Malaria immunology

Contents......Page 6
Preface......Page 16
Life Cycle......Page 18
Host Cell Entry......Page 21
Trophozoites and Schizonts......Page 24
Knob Formation and Cytoadherence......Page 25
Cytoplasmic Clefts......Page 27
Sexual Forms......Page 28
Fertilization and Zygote Formation......Page 30
Ookinete and Oocyst......Page 31
Sporozoite......Page 33
Preerythrocytic Schizogony......Page 34
Acknowledgements......Page 36
References......Page 37
Introduction......Page 44
Gametocytes......Page 45
Zygote-Ookinete Differentiation......Page 47
Biology of Oocyst Differentiation......Page 49
Biology of Sporozoite Development......Page 51
Insect Innate Immunity......Page 52
Melanisation and Encapsulation of Malaria Parasites......Page 53
Spatio-Temporal Immune Responses to Malaria Infection......Page 55
Serine Proteases and Serpins......Page 56
Transcriptional Control of Immune Responses......Page 57
Parasite Development in the Mosquito as a Target for Malaria Control......Page 58
Engineering Parasite Refractory Mosquitoes......Page 59
References......Page 60
Epidemiology of Disease......Page 67
Reactive Oxygen Species......Page 68
Cytokines......Page 69
Nitric Oxide......Page 71
Mild Malaria......Page 72
Severe Malarial Anaemia......Page 73
Respiratory Distress......Page 75
Disturbances of Consciousness and CM......Page 76
Brain Swelling......Page 77
Renal Disease......Page 78
Shock, Cardiovascular and Pulmonary Disease......Page 79
Disease in Pregnancy......Page 80
References......Page 81
Introduction......Page 87
CS Protein......Page 88
Thrombospondin-Related Anonymous Protein......Page 90
Sporozoite Development in the Mosquito......Page 91
Sporozoite Invasion of Salivary Glands......Page 92
Development of Infectivity by Sporozoites......Page 93
Sporozoite Invasion of Hepatocytes......Page 94
Experimental and Naturally Acquired Immunity to Sporozoites......Page 97
Immune Effector Mechanisms......Page 98
T and B Cell Epitopes of CS Proteins......Page 100
Synthetic Peptide Vaccines Based on the CS Protein......Page 102
Targeting the Intracellular Parasite......Page 106
Conclusions......Page 107
References......Page 108
Introduction......Page 114
Biology of Liver-Stage Malaria Parasites......Page 115
Liver-Stage Antigen-1......Page 116
Liver-Stage Antigen-3......Page 117
CSP-2......Page 118
Mechanisms of Protective Immunity to Liver-Stage Parasites......Page 119
LSA-1......Page 124
GLURP......Page 126
HLA and Genetic Resistance to Liver-Stage Antigens......Page 127
Adjuvants and Delivery Systems......Page 128
Granulocyte-Macrophage Colony-Stimulating Factor......Page 129
LSA-1......Page 130
Ty and VLP Articulate Delivery Systems: The Importance of Prime-Boost Strategies......Page 131
Ty Particle Prime, Vaccinia Virus Boost......Page 132
References......Page 133
Merozoite Antigens Involved in Invasion......Page 142
Erythrocyte Receptors......Page 143
Integral Membrane Proteins......Page 145
Merozoite Surface-Associated Antigens......Page 149
Antigens of Micronemes......Page 151
Rhoptry Antigens......Page 152
Antigens of Dense Granules......Page 153
Acknowledgements......Page 154
References......Page 155
Asexual Blood Stages of Malaria Antigens: Cytoadherence......Page 161
Host Adhesion Receptors......Page 162
Adhesion and Pathogenesis......Page 164
Var Genes and the P. falciparum Adhesion Receptor, PfEMP1......Page 166
Adhesion Domains in PfEMP1......Page 168
CIDR1-α: A Multi-Adhesive Domain that Binds to CD36......Page 169
DBL-γ  and Adhesion to CSA......Page 170
Modulation of Parasite Adhesion......Page 171
Adhesion of PEs under Flow......Page 172
References......Page 174
Rosetting......Page 180
Prevalence of Rosetting and Autoagglutinating Malaria Parasites......Page 182
Association of Rosetting and Autoagglutination with Severe Disease......Page 186
The Molecular Basis of Rosetting: Multiple Host Receptors......Page 187
Several Serum Proteins......Page 191
One Parasite Ligand Family......Page 192
Autoagglutination Mechanisms......Page 195
Rosetting, Autoagglutination, Multiadhesion, and Severe Malaria......Page 196
References......Page 198
Introduction......Page 205
Antigens Expressed on Surface Membrane of Red Blood Cells with Gametocytes......Page 206
Pfs16......Page 207
Pfg27......Page 208
Pfs48/45......Page 209
Pfs230......Page 211
Pfs25 and Pfs28......Page 212
Circumsporozoite and TRAP-Related Protein......Page 214
Conclusions......Page 215
References......Page 216
Introduction......Page 221
Mechanisms of Protective Immunity to Blood-Stage Infections......Page 222
Activation of T Cells in a Malaria Infection in Mice......Page 224
Heterogeneity of CD4 T Cells in Malaria......Page 227
Regulation of the Immune Response......Page 231
Pathology of Mouse Malaria Infections......Page 232
Cerebral Malaria......Page 233
Anemia in Malaria Infection......Page 235
Hypoglycemia in Malaria......Page 236
References......Page 238
Innate Immunity......Page 246
Some Important Malaria Antigens......Page 248
Antibody-Dependent Protection......Page 249
CD4+  and CD8+ T Cells......Page 250
γδ T Cells......Page 251
Nitric Oxide......Page 252
Malaria and Pregnancy......Page 253
References......Page 254
Genomics of the P. falciparum Parasite......Page 260
