Norovirus

This book addresses the molecular biology of noroviruses (NoVs), pathogenesis, viral diversity and its impact on selective pressure, host susceptibility and outbreaks, clinical diagnosis, and the latest advances in the management and treatment of disease caused by NoVs. It offers a detailed analysis of our current understanding of the innate and the adaptive immune responses stimulated by NoVs, and discusses the complexity of the ongoing vaccine development and the urgent need for specific immune correlates of protection to advance the field. This is the first book on noroviruses. Written by leading specialists, it is essential reading for virologists and immunologists. Preface 5 Contents 8 1: Global Burden of Norovirus 9 1.1 Introduction 9 1.2 Approaches to Estimating Disease Burden Associated with Norovirus 10 1.2.1 Global Incidence of Diarrheal Diseases 11 1.2.2 Attributing Disease Cases to Norovirus 12 1.2.2.1 Attributable Proportion Extrapolation 12 1.2.2.2 Indirect Attribution from Regression Modeling 14 1.2.2.3 Lab-Confirmed Population-Based Surveillance 14 1.2.3 Adjustment for Vomiting-Only Presentations of Norovirus 18 1.3 Estimates of Norovirus Disease Burden 18 1.3.1 Overall 18 1.3.2 By Geography 19 1.3.3 By Age 19 1.3.4 By Genogroup 19 1.3.4.1 GII.4 Noroviruses 26 1.3.4.2 Emerging Non-GII.4 Noroviruses 26 1.4 Economic Burden of Norovirus 27 1.5 Critical Data Gaps 27 1.6 Additional Areas of Research 29 1.7 Conclusions 29 References 30 2: The Virus 38 2.1 Norovirus Classification and Genome Organization 38 2.2 The Viral Particle 41 2.3 Capsid Immunogenetic Epitopes 43 2.4 Host Genetic Susceptibility 44 2.5 Cell Tropism of Noroviruses 47 2.6 The Norovirus Replication Cycle 50 2.7 Summary 56 References 57 3: Viral Diversity, Evolution, and Selective Pressure 66 3.1 Norovirus Viral Diversity 66 3.2 General Mechanisms of Evolution and Experimental Systems 69 3.3 Human Norovirus Evolutionary Mechanisms: Antigenic Variation 71 3.4 Human Norovirus Evolutionary Mechanisms: Receptor Switching 76 3.5 Human Norovirus Evolutionary Mechanisms: Recombination 79 3.6 Norovirus Evolution Concluding Remarks 80 References 81 4: Pathogenesis and Clinical Features 86 4.1 Introduction 86 4.2 Incubation, Symptoms, and Duration of Infectiousness and Illness 87 4.3 Infectivity and Pathogenesis 87 4.4 Shedding 89 4.4.1 Stool 89 4.4.2 Vomit 90 4.5 Shedding Among Immunocompromised 91 4.6 Transmission 92 4.6.1 Person-to-Person 92 4.6.2 Foodborne 93 4.6.3 Waterborne 95 4.6.4 Environmental 96 4.7 Controlling Transmission 96 4.8 Conclusion 97 References 97 5: Antinorovirus Drugs: Current and Future Perspectives 108 5.1 Introduction 108 5.1.1 A Case for Antiviral Approaches Against Norovirus Infection 108 5.1.2 Norovirus Genome Organization and Life Cycle 109 5.1.3 Genetics and Evolution of Noroviruses 111 5.2 Tools to Study Norovirus Biology and the Development of Antiviral Drugs 112 5.2.1 Establishment of Cell Culture Methods 112 5.2.2 Animal Models 113 5.2.3 Murine Norovirus as a Surrogate System 114 5.3 Drugs Targeting the Viral Capsid 115 5.3.1 Molecules Inhibiting Capsid Binding to Cellular Receptors 115 5.3.1.1 Identification of Inhibitors Blocking the HBGA-Receptor Site in VP1 115 5.3.1.2 Fucose Mimetics 115 5.3.1.3 Human Milk and Other Natural Resources for the Identification of Antiviral Drugs 121 5.3.1.4 Citrate-Based Inhibitors 122 5.3.1.5 Drugs Targeting Other Cellular Co-receptors 123 5.3.2 Virucidal Compounds and Other Molecules Binding to the Viral Capsid 123 5.3.2.1 Phenolic Based Inhibitors 123 5.3.2.2 Egg