronavirus (MERS-CoV), influenza virus H7N9 or Crimean-Congo haemorrhagic fever virus (CCHFV). Insertions of antigen-encoding genes resulted in the detectable expression of the MERS-CoV spike glycoprotein in both membrane-bound (MERS-S) and soluble form (MERS-solS), the MERS-CoV nucleocapsidprotein (MERS-N), haemagluttinin or neuraminidase of H7N9 (H7 or N9), the CCHFV glycoprotein Gc (CCHFV-Gc); and the CCHFV-nucleocapsid protein (CCHFV-N), in cells infected with respective vaccines. Immunisation of MV susceptible mice with MERS-S-, MERS-solS-, H7-, or N9-encoding vaccines also resulted in the induction of humoral immune responses. These included virus-neutralising antibodies (nAbs), if mice were vaccinated with MV-MERS-S, MV-MERS-solS or MV-H7. Generation of syngeneic for the respective antigens' transgenic dendritic cell (DC) cell lines, moreover, enabled an efficient re-stimulation of antigen-specific T cells without knowledge of immunogenic epitopes or the availability of antigens as proteins. When using these transgenic DC cell lines, MV-MERS-S-, MV-MERS-solS-, MV-MERS-N-, and MV-H7-induced cellular immune responses were demonstrated in an IFN-γ-ELISpot. Moreover, MERS-S specific CD8+T cells of immunised mice responded to respective re-stimulation by MERS-S-dependent proliferation and MERS-S-specific cytotoxicity. A reduction of viral loads, as well as virus-induced inflammation of lung tissue, was observed in MV-MERS-S- or MV-MERS-solS-vaccinated mice within a MERS-CoV challenge model. This impressively demonstrated the protective efficacy of an MV-based vaccine against MERS-CoV. In the second part of this thesis, MERS-CoV-induced innate immune responses in human and murine antigen-presenting cells (APCs) were analysed. As a result, human plasmoid DCs (pDCs) were identified as a source of significant amounts of antiviral type I (IFN-α, IFN-β) and Typ III (IFN-λ) interferons (IFNs), which were secreted upon infection with MERS-CoV. As a so far exclusively-identified source of type I and III IFNs pDC might hence play a significant role in MERS-CoV-induced pathogenesis in humans. Thus, by using MERS-CoV as an example, this thesis identified several key interactions between an emerging pathogen and defined immune cells, which might prove to be of clinical significance, particularly in the future development of antiviral drugs. As potential vaccine candidate, an MV-based vaccine platform was generated as part of this thesis; and its protection efficacy was demonstrated. A rapidly conducted production of MV-based vaccine platforms against three different viral pathogens, an efficient induction of humoral and cellular immunity as well as protection efficacy in a challenge model indicated the potential of recombinant MV to be used as an effective vaccine platform to protect against emerging viral pathogens.

