The authoritative guide to the revolutionary concept behind the successful Covid-19 vaccines
In Trends in m RNA Vaccine Research, a team of distinguished researchers delivers a practical and up-to-date discussion of the biochemical and biomedical foundations of m RNA vaccines. They also explore the manufacturing conditions required for successful vaccine development and review recent progress in a variety of medical fields, including vaccines against pathogens like SARS-Co V-2, HIV, plasmodium, Mycobacterium tuberculosis, as well as anticancer vaccines.
Volume highlights include:
- A historical overview of m RNA vaccine development
- Immune responses to modified or unmodified m RNA vaccines
- A description of the different m RNA vaccine platforms
- Latest data on current m RNA vaccine developments against infectious diseases and cancer
Perfect for medicinal chemists, immunologists, and epidemiologists, Trends in m RNA Vaccine Research will also benefit researchers and scientists working in the pharmaceutical industry, as well as cancer researchers with an interest in vaccine development.
İçerik tablosu
Preface xiii
Preface from the Volume Editors xv
Part I How m RNA Vaccines Work 1
1 A Historical Overview on m RNA Vaccine Development 3
Rein Verbeke, Miffy H.Y. Cheng, and Pieter R. Cullis
1.1 Introduction 3
1.2 The Path of m RNA as an Unstable and Toxic Product to a New Class of Medicine 5
1.2.1 The Discovery and In Vitro Production of m RNA 5
1.2.2 The Inflammatory Nature of m RNA 7
1.3 How Studying Lipid Bilayer Structures in Cell Membranes Gave Rise to the Eventual Development of Lipid Nanoparticles for RNA Delivery 8
1.3.1 From Biological Cell Membranes to Liposomal Drugs 8
1.3.2 Ionizable Lipid Nanoparticles for Systemic Delivery of Nucleic Acids 10
1.4 The Journey of Developing Clinical m RNA Vaccines 12
1.5 Concluding Remarks 14
References 15
2 Immune Responses to m RNA Vaccine 29
Jean-Yves Exposito, Claire Monge, Danielle C. Arruda, and Bernard Verrier
2.1 Introduction 29
2.2 Innate Sensing of RNA Molecules 30
2.3 Innate Immune Response to m RNA Vaccines 32
2.3.1 Innate Immune Response in Humans 33
2.3.2 Tissue Innate Immune Response in Mice 34
2.4 m RNA Design and Innate Immunity 35
2.4.1 Cap 35
2.4.2 Untranslated Regions 37
2.4.3 Poly(A) 39
2.4.4 Coding Sequence 41
2.5 Optimization and Production of m RNA for an Adequate Innate Immune Response 42
2.5.1 IVT Production 42
2.5.2 Posttranscriptional Modification 44
2.5.3 Purification 45
2.6 m RNA Delivery Systems and Immune Response: The Role of Formulation Composition 45
2.7 Concluding Remarks and Perspectives 51
Acknowledgments 54
References 54
3 Modified or Unmodified m RNA Vaccines? – The Biochemistry of Pseudouridine and m RNA Pseudouridylation 69
Pedro Morais and Yi-Tao Yu
3.1 Pseudouridine (Ψ): The Fifth Nucleoside 69
3.2 RNA Pseudouridylation Mechanism 70
3.2.1 Naturally Occurring RNA Pseudouridylation 71
3.2.1.1 RNA-independent Pseudouridylation Catalyzed by PUS Enzymes 71
3.2.1.2 RNA-dependent Pseudouridylation Catalyzed by Box H/ACA sno RNP 71
3.2.2 Artificially Introduced RNA Pseudouridylation 73
3.2.2.1 Targeted Pseudouridylation of RNA Using Artificial Guide RNAs 73
3.2.2.2 Incorporation of Ψ During In Vitro Transcription of RNA 74
3.3 Ψ detectionin RNA 75
3.3.1 Indirect Ψ Sequencing Methods 76
3.3.2 Direct Ψ Sequencing Methods 76