Lysozyme 124 5.3.2.3 DNA Aptamers Directed Against the Viral Capsid 124 5.3.2.4 Synbodies 125 5.3.2.5 Miscellaneous Compounds with Virucidal Activity 125 5.3.3 Antiviral Strategies Based on Antibodies 126 5.3.3.1 Immunotherapeutic Approaches 126 5.3.3.2 Nanobodies 127 5.4 The Noroviral Protease NS6: a Major Target for Antiviral Compounds 128 5.4.1 Di- and Tripeptidyl Inhibitors 129 5.4.2 Peptide Macrocyclisation 130 5.4.3 Peptidomimetic Inhibitors 131 5.5 Antiviral Drugs Targeting Norovirus Genome Replication 131 5.5.1 Viral RNA Replication as an Antiviral Target: Mutagens and Polymerase Chain-Terminators 131 5.5.1.1 Favipiravir 132 5.5.1.2 Valopicitabine (2′-C-methylcytidine) 133 5.5.1.3 Ribavirin 134 5.5.1.4 Uracil Analogues 134 5.5.1.5 Other Nucleoside Analogues 135 5.5.2 Non-nucleoside Inhibitors of Viral Replication 135 5.5.2.1 Suramin and Naphthalene Derivatives 135 5.5.2.2 Broad-Spectrum Inhibitors Isolated for Other Viral Polymerases 137 5.5.2.3 Styrylchromone Derivatives 137 5.5.2.4 Molecules Targeting the Viral RNA 137 5.5.2.5 High Throughput Screening for the Identification of Novel Inhibitors of Norovirus Polymerase 138 5.6 Antiviral Molecules Directed Against Host Factors Regulating Norovirus Replication 139 5.6.1 Cellular Chaperones as an Antinoroviral Target 139 5.6.2 Deubiquitinases and Unfolded Protein Response 140 5.6.3 Drugs Modulating Host Cell Lipid Metabolism to Control Norovirus Replication 141 5.6.4 Immunosuppressant Drugs Targeting Calcineurin and Inosine-5′-Monophosphate Dehydrogenase (IMPDH) 142 5.6.5 Inhibitors of Viral Protein Translation 143 5.6.6 Interferon Treatment 143 5.7 Norovirus Inhibitors with Unknown Targets 144 5.7.1 Nitazoxanide 144 5.7.2 Other Compounds 145 5.8 Final Remarks and Future Perspectives on the Development of Antinoroviral Strategies 146 5.8.1 Recent Developments in the Treatment of Disease and Prospective Therapies 146 5.8.2 Combination Therapies in the Control of Noroviral Infection 147 5.8.3 New Prospective Host Targets for the Design of Antiviral Compounds 147 5.8.3.1 Targeting Host Cell Factors Contributing to Viral Genome Replication and Translation 147 5.8.3.2 Targeting the Commensal Microbiota in the Control of HuNoV Infection 148 References 149 6: Norovirus Correlates of Protection 163 6.1 Introduction 163 6.2 Innate Immune Responses 164 6.3 Adaptive Immune Responses 168 6.4 Correlates of Protection 173 6.4.1 Histo-Blood Group Antigen (HBGA) and Norovirus 173 6.4.2 HBGA-Blocking Antibodies 175 6.4.3 Other Correlates of Protection 182 6.5 Duration of Immunity 183 6.6 In Vitro Culture Systems and Impact on NoV Correlates of Protection 185 6.7 Conclusion 186 References 187 7: The Current Status of Norovirus Vaccine Development 194 7.1 Introduction 194 7.2 Challenge Studies 195 7.3 Preclinical Studies 200 7.4 Clinical Studies 229 7.5 The Future of Norovirus Vaccines 239 References 241 Index 248 Front Matter ....Pages i-ix Global Burden of Norovirus (Rachel M. Burke, Aron J. Hall)....Pages 1-29 The Virus (Christopher Ruis, Lucy Thorne, Judith Breuer)....Pages 31-58 Viral Diversity, Evolution, and Selective Pressure (Angelique Ealy, Kari Debbink)....Pages 59-78 Pathogenesis and Clinical Features (Molly Steele, Ben Lopman)....Pages 79-100 Antinorovirus Drugs: Current and Future Perspectives (Armando Arias)....Pages 101-155 Norovirus Correlates of Protection (Nada M. Melhem, Farouk F. Abou Hassan)....Pages 157-187 The Current Status of Norovirus Vaccine Development (Nada M. Melhem, Farouk F. Abou Hassan, Mohammad Ramadan)....Pages 189-242 Back Matter ....Pages 243-251