Immunopotentiators in Modern Vaccines (eBook)

Immunopotentiators in ModernVaccines 5
Contents 7
Preface 9
Listof contributors 11
Unraveling "the immunologist's dirty little secret" 23
Introduction 23
Adjuvants provide start signals for immune reactivity and guide the response to an acceptable magnitude 24
Regulation of immune responses by antigen deliverance (signal 1) 24
Facilitation of signal 1 26
Regulation of signal 2 28
Signal 0 (recognition of stranger) concept 28
Danger concept 29
Facilitation of signal 2 30
Adjuvants provide signal 3, regulating the quality of immunity 32
Outlook 33
Acknowledgments 34
References 34
Dendritic cells as targets and tools in vaccines 39
Introduction 39
DCs as targets for modern vaccines 41
New adjuvants and DCs 41
Pathogen-associated molecular pattern—dependent DC targeting 41
Cytokines and DCs 44
In vivo targeting of DCs 46
DCs as tools for the development of therapeutic vaccines 47
Clinical studies with DC-based vaccines 47
Protocols for the preparation of DC—based vaccines 48
Final remarks 51
Acknowledgments 51
Host-derived molecules as adjuvants 57
Introduction 57
Cytokines as immunological adjuvants 57
Interferon gamma 58
Interleukin 2 58
Interleukin 1 59
GM-CSF 59
Interleukin 12 and similar cytokines 59
Type I interferon 60
Anti-cytokine antibodies 60
Improvement of cytokine activity: incorporation into liposomes or other carriers 60
Improvement of cytokine activity: fusion to antigen 60
C3d-based adjuvants 62
Heat shock proteins 64
Host cell surface proteins 66
TNFR and TNF superfamiles 66
Fms-like tyrosine kinase 3 ligand (Flt3L) 72
Special applications of host-derived adjuvants 72
Concluding remarks 72
Acknowledgments 73
Innate immune mechanisms and the identification of immune potentiators as vaccine adjuvants 79
Introduction 79
Innate immunity: a trigger point for the immune system 79
Pathogen-associated molecular patterns and pattern recognition receptors 80
Innate immunity conditions the host for subsequent adaptive immunity 82
Adjuvants in vaccine research 83
Structure and function of TLRs and Nods 84
Ligands of TLRs and Nods 84
Signaling through PRRs 86
Small-molecule immune potentiators: the future of adjuvants? 87
Drug discovery strategies for immune potentiators 88
Random screening based on functional outcome 89
Targeted screening 89
Future directions 90
Acknowledgment 91
CpG oligodeoxynucleotides as vaccine adjuvants 95
Introduction 95
CpG oligodeoxynucleotides 96
Mechanism of action of CpG ODN 96
Classes of CpG ODN 96
CpG as a vaccine adjuvant 97
Infectious disease vaccines 98
Cancer vaccines 103
Vaccines against asthma and allergy 105
Safety of CpG ODN as a vaccine adjuvant 107
Conclusions 107
Toll-like receptor 4 agonists as vaccine adjuvants 115
Introduction 115
Toll-like receptors: the missing link between innate and adaptive immunity 116
MPL and AGPs: TLR4 agonists as vaccine adjuvants 116
Clinical experience with TLR4 agonists as adjuvants 120
Safety of TLR agonists as vaccine adjuvants 122
Regulatory approval of the first TLR agonist as a vaccine adjuvant 123
Mechanism(s) of action of TLR4 agonists 123
TLR4 agonists as nonspecific immunomodulators 125
Rapid-acting vaccines 126
Concluding remarks 126
Immunomodulatory adjuvants from Quillaja saponaria 131
Introduction 131
Structure of Quillaja saponaria saponins 131
Saponin purification and development 133
Purification 133
Adjuvants in development 133
Adjuvant activity of saponins 134
Adjuvants for antibody response 134
Adjuvants for T cell response 134
Adjuvants for mucosal immune response 135
Structure/function studies 135
Saponin adjuvants in clinical trials 136
QS-21 136
Other saponin adjuvants in clinical studies 140
