Measles virus as vaccine platform against highly pathogenic emerging viruses
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 th...
Keine Tags, Fügen Sie den ersten Tag hinzu!
|Zusammenfassung:||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.|