Host Genetic Contributions to Malaria Susceptibility......Page 261
Red Blood Cell Polymorphisms......Page 262
Linkage of MHC (and Non-MHC) Genes with Immunity and Pathogenesis in Malaria......Page 263
Other Genes Associated with Immune Responsiveness......Page 264
References......Page 265
Design Considerations for a Malaria Vaccine......Page 270
The Circumsporozoite Protein as the Basis of a Malaria Vaccine......Page 271
Initial Development of Candidate Malaria Vaccine ‘RTS,S’......Page 272
Initial Field Trials of Candidate Malaria Vaccine ‘RTS,S’......Page 273
Platform Technologies for a Multicomponent, Multistage Vaccine......Page 275
References......Page 276
Introduction......Page 279
Attacking Parasites Developing within Erythrocytes......Page 282
Blocking/Reversing Cytoadherence......Page 283
Candidate Antigens for Vaccine Development......Page 284
MSP1......Page 285
MSP3......Page 286
AMA1......Page 287
SERA......Page 288
RAP1 and RAP2......Page 289
PfEMP1......Page 290
Recombinant Protein and Synthetic Peptide Based-Vaccines......Page 291
DNA Vaccines......Page 292
Prime-Boost Strategy for Optimization of Vaccine-Induced Immune Responses......Page 293
Future Direction: Antigen Discovery through Genomics Research......Page 294
Acknowledgements......Page 295
References......Page 296
The Goals of Attacking Sexual-Stage Parasites with Transmission-Blocking Vaccines......Page 304
The Path Leading to and the Biological Basis for Transmission-Blocking Vaccine Development......Page 305
Late Gametocytes......Page 306
Invasion of the Mosquito......Page 307
Mechanisms of Transmission-Blocking Immunity and Immune Evasion: The Basis for Clinical Assays in Support of Vaccine Development......Page 308
Immune Response to Pre-Fertilization Target Antigens – The Basis for in vitro Surrogate Assays of Vaccine Efficacy......Page 309
Complement-Mediated Lysis......Page 310
Antigenic Diversity – The Need for Polyvalent Transmission-Blocking Vaccines......Page 311
Boosting after a Natural Infection......Page 312
Immune Responses to Post-Fertilization Target Antigens – The Basis for Early Clinical Field Trials......Page 313
Immunogen Production......Page 314
Safety Studies and Interpretation of Early Phase-I Immunogenicity Data......Page 316
Initial Proof of Concept: Phase-IIb Studies......Page 317
Analytical and Clinical Validation of Clinical Surrogate Assays......Page 318
Paths Forward......Page 319
Vaccine Formulations......Page 320
Roadblocks to Essential Clinical Trials......Page 321
References......Page 322
Rationale and Strategy for Development of a Malaria Vaccine......Page 325
Multistage Malaria DNA Vaccine Operation......Page 326
Preclinical Studies of Malaria DNA Vaccines in Animal Models......Page 327
Preclinical Studies Investigating Route of Administration in Animal Models......Page 328
Phase-I Clinical Trial of a PfCSP DNA Vaccine: Route of Administration......Page 329
First-Generation DNA Vaccines Are Suboptimal......Page 330
Heterologous Prime/Boost Immune Enhancement Strategies in Animal Models......Page 331
Immune Enhancement Strategies: Coadministration of Immunomodulatory Molecules......Page 333
Immune Enhancement Strategies: Modification of Target Gene for Optimal Expression in Mammalian Cells......Page 334
Genomes to Vaccines......Page 335
Acknowledgements......Page 336
References......Page 337
Introduction......Page 339
Arguments from Acquired Immunity......Page 341
Reducing Malaria Transmission May Increase Mortality and Morbidity......Page 343
Mechanisms of Malarial Pathogenesis......Page 345
Identity of the Malarial Toxin......Page 348
Biological Activities of Parasite GPIs......Page 349
GPI Appears to Be the Dominant Proinflammatory Agent of Parasite Origin......Page 350
Signal Transduction by Parasite GPIs......Page 351
Human Immune Responses to the GPI Toxin of Malaria......Page 352
GPI as a Target for Immunotherapy......Page 353
GPI as an Antidisease Vaccine Candidate......Page 354
References......Page 355
Introduction......Page 360
Definitions and Properties of Adjuvants......Page 363
Mechanisms of Adjuvants......Page 364
Freund’s Adjuvants......Page 366
Alum......Page 367
QS-21......Page 368
Montanide ISA 720......Page 369
Block Copolymer......Page 370
MPL......Page 371
CpG......Page 372
Cytokines......Page 373
Concluding Remarks......Page 374
References......Page 376
Introduction......Page 383
Vaccines for Travellers......Page 388
Vaccines for the Population of Malaria-Endemic Areas......Page 389
Justification for Taking a Candidate Antigen into Human Vaccine Trials......Page 390
Single Candidates or Combinations......Page 392
The Developmental Pathway......Page 393
Phase-I Trials......Page 395
Phase-II Trials......Page 396
Phase-III Trials......Page 398
Trial Objectives and End-Points......Page 399
Study Design......Page 400
Study Population......Page 401
End-Points......Page 402
Analysis......Page 405
After the Trial Is Over......Page 406
Phase IV......Page 407
Conclusions......Page 408
References......Page 409
Z......Page 413
A......Page 414
C......Page 415
F......Page 416
I......Page 417
M......Page 418
P......Page 419
R......Page 420
T......Page 421
V......Page 422
Z......Page 423