Research Group of M. Tenbusch

Virology

Head of Institute:
Prof. Dr. med. Klaus Überla

Gene-based vaccines

Without any doubt vaccines are the most effective measures to prevent infectious diseases and promote individual and public health. Nevertheless, there are still a number of infectious disease where no or only inadequate vaccines are available. Therefore new vaccines and alternative vaccination platforms are still urgently needed. Currently, we address the potency of different gene-based vaccines in following projects:

Mucosal immunity against viral respiratory tract infections induced by gene-based immunizations.

Influenza A Virus (IAV) and the Respiratory Syncytial Virus (RSV) are causative agents of severe respiratory tract infection especially in young children and elderly people. The global disease burden is estimated to ~ 650 million cases per year for these two viruses leading to estimated 0.5 million deaths/year worldwide. While there is no prophylactic vaccine against RSV available at the time at all, there is an annual vaccination program against influenza viruses based mainly on trivalent inactivated influenza vaccines (TIV) which is recommended for certain risk groups (i.a. elderly or people with chronic lung diseases). Nevertheless, the overall vaccine efficacy is modest and the antibody mediated protection is rather short-lived and very strain-specific providing nearly no protection against drifted IAVs.
We developed in the last years DNA and adenoviral vector vaccines encoding the viral antigens hemagglutinin and nucleoprotein from IAV and the F protein from RSV. Furthermore, we evaluated a variety of application forms and determined the vaccine efficacy in the mouse and rhesus macaque model.
The most protective vaccination strategies included at least one immunization delivered via the mucosal route highlighting the exceptional role of local immune responses. We analyzed in detail the T-cell and antibody responses in the mucosal and in the systemic compartment. Interestingly, a combination of a systemic DNA prime immunization with an intranasal adenoviral boost was the most effective schedule. This results in huge numbers of tissue-resident memory T-cells in the lungs which can very rapidly control infections with different heterologous IAV strains in the mouse model. Furthermore, this strategy also proved efficacy against an RSV infection in the rhesus macaque model.
In our recent work, we would like to decipher the correlates of protection for the different infection models and learn how the systemic and mucosal immune cells act together. Furthermore, we compare different viral vector systems and analyze possible synergistic effects in term of protection.

Signal molecules of the innate immune system as genetic adjuvants.

From influenza infection models, it is known that not only the local antigen expression is important for the efficient induction of adaptive immune responses but also the induction of innate immune signaling. To make our gene-based vaccines also more comparable to natural infections in this regard, we decided to express selected effector molecules from different innate signaling pathways along with our antigens.
Mainly, we generated adenoviral vectors encoding Interferons or components of the RIG-I/MAVS pathway or the effector molecules Interleukin-1ß and IL-18 derived from the inflammasome activation pathway.
We would like to analyze the impact of the gene-based adjuvants on the antigen-specific T- and B-cell responses and on the resulting protection against challenge infection. It will be of special interest to see if these two classes of molecules will act in concert or counteract each other at some point.
So far, we could demonstrate that the co-delivery of an adenoviral vector encoding IL-1ß results in a dramatic improvement of the induction of the tissue-resident memory compartment correlating with enhanced protection. Revealing the underlying mechanisms will have huge impact on the further development of mucosal vaccines.

Immune modulation by gene-based vaccines encoding DC-targeting antigens.

Dendritic cells (DC) are professional antigen-presenting cells and play an essential role in the induction of adaptive, antigen-specific T-cell responses. DCs capture the antigen via phagocytosis, pinocytosis or receptor-mediated endocytosis and could depending on their maturation status induce either T-cell tolerance or immunity. In the past, numerous studies could demonstrate that loading DC with antigens via specific antibodies recognizing DC-specific receptors, like DEC205, DC-SIGN or MMR, results in enhanced antigen presentation and T-cell activation. Given these fusion proteins together with appropriate maturation stimuli, like Poly I:C and CD40 antibodies, revealed promising vaccination approaches against a variety of different pathogens.
In our group, we wanted to combine the advantages of gene-based vaccines with the efficient antigen presentation observed after DC targeting. We generated single chain antibodies recognizing the DC-endocytic receptor DEC205, fused it to our antigen of interest and cloned the whole expression cassette in our gene-based vaccines. We could clearly demonstrate that this leads to an enhanced antigen presentation, but unfortunately it did not translate into improved vaccine efficacy.
In contrast, our studies revealed that we rather generate a local T-cell tolerance than antigen-specific effector T-cells probably due to missing maturation signals for the antigen-presenting DCs. Nevertheless, the induction of antigen-specific T-cell tolerance is also a very attractive goal, e.g. for the treatment of autoimmunity or allergies where you want to down-regulate the self-reactive or allergen-induced immune responses. A possible mechanism might be the induction of antigen-specific, regulatory cells instead of effector cells by immature DCs.

Therapeutic immunization in the allergen-induced asthma model.

Based on our findings from gene-based vaccines encoding DC-targeted antigens, we evaluated if the local induction of tolerance by this strategy might be suitable to dampen the allergen-specific immune response in a murine asthma model.
In this model, mice were sensitized with the model allergen ovalbumin resulting in a Th2 biased immune response which leads to airway hyperresponsiveness after inhalation of an OVA-containing aerosol. We treated this animal after the sensitization phase with adenoviral vectors encoding DC-targeted or non-targeted OVA and characterized the impact on the immunological and functional parameters of the asthma phenotype after challenge.
Indeed, only the intranasal application of vectors encoding the DC-targeted antigens was able to dampen the Th2 T-cell response and thereby reduce the strong eosinophilic infiltration and the airway hyper- responsiveness which are characteristics for the asthmatic phenotype.
This interesting approach should be further analyzed by using different vector systems and possibly new targeting strategies to improve the long-term effects of such a treatment. It might become an attractive alternative to the specific immune therapy which is until now the only causative treatment for allergies in patients.

 
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Summary