Abstract
Influenza A viruses (IAV) are commonly used to infect animal cell cultures for research purposes and vaccine production. Their replication is influenced strongly by the multiplicity of infection (MOI), which ranges over several orders of magnitude depending on the respective application. So far, mathematical models of IAV replication have paid little attention to the impact of the MOI on infection dynamics and virus yields. To address this issue, we extended an existing model of IAV replication in adherent MDCK cells with kinetics that explicitly consider the time point of cell infection. This modification does not only enable the fitting of high MOI measurements, but also the successful prediction of viral release dynamics of low MOI experiments using the same set of parameters. Furthermore, this model allows the investigation of defective interfering particle (DIP) propagation in different MOI regimes. The key difference between high and low MOI conditions is the percentage of infectious virions among the total virus particle release. Simulation studies show that DIP interference at a high MOI is determined exclusively by the DIP content of the seed virus while, in low MOI conditions, it is predominantly controlled by the de novo generation of DIPs. Overall, the extended model provides an ideal framework for the prediction and optimization of cell culture-derived IAV manufacturing and the production of DIPs for therapeutic use.
Highlights
Influenza A virus (IAV) is an enveloped, segmented, single-stranded RNA virus that infects humans, livestock and various wild animals
While influenza vaccines are mostly produced in embryonated chicken eggs, cell culturebased vaccine production is developing as an alternative providing controlled process
Our results provide insights into IAVinduced apoptosis and the switch from transcription to replication in intracellular IAV replication
Summary
Influenza A virus (IAV) is an enveloped, segmented, single-stranded RNA virus that infects humans, livestock and various wild animals. Influenza vaccine is manufactured mainly in embryonated chicken eggs, an established process dating back to the middle of the 20th century. The egg-based vaccine production is constrained by scale-up restrictions, low yields for some virus strains, and potential allergic reactions [3,4,5]. Cell culture-based production is considered as an alternative to overcome these limitations. Cell cultures provide scalability and controlled sterile process settings in bioreactors [3,4]. Cell culture-based influenza vaccine production is still facing challenges regarding yields, process costs and the adaptation of seed viruses to the desired cell line. Deeper insights into the virus replication and spread in cell cultures in different infection conditions are vital to overcome these challenges
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