3.4 Impact of Ψ in Pre-m RNA Splicing and Protein Translation 77
3.4.1 Effect of Ψ in sn RNA and Pre-m RNA on Pre-m RNA Splicing 77
3.4.2 Effect of Ψ in r RNA and t RNA on Protein Translation 77
3.4.3 Effect of m RNA Pseudouridylation on Nonsense Suppression 78
3.4.4 Effect of m RNA Pseudouridylation on the Coding Specificity of Sense Codons 80
3.5 Ψ and the Immune System 80
3.6 Pseudouridylated Versus Unmodified m RNA Vaccines 82
3.6.1 Ψ Successor: N1-methyl-Ψ 82
3.6.2 Nucleoside-modified COVID-19 m RNA Vaccines 84
3.6.3 Unmodified m RNA COVID-19 vaccines 85
3.6.4 Cancer m RNA Vaccines 89
3.7 Conclusions 90
Acknowledgments 92
Conflict of Interest 92
References 92
4 Self-Replicating RNA Viruses for Vaccine Development 109
Kenneth Lundstrom
4.1 Introduction 109
4.2 Expression Systems For Self-Replicating RNA Viruses 109
4.3 Vaccines Against Infectious Diseases 113
4.4 Vaccines Against Cancers 130
4.4.1 Reporter Gene Expression 131
4.4.2 Tumor-associated Antigens 131
4.4.3 Cytotoxic and Anti-tumor Genes 139
4.4.4 Immunostimulatory Genes 139
4.4.5 Oncolytic Viruses 140
4.5 Conclusions and Future Aspects 143
References 144
5 Circular RNA Therapeutics and Vaccines 161
Xiang Liu and Guizhi Zhu
5.1 Introduction 161
5.2 The Biogenesis and Physiological Functions of Natural circ RNA 162
5.2.1 The Biogenesis of Natural circ RNA 162
5.2.2 The Physiological Functions of Natural circ RNA 162
5.3 The Design and Synthesis of Synthetic circ RNA 163
5.3.1 Design Considerations of Synthetic circ RNAs for Vaccines 163
5.3.2 Approaches to circ RNA Synthesis 164
5.4 The Applications of Synthetic circ RNA as Novel Therapeutics and Vaccines 168
5.5 The Delivery Systems of Synthetic circ RNA 170
5.6 Conclusion 170
References 171
6 Good Manufacturing Practices and Upscaling of m RNA Vaccine Production 177
Eleni Stamoula, Theofanis Vavilis, Ioannis Dardalas, and Georgios Papazisis
6.1 Introduction 177
6.2 Plasmid Production 178
6.3 Considerations of In Vitro Transcription Stage 180
6.3.1 The In Vitro Transcription Reaction 180
6.3.2 Purification of the In Vitro Transcribed RNA 181
6.4 Considerations of Lipid Nanoparticles (LNPs) 185
6.4.1 Synthesis of LNP and m RNA Encapsulation 185
6.4.2 Scaling Up Production of LNPs to Industrial Standards 186
6.5 Considerations of Fill-to-Finish and Storage 186
6.6 m RNA and m RNA–LNP Critical Quality Attribute Analysis 187
6.7 General Remarks and Further Considerations 189
References 191
7 m RNA Vaccination for Induction of Immune Tolerance Against Autoimmune Disease 201
Mark C. Gissler, Felix S.R. Picard, Timoteo Marchini, Holger Winkels, and Dennis Wolf
7.1 Role of Adaptive Immune Cells in Autoimmunity and Tolerance 201
7.1.1 Development of the Adaptive Immune System – Defining the Boundaries of Autoimmunity 201
7.1.2 Diversity of Adaptive Immunity 201
7.1.3 Antigen-Specific T Cells 202
7.1.4 T-cell Phenotypes and Functions 203
7.1.4.1 CD4 + T Cells 203
7.1.4.2 CD8 + T Cells 204
7.1.5 Role of B Cells and Autoantibodies 204
7.1.5.1 Development of B Cells 204
7.1.5.2 Somatic Hypermutations in B Cells – Refining High-Affinity Antibodies 205
7.1.5.3 Noncanonical Functions of B Cells 206
7.1.6 Autoimmune Diseases – Break of Tolerance Against Self-antigens 206
7.1.7 Immunomodulation of Autoimmune Diseases 207
7.1.7.1 Tolerogenic Vaccination to Dampen MHC-II-Dependent Autoimmunity 208
