Malaria Immunology
Chemical Immunology Vol. 80 Series Editors Luciano Adorini Milan Ken-ichi Arai Tokyo Claudia Berek Berlin Anne-Marie Schmitt-Verhulst Byron H. Waksman Marseille New York, N.Y.
Malaria Immunology 2nd, revised and enlarged edition Volume Editors Peter Perlmann Stockholm Marita Troye-Blomberg Stockholm 29 figures and 13 tables, 2002 Basel Freiburg Paris London New York New Delhi Bangkok Singapore Tokyo Sydney
Chemical Immunology Formerly published as Progress in Allergy Founded in 1939 by Paul Kallòs Vol. 41 (1st edition) Malaria Immunology Editors: Hans Wigzell; Peter Perlmann, Stockholm X+374 p., 38 fig., 13 tab., hard cover, 1988. ISBN 3 8055 4672 6 Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents and Index Medicus. Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Copyright 2002 by S. Karger AG, P.O. Box, CH 4009 Basel (Switzerland) www.karger.com Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISSN 1015 0145 ISBN 3 8055 7376 6
Contents XV Preface Malaria Parasites and Disease 3 Structure and Life Cycle Fujioka, H., Cleveland, Ohio; Aikawa, M., Kanagawa 3 Introduction 3 Life Cycle 4 Erythrocytic Schizogony Merozoites 4 Host Cell Entry 7 Trophozoites and Schizonts 8 Host Cell Alterations by Malaria Parasites 8 Knob Formation and Cytoadherence 30 Cytoplasmic Clefts 33 Tubovesicular Network 33 Caveola-Vesicle Complexes 33 Sexual Forms 33 Mosquito Stages 33 Fertilization and Zygote Formation 34 Ookinete and Oocyst 36 Sporozoite 37 Preerythrocytic Schizogony 39 Acknowledgements 20 References
27 Malaria Parasites and the Anopheles Mosquito Dimopoulos, G., London; Kafatos, F.C., Heidelberg; Waters, A.P., Leiden; Sinden, R.E., London 27 Introduction 28 The Biology of Malaria Development in the Mosquito Bloodmeal 28 Gametocytes 30 Gametogenesis 30 Zygote-Ookinete Differentiation 32 Biology of Malaria Development within and beyond the Midgut Epithelium 32 Biology of Oocyst Differentiation 34 Biology of Sporozoite Development 35 Insect Innate Immunity 36 Mosquito Antimalarial Defence 36 Melanisation and Encapsulation of Malaria Parasites 38 Spatio-Temporal Immune Responses to Malaria Infection 39 Immunity Genes of A. gambiae 39 Pattern Recognition Receptors 39 Serine Proteases and Serpins 40 Transcriptional Control of Immune Responses 43 Antimicrobial Peptides 43 Prophenoloxidases 43 Parasite Development in the Mosquito as a Target for Malaria Control 42 Antibodies and Drugs Delivered from the Host 42 Engineering Parasite Refractory Mosquitoes 43 Acknowledgements 43 References 50 Malaria: Pathogenicity and Disease English, M.; Newton, C.R.J.C., Kilifi 50 Introduction 50 Epidemiology of Disease 53 Virulence of Falciparum Malaria 53 Mediators of Severe Disease 53 Reactive Oxygen Species 52 Cytokines 54 Nitric Oxide 55 Red Cell Deformability 55 Disease Caused by Malaria 55 Mild Malaria 56 Syndromes of Severe Malaria 56 Severe Malarial Anaemia 58 Respiratory Distress 59 Neurological Manifestations of Malaria 59 Disturbances of Consciousness and CM 60 CM in African Children Contents VI
