Replicating Vaccines (eBook)

Preface 5
Contents 9
Contributors 11
Part I Today´s Live Attenuated Vaccines 15
Live Vaccines and Their Role in Modern Vaccinology 16
1 Introduction 16
2 Live Vaccines, a Brief History 17
3 A Brief Summary of the Modern Perspective 18
4 Rational Attenuation 19
5 Creating a Rationally Attenuated Vaccine 20
6 Creating Rationally Attenuated Live Enteric Bacterial Vaccines 20
7 Typhoid as an Example 21
8 Mice Are Not Men 22
9 The Delivery of Antigens by Live Vectors 23
10 Conclusions 24
References 25
Live Attenuated Vaccines: Influenza, Rotavirus and Varicella Zoster Virus 28
1 Introduction 28
2 Influenza 29
2.1 Introduction 29
2.2 Virology, Epidemiology and Pathogenesis 30
2.3 Immunology 31
2.4 Vaccine Development, Composition, and Mechanism of Attenuation 33
2.5 Safety and Efficacy 35
2.6 Issues for the Future 36
3 Rotavirus 37
3.1 Introduction 37
3.2 Virology, Epidemiology and Pathogenesis 37
3.3 Immunology 39
3.4 Vaccines Development, Composition and Mechanism of Attenuation 40
3.5 Safety and Efficacy 42
3.6 Issues for the Future 43
4 Varicella Zoster Virus 44
4.1 Introduction 44
4.2 Epidemiology 44
4.3 Pathogenesis of Primary and Recurrent VZV Infection 45
4.4 Host Response 46
4.5 VZV Vaccines 47
References 53
Classical Live Viral Vaccines 60
1 Introduction 61
2 Timelines for Vaccine Development 61
3 Development of Classical Vaccines 64
4 Genetic Basis of Attenuation 65
5 Advantages of Live Viral Vaccines 67
6 Benefits of Live Virus Vaccine Utilization 68
7 Problems with Live Vaccines 69
7.1 Shedding, Viremia, and Recombination 69
7.2 Genetic Instability 71
7.3 Thermostability and Microbial Contamination 72
7.4 Adventitious Viruses 73
7.5 Adverse Events due to Unchecked Replication in the Host 75
7.6 Precautions and Contraindications 76
References 76
Part II Genetically Attenuated Micro-Organisms as Vaccines 83
Recombinant Live Vaccines to Protect Against the Severe Acute Respiratory Syndrome Coronavirus 84
1 The Disease 85
2 Types of SARS-CoV Vaccines and Prospects of Protection Against SARS by Vaccination 85
2.1 Inactivated and Vectored Vaccines Developed to Prevent SARS 86
3 The Virus 87
4 Generation of Recombinant SARS-CoV Vaccines Based on the Deletion or Modification of Genes 88
4.1 Vaccines Based on the Deletion of E Protein 90
4.2 Evaluation of SARS-CoV-DeltaE Vaccine Candidate in Different Animal Model Systems 91
4.3 SARS-CoV E Gene Is a Virulence Gene 93
4.4 Future Improvement of rSARS-CoV-DeltaE Vaccine 94
4.4.1 To Increase Virus Titers While Maintaining the Attenuated Phenotype 94
4.4.2 Deletion of a Second Gene That Interferes with Host-Immune Response 95
4.4.3 Construction of rSARS-CoV Mutants with Modified E Protein (E*) Eliciting Higher Immune Responses to the Virus Than rSARS-CoV Without E Protein 95
4.5 Live SARS-CoV Vaccines Based on Viruses Attenuated by Modification of Structural or Nonstructural Proteins 96
4.5.1 Modification of the Replicase nsp1 Gene 96
4.5.2 Modification of Replicase nsp2 Gene 96
4.5.3 Modification of Protein 3a 96
5 Development of a SARS-CoV Vaccine by Modification of the Transcription-Regulating Sequences 97
6 Potential Side Effects of SARS-CoV Vaccines 97
7 Future Trends to Increase Biosafety of Live Modified SARS-CoV Vaccines 98
7.1 Gene Scrambling to Prevent the Rescue of a Virulent Phenotype by Recombination 98
