Analyzing the Impact of Heterogeneity in Genetically Engineered Cell Lines for Influenza Vaccine Production Using Population Balance Modeling

Engineering of novel cell lines for biotechnological processes, e.g. influenza virus vaccine production, can be achieved by the genetic modification of host cell gene expression. Therefore, versatile genome editing methods such as lentiviral transduction can be applied to improve the production process. However, due to random integration of lentiviral-delivered genes in the host cell genome, nonuniform, i.e. heterogeneous, gene expression within the host cell population is expected. Within this contribution we investigate the influence of this cell-to-cell variability on important process variables like the maximum virus yield. Therefore, a multi dimensional population balance model is proposed which, on the one hand comprises a detailed description of the intracellular viral replication cycle and, on the other, also accounts for the expected heterogeneity in the host cell population. The results indicate that the overall vaccine production process can be improved by enhancement or inhibition of certain steps in the viral replication cycle. Furthermore, the achieved improvements show robustness against moderate degrees of cell-to-cell variability from genetic modification of host cells via transduction.