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Integrated production of an influenza A vaccine candidate with MDCK suspension cells
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  • Thomas Bissinger,
  • Yixiao Wu,
  • Pavel Marichal-Gallardo,
  • Dietmar Riedel,
  • Xuping Liu,
  • Y Genzel,
  • wen Tan,
  • Udo Reichl
Thomas Bissinger
Max Planck Institute for Dynamics of Complex Technical Systems
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Yixiao Wu
Max Planck Institute for Dynamics of Complex Technical Systems
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Pavel Marichal-Gallardo
Max Planck Institute for Dynamics of Complex Technical Systems
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Dietmar Riedel
Max Planck Institute for Biophysical Chemistry
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Xuping Liu
East China University of Science and Technology
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Y Genzel
Max Planck Institute for Dynamics of Complex Technical Systems
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wen Tan
East China University of Science and Technology
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Udo Reichl
Max Planck Institute for Dynamics of Complex Technical Systems
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Abstract

Seasonal influenza infection waves occur both in northern and southern hemispheres every year. Despite the differences in influenza virus surface antigens and virulence of seasonal subtypes, manufacturers are well-adapted to respond to this periodical vaccine demand. Due to decades of influenza virus research, the development of new influenza vaccines is relatively straight-forward. Nevertheless, compared to the recent Covid-19 pandemic where a vaccine is not yet available, influenza vaccine manufacturing would be a major bottleneck for the rapid supply of billions of doses required worldwide. In particular, egg-based vaccine production would be difficult to schedule and shortages of other egg-based vaccines with high demands also have to be anticipated. Cell culture-based production systems enable manufacturing of large amounts of vaccines within a short time frame and expand significantly our options to respond to pandemics and emerging viral diseases. In this work, we present an integrated process for the production of inactivated influenza A virus vaccines based on a MDCK suspension cell line cultivated in a chemically defined medium. Very high titers of 3.6 log10(HAU/100 µL) were achieved using fast growing MDCK cells at concentrations up to 9.5 × 106 cells/mL infected with influenza A/PR/8/34 H1N1 virus in 1 L stirred tank bioreactors. A combination of two membrane-based chromatography steps enabled full recovery for the virus capture and up to 80 % recovery for the virus polishing step, respectively. Purified virus particles showed a homogenous size distribution around a mean diameter of 80 nm. Based on a monovalent dose of 15 µg hemagglutinin (SRID assay), the level of total protein was 58 µg and the level of host cell DNA contamination was below 10 ng. Furthermore, all process steps can be fully scaled up to industrial quantities for commercial manufacturing of either seasonal or pandemic influenza virus vaccines. Fast production of up to 300 vaccine doses per liter within 4 to 5 days makes this process competitive not only to other cell-based processes, but to egg-based processes as well.

Peer review status:UNDER REVIEW

15 Feb 2021Submitted to Biotechnology and Bioengineering
16 Feb 2021Submission Checks Completed
16 Feb 2021Assigned to Editor
03 Mar 2021Reviewer(s) Assigned
31 Mar 2021Editorial Decision: Revise Minor
31 Mar 2021Review(s) Completed, Editorial Evaluation Pending
01 Jun 20211st Revision Received
01 Jun 2021Submission Checks Completed
01 Jun 2021Assigned to Editor
01 Jun 2021Reviewer(s) Assigned