Influenza Vaccines for the Future (eBook)

Preface 5
Contents 9
Contributors 11
Part I: Evolution and Epidemiology 15
Influenza Virus: The Biology of a Changing Virus 16
1 Introduction 16
2 Overview and Classification 17
3 Structure and Genomic Organization 18
4 Influenza Virus Life Cycle 18
4.1 Attachment, Entry, and Nuclear Import 18
4.2 Transcription, Replication, and Nuclear Export 22
4.3 Viral Assembly, Budding, and Release 23
5 Evolution 24
6 Host Range 26
7 Clinical Manifestations, Pathogenesis, and Virulence 27
7.1 Clinical Manifestations 27
7.2 Pathogenesis 28
7.3 Virological Determinants of Virulence 29
8 Seasonality and Transmission 30
9 Perspectives 31
References 32
The Epidemiology of Influenza and Its Control 40
1 Introduction 41
2 Seasonal Influenza: New Insights 43
2.1 Methods Used to Estimate the Mortality Burden of Influenza 43
2.2 Age and Time Variability in Influenza-Related Mortality in Temperate Climates 44
2.3 Burden and Circulation Patterns of Influenza in the Tropics 44
2.4 The Burden of Influenza in Infants and Young Children 46
2.5 The Impact of Influenza on Morbidity 46
2.6 The Relative Contribution of Influenza and RSV 47
2.7 Observational Transmission Studies 48
2.8 Syndromic Surveillance and Its Contributions to Influenza Epidemiology 49
2.9 Influenza Genomics and Molecular Epidemiology 49
3 Pandemic Influenza: Lessons from Historical Data and Modeling 50
3.1 History Lessons from the Field of Archaeo-Epidemiology 51
3.2 Transmission Models Used to Predict Future Pandemic Scenarios 54
3.3 Predicting the Impact of Pandemics 54
4 Epidemiology and the Control of Influenza 55
4.1 The Scarce Evidence from Clinical Trials 56
4.2 Evidence from Observational Studies 56
4.3 Revisiting the Evidence Base Supporting Strategies for Protecting Populations with Vaccine 57
4.4 Vaccines for the Control of Pandemic Influenza 58
5 Remaining Questions in Influenza Epidemiology and Considerations About the 2009 Pandemic 59
References 61
Epidemiology of Influenza in Tropical and Subtropical Low-Income Regions 68
1 Purpose and Background 69
2 Geographical Distribution 69
2.1 North/South East Asia and Pacific (1.99 Billion 29% of Global Population)71
2.2 South Asia (1.5 Billion 24% of World Population)73
2.3 Middle East/North Africa (405 Million 6% of World Population)76
2.4 Sub-Saharan Africa (821 Million 12% of World Population)77
2.5 Central and South America (570 Million 8% of World Population)77
2.6 Comparison of Influenza Burden Between Tropical/Subtropical Countries and North America/Europe [North America (452 Million) and Europe (502 Million) Together Equal About 14% of World Population] 78
3 Global Influenza Circulation 81
4 Vaccine Strategies for Tropical/Subtropical Regions 82
5 Summary 83
References 83
The Origin and Evolution of H1N1 Pandemic Influenza Viruses 89
1 Introduction 90
2 The Ultimate Reservoirs 90
3 Intermediate Hosts 91
4 Transmission 93
5 H1N1 Influenza in Pigs, People, and Poultry in USA 1918-1998 93
6 European Swine Influenza 95
7 Asian Swine Influenza Viruses 97
8 Pandemics in Humans 98
9 Pandemic H1N1 2009 in Pigs and Poultry 100
10 Perspective 101
References 102
The Emergence of 2009 H1N1 Pandemic Influenza 106
1 Introduction 106
2 The Origins 108
2.1 Ancestral Strains 108
2.2 Recent Emergence 112
2.3 The Increasing Diversity of the Pandemic Virus 113
3 Pathogenicity 114
4 Previous Immunity 117
5 Conclusion 118
References 119
Part II: Immunity and Vaccine Strategies 123
Influenza Vaccines Have a Short but Illustrious History of Dedicated Science Enabling the Rapid Global Production of A/Swine ((H1N1) Vaccine in the Current Pandemic 124
1 Introduction 125
2 A Snapshot of the First Six Decades of Influenza Virology 126
3 The Historical Steps in Killed Vaccine Development 129
4 Vaccine Purification Historical and Present 132
5 Early Progress: The Standardization of Potency, Composition, and Dosage of Inactivated Vaccines 132
6 HA Dosage of Vaccines and Relationship to HI Antibody Response 133
7 The Route of Vaccination 136
8 Early Quantification of Side Reactions to Vaccines: Whole-Virus Versus Split and Subunit 137