7.2 Vaccines Based on Codon Deoptimization of Viral Genome 99
8 Concluding Remarks 99
References 100
Live-Attenuated Shigella Vaccines. Is Encouraging Good Enough? 109
1 Introduction 110
2 The Need for an Epidemiologically Valid Shigella Vaccine 111
3 Pathogenesis 112
4 Immune Response to Natural Infection with Wild Shigella spp. 113
5 Rational Selection of Genes to Develop Live-Attenuated Deleted Mutants and Clinical Trials 113
5.1 Pioneer Vaccine Candidates 114
5.2 Rational Selection of Genes 115
6 Alternative Strategy: Hybrid Live Vector Shigella Vaccines 119
7 Vaccine Candidates in Less Developed Countries 120
8 Conclusion 121
References 121
New Generation BCG Vaccines 128
1 Introduction 129
2 A Brief History of BCG 129
3 Why Is the Efficacy of BCG so Inconsistent? 130
3.1 Prior Exposure to Atypical Environmental Mycobacteria That Mask or Interfere with the Immune Response to BCG 131
3.2 Malnutrition That Interferes with the Development of a Protective Immune Response 131
3.3 Use of Different BCG Strains 131
3.4 Exposure to Helminths 131
3.5 High Levels of IL-4 132
4 Recombinant BCG Overexpressing Native Proteins as Vaccines Against Tuberculosis 132
4.1 Rationale for the Choice of BCG as Vector 132
4.2 rBCG30 133
4.2.1 Rationale for Selecting the M. tuberculosis 30kDa Protein for a Recombinant BCG Vaccine 133
4.2.2 Construction of rBCG30 134
4.2.3 Preclinical Studies 134
4.2.4 Clinical Studies 136
4.3 rBCG Expressing Other Native M. tuberculosis Proteins 136
4.3.1 rBCG/Antigen 85A 136
4.3.2 rBCG/Antigen 85C 137
4.3.3 rBCG/ESAT-6 ( CFP10) 138
4.3.4 rBCG/38kDa Protein 138
4.3.5 rBCG/19kDa Protein 139
4.4 rBCG Expressing M. tuberculosis Fusion Proteins 139
4.4.1 rBCG/72f 139
4.4.2 rBCG/Antigen 85B-ESAT-6 139
4.4.3 rBCG/Antigen 85B-Mpt64190-198-Mtb8.4 139
5 Recombinant BCG Overexpressing Native Proteins as Vaccines Against Leprosy 140
5.1 rBCG30 140
5.2 rBCG/Antigen 85A, Antigen 85B, and MPB51 140
6 Recombinant BCG Overexpressing Native Proteins and Attenuated M. bovis as Vaccines Against Bovine Tuberculosis 140
6.1 rBCG30 141
6.2 WAg533 141
7 Recombinant BCG Overexpressing Native Proteins and Additionally Attenuated for Safety in HIV-Positive Persons 141
7.1 rBCG(mbtB)30 142
7.2 rBCG(panCD)30 142
8 Recombinant BCG Expressing Immunomodulatory Cytokines 144
8.1 Cytokine-Secreting Vaccines for Tuberculosis 144
8.1.1 rBCG/GM-CSF 144
8.1.2 rBCG/IFNgamma and rBCG30/IFNgamma 145
8.1.3 rBCG/IL-2 145
8.1.4 rBCG/IL-18 145
8.1.5 rBCG/IL-15 146
8.2 Cytokine-Secreting Vaccines for Therapy of Bladder Cancer 146
8.2.1 rBCG/IFNgamma 146
8.2.2 rBCG/IFNa 146
8.2.3 rBCG/IL-2 147
8.2.4 rBCG/IL-18 147
8.3 Cytokine-Secreting Vaccines for Allergy 147
8.3.1 rBCG/IL-18 147
9 Recombinant BCG with Enhanced Antigen Presentation 148
9.1 BCG with Altered Intracellular Pathway 148
9.2 rBCG/Cathepsin S 148
10 Recombinant BCG Overexpressing Native Proteins and Escaping the Phagosome 149
11 Recombinant BCG Expressing Foreign Antigens 149
11.1 HIV 150
11.1.1 Recent Studies 161
11.2 Other Viral Diseases 164
11.3 Parasitic Diseases 164
11.4 Bacterial Diseases 165
12 Conclusions 166
References 167
Part III Manipulating Host-Pathogen Interactions to Make Vaccines 179
Basic Science Paves the Way to Novel Safe and Effective Pestivirus Vaccines 180
1 Introduction 181
2 Pestivirus Molecular Biology 182
3 Prerequisites for Pestivirus Persistence 183
3.1 Time Point of Infection, Biotype, and Beyond 184