Conclusions 140
Acknowledgments 140
Microparticles as vaccine delivery systems 145
Introduction 145
Role of adjuvants in vaccine development 147
Immunopotentiator adjuvants 148
Particulate vaccine delivery systems 149
Adjuvant effect of synthetic microparticles 150
Uptake of microparticles into APC 150
Microparticles as adjuvants for antibody induction 150
Induction of cell-mediated immunity with microparticles 152
Microparticles as delivery systems for DNA vaccines 152
Microparticles as delivery systems for adjuvants 154
Microparticles as single-dose vaccines 155
Alternative particulate delivery systems 157
Alternative routes of immunization 158
Mucosal immunization with microparticles 158
Microparticles as delivery systems for mucosal adjuvants 159
Adjuvants for therapeutic vaccines 160
Future of microparticles for vaccine delivery 160
Acknowledgments 161
MF59: a safe and potent adjuvant for human use 171
Introduction 171
Initial development of MF59 adjuvant 171
Mechanism of action of MF59 172
Composition of MF59 173
Manufacturing of MF59 174
Preclinical experience with MF59 174
Clinical experience with MF59 adjuvant 175
Combination of MF59 with immunopotentiators 177
Use of MF59 in prime/boost settings 178
Future perspectives on the use of MF59 179
Development and evaluation of AS04, a novel and improved adjuvant system containing MPL and aluminum salt 183
Introduction 183
AS04 adjuvant system 184
Aluminum salt adjuvant 184
Monophosphoryl lipid A adjuvant 185
AS04 formulation process 187
MPL dose selection 187
Safety aspects of adjuvants for use in vaccines 188
Evaluation of aluminum 188
Preclinical evaluation of MPL 190
Preclinical evaluation of AS04 190
Clinical safety studies with AS04-containing vaccines 191
Examples of AS04-based vaccines 192
AS04 improves the kinetics and persistence of the humoral response to hepatitis B antigen 192
AS04 abrogates the enhanced pathology observed with the original formalin-inactivated RSV vaccine 192
AS04 affords increased protection compared with aluminum salt alone 194
Summary 196
Abbreviations 197
Acknowledgments 197
Virosomes for vaccine delivery 201
Introduction 201
Adjuvants 201
Routes of administration 202
Development of the IRIV concept 203
Fusogenic properties of IRIVs 203
Immunopotentiation 203
Incorporation of antigens into IRIVs 204
IRIVs and registered vaccines 205
IRIVs and malaria prophylaxis 206
IRIVs and cancer therapy 208
The ISCOMATRIX adjuvant 213
Introduction 213
Preparation and properties of ISCOMATRIX™ adjuvant 213
Composition 213
Physical properties 214
Manufacturing 216
Formulation methods 216
Nonclinical studies 218
Humoral immune responses 218
Cellular immune responses 220
Mucosal immune responses 221
Tumour immunotherapy 222
Clinical experience 222
Clinical overview 222
Humoral immune responses 224
Cellular immune responses 225
Mucosal immune responses 226
Safety and tolerability 227
Mechanism of Action 228
Immunomodulation 229
Antigen delivery 230
Antigen processing 231
Summary 233
Acknowledgments 234
Mineral adjuvants 239
Introduction 239
Preparation and crystalline structure of mineral adjuvants 240
Application of mineral adjuvants 240
Dosing mineral adjuvants 242
Mechanisms of adjuvant activity 244
Antigen adsorption 244
T cell reactivity, antibody subclasses, and stimulation of cytokines 246
APC surface marker differentiation 247
Mineral adjuvants and stimulation of IgE 247
Limitations to the applicability of mineral adjuvants 248
In vivo clearing of aluminum and calcium adjuvants 249
Side effect profile of mineral adjuvants 249
The inflammatory focus 250
Effect of the injection modus 251
Mineral adjuvants and Toll-like receptors 251
