Elucidating bottlenecks in influenza virus replication to optimize vaccine production

Influenza viruses cause seasonal epidemics with up to 500,000 deaths each year and have the potential of becoming pandemic. The most effective way to prevent a severe infection is vaccination. However, ensuring an adequate and timely supply with vaccines poses a serious challenge as manufacturing capacities are limited and yields heavily depend on the host system's ability to produce large amounts of virus particles. To optimize influenza vaccine production in mammalian cell culture, we developed a quantitative model of the viral life cycle. It comprises key steps of intracellular replication from virus entry to the release of progeny virus particles. By integrating a variety of published data sets on different aspects of infection, we were able to capture the time course of viral protein and genome synthesis. Further analyses showed that the virus can regulate these dynamics by controlling the stability and the transport of its genomic RNAs. Interestingly, simulations also predict an accumulation of viral genomes and proteins toward the end of infection indicating that virus assembly and budding are potential bottlenecks and that in principle cells could release more virions. Hence, viral control mechanisms and the steps involved in virus release may provide promising targets for the optimization of cell culture-based vaccine production. Modeling can contribute to this optimization by facilitating a systems-levels understanding of the influenza virus life cycle