Enhancing enterovirus A71 vaccine production yield by microcarrier profusion bioreactor culture |
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| Institution: | 1. National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan Town, Miaoli County, Taiwan;2. Institute of Biotechnology, Department of Medical Science, National Tsing Hua University, Hsinchu, Taiwan;3. Institute of Oral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan;4. Graduate Institute of Immunology, China Medical University, Taichung, Taiwan;5. Vaccine Center, Centers for Disease Control, Taipei, Taiwan;1. Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Mexico;2. Department of Biomechanical Engineering, University College London, London, UK;3. Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany;4. Protein Expression Facility, The University of Queensland, Brisbane, Australia;5. NextWaveBio, CT, USA;1. Shanghai Municipality Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China;2. Laboratory of Regenerative Medicine, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China;3. Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated First People''s Hospital, Shanghai 200080, China;1. State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, PR China;2. Shanghai Collaborative Innovation Center for Biomanufacturing Technology, 130 Meilong Road, Shanghai 200237, PR China;3. Institute of Functional Biomolecules, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, PR China;1. Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstr. 1, 39106 Magdeburg, Germany;2. ProBioGen AG, Goethestr. 54, 13086 Berlin, Germany;3. Chair for Bioprocess Engineering, Otto-von-Guericke-University Magdeburg, Universitätsplatz 2, 39106 Magdeburg, Germany;1. Key Laboratory of System Bioengineering (Tianjin University), Ministry of Education, Tianjin 300072, People''s Republic of China;2. School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, People''s Republic of China;3. Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 300072, People''s Republic of China;4. Tianjin Vocation Technology College of Bioengineering, Tianjin 300462, People''s Republic of China;1. Bio-Manguinhos—FIOCRUZ, Technological Development Vice-directory, Rio de Janeiro, RJ, Brazil;2. Federal University of Rio de Janeiro (UFRJ), COPPE, Chemical Engineering Program, Rio de Janeiro, RJ, Brazil |
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| Abstract: | Hand, foot and mouth diseases (HFMD) are mainly caused by Enterovirus A71 (EV-A71) infections. Clinical trials in Asia conducted with formalin-inactivated EV-A71 vaccine candidates produced from serum-free Vero cell culture using either roller bottle or cell factory technology, are found to be safe and highly efficacious. To increase vaccine yields and reduce the production costs, the bioprocess improvement for EV-A71 vaccine manufacturing is currently being investigated. The parameters that could affect and enhance the production yields of EV-A71 virus growth in the microcarrier bioreactor were investigated. The medium replacement culture strategy included a multi-harvested semi-batch process and perfusion technology and was found to increase the production yields more than 7–14 folds. Based on the western blot and cryo-EM analyses of the EV-A71 virus particles produced from either the multi-harvested semi-batch (MHSBC) or perfusion cultures were found to be similar to those virus particles obtained from the single batch culture. Mouse immunogenicity studies indicate that the EV-A71 vaccine candidates produced from the perfusion culture have similar potency to those obtained from single batch bioprocess. The physical structures of the EV-A71 particles revealed by the cryo-EM analysis were found to be spherical capsid particles. These results provide feasible technical bioprocesses for increasing virus yields and the scale up of EV-A71 vaccine manufacturing using the bioreactor cell culture methods. |
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| Keywords: | Enterovirus A71 Inactivated whole virion vaccine Serum-free bioreactor Microcarrier culture Perfusion technology |
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