9 Advent of the 1968 (H3N2) Pandemic Virus and Use of Inactivated Vaccines 138
10 First Studies with Live Influenza Vaccines 139
11 Host Range Virus Mutants as Live Vaccines 140
12 Temperature-Sensitive Virus Mutants as Live Vaccines 141
13 Cold-Adapted Virus Mutants as Live Vaccines 142
14 Mammalian Cell Culture Vaccines 143
15 The Current Pandemic of A/Swine H1N1 and Vaccine Production and Efficacy 144
16 Unlike Historical Vaccines Could Newly Developed Twenty-First Century Vaccines Induce Protection Across the Different Virus Subtypes? 145
17 The Historical Use of Volunteers to Study Influenza and Vaccines 146
18 The MRC Common Cold and Influenza Quarantine Unit in Salisbury (UK) 147
19 Estimates of Vaccine Protection Obtained in the Past by Deliberate Challenge in Quarantine Units 148
20 A New Retroscreen Quarantine Unit in London 149
21 Conclusion 150
References 151
Influenza and Influenza Vaccination in Children 157
1 Introduction 158
2 Emergence of Pandemic H1N1 Virus 161
3 The Role of Children in the Spread of Influenza Disease 161
4 Influenza Vaccination in Children 162
5 Efficacy of TIV 163
6 Safety of TIV 165
7 Efficacy and Safety of LAIV 166
8 H1N1 Vaccines 168
9 New Vaccine Approaches 169
9.1 Adjuvants 169
9.2 Cell Culture-Derived Vaccines 171
10 Can Herd Immunity for Influenza be Achieved? 171
11 Practical Implications for Influenza Vaccination of Children 172
12 Conclusion 175
References 175
The Immune Response to Influenza A Viruses 180
1 Introduction 180
2 Detection of Influenza A Virus 181
3 Innate Immunity and the Influenza A Viruses 182
4 Humoral Immunity and the Influenza A Viruses 184
5 T-Cell Immunity and the Influenza A Viruses 185
5.1 Dendritic Cells 185
5.2 Costimulation 186
5.3 CD8+ T Cells 187
5.4 CD4+ T Cells 188
6 Influenza A Virus Escape 189
7 Heterotypic Influenza A Virus Immunity 190
8 Influenza A Virus Immunity and Vaccination 190
9 Conclusion 191
References 191
Correlates of Protection Against Influenza 205
1 Introduction 206
2 Influenza Vaccines and Criteria for Licensure 207
3 In Vitro Assays to Assess Protective Antibody Levels 211
3.1 Hemagglutination Inhibition 211
3.2 Single Radial Hemolysis 213
3.3 Microneutralization 216
3.4 Pseudotyped Assays 217
3.5 Other Assays 220
4 Conclusion 224
References 225
The Role of Animal Models In Influenza Vaccine Research 229
1 Influenza Viruses 230
2 Influenza Vaccines 231
3 Animal Models for Influenza 232
3.1 Rodent Models 232
3.2 Mice 236
3.3 Hamsters 237
3.4 Guinea Pigs 238
3.5 Rats 238
3.6 Ferrets 239
3.7 Non-Human Primates 239
4 Animal Models in Influenza Vaccine Research 241
4.1 Safety 241
4.2 Immunogenicity 243
4.3 Strain-Specific Immunity Directed Against the HA 244
4.4 Heterosubtypic Immunity 245
4.5 Immune Responses to Other Influenza Proteins 246
4.6 Efficacy 246
5 Vaccines for Pandemic Influenza 247
6 Animal Models 247
6.1 Mice 247
6.1.1 H5N1 Viruses and Vaccines 247
6.1.2 H7 Viruses and Vaccines 249
6.1.3 H9 Viruses and Vaccines 251
6.1.4 1918 H1N1 Pandemic Virus 252
6.1.5 H6 Viruses and Vaccines 253
6.2 Ferrets 254
6.2.1 H5N1 Viruses and Vaccines 254
6.2.2 H7 Viruses and Vaccines 256
6.2.3 Other AI Subtypes 257
6.2.4 1918 H1N1 Pandemic Virus 257
6.3 Cats 258
6.3.1 H5N1 AI Viruses 258
6.4 Hamsters 259
6.4.1 H9 Viruses and Vaccines 259
6.4.2 Non-Human Primates 259
6.4.3 H5N1 AI Viruses 260
6.4.4 1918 H1N1 Pandemic Virus 261
Clinical Evaluation of Live Attenuated Candidate Vaccines for Pandemic Influenza 262
Pandemic 2009 H1N1 Influenza Vaccines 263
6.5 Mice 263
6.6 Ferrets 264
6.7 Non-Human Primates 265
7 Correlates of Protection from AI Viruses and Regulatory Concerns 266
8 Conclusion 267
References 268
Live Attenuated Influenza Vaccine 279
1 Introduction 280
2 Background 281
3 Development of Cold-Adapted Influenza Vaccine Strains 281
4 Basic Properties of the Vaccine 282
4.1 Genetic Basis of Biological Properties of the Vaccine 282
4.2 Genetic Stability of the Vaccine in Manufacturing 284
4.3 Genetic Stability of the Virus In the Respiratory Tract and Transmission 285
5 Basis of the Immune Response 286
6 Performance of the Vaccine in Clinical Studies 289
7 LAIV Results During Circulation of Antigenically Different Strains 290
