mRNA Vaccines

Description

The formulation and the technological advancements in RNA biology, chemistry, stability, and encapsulated delivery systems that have enabled the development of fully synthetic mRNA vaccines are discussed in this volume. The applications of the mRNA technology is covered, focusing on infectious diseases but also touching on other indications, such as immunotherapies and molecular therapies. Potent and long-lasting immune responses observed in animal models, encouraging data from early human clinical studies, together with the success of two mRNA-based COVID-19 vaccines support the use of mRNA-based vaccination as an attractive alternative to conventional vaccine approaches. Consequently, the development progress of the technology, particularly on production, capabilities, and clinical development is reviewed. Topics on safety, regulatory issues, and possible challenges to the mRNA vaccination approach round off this book. Thanks to their high potency, the prospect for generic, low-cost manufacturing processes, and entirely synthetic nature, the future for mRNA vaccines is highly promising. Importantly, mRNA vaccines have the potential to minimize the time between pathogen identification and vaccine release with a huge impact on public health. As the mRNA-based vaccination technology has been progressing rapidly, the book is intended to be an end-to-end review series, covering everything from basic RNA biology and preclinical studies to the manufacturing strategy, clinical development and regulatory approval. It provides established RNA researchers and developers with updates on the latest advancements in the field and allows for a quick but comprehensive overview of this transformative technology, its application, and future potential. Preface Contents 230 mRNA-Based Vaccines and Mode of Action Abstract 1 Introduction 1.1 Established Vaccination Approaches 1.2 Novel Vaccination Approaches 2 mRNA Technology 2.1 5′ Cap Structure 2.2 Untranslated Regions (UTR) of mRNA 2.3 3′End of the mRNA 2.4 ORF Optimization and Global Modifications 3 Mode of Action of mRNA Vaccines 3.1 Innate Immune Sensors Detecting mRNAs 3.2 Immune Activation by mRNA Vaccines (Adjuvancy vs. Overactivation) 3.3 Adaptive Immune Response 3.3.1 Humoral Immunity 3.3.2 Cellular Immunity 4 Conclusion Acknowledgements References 233 Self-amplifying mRNA-Based Vaccine Technology and Its Mode of Action Abstract 1 Introduction 2 Self-amplifying mRNA: From Viruses to Synthetic Vaccines 2.1 Self-amplifying mRNA Biology and Mechanistic Clues from the Alphavirus Self-amplification Pathway 2.2 Main Characteristics of Synthetic Self-Amplifying mRNA Vaccines 3 Decoding the Balance Between Innate and Adaptive Immune Responses for Potent Self-amplifying mRNA Vaccines 3.1 Mechanistic Insights from Alphaviruses: Immune Recognition and Evasion of IFN-Mediated Defenses 3.2 Innate Immune Response to Synthetic Self-amplifying mRNA Vaccines 3.3 Self-adjuvanting Effect of the Self-amplifying mRNA 4 Recent Advances and Optimization Approaches of Self-amplifying mRNA Vaccines 5 Conclusions and Perspectives Acknowledgements References 217 Formulation and Delivery Technologies for mRNA Vaccines Abstract 1 Introduction 2 Administration Routes for mRNA Vaccines 3 Delivery Strategies for mRNA Vaccines 3.1 Delivery Carriers of mRNA Vaccines 3.1.1 Lipid-based Delivery 3.1.2 