Bioprocessing of Viral Vaccines

Cover
Half Title
Title Page
Copyright Page
Contents
Editors
List of abbreviations
1. Bioprocessing of viral vaccines--Introduction
1.1 An Abbreviated Historical Background of Vaccines
1.2 Role of Public Health Organizations and Industry
1.3 The Vaccine Market and Economic Drivers
1.4 Safety and Regulation of Vaccines
1.5 Basic Principles of Viral Vaccine Design and Traditional Production
1.6 Cell-Culture Production Processes
1.7 Manufacturing Challenges of Viral Vaccines
1.8 Pandemic Preparedness and Outlook
References
2. Introduction to virology
2.1 Introduction
2.1.1 What Are Viruses?
2.1.2 Virus Characteristics
2.1.3 Virus Evolution and Classification
2.2 Structure and Genome
2.2.1 Virus Structure and Function
2.2.1.1 Capsid
2.2.1.2 Envelope
2.2.2 Viral Genome
2.2.3 Viral Genome Transcription Via Intermediates
2.3 Viral Infection Cycle
2.3.1 Lytic Cycle
2.3.2 Lysogenic Cycle
2.3.3 Infection in Eukaryotic Host
2.4 Virus-Host Interactions
2.4.1 Types of Virus-Host Interactions
2.4.2 Components of a Host Cell Interacting with Viral Elements
2.4.3 Types of Infection
2.4.4 Key Elements of a Viral Infection
2.4.5 Disease Occurrence
References
3. Introduction to basic immunology and vaccine design
3.1 Introduction
3.2 Innate Immune System
3.2.1 Pattern Recognition Receptors
3.2.2 Cytokines and Chemokines
3.2.3 Cells of the Innate Immune System
3.2.3.1 Phagocytes
3.2.3.2 Natural Killer Cells
3.3 The Adaptive Immune System
3.3.1 Humoral Response
3.3.1.1 B-Cells
3.3.1.2 Immunoglobulin/Antibodies
3.3.1.2.1 Heavy and Light Chain Isotypes
3.3.1.3 Antigens and Epitopes
3.3.1.4 Antibody Effector Functions
3.3.2 Cell-Mediated Response
3.3.2.1 T-Cell Recognition
3.3.2.2 Helper T-Cells
3.3.2.3 Cytotoxic T-Cells
3.4 Vaccines
3.4.1 Vaccine Design
3.4.2 Live Attenuated Virus
3.4.3 Inactivated Virus
3.4.4 Subunit Vaccine
3.4.5 DNA Vaccine
3.4.6 RNA Vaccine
3.5 Conclusion
References
4. Cell lines for vaccine production
4.1 Introduction
4.2 Basic and Technical Considerations
4.2.1 Basic Considerations (Including Vaccine Types and Cell Lines)
4.2.2 Technical Considerations
4.2.2.1 Cell Banks
4.2.2.2 Viral Seeds
4.2.2.3 Technology Evolution
4.3 Viral Safety
4.3.1 Risk and Impacts
4.3.2 Sources of Viral Contaminations
4.3.3 Levels of Risk
4.3.4 Case Study: The PCV1/Rotarix Incident
4.3.5 Viral-Risk Assessment
4.3.6 Regulatory Considerations
4.3.7 Raw Materials: From Biological Materials to Chemically Defined Materials for Cell Lines
4.4 Analytical Considerations and Cell-Based Assays
4.4.1 Safety Tests and Future
4.4.1.1 In Vitro and in Vivo Safety Tests
4.4.1.2 New Technologies
4.4.1.2.1 PCR-Based Methods
4.4.1.2.2 Microarrays
4.4.1.2.3 Mass Spectrometry
4.4.2 Cell Line-Based Assays and the Future
4.4.2.1 Potency Tests
4.4.2.1.1 In Vivo Potency
4.4.2.1.2 In Vitro Potency
4.4.2.1.3 Live-Attenuated Vaccines
4.4.2.1.4 Live-Vectored Recombinant Virus
4.4.2.1.5 Validation
4.4.3 Molecular Assays and Control of the Viral Risk in the Future
4.5 Conclusions
Acknowledgments
References
5. Upstream processing for viral vaccines-General aspects
5.1 Introduction
5.2 Basic Design of a Virus Production Process
5.3 Vaccine Candidates
5.4 Cell Lines for Virus Production
5.4.1 Selection of Host Cell Lines
5.4.2 Cell Banking
5.4.3 Preculture and Maintenance of Cells
5.4.4 Adherent Versus Suspension Cells
5.4.4.1 Cell Attachment and Use of Microcarriers
5.5 Cultivation Media and Metabolism
5.5.1 Media and Additives
5.5.2 Monitoring Cell Metabolism
5.6 Cultivation Vessels at Small and Larger Scale and Process Variables
5.6.1 Cultivation Vessels
5.6.2 Process Variables
5.6.2.1 Temperature
5.6.2.2 pH and CO2
5.6.2.3 Shear Stress
5.6.2.4 Oxygen Supply
5.6.3 Choosing a Production Vessel
5.7 Virus Production and Process Development
5.7.1 Virus Production
5.7.2 Process Development and Optimization
5.7.2.1 Seed Virus Generation
5.7.2.2 Process Optimization Options
5.8 Sometimes Nothing Makes Sense—Some Ideas on Trouble Shooting...
5.9 CMC and GMP Considerations Right from the Start
5.9.1 Cellular Sources
5.9.2 Virus Sources
5.9.3 Cell Growth and Harvesting
5.9.4 Purification and Downstream Processing
5.10 Other Points to Consider
5.10.1 Manufacturing Options
5.10.2 Biosafety
5.11 Conclusion
References
6. Upstream processing for viral vaccines-Process intensification
6.1 Introduction