Zusammenfassung:
Hochpathogene Viren stellen eine globale Gefahr dar, da sie im Zuge des internationalen Personen- und Warentransportes fast ungehindert verbreitet werden können. Eine besondere Bedrohung geht dabei von neuartigen viralen Erregern aus, für die keine adäquaten Behandlungsmethoden implementiert sind. Um auf lokale oder sogar globale Ausbrüche dieser Viren angemessen reagieren zu können, besteht eine Maßnahme in der frühzeitigen Entwicklung schützender Impfstoffe. Vektorbasierende Impfstoffplattformen, wie z. B. replikationskompetente rekombinante Masernviren (rMV), sind für diese Zwecke besonders interessant, da diese nach Standardisierung einen einfachen Austausch der für Antigene kodierender Genabschnitte ermöglichen und somit eine schnelle Produktion erlauben können. Um ihre Eignung als protektive Impfstoffplattform gegen hochpathogene virale Erreger zu untersuchen, wurden innerhalb der vorliegenden Arbeit rMV hergestellt, welche jeweils für Antigene der neuartigen Erreger Middle East respiratory syndrom coronavirus (MERS-CoV), Influenza-Virus H7N9 oder des Erregers des hämorrhagischen Krim-Kongo-Fiebers (engl. Crimean-Congo haemorrhagic fever virus, CCHFV) kodierende Gene enthalten. Dieser Einbau ermöglichte eine hier nachgewiesene Expression des MERS-CoV Spike Oberflächenproteins in membrangebundener (MERS-S) oder löslicher Form (MERS-solS), des MERS-CoV Nukleokapsidproteins (MERS-N), des Hämagglutinins bzw. der Neuraminidase von H7N9 (H7 bzw. N9), des CCHFV Glycoproteins Gc (CCHFV-Gc) oder des CCHFV-Nukleokapsidproteins (CCHFV-N) in mit dem jeweiligen Impfstoff infizierten Zellen. Die Immunisierung MV-suszeptibler Mäuse mit MERS-S-, H7- oder N9-exprimierenden rMVs zeigte, dass humorale Immunantworten ausgelöst werden, bei denen nach Vakzinierung mit MV-MERS-S, MV-MERS-solS oder MV-H7 Virus-neutralisierende Antikörper (nAKs) nachgewiesen werden konnten. Die Herstellung von für die jeweiligen Antigene transgenen, zum Mausmodell syngenen Dendritische Zellen (Dendritic cells, DC)- Zelllinien ermöglichte zudem eine effiziente Re-stimulation von Antigen-spezifischen T-Zellen unabhängig der Kenntnis jeweils immunogener Epitope oder der Verfügbarkeit des Antigens in Proteinform. Mit Hilfe dieser Antigen-spezifischen DC-Zelllinien konnten durch MV-MERS-S, MV-MERS-solS, MV-MERS-N sowie MV-H7 induzierte zelluläre Immunantworten über IFN-γ-ELISpot nachgewiesen werden. MERS-S spezifische CD8+ T-Zellen aus immunisierten Tieren reagierten zudem mit einer MERS-S-abhängigen Proliferation und MERS-S spezifischen Zytotoxizität auf entsprechende Re-stimulation. Mit MV-MERS-S oder MV-MERS-solS vakzinierte Mäuse zeigten im Belastungsversuch mit MERS-CoV eine Reduktion der Viruslast sowie Virus-induzierter Entzündungsreaktionen im Lungengewebe. Dies demonstrierte eindrucksvoll die Schutzwirkung eines MV-basierenden Impfstoffkandidaten gegen MERS-CoV. In einem zweiten Teil dieser Arbeit wurden zudem durch MERS-CoV ausgelöste angeborene Immunreaktionen in humanen und murinen Antigen-präsentierenden Zellen untersucht. Dabei wurden humane plasmazytoide DCs (pDCs) als Quelle erheblicher Mengen antiviraler Typ I (IFN-α, IFN-β) oder Typ III (IFN-λ) Interferone identifiziert, die in Folge einer Infektion dieser Zellen mit MERS-CoV ausgeschüttet wurden. pDCs könnten als bisher einzig nachgewiesene Quelle antiviraler Typ I Interferone eine wichtige Rolle innerhalb der Pathogenese von MERS-CoV im Menschen einnehmen. Diese Arbeit zeigte folglich beispielhaft Interaktionen eines neuartigen Erregers, MERS-CoV, mit genau definierten Immunzellen, was die Entwicklung zukünftiger Therapien maßgeblich unterstützen könnte. Als potentieller Impfstoffkandidat wurde innerhalb dieser Arbeit eine MV-basierende Impfstoffplattform erzeugt und deren Schutzwirkung gezeigt. Die schnell umsetzbare Erzeugung solcher MV-basierenden Impfstoffkandidaten gerichtet gegen drei unterschiedliche virale Erreger, die effiziente Induktion humoraler und zellulärer Immunantworten sowie die Schutzwirkung im Belastungsversuch verdeutlichen das Potential von rMV als effiziente Impfstoffplattform gegen neuartige Erreger.

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