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Abstract

Viral vaccines decrease the economic and social costs due to annual reoccurrence of worldwide flu infections. The aim of our research group is the development of integrated concepts to design and optimize cell growth and virus yield in vaccine production and the establishment of downstream processing methods to improve efficacy, purity and safety of vaccines. With a process of equine influenza virus production as an example we investigate: (a) Cultivation and scale-up of animal cells (MDCK) using microcarrier systems (b) Replication of influenza viruses (equine influenza Newmarket 1/93 H3N8)(c) Downstream processing to subunit or split vaccines. The process consists of a cell growth phase and a virus replication phase. Theoretical considerations have demonstrated that besides virus replication rate and survival of cells after infection, biomass concentration at time of infection has the main impact on virus yield. However, the increase in microcarrier concentration in the growth phase of the adhaerent MDCK cells to increase biomass concentration is only partly sucessful so far due to media limitations and inhibition effects. Therefore a detailed analysis of different metabolite concentrations e.g. lactate, ammonia, osmolality and the soluble concentrations of oxygen and carbon dioxide are essential for high density cell culture systems. Based on mathematical models for cell growth, virus replication, oxygen supply and carbon dioxide removal different control strategies will be established. A comparison of cultivation experiments shows the advantages of perfusion systems over the existing batch cultivations.