Development of Modified Vaccinia Virus Ankara-based Influenza Vaccines

Influenza viruses continuously circulate in the human population and are estimated to cause 3-5 million cases of severe respiratory illness annually worldwide of which 250.000-500.000 have a fatal outcome. Vaccination is the most efficient measure to control infectious diseases, however, vaccination against influenza viruses is complicated by their antigenic variability. Current seasonal influenza vaccines are comprised of components from influenza A (H1N1 & H3N2) and B viruses that are expected to circulate in the next influenza season. These seasonal vaccines aim at the induction of virus neutralizing antibodies against the surface glycoprotein hemagglutinin (HA) and are efficient in providing protective immunity against antigenically similar influenza viruses. However, they afford little or no protection from infection with antigenically distinct seasonal or pandemic influenza viruses. In order to induce broadly protective immunity against multiple and antigenically distinct influenza viruses, novel vaccine targets and antigen delivery systems are investigated. Furthermore, novel techniques are under development to facilitate production of large quantities of vaccine doses in a short period of time. The vaccine vector Modified Vaccinia virus Ankara (MVA) expressing one or multiple influenza virus antigens could potentially provide in these needs. In this thesis, the development and use of rMVA-based influenza vaccines was addressed. Even though MVA has been tested extensively in various animal models and has been administered to >100.000 human subjects, a few key questions regarding the MVA vaccine vector remained to be answered. To that end, the studies described in this thesis elucidated the in vivo cell tropism of MVA-based vaccines and assessed the potential risk of interference with rMVA-based vaccination by orthopoxvirus-specific pre-existing immunity. Furthermore, novel rMVA-based influenza vaccine candidates were developed and evaluated by pre-clinical and clinical testing. These studies contribute to the development of next-generation influenza vaccines.

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