60 Pathogenesis of CM 60 Brain Swelling 63 Neurological Sequelae 63 Seizures and Malaria 63 Other Manifestations of Severe Disease 63 Renal Disease 62 Shock, Cardiovascular and Pulmonary Disease 63 Hypoglycaemia 63 Disease in Pregnancy 64 Future Approaches to the Treatment of Clinical Malaria 64 References Malaria Antigens 70 Sporozoite Antigens: Biology and Immunology of the Circumsporozoite Protein and Thrombospondin-Related Anonymous Protein Sinnis, P.; Nardin, E., New York, N.Y. 70 Introduction 73 Identification of Sporozoite Antigens 73 CS Protein 73 Thrombospondin-Related Anonymous Protein 74 Biological Function of Sporozoite Antigens 74 Sporozoite Development in the Mosquito 75 Sporozoite Invasion of Salivary Glands 76 Development of Infectivity by Sporozoites 77 Sporozoite Inoculation into the Skin of the Vertebrate Host 77 Sporozoite Invasion of Hepatocytes 80 Immunologic Responses to Sporozoites 80 Experimental and Naturally Acquired Immunity to Sporozoites 83 Immune Effector Mechanisms 83 Subunit Vaccines Based on Sporozoite Antigens 83 Targeting the Extracellular Sporozoite 83 T and B Cell Epitopes of CS Proteins 85 Synthetic Peptide Vaccines Based on the CS Protein 89 Targeting the Intracellular Parasite 90 Conclusions 93 References 97 Immune Responses to Liver-Stage Parasites: Implications for Vaccine Development Hollingdale, M.R., London; Krzych, U., Silver Spring, Md. 97 Introduction 98 Biology of Liver-Stage Malaria Parasites Contents VII
99 Antigens Detected in Liver Stages 99 Liver-Stage Antigen-1 300 Liver-Stage Antigen-2 300 Liver-Stage Antigen-3 303 P. falciparum Sporozoite and Liver Stage Antigen 303 Sporozoite Threonine- and Asparagine-Rich Protein 303 PfEXP-1/PyHEP17 303 Glutamate-Rich Protein 303 Other Antigens 303 CSP-2 302 Pbl.1 302 Heat Shock Proteins 302 Blood-Stage Antigens 302 Mechanisms of Protective Immunity to Liver-Stage Parasites 307 Evidence that Liver Stage Immunity Is Protective in Humans 307 LSA-1 309 LSA-3 and PfEXP-1 309 SALSA 309 SALSA and STARP 309 GLURP 330 Heat Shock Protein Pfhsp60 330 HLA and Genetic Resistance to Liver-Stage Antigens 333 Experimental Immunization with Liver-Stage Antigens 333 Adjuvants and Delivery Systems 332 CpG 332 Granulocyte-Macrophage Colony-Stimulating Factor 333 Lipopeptides 333 Immunization with Individual Liver-Stage Antigens 333 LSA-1 334 LSA-3/SALSA/STARP 334 GLURP 334 Ty and VLP Articulate Delivery Systems: The Importance of Prime-Boost Strategies 335 Recombinant Viruses 335 DNA Prime, Vaccinia Virus Boost 335 Ty Particle Prime, Vaccinia Virus Boost 336 Conclusions 336 References 325 Merozoite Antigens Involved in Invasion Berzins, K., Stockholm 326 Erythrocyte Receptors 328 Merozoite Surface Antigens 328 Integral Membrane Proteins 332 Merozoite Surface-Associated Antigens 334 Antigens Present in the Apical Organelles of Merozoites 334 Antigens of Micronemes Contents VIII
335 Rhoptry Antigens 336 Antigens of Dense Granules 337 Concluding Remarks 337 Acknowledgements 338 References 344 Asexual Blood Stages of Malaria Antigens: Cytoadherence Baruch, D.I., Bethesda, Md.; Rogerson, S.J., Parkville; Cooke, B.M., Melbourne 345 Host Adhesion Receptors 347 Adhesion and Pathogenesis 349 Antigenic Diversity and Antigenic Variation 349 Var Genes and the P. falciparum Adhesion Receptor, PfEMP1 353 Adhesion Domains in PfEMP1 352 DBL1- : A GAG-Binding Domain that Mediates Rosetting 352 CIDR1- : A Multi-Adhesive Domain that Binds to CD36 353 DBL- -C2: An ICAM-1-Binding Domain 353 DBL- and Adhesion to CSA 354 DBL- : Role in PECAM-1/CD31 Binding 354 Other Host Receptors 354 Modulation of Parasite Adhesion 355 Other Parasite-Derived or Parasite-Induced Adhesion Receptors 355 Adhesion of PEs under Flow 357 Acknowledgements 357 References 363 Rosetting and Autoagglutination in Plasmodium falciparum Fernandez, V.; Wahlgren, M., Stockholm 363 Rosetting 365 Autoagglutination 365 Giant Rosetting 365 Prevalence of Rosetting and Autoagglutinating Malaria Parasites 369 Association of Rosetting and Autoagglutination with Severe Disease 370 The Molecular Basis of Rosetting: Multiple Host Receptors 374 Several Serum Proteins 375 One Parasite Ligand Family 378 Autoagglutination Mechanisms 379 RBC Polymorphisms and Rosetting 379 Rosetting, Autoagglutination, Multiadhesion, and Severe Malaria 383 Closing Remarks 383 References 388 Sexual and Sporogonic Stage Antigens Sauerwein, R.W.; Eling, W.M.C., Nijmegen 388 Introduction 389 Antigens Expressed on Surface Membrane of Red Blood Cells with Gametocytes Contents IX