7.2 Atherosclerosis – An Unprecedented Autoimmune Disease 208
7.2.1 Autoimmune Component of Atherosclerosis 208
7.2.1.1 Role of Antigen-Specific T-Helper Cells in Atherosclerosis 209
7.2.1.2 B Cells and Autoantibodies in Atherosclerosis 209
7.2.2 Established Autoantigens in Atherosclerosis 210
7.2.2.1 LDL-C and Apo B 210
7.2.2.2 Heat-Shock Proteins 211
7.2.2.3 Beta-2-Glycoprotein I 211
7.2.2.4 Virus-Derived Antigens 211
7.2.3 Mechanism of Tolerogenic Peptide Vaccination in Atherosclerosis 212
7.2.4 Alternative Immunomodulation Against Cardiovascular Disease (CVD) Autoimmunity 212
7.2.4.1 DNA and m RNA Vaccination 212
7.2.4.2 Immunotherapy with Immunoglobulins 214
7.2.4.3 TCR/CAR T-cell Immunotherapy 215
7.3 The Autoimmune Component of MS 215
7.3.1 Pathophysiology of MS 215
7.3.2 Role of Antigen-Specific Immunity in MS 215
7.3.3 Mimicking MS by EAE Model 216
7.3.4 Vaccination Approaches to Prevent EAE 216
7.3.4.1 m RNA-Based Tolerogenic Vaccination Against EAE 217
7.4 Framework and Rationale for Future m RNA-Based Peptide Vaccination Strategies in Autoimmune Diseases 218
7.4.1 Evidence for m RNA Vaccination to Induce Tolerance in Animal Models 219
7.4.2 Limitations of Traditional Peptide Vaccination 220
7.4.3 Challenges of Future Vaccination Strategies 221
7.4.3.1 Antigen Targets and MHC Variability 221
7.4.3.2 Clinically Applicable Adjuvants and Routes of Administration 222
7.4.3.3 Effectiveness and Safety of Peptide Vaccination 223
7.4.3.4 Requirement of Clinical Biomarkers 223
7.4.4 Outlook: Chances of m RNA-Based Approaches in Future Clinical Immunomodulation in Allergy 224
List of Abbreviations 227
Acknowledgements 228
Conflict of Interest 228
References 228
Part II Recent Progress in Vaccine Research and Development 241
8 Design and Development of m RNA Vaccines to Combat the COVID-19 Pandemic 243
Istvan Tombacz
8.1 Introduction 243
8.2 SARS-Co V-2 Vaccine Design 244
8.3 Development of SARS-Co V-2 m RNA Vaccines 247
8.3.1 m RNA-1273 – Moderna 247
8.3.2 BNT162b2 – Pfizer/Bio NTech 248
8.4 Other SARS-Co V-2 m RNA Vaccines Developments 249
8.4.1 CVn Co V – Cure Vac 249
8.4.2 Additional m RNA-based SARS-Co V-2 Vaccines Evaluated in Clinical Trials 250
8.5 Booster Immunizations and Variants of Concern 251
8.6 Future Directions 252
References 253
9 m RNA Vaccines for HIV- 1 259
Paolo Lusso
9.1 Introduction 259
9.1.1 A Long and Winding Road: 40 Years and Counting 259
9.1.2 A Very High Bar: Failure of Traditional Approaches 260
9.1.3 A New Era: An HIV-1 Vaccine Is Feasible 260
9.2 Strategies for HIV-1 Vaccine Design 261
9.2.1 Main Strategies 261
9.2.1.1 Lineage-Based Vaccines 261
9.2.1.2 Mutation-Guided Vaccines 262
9.2.1.3 Structure-Based Vaccines 262
9.2.1.4 Epitope-Based Vaccines 262
9.2.1.5 Combination Strategies 263
9.3 m RNA-Based HIV-1 Vaccines 263
9.3.1 Why m RNA? 263
9.3.2 Key Technological Breakthroughs 265
9.3.3 Main Platforms for m RNA-Based HIV-1 Vaccines 265
9.3.3.1 m RNA-Transduced Dendritic Cells 267
9.3.3.2 Direct In Vivo m RNA Delivery 267
9.3.3.3 The Rise of the LNPs 269
9.3.3.4 Self-Amplifying m RNA 270
9.4 Recent Advances in HIV-1 m RNA Vaccine Design 271
9.4.1 The Medium Is Not the Message 271
9.4.2 Specific Approaches 271
9.4.2.1 A VLP-Forming env-gag m RNA Platform 272
9.4.2.2 Self-Assembling Nanoparticles 274
9.4.2.3 Engineered Germline-Engaging gp120 Cores 274