Polymer-based Delivery 3.1.3 Peptide-based Delivery 3.1.4 Virus-Like Replicon Particle 3.1.5 Cationic Nanoemulsion 3.2 Naked mRNA Vaccines 3.3 Dendritic Cells-Based mRNA Vaccines 3.4 Co-delivery of mRNA Vaccines 3.4.1 Co-delivery of mRNAs to Assemble Protein Complexes 3.4.2 Co-delivery of mRNAs Encoding Multiple Antigens 3.4.3 Co-delivery of mRNAs Encoding Antigens and Immunostimulatory Proteins 4 Current Challenges and Future Perspectives 5 Conclusion Acknowledgments References 202 Messenger RNA-Based Vaccines Against Infectious Diseases Abstract 1 Introduction 2 mRNA Vaccine Formats and Delivery Materials 2.1 Optimization of mRNA Production 2.2 mRNA Vaccine Types 2.3 Delivery Materials for mRNA Vaccines 3 Preclinical and Clinical Application of Infectious Disease mRNA Vaccines 3.1 Influenza Virus mRNA Vaccines 3.2 HIV-1 mRNA Vaccines 3.3 Zika and Other Flavivirus mRNA Vaccines 3.4 Rabies mRNA Vaccines 3.5 Ebola Virus mRNA Vaccines 3.6 Other mRNA Vaccines Against Viruses 3.7 mRNA Vaccines Against Bacteria 3.8 mRNA Vaccines Against Parasites (Malaria, Leishmania, Toxoplasma) 4 Passive Immunization with mRNA-Encoded Monoclonal Antibodies Against Infectious Diseases 5 Conclusions and Future Perspective Acknowledgements References 222 Advances in Development of mRNA-Based Therapeutics Abstract 1 Introduction 2 Delivery Platforms for mRNA Therapeutics 3 In Vitro Synthesis of mRNA Molecules 4 Clinical Application of mRNA Therapeutics 4.1 mRNA in Cancer Immunotherapy 4.2 Cancer Vaccine 4.2.1 Tumor-Associated Antigen (TAA)-Based Cancer Vaccine 4.2.2 Neoantigens Antigen-Based Cancer Vaccine 4.2.3 Dendritic Cell Vaccine 4.3 Therapeutic mRNA Encoding Cytokines and Other Immune-Modulating Factors 4.4 CAR-T Cells 4.5 mRNA Vaccines in Infectious Diseases 4.6 mRNA in Protein Replacement Therapy 4.6.1 Local Injection-Based Protein Replacement Therapy Myocardial Infarction Diabetes Foot 4.6.2 Liver Diseases 4.6.3 Lung Diseases 4.7 Genome Editing 5 Conclusions References 259 Clinical Development of mRNA Vaccines: Challenges and Opportunities Abstract 1 Introduction 2 Development of Nucleic Acid-Based Vaccines 3 Clinical Experience with mRNA Vaccines 3.1 SARS-CoV-2: mRNA-1273 and BNT162b2 3.2 Other Infectious Disease Vaccines 4 Key Questions for mRNA Vaccine Clinical Development 4.1 Do Correlates of Protection Generated by Conventional Vaccines Apply to mRNA Vaccines? 4.2 Are Packaged mRNA Vaccines Considered an Adjuvanted Vaccine? 4.3 mRNA Lends Itself to the Development of Combination Vaccines - What are the Implications? 4.4 mRNA Is a Platform Technology: Does Accumulated Safety Data with One mRNA Vaccine Predict Safety to an Unrelated mRNA Vaccine? 5 Summary References 220 Regulatory Considerations on the Development of mRNA Vaccines Abstract 1 Introduction 2 RNA Vaccine Development 3 Production Limitations 4 Product Quality Issues 4.1 Chemistry, Manufacture and Controls (CMC) of Drug Substance 4.2 Identity 4.3 Consistency of Production 4.4 Purity of the DS 4.5 Stability of the DS 4.6 CMC of Drug Product (DP) 4.7 Potency Determination 4.8 Stability of the DP 5 Potential Safety Issues 5.1 Immunogenicity of RNA 5.2 Reactogenicity of RNA 5.3 Self-Amplifying mRNA (SAM) Vaccines 6 Safety Evaluation 6.1 Toxicity 6.2 Genotoxicity 6.3 Biodistribution and Retention of the DP 6.4 Adjuvant Versus Delivery Vehicle 7 Concluding Remarks Acknowledgements References