335 Rhoptry Antigens 336 Antigens of Dense Granules 337 Concluding Remarks 337 Acknowledgements 338 References 344 Asexual Blood Stages of Malaria Antigens: Cytoadherence Baruch, D.I., Bethesda, Md.; Rogerson, S.J., Parkville; Cooke, B.M., Melbourne 345 Host Adhesion Receptors 347 Adhesion and Pathogenesis 349 Antigenic Diversity and Antigenic Variation 349 Var Genes and the P. falciparum Adhesion Receptor, PfEMP1 353 Adhesion Domains in PfEMP1 352 DBL1- : A GAG-Binding Domain that Mediates Rosetting 352 CIDR1- : A Multi-Adhesive Domain that Binds to CD36 353 DBL- -C2: An ICAM-1-Binding Domain 353 DBL- and Adhesion to CSA 354 DBL- : Role in PECAM-1/CD31 Binding 354 Other Host Receptors 354 Modulation of Parasite Adhesion 355 Other Parasite-Derived or Parasite-Induced Adhesion Receptors 355 Adhesion of PEs under Flow 357 Acknowledgements 357 References 363 Rosetting and Autoagglutination in Plasmodium falciparum Fernandez, V.; Wahlgren, M., Stockholm 363 Rosetting 365 Autoagglutination 365 Giant Rosetting 365 Prevalence of Rosetting and Autoagglutinating Malaria Parasites 369 Association of Rosetting and Autoagglutination with Severe Disease 370 The Molecular Basis of Rosetting: Multiple Host Receptors 374 Several Serum Proteins 375 One Parasite Ligand Family 378 Autoagglutination Mechanisms 379 RBC Polymorphisms and Rosetting 379 Rosetting, Autoagglutination, Multiadhesion, and Severe Malaria 383 Closing Remarks 383 References 388 Sexual and Sporogonic Stage Antigens Sauerwein, R.W.; Eling, W.M.C., Nijmegen 388 Introduction 389 Antigens Expressed on Surface Membrane of Red Blood Cells with Gametocytes Contents IX
390 Pfs16 393 Pfg27 392 The Six-Cys Domain Superfamily 392 Pfs48/45 394 Pfs230 395 Pfs25 and Pfs28 397 Circumsporozoite and TRAP-Related Protein 398 Chitinase 398 Conclusions 399 Acknowledgement 399 References Malaria Infection: Immunity and Regulation 204 Mouse Models of Blood-Stage Malaria Infections: Immune Responses and Cytokines Involved in Protection and Pathology Langhorne, J.; Quin, S.J.; Sanni, L.A., London 204 Introduction 205 Mechanisms of Protective Immunity to Blood-Stage Infections 207 Activation of T Cells in a Malaria Infection in Mice 230 Heterogeneity of CD4 T Cells in Malaria 234 Regulation of the Immune Response 235 Immune Evasion and Antigenic Variation 235 Pathology of Mouse Malaria Infections 236 Cerebral Malaria 238 Anemia in Malaria Infection 239 Hypoglycemia in Malaria 223 Susceptibility and Resistance to Lethal Infections 223 References 229 Malaria and the Immune System in Humans Perlmann, P.; Troye-Blomberg, M., Stockholm 229 Introduction 229 Innate Immunity 233 Humoral Immunity 233 Some Important Malaria Antigens 232 Antibodies 232 Antibody-Dependent Protection 233 Cell-Mediated Immunity 233 CD4 and CD8 T Cells 234 T Cells 235 The Cytokine Network 235 Nitric Oxide 236 Malaria and Pregnancy 237 References Contents X