8 Influenza Vaccination on Large Population 291
9 LAIV Technology and Pandemic Preparedness 292
10 Conclusion 293
References 294
Cell Culture-Derived Influenza Vaccines 298
1 Introduction 299
2 Isolation of Viruses for Vaccine Seeds 300
3 Reassortment and Backbone Selection 302
4 Eliminating Adventitious Agents from Vaccine Seeds 303
5 The Cell Lines Used in Influenza Vaccine Manufacture 305
6 Egg-Based and Cell-Based Vaccine Production Processes 306
7 Clinical Testing of Cell-Based Influenza Vaccines 309
8 Role of Cell-Based Vaccine Manufacture in the Response to the Swine-Origin H1N1 Influenza Pandemic 311
9 The Future of Cell-Based Influenza Vaccine Manufacture 311
References 312
Conserved Proteins as Potential Universal Vaccines 318
1 Introduction 318
2 M2 Ion Channel 319
3 Mechanism of Action 325
4 Other Conserved Antibody Targets 326
5 T-Cell Targets 327
6 Summary 328
References 328
Emulsion-Based Adjuvants for Improved Influenza Vaccines 331
1 Introduction 332
2 Emulsion Technologies 332
3 The History of Emulsions as Adjuvants 333
3.1 Water-in-Oil Emulsion Adjuvants 333
3.2 Oil-in-Water Emulsion Adjuvants: The Early Years 335
3.3 The Development of Oil-in-Water Emulsions as Adjuvants for Flu Vaccines 336
4 The Current Status of Emulsion Adjuvants for Flu Vaccines 339
4.1 The Composition of MF59 340
4.2 Manufacturing of MF59 341
4.3 The Mechanism of Action of MF59 Adjuvant 341
4.4 Preclinical Experience with MF59 343
4.5 Clinical Experience with MF59 Adjuvant: Fluad Seasonal Influenza Vaccine 344
4.6 Safety Evaluations of MF59 349
4.7 Pandemic Influenza Vaccines Containing MF59: Avian Influenza Viruses 350
4.8 Pandemic H1N1 Virus 353
4.9 MF59 with Other Antigens 353
4.10 Additional Oil-in-Water Adjuvant Formulations in Development 354
5 The Future 354
References 354
Lessons Learned from Clinical Trials in 1976 and 1977 of Vaccines for the Newly Emerged Swine and Russian Influenza A/H1N1 Viruses 362
1 Introduction 363
2 The Vaccines and Evaluations 363
3 Reactogenicity 364
4 Immunogenicity 366
5 Comment 370
References 373
Occurrences of the Guillain-Barré Syndrome (GBS) After Vaccinations with the 1976 Swine A/H1N1 Vaccine, and Evolution of the Concernfor an Influenza Vaccine-GBS Association 375
1 Introduction 376
2 The A/New Jersey Vaccine Experience 376
3 The Guillain-Barré Syndrome 377
4 A/New Jersey Vaccine and Pathogenesis of GBS 378
5 GBS and Influenza Vaccines Other than the A/New Jersey Vaccine 379
6 Recent Contributions 379
7 Comment 381
References 382
Human Monoclonal Antibodies for Prophylaxis and Treatment of Influenza 385
1 Introduction 386
2 Immune Response to Influenza 386
3 Vaccination Against Influenza 386
4 Treatment 387
5 Passive Immunotherapy 388
6 Neutralizing Influenza 389
7 Human mAbs Against Influenza 390
8 Perspectives 395
References 395
Part III: Economic and Social Implications 401
Learning from the First Pandemic of the Twenty-First Century 402
1 Of Birds and Humans: The Lessons Learned 402
1.1 The Need of Adjuvants 404
1.2 Dose-Sparing and Increased Dose Availability 406
1.3 Broadening of the Antibody Response to Drifted Influenza Virus Strains 407
1.4 Induction and Persistence of Immunological Memory 408
2 Of Pigs and Humans: How to Apply This Learning? 411
2.1 Adjuvants and A/H1N1 Vaccines? 412
2.2 Immunological Memory: Priming by Previous Influenza Infection/Vaccination 415
2.3 Shaping of the Repertoire of the Influenza B-Cell Epitopes by Adjuvants 417
3 Conclusions: Rethinking Influenza 418
References 419
Economic Implications of Influenza and Influenza Vaccine 425
1 Introduction 425
2 Methods 426
2.1 Societal Costs of Pandemic Influenza 426
2.2 Societal Costs of Seasonal Influenza 427
2.3 Cost-Effectiveness: Children 427
2.4 Cost-Effectiveness: Elderly 427
3 Results 428
3.1 Macroeconomic Costs of Seasonal Influenza 428
3.2 Macroeconomic Costs of Pandemic Influenza 429
3.3 Cost-Effectiveness of Vaccination 431
3.3.1 Children 432
3.3.2 Elderly 435
3.3.3 Working Adults 435
4 Discussion 437
4.1 Cost-Effectiveness and Cost-Benefit Analysis: Methodological Issues 437
4.2 Policy Implications 438
References 438
Index 441