9.5 The Future 275
9.5.1 Room for Improvement 276
9.5.1.1 Mucosal Delivery and Other Alternative Routes 276
9.5.1.2 Slow Delivery 276
9.5.1.3 Env-Gag VLP Optimization 277
9.5.1.4 Multiple-Array Antigen Presentation 277
9.5.1.5 Supplemental Adjuvants 278
9.5.1.6 Combination of m RNA with Other Platforms 278
9.6 Concluding Remarks 279
Acknowledgment 279
References 279
10 m RNA Vaccines Against Tick-borne Diseases 285
Gunjan Arora and Erol Fikrig
10.1 Introduction 285
10.2 Vector-borne Diseases 285
10.3 Tick-borne Diseases 286
10.4 Tick Saliva Antigens as Vaccine Candidates 286
10.5 Vaccines Targeting Pathogens That Cause Tick-borne Diseases 288
10.6 m RNA Vaccines 288
10.7 An m RNA Vaccine Against Ticks 289
10.8 Powassan Vaccine 291
10.9 RNA Vaccine Against Crimean–Congo Hemorrhagic Fever Virus 291
10.10 Conclusions 292
References 293
11 m RNA Vaccines for Malaria and Other Parasitic Pathogens 303
Leroy Versteeg and Jeroen Pollet
11.1 The Global Burden of Parasitic Pathogens 303
11.2 Challenges of Vaccine Development Against Parasitic Pathogens 305
11.3 m RNA Technology to Accelerate the Development of Advanced Next-Generation Vaccines 307
11.4 Accessibility, Manufacturing Capacity, and Logistics of m RNA for Lowand Mid-Income Countries 308
11.5 Published Data on m RNA Vaccines Against Parasitic Pathogens 311
11.5.1 Malaria 311
11.5.2 Toxoplasmosis 314
11.5.3 Leishmaniasis 315
11.5.4 Chagas Disease 316
11.5.5 Helminths 317
11.6 Conclusions and Prospects 317
References 318
12 Current State of m RNA Vaccine Development Against Mycobacterium tuberculosis 325
Ilke Aernout, Rein Verbeke, Stefaan C. De Smedt, Francis Impens, and Ine Lentacker
12.1 Introduction 325
12.2 Immune Responses Responsible for Protective Immunity Against Mycobacterium tuberculosis 326
12.3 Suitability and Advantages of an m RNA Vaccine Platform Against Mycobacterium tuberculosis 328
12.4 m RNA TB Vaccines in (Pre-)clinical Development 330
Acknowledgments 332
References 332
13 Cancer Vaccines Based on m RNA: Hype or Hope? 337
Wout de Mey, Dorien Autaers, Giada Bertazzon, Arthur Esprit, Marta Marco Aragon, Lorenzo Franceschini, and Karine Breckpot
13.1 Tumors: Setting the Scene for Cancer Immunotherapy 337
13.2 Cancer Vaccination 339
13.3 Vaccine Development Rules: A Brief Overview of Lessons Learned 342
13.3.1 Use Multiple and Highly Immunogenic Tumor-Specific Antigens 342
13.3.2 Use a Potent Adjuvant 343
13.3.3 Use an Efficacious, Flexible, Safe, and Preferably Low-Cost Vaccine Vector 345
13.3.4 Choose the Best Route of Delivery 346
13.3.5 Incorporate Strategies to Subdue Tumor-Mediated Immunosuppression 349
13.4 m RNA: From Discovery to Application in Vaccinology 351
13.5 m RNA Manufacturing and Design 353
13.6 m RNA Delivery and Formulation 358
13.7 Controlling the Innate Immune Sensing of m RNA 362
13.8 Adjuvants for m RNA-Based Vaccines 366
13.9 Clinical Application 368
13.10 Conclusion 373
References 374
Index 401
Yazar hakkında
Gabor Tamas Szabo, MD, Ph D, is an Associate Director at Bio NTech SE. His work is focuses on m RNA technology optimization and applications.
Norbert Pardi, Ph D, is an Assistant Professor at the University of Pennsylvania, USA. His research is focused on the development of m RNA-based therapeutics with a focus on vaccines.
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