3.2 Mutation of Viral Factors Interfering with the Innate Immune Response as a Strategy for Pestivirus Attenuation 186
3.2.1 How Can Innate Immune Reactions Be Reduced to a Tolerable Level? 186
3.2.2 Npro 187
3.2.3 Erns 187
3.2.4 Npro, Erns, and Persistence 189
3.3 Textbook of BVDV Persistence and Lessons for Vaccine Approaches 190
4 Pestiviruses Other Than BVDV 191
5 Alternative Approaches to Virus Attenuation 192
6 Marker Vaccines 194
7 Conclusion 195
References 196
Live Attenuated Influenza Virus Vaccines: NS1 Truncation as an Approach to Virus Attenuation 201
1 Influenza Virus Vaccines: The Current Standard 201
1.1 Inactivated Influenza Vaccines 202
2 Live Attenuated Cold-Adapted Influenza Vaccine 202
2.1 Molecular Mechanisms of Protection 204
2.2 Trivalent Live-Attenuated Influenza Virus Vaccines: Protection for a Variety of Groups 204
2.2.1 Protection in Children 204
2.2.2 Protection in Adults 205
2.2.3 Protection in the Elderly 206
2.2.4 Protection in the Immunocompromised 206
3 Live Attenuated Influenza Virus Vaccines Using Micro-RNA Technology 206
4 Influenza Virus Immunity Through Other Viral Vectors 207
5 Novel Live Attenuated Virus Vaccines Based on Modifications of the M2 Ion Channel 207
6 Novel Live Attenuated Virus Vaccines Based on Modification of Viral Interferon Antagonists 208
6.1 The NS1 Protein of Influenza Viruses 208
6.2 Mechanisms of NS1 Function 209
7 Testing the Concept: Vaccination Studies with NS1-Truncated Viruses 210
7.1 Studies in Mice 210
7.2 Studies in Pigs 212
7.3 Studies in Horses 213
7.4 Studies in Birds 213
7.5 Studies in Macaques 217
8 Blocking Influenza Transmission by Vaccination with NS1-Modified LAIV 219
9 Conclusions 220
References 220
An Attenuated HSV-1 Live Virus Vaccine Candidate that is Replication Competent but Defective in Epithelial Cell-to-Cell and Neuronal Spread 228
1 Introduction 228
2 Lifecycle of Alphaherpesviruses 229
3 Varicella Zoster Virus 229
4 Pseudorabies Virus and Equine Herpes Virus 1 230
5 Characterization of HSV-1 gE 230
6 Defining the Role of HSV-1 gE in Anterograde and Retrograde Spread 231
7 Defining the Role of HSV-1 gE in IgG Fc Binding Activity 235
8 NS-gEnull as an Attenuated Vaccine Candidate 236
9 Conclusions 238
References 239
Live Attenuated Vaccines for Respiratory Syncytial Virus 242
1 Respiratory Syncytial Virus 243
2 Agent 244
3 Treatment 246
4 RSV Vaccines 246
5 Live Vectored RSV Vaccines 250
6 Future Directions 252
7 Summary 255
References 256
Live Attenuated Cholera Vaccines: Flagella and Reactogenicity 265
1 Vibrio cholerae and Disease 265
2 Ecology of V. cholerae 266
3 Virulence Mechanisms of V. cholerae 266
4 Cholera Disease Dynamics 267
5 Immunity to Cholera 268
6 Killed Whole-Cell Cholera Vaccines: Parenteral and Oral Inoculation 269
7 Live Attenuated Cholera Vaccines 270
8 New Insights and New Approaches toward Stable Attenuation of V. cholerae 271
9 Development of the Concept: Evaluation of Motility Defective Vaccine Candidates 272
10 Peru-15: an Aflagellar, Nonreactogenic Cholera Vaccine 272
11 Bengal-15 and More Evidence for the Link between Motility and Reactogenicity 274
12 Field Trials of Peru-15 in a Cholera-Endemic Region 274
13 Host-Innate Immunity and Flagellin Signaling 275
14 Motility and Reactogenicity: The Infant Rabbit Model 277
15 Perspective on other Live Attenuated Vaccines vis-à-vis Flagellins and Reactogenicity 278