6.2 Motivation for Process Intensification
6.3 Parameters for Process Comparison and Evaluation
6.4 From Batch Cultures to Intensified Processes
6.5 Critical Factors for Virus Production at High Cell Density
6.6 Cell Retention Devices
6.6.1 Spin Filters
6.6.2 Tangential Flow Filtration
6.6.3 Alternating Tangential Flow
6.6.4 Disc Centrifuge
6.6.5 Inclined Settler
6.6.6 Hydrocyclone
6.6.7 Acoustic settler
6.7 Use of Disposables
6.8 Conclusion
References
7. Downstream processing of viral-based vaccines
7.1 Introduction
7.1.1 Viral-Based Vaccines Manufacturing--Current Challenges in Downstream Processing
7.1.2 Traditional Methods for Virus Purification
7.2 Purification Strategies for Viruses
7.2.1 Harvest and Clarification
7.2.2 Intermediate Purification--Virus Concentration and Chromatography
7.2.3 Polishing
7.3 Analytics Tools on Process Understanding and High Throughput Process-Development
7.4 The Future in Purification Technology
7.4.1 New Facility Design
7.4.2 Process Intensification
7.5 Concluding Remarks
References
8. Analytics and virus production processes
8.1 Introduction: Regulatory Context for Analytics Development
8.2 Analysis of Viral Products
8.2.1 Biological Attributes of Virus-Based Products
8.2.2 Implications of Process Phase on Analytics Choices
8.3 Viral Quantification Methods
8.3.1 Infectious Particle Quantification
8.3.2 Total Viral Particles Quantification
8.3.2.1 Immuno-Based Assay
8.3.2.2 Particle Counters
8.4 Process Analytical Technologies and in-Line Analytics for Viral Production Processes
8.4.1 Off-line, At-line, On-line, and In-line Definitions
8.4.2 Process Analytical Technology for Viral Production Processes
References
9. Manufacturing of seasonal and pandemic influenza vaccines-A case study
9.1 Introduction
9.2 The Influenza Virus
9.3 The Annual Cycle for Influenza Vaccine Manufacturing
9.4 Influenza Vaccines
9.4.1 Inactivated Influenza Vaccine (IIV)
9.4.2 Live Attenuated Influenza Vaccines (LAIVs)
9.4.3 Recombinant Vaccines
9.4.4 Emerging Technologies for Influenza Vaccine Production
9.5 Influenza Virus Quantification
9.6 Downstream Processing of Influenza Vaccines
9.7 Conclusion
References
10. Recombinant vaccines: Gag-based VLPs
10.1 Virus-Like Particles
10.2 HIV-1 Gag VLPs
10.3 Production of HIV-1 Gag VLPs
10.3.1 PEI-Mediated Transient Transfection
10.4 Methods to Improve the Production Process
10.4.1 Serum-Free Media
10.4.2 Cell Lines/Plasmids
10.4.3 Optimization of TGE
10.4.4 Additives to Increase Transient Transfection and Protein Production
10.4.5 Cell Culture Modes
10.5 Examples of Gag-Based VLPs
10.6 Scalable DSP for HIV-1 Gag VLPs
10.7 Characterization and Quantification of VLPs
References
11. Vectored vaccines
11.1 Introduction
11.2 Adenovirus-Vectored Vaccines
11.2.1 AdV Structure and Vector Design
11.2.2 Production Process of AdV Vectors
11.2.2.1 Cell Line Selection
11.2.2.2 Limitations in the Production of AdV
11.2.2.3 Productivity of AdV in Different Operation Modes
11.2.2.4 Quantitation Methods of AdV Vector
11.2.3 Examples of AdV-Based Vaccines
11.2.3.1 Veterinary Vaccines
11.2.3.1.1 AdV-Based Rabies Vaccine
11.2.3.1.2 AdV-Based Foot and Mouth Disease (FMD) Vaccine
11.2.3.2 AdV-Based Ebola Vaccine
11.2.3.3 AdV-Based COVID-19 Vaccine
11.3 Vesicular Stomatitis Virus (VSV) Vectored Vaccines
11.3.1 Vesicular Stomatitis Virus
11.3.2 Construction and Production Process of VSV Vectors
11.3.2.1 Pseudotype and Recombinant VSV
11.3.2.2 VSV As a Vaccine Vector
11.3.2.3 Cell-Line Selection
11.3.2.4 Production Process of VSV Vector
11.3.3 Example of VSV-Based Vaccines
11.3.3.1 VSV-Based Ebola Vaccine
11.3.3.2 VSV-Based COVID-19 Vaccine Candidates
11.4 Overall Conclusion on Vectored Vaccines
References
12. Design and production of vaccines against COVID-19 using established vaccine platforms
12.1 Introduction
12.2 SARS-CoV-2 Biology
12.3 SARS-CoV-2 Immunology and Vaccine Rationale
12.4 Vaccine Development for SARS-CoV-2
12.4.1 RNA Vaccines
12.4.1.1 mRNA Vaccine Design
12.4.1.2 mRNA Vaccine Manufacturing
12.4.1.3 Stability of mRNA Vaccines and Their Efficacy
12.4.2 Viral Vector Vaccines
12.4.2.1 Adenovirus Vectored Vaccines
12.4.2.2 Adenovirus Vectored COVID-19 Vaccines: Design, Manufacturing, and Efficacy
12.4.3 Whole Virus Vaccines
12.4.4 Protein Sub-Unit Vaccines
12.5 Next Steps and Future Perspectives
References
Index