Servicio de Información Comunitario sobre Investigación y Desarrollo - CORDIS

FP6

CHIMERIC VACCINES Informe resumido

Project ID: 512864
Financiado con arreglo a: FP6-SME
País: Austria

Final Report Summary - CHIMERIC VACCINES (Development of influenza delNS1 virus as a vector for foreign antigens)

The ultimate aim of the CHIMERIC VACCINES project was to develop a novel chimeric vaccine against avian influenza, based on an attenuated, replication deficient influenza virus. This virus would harbour a deletion of the pathogenicity factor NS1, therefore, the resulting virus would be replication deficient and thus, attenuated. The NS1 influenza protein is an immunosuppressant while the delNS1 virus is an immunostimulatory virus so it can be used either as a vaccine to express foreign epitopes or as an adjuvant. To reach the goal of providing a vaccine against avian and human influenza, several objectives had to be fulfilled:
- One task was to identify immunogenic human and avian influenza virus antigens. This was achieved by analysing the sequences of the respective influenza viruses employing state-of-the-art bioinformatic methods. Promising predicted epitopes were experimentally verified in biological assays. Most immunogenic epitopes were identified and could then be inserted into a novel generation of delNS1 virus vectors.
- Another objective was to define an optimal vector. Specifically, an influenza delNS1 virus that would be capable of effectively expressing antigens of foreign pathogens was developed. As an important supportive tool, a method to generate viruses using reverse genetics was established allowing the fast generation of new constructs and in a highly efficient manner. A model antigen was inserted in different positions of the delNS1 virus. Several constructs were tested for the successful expression of foreign antigen and for vector stability. As several influenza delNS1 constructs failed to induce sufficient expression or were found to be genetically unstable, the project was extended six months to allow more time for the optimisation of the vector. As a contingency strategy, in addition the potential of the delNS1 vector as an adjuvant was analysed in animals.
- The last objective was to analyse the potential of delNS1 vectors in suitable animal models. Ferret experiments were carried out that clearly showed that the delNS1 vector system could be used for the desired vaccination purposes both in terms of immunogenicity and safety. In addition to animal experiments, a number of immunological and virological tests (e.g. TCID50, neutralisation assay, Elisa, microneutralisation) were set up and standardised. These tests were used to assess the immunological potential of predicted epitopes and to analyse samples from animal experiments. A close collaboration between the bioinformatic groups, the animal facility and immunological and virological laboratories evolved and efficient logistics to handle biological samples was established.

Based on proof-of-principle experiments and a series of optimisations, finally a suitable stable expression vector was found and a corresponding joint patent was filed. The consortium planned to further develop this vector into a flexible chimeric vaccine that would be useful for a variety of diseases. Furthermore, methods for reverse genetics were established and optimised in the project. Therefore, it was easy to insert different and optimised epitopes either from influenza of from other targets of interest. It was also noteworthy that influenza epitopes not only were predicted by bioinformatics but were already validated in experimental systems. Moreover, the production process development was a clear success. Good manufacturing practices (GMP) materials of a delNS1 virus vector grown on certified Vero cells were successfully produced that could be used in clinical trials and in proof-of-principle experiments. Likely was the fact that also future chimeric vaccines would follow this production process.

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GREEN HILLS BIOTECHNOLOGIY RESEARCH DEVELOPMENT TRADE GMBH
Gersthofer Straße, 29-31
VIENNA
Austria
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