References 279
Part IV New Types of Replicating Vaccines 286
Replication-Defective Herpes Simplex Virus Mutant Strains as Genital Herpes Vaccines and Vaccine Vectors 287
1 Introduction 287
2 History of HSV Vaccines 288
3 Replication-Impaired HSV Mutants 289
4 Durability 290
5 Safety 290
6 Pre-Existing Immunity 291
7 Route of Immunization 291
8 Cross Protection Against HSV-1 291
9 Single-Cycle Mutant Viral Vaccine 292
10 Future Improvements 292
10.1 Immune Evasion 292
11 Coexpression of Immune Stimulatory Molecules 293
12 Genetic Diversity of HSV-2 Strains 293
13 HSV as a Vaccine Vector 294
14 HSV Amplicons as Vaccine Vectors 295
15 Perspectives 296
References 296
Nucleic Acid-Based Infectious and Pseudo-Infectious Flavivirus Vaccines 301
1 Introduction 302
2 Infectious cDNA Clones 303
3 Capsid-Deleted Genomes 307
4 VLPs for Delivery of Capsid-Deleted RNAs 309
5 DNA-Based Vaccine Producing SRIPs In Vivo 312
6 Summary 315
References 316
Application of Cleavage Activation Mutants of Influenza Virus as Live Vaccines 323
1 Cleavage Activation of the Influenza Virus Hemagglutinin 323
2 Attenuation by Exchange of a Polybasic for a Monobasic Cleavage Site 326
3 Attenuation by Introduction of an Elastase Cleavage Site 327
4 Conclusions 329
References 330
Alphavirus Particle-Based Vaccine Vectors 333
1 Overview 333
2 Alphavirus Biology 334
2.1 Classification, Transmission and Epidemiology 334
2.2 Alphavirus Molecular Biology 334
2.3 Pathogenesis 336
2.4 Alphaviruses as Vectors 337
3 Alphavirus Vector Vaccine Production 340
3.1 Electroporation Systems 340
3.2 VRP By-Products 340
3.3 Safety Improvements 341
3.4 Industrial-Scale Production 344
4 Preclinical/Clinical Evaluation 344
5 Future Prospects 346
References 346
Recombinant, Chimeric, Live, Attenuated Vaccines Against Flaviviruses and Alphaviruses 350
1 Introduction 351
2 Principles for Use and General Properties of Chimeric Vaccines 352
3 Flavivirus Vaccines 353
3.1 Molecular Construction and Rationale Design 353
3.2 Chimeric Flaviviruses Using Yellow Fever 17D Vaccine as the Vector 356
3.2.1 Chimeric JE/YF Vaccine (ChimeriVax-JE, IMOJEV) 359
3.2.2 Chimeric Flavivirus Vaccines Against Dengue 375
3.2.3 Chimeric DEN/YF Vaccines (ChimeriVax-DEN and Others) 376
3.2.4 Chimeric Dengue/Dengue and Deletion Mutant Vaccine Candidates Developed at NIAID 389
Tetravalent 1 396
Tetravalent 2 396
3.2.5 Chimeric Dengue Vaccines Employing Attenuated Dengue Type 2 Vector 398
3.2.6 Single Vector Constructs That Induce Immunity to Multiple Dengue Serotypes 400
3.2.7 Vaccines Against West Nile 401
Chimeric West Nile/Yellow Fever 17D Vaccine 401
3.3 Development of a Suitably Attenuated WN/YF Vaccine for Humans 403
3.4 Development of a Veterinary Chimeric WN/YF Vaccine 407
3.4.1 Dengue Type 4 Delta30 Vectored Vaccine Against West Nile Virus 408
3.4.2 Dengue Type 2 PDK53 Vectored Vaccine Against West Nile Virus 409
3.4.3 Chimeric Vaccines Against Tick-Borne Encephalitis 409
3.4.4 Chimeric TBE/DEN4 Vaccine 410
3.4.5 Chimeric LGT(TP21)/LGT and LGT(E5)DEN4 viruses 410
3.4.6 Chimeric Vaccines Against Other Flaviviruses of Medical Importance 414
4 Alphavirus Vaccines 414
4.1 Chimeric Vaccine Candidates Using Sindbis Virus as a Vector 416
5 Use of Chimeric Viruses in Diagnostic Tests 425
6 Recombination Events and Mutagenesis: Cause for Concern? 425
References 427
Index 440