243 Genetic Regulation of Malaria Infection in Humans Troye-Blomberg, M., Stockholm 243 Introduction 243 Genomics of the P. falciparum Parasite 244 Genetics of Malaria Infection 244 Host Genetic Contributions to Malaria Susceptibility 245 Red Blood Cell Polymorphisms 246 Genetic Regulation of the Immune Response 246 Linkage of MHC (and Non-MHC) Genes with Immunity and Pathogenesis in Malaria 247 Other Genes Associated with Immune Responsiveness 248 References Malaria Vaccines 253 Pre-Erythrocytic Malaria Vaccines to Prevent Plasmodium falciparum Malaria Ballou, W.R., Gaithersburg, Md.; Kester, K.E., Silver Spring, Md.; Heppner, D.G., Silver Spring, Md. 253 Imperative for a Malaria Vaccine 253 Design Considerations for a Malaria Vaccine 254 The Circumsporozoite Protein as the Basis of a Malaria Vaccine 255 Initial Development of Candidate Malaria Vaccine RTS,S 256 Initial Field Trials of Candidate Malaria Vaccine RTS,S 258 Platform Technologies for a Multicomponent, Multistage Vaccine 259 References 262 Vaccines against Asexual Stage Malaria Parasites Kumar, S.; Epstein, J.E.; Richie, T.L., Silver Spring, Md. 262 Introduction 265 Approaches to Development of an Asexual Stage Vaccine 265 Preventing Clinical Malaria by Attacking Erythrocytic Stage Parasites 265 Inhibition of Merozoite Invasion into Erythrocytes 265 Attacking Parasites Developing within Erythrocytes 266 Preventing Clinical Malaria by Blocking Pathogenesis 266 Blocking/Reversing Cytoadherence 267 Blocking Malaria Toxins 267 Candidate Antigens for Vaccine Development 268 MSP1 269 MSP2 269 MSP3 270 MSP4/MSP5 270 AMA1 273 EBA-175 Contents XI
273 SERA 272 RESA 272 RAP1 and RAP2 273 PfEMP1 274 Clinical Trials: Current Status 274 SPf66 Vaccine 274 Recombinant Protein and Synthetic Peptide Based-Vaccines 275 DNA Vaccines 276 Prime-Boost Strategy for Optimization of Vaccine-Induced Immune Responses 277 Future Direction: Antigen Discovery through Genomics Research 278 Conclusions 278 Acknowledgements 279 References 287 Transmission-Blocking Vaccines Kaslow, D.C., West Point, Pa. 287 The Goals of Attacking Sexual-Stage Parasites with Transmission-Blocking Vaccines 288 The Path Leading to and the Biological Basis for Transmission-Blocking Vaccine Development 289 Gametocyte Development in the Vertebrate Host 289 Initiation of Gametocytogenesis 289 Early Gametocytes 289 Late Gametocytes 290 Gametogenesis and Fertilization The First Golden Hour in the Midgut 290 The Trigger 290 Exflagellation of Male Gametocytes 290 Emergence of Female Gametocytes and Fertilization 290 Development of the Zygote within the Bloodmeal 290 Invasion of the Mosquito 293 Mechanisms of Transmission-Blocking Immunity and Immune Evasion: The Basis for Clinical Assays in Support of Vaccine Development 292 Immune Response to Pre-Fertilization Target Antigens The Basis for in vitro Surrogate Assays of Vaccine Efficacy 293 Complement-Mediated Lysis 294 Phagocytosis 294 Antigenic Diversity The Need for Polyvalent Transmission-Blocking Vaccines 295 Boosting after a Natural Infection 296 Immune Responses to Post-Fertilization Target Antigens The Basis for Early Clinical Field Trials 297 Critical Path for Transmission-Blocking Vaccines 297 Immunogen Production 299 Vaccine Formulation and Delivery 299 Safety Studies and Interpretation of Early Phase-I Immunogenicity Data 300 Initial Proof of Concept: Phase-IIb Studies 303 Analytical and Clinical Validation of Clinical Surrogate Assays 302 Paths Forward 303 Bulk Immunogen Production Contents XII