Conclusion 251
Mucosal adjuvants based on cholera toxin and E. coli heat—labile enterotoxin 257
Introduction 257
The need for mucosal vaccines and adjuvants 258
Cholera toxin and E. coli heat-labile enterotoxin as mucosal immunogens and adjuvants 260
Development of nontoxic derivatives as mucosal adjuvants 264
CT and CTB as adjuvants for dendritic cell vaccination 268
Mucosal immunotherapy based on cholera toxin B subunit 269
Conclusions 271
Transcutaneous immunization using the heat-labile enterotoxin of E. coli as an adjuvant 275
Introduction 275
Background 275
Molecular structure 277
Trafficking within the cell 277
Cell biology 278
Safety and efficacy of bAREs 279
Systemic and mucosal responses 284
Delivery optimization 285
Regulatory considerations 287
Comparison with other skin delivery technologies 288
Summary 289
Acknowledgments 289
T cell adjuvants and novel strategies for their identification 297
Status of T cell adjuvant testing in humans 297
T lymphocyte polarization 298
Th1/Th2 balance 298
Regulatory T cells 302
Nonconventional natural T lymphocytes 303
Memory T cells 303
Implications for vaccine design 304
Designing immunogenic T cell antigens 304
Targeting and conditioning antigen-presenting cells 304
New schemes and routes of immunization 305
New strategies to screen synthetic T cell adjuvants 305
Conclusions 306
Vaccination to treat noninfectious diseases: surveying the opportunities 311
Introduction 311
The immune system 311
Induction of an immune response by vaccination: general considerations 313
Adjuvants in antibody-based immunotherapy 313
Overview 313
Passive vaccination 314
Active vaccination 315
Adjuvants to stimulate T cell immunity 318
Outlook 318
Adjuvants and vaccines to enhance innate immunity 319
Adjuvants and vaccines based on humoral immunity 319
Adjuvants and vaccine strategies to enhance the immunogenicity of tumor antigens 320
Approaches to downmodulate immunosuppressive pathways 321
Adjuvants inducing immune deviation or immunosuppression 321
Overview 321
Adjuvants in the immunotherapy of allergy 323
Adjuvants in the immunotherapy of autoimmunity 326
Summary and conclusions 327
Clinical evaluation of adjuvants 341
Introduction 341
Definitions 341
Characteristics of an ideal adjuvant 341
Components of rational adjuvant development 343
Safety 343
Variable adjuvanticity 344
Suboptimal use of aluminum adjuvants 345
Animal models 345
Immunoassays 346
Regulatory issues 346
Preclinical 347
Clinical 347
Adjuvants used in licensed vaccines for humans 347
Mineral salts 347
Emulsions 348
Particulate immunomodulators 349
Microbial derivatives 349
Experimental adjuvants in humans 351
Microbial derivatives 351
Endogenous human agents 352
Saponins 353
Emulsions 354
Particulate immunomodulators 355
Summary and conclusion 355
Regulatory considerations in the nonclinical safety assessment of adjuvanted preventive vaccines 365
Introduction 365
Definitions 366
Current status of relevant, global regulatory guidance and initiatives 367
Relevant US (FDA) regulatory requirements and considerations 369
Investigational new drug applications (INDs) (21 CFR 312) 370
Pre-IND meetings 372
Master files 373
Toxicity studies for preventive vaccines 373
Objectives 373
Timing 374
Approaches to study design 375
Animal species 376
Route of administration, dose, and controls 376
Parameters monitored 377
Special considerations for adjuvanted vaccines 377
Additional safety assessment of the adjuvant alone 377
Considerations for bacterial toxin adjuvants delivered intranasally 378
Clinical assessment of adjuvanted preventive vaccines 378
Conclusions 379
Additional information 379
Acknowledgments 379
Index 383