Title: New facets of poxvirus-mediated T cell immunity

Presenter: Prof. Ingo Drexler

University: Institute for Virology, Heinrich-Heine-University (Germany)

Time: 10:00-11:00, 20 May, 2011

Venue: A203, Institute of Microbiology, Chinese Academy of Sciences

Abstract: Poxviruses engineered to express foreign genes are established tools for target protein synthesis and vaccine development in biomedical research. Modified vaccinia virus Ankara (MVA) was originally developed through attenuation by serial passage in primary chicken embryo cells to serve as a safer vaccine against smallpox. MVA has lost the broad cellular host range of vaccinia virus (VACV), being unable to productively grow in many cells of mammalian origin. MVA is a valuable tool for the expression of recombinant genes used for such purposes as the study of protein functions or characterization of innate or adaptive cellular and humoral immune responses. MVA-based vaccines are currently evaluated in numerous clinical studies for immunotherapy of infectious diseases and cancer.

However, knowledge about essential biological properties of target antigens or modalities of antigen delivery to efficiently induce or expand MVA-mediated T cell responses in vivo is still sparse. The recent identification of immunodominant poxviral T cell epitopes in mice and men allowed us to elucidate some of the mechanisms which are relevant for the induction and maintenance of VACV-mediated cytotoxic CD8+ T cell (CTL) responses in vivo. These include the requirement of cross-presentation of MVA-encoded antigens to efficiently prime naïve T cells as well as the shaping of the immunodominance hierarchy pattern in the recall by competing CTL. CD4+ regulatory T cells (Tregs) are a crucial component of the adaptive immune system. In order to investigate the role of Tregs for poxviral immunity, we used a mouse model that allows for specific depletion of Foxp3+ Tregs during the time of vaccination with MVA. We found that Tregs regulate the number of fully differentiated T cellsduring the acute immune response but have no influence on the long-term memory T cell pool. Therefore, removal of Tregs may be of great importance in therapeutic settings but might be of little value in the case of prophylactic vaccinations.

In attempt to optimize MVA vaccination strategies, we tested alternative delivery methods such as intradermal skin tattooing or direct intranasal application of lyophilized virus. The direct mucosal application of freeze-dried MVA into the nostrils of mice without prior reconstitution induced systemic antibody and T cell responses comparable to those achieved by standard intramuscular administration. Importantly, mucosal application of lyophilized MVA induced long-term and protective immunity against lethal viral or bacterial challenges. The data clearly demonstrate the potency of a simple needle-free vaccination applicable even in developing countries to protect against infectious diseases, combining the advantages of mucosal application with the stability and efficiency of lyophilized MVA.