303 Clinical Validation of the Membrane-Feeding Assay 303 Vaccine Formulations 304 Roadblocks to Essential Clinical Trials 305 References 308 Nucleic Acid Vaccines against Malaria Doolan, D.L., Silver Spring, Baltimore, Md.; Hoffman, S.L., Silver Spring, Rockville, Md. 308 Rationale and Strategy for Development of a Malaria Vaccine 309 Multistage Malaria DNA Vaccine Operation 330 Preclinical Studies of Malaria DNA Vaccines in Animal Models 333 Phase-I Clinical Trial of a PfCSP DNA Vaccine Administered Intramuscularly 333 Preclinical Studies Investigating Route of Administration in Animal Models 332 Phase-I Clinical Trial of a PfCSP DNA Vaccine: Route of Administration 333 First-Generation DNA Vaccines Are Suboptimal 334 Heterologous Prime/Boost Immune Enhancement Strategies in Animal Models 336 Immune Enhancement Strategies: Coadministration of Immunomodulatory Molecules 337 Immune Enhancement Strategies: Modification of Target Gene for Optimal Expression in Mammalian Cells 338 Genomes to Vaccines 339 Conclusion 339 Acknowledgements 320 References 322 Antidisease Vaccines Schofield, L., Melbourne 322 Introduction 324 Arguments from Acquired Immunity 326 Reducing Malaria Transmission May Increase Mortality and Morbidity 328 Mechanisms of Malarial Pathogenesis 333 Identity of the Malarial Toxin 332 Biological Activities of Parasite GPIs 333 GPI Appears to Be the Dominant Proinflammatory Agent of Parasite Origin 334 Signal Transduction by Parasite GPIs 335 Human Immune Responses to the GPI Toxin of Malaria 336 GPI as a Target for Immunotherapy 337 GPI as an Antidisease Vaccine Candidate 338 Note Added in Proof 338 Acknowledgements 338 References 343 Adjuvants and Malaria Vaccine Development Xiao, L.; Rafi-Janajreh, A.; Patterson, P.; Zhou, Z.; Lal, A.A., Atlanta, Ga. 343 Introduction 346 Definitions and Properties of Adjuvants Contents XIII
347 Mechanisms of Adjuvants 349 Currently Available Adjuvants 349 Freund s Adjuvants 350 Alum 353 Adjuvants Potentially Usable in Humans 353 QS-21 352 Montanide ISA 720 353 Block Copolymer 354 MPL 355 MF59 355 CpG 356 Cytokines 357 Concluding Remarks 359 References 366 Malaria Vaccine Trials Greenwood, B., London; Alonso, P., Barcelona, Maputo 366 Introduction 373 What is Needed from a Malaria Vaccine? 373 Vaccines for Travellers 372 Vaccines for the Population of Malaria-Endemic Areas 373 Justification for Taking a Candidate Antigen into Human Vaccine Trials 375 Single Candidates or Combinations 376 The Developmental Pathway 378 Phase-I Trials 379 Phase-II Trials 383 Phase-III Trials 382 Trial Objectives and End-Points 383 Study Design 384 Study Site 384 Study Population 385 Study Size 385 End-Points 388 Economic Evaluation 388 Analysis 389 After the Trial Is Over 390 Phase IV 393 Ethics 393 Financing Vaccine Trials 393 Conclusions 392 References 396 Author Index 397 Subject Index Contents XIV
Preface In spite of all the efforts to control this infection, malaria is as frequent and deadly today as it was 12 years ago when this book was first published. However, due to the rapid development of immunology and parasitology, an enormous amount of new results in malaria immunology has come forth during this period and provided a basis for this 2nd edition. The book is now composed of 19 chapters, arranged in four major sections. The first section (3 chapters) deals with the malaria parasite and its interactions both with the vertebrate host and with the mosquitoes which transmit the disease. The second section (6 chapters) presents a detailed account of the many antigens giving rise to important immune responses in the vertebrate host while section three (3 chapters) reports on the mechanisms of immunity and their regulation by environmental and genetic factors. Finally, this volume