Bioprocessing of Viral Vaccines

Description

This book focuses on cell culture-produced viral vaccines to meet the needs of the rapidly expanding research and development in academia and industry in the field. This book introduces the basic principles of vaccination and the manufacturing of viral vaccines. Bioprocessing of Viral Vaccines, will provide an overview of the advanced strategies needed to respond to the challenges of new and established viral infection diseases. The first few chapters cover the basics of virology and immunology as essential concepts to understand the function and design of viral vaccines. The core of the content is dedicated to process development, including upstream processing and cell culture of viral vaccines, downstream processing, and extensive analytical technologies specific to viral vaccines. Advanced process analytical technologies (PAT) and Quality by Design (QbD) concepts are also introduced in the context of vaccine manufacturing. The case studies included cover inactivated, attenuated vaccines exemplified by influenza vaccines, sub-unit vaccines exemplified by Virus Like Particles (VLPs: HPV vaccines) and sub-unit vaccines (Flublock), vectored vaccines: adenoviruses and Vesicular stomatitis Virus (VSV) vectored vaccines, genomic vaccines (DNA and mRNA) vaccines as developed for COVID-19 response in particular and a review of COVID-19 vaccines approved or in advanced clinical trials. This book is aimed at graduate engineers and professionals in the fields of vaccinology, bioprocessing, and biomanufacturing 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