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 cel

Matrix-M™ adjuvant enhances immunogenicity of both protein- and modified vaccinia virus Ankara-based influenza vaccines in mice

Influenza viruses continuously circulate in the human population and escape recognition by virus neutralizing antibodies induced by prior infection or vaccination through accumulation of mutations in the surface proteins hemagglutinin (HA) and neuraminidase (NA). Various strategies to develop a vaccine that provides broad protection against different influenza A viruses are under investigation, including use of recombinant (r) viral vectors and adjuvants. The replication-deficient modified vaccinia virus Ankara (MVA) is a promising vaccine vector that efficiently induces B and T cell responses specific for the antigen of interest. It is assumed that live vaccine vectors do not require an adjuvant to be immunogenic as the vector already mediates recruitment and activation of immune cells. To address this topic, BALB/c mice were vaccinated with either protein- or rMVA-based HA influenza vaccines, formulated with or without the saponin-based Matrix-M™ adjuvant. Co-formulation with Matrix-M significantly increased HA vaccine immunogenicity, resulting in antigen-specific humoral and cellular immune responses comparable to those induced by unadjuvanted rMVA-HA. Of special interest, rMVA-HA immunogenicity was also enhanced by addition of Matrix-M, demonstrated by enhanced HA inhibition antibody titres and cellular immune responses. Matrix-M added to either protein- or rMVA-based HA vaccines mediated recruitment and activation of antigen-presenting cells and lymphocytes to the draining lymph node 24 and 48 h post-vaccination. Taken together, these results suggest that adjuvants can be used not only with protein-based vaccines but also in combination with rMVA to increase vaccine immunogenicity, which may be a step forward to generate new and more effective influenza vaccines

Monday Musing, February 8, 2016, Vol 3, no.6

It is a compilation of information, practical advice, training announcements, and/or success stories. Monday Musings is intended to disseminate information to Early Childhood Iowa Stakeholders in a timely fashion

Modified Vaccinia Virus Ankara Preferentially Targets Antigen Presenting Cells in Vitro, Ex Vivo and in Vivo

Modified Vaccinia virus Ankara (MVA) is a promising vaccine vector with an excellent safety profile. However, despite extensive pre-clinical and clinical testing, surprisingly little is known about the cellular tropism of MVA, especially in relevant animal species. Here, we performed in vitro, ex vivo and in vivo experiments with recombinant MVA expressing green fluorescent protein (rMVA-GFP). In both human peripheral blood mononuclear cells and mouse lung explants, rMVA-GFP predominantly infected antigen presenting cells. Subsequent in vivo experiments performed in mice, ferrets and non-human primates indicated that preferential targeting of dendritic cells and alveolar macrophages was observed after respiratory administration, although subtle differences were observed between the respective animal species. Following intramuscular injection, rMVA-GFP was detected in interdigitating cells between myocytes, but also in myocytes themselves. These data are important in advancing our understanding of the basis for the immunogenicity of MVA-based vaccines and aid rational vaccine design and delivery strategies

Universal influenza vaccines, science fiction or soon reality?

Currently used influenza vaccines are only effective when the vaccine strains match the epidemic strains antigenically. To this end, seasonal influenza vaccines must be updated almost annually. Furthermore, seasonal influenza vaccines fail to afford protection against antigenically distinct pandemic influenza viruses. Because of an ever-present threat of the next influenza pandemic and the continuous emergence of drift variants of seasonal influenza A viruses, there is a need for an universal influenza vaccine that induces protective immunity against all influenza A viruses. Here, we summarize some of the efforts that are ongoing to develop universal influenza vaccines