also contains 7 chapters on malaria vaccine development, dealing both with the application of the most recent vaccine technologies and with the ongoing or planned malaria vaccine trials. Altogether the 19 chapters, which are authored by well-recognized experts, provide a broad and up-to-date overview of the rapidly expanding field of malaria immunology, an area of critical importance both for an understanding of immunity to infection in general and for coming to grips with one of the biggest and most devastating infectious diseases worldwide. Peter Perlmann Marita Troye-Blomberg XV
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Malaria Parasites and Disease Perlmann P, Troye-Blomberg M (eds): Malaria Immunology. Chem Immunol. Basel, Karger, 2002, vol 80, pp 1 26 Structure and Life Cycle Hisashi Fujioka a, Masamichi Aikawa b a Institute of Pathology, Case Western Reserve University, Cleveland, Ohio, USA, and b Institute of Medical Sciences, Tokai University, Kanagawa, Japan Introduction Plasmodium species, as members of Apicomplexa, share many common morphological features. Each of the developmental stages in the life cycle of malaria parasites exhibits a remarkable conservation and distinct patterns of structural organization [1, 2]. These conservations are supposed to have originated in the special adaptation to the tissues and/or cells in the different hosts of malaria parasites. As the technology of electron microscopy has improved, more detailed electron microscopic observations of the various stages of malaria parasites have been carried out and greatly advanced our knowledge of the life cycle and the fine structure of malaria parasites. Although the significance of the morphological changes is not fully understood, the introduction of the techniques of immunoelectron microscopy to the field of malaria parasites [3] has helped us in the meaningful and dynamic analysis of parasite morphology and cell biology, and our knowledge of the subcellular localization of malaria antigens and their functions in specific parasite organelles has been accumulated. Structural, biochemical and molecular biological aspects are different among the complex cycle comprising the erythrocytic schizogony, mosquito stages, and preerythrocytic (exoerythrocytic) schizogony. In this chapter, we will describe the ultrastructure of each specific stage, and the morphological and functional changes of the host cells induced by malaria parasites. Life Cycle The life cycle of the malaria parasite is complex (fig. 1). The sporozoites are transmitted to the vertebrate host by the bite of infected female mosquitoes
Fig. 1. Schematic drawing of the life cycle of malaria parasites. of the genus Anopheles. The sporozoites enter hepatocytes shortly after inoculation into the blood circulation. This process has demonstrated that sporozoite invasion of hepatocytes involves surface proteins of the sporozoite and host cell surface molecules. Sporozoites infected in the hepatocytes develop into preerythrocytic (exoerythrocytic, EE stage; fig. 9) schizonts during the next 5 15 days depending on the Plasmodium species. Plasmodium vivax, Plasmodium ovale and Plasmodium cynomolgi have a dormant stage, named hypnozoite [4, 5], that may remain in the liver for weeks to many years before the development of preerythrocytic schizogony. This results in relapses of malaria infection. Plasmodium falciparum and Plasmodium malariae have no persistent phase. A preerythrocytic schizont contains 10,000 to 30,000 merozoites, which are Fujioka/Aikawa 2