Sachin Kumar, PhD is an Assistant Professor in the Department of Pharmacology, Delhi Pharmaceutical Sciences and Research University, New Delhi, India. He has published more than 60 peer-reviewed papers in national and international journals and six book chapters. His research interests include diagnosis, biomarkers, meta-analysis, and pharmacoeconomic analysis. Shriyansh Srivastava is a PhD Research Scholar in the Department of Pharmacology at Delhi Pharmaceutical Sciences and Research University, New Delhi India. He has published more than 60 research articles in prestigious international journals, ten book chapters, five books, and two patents. Rishabha Malviya, PhD is an Associate Professor in the Department of Pharmacy in the School of Medical and Allied Sciences at Galgotias University, Greater Noida, India, with more than 13 years of experience. He has authored more than 150 research papers for national and international journals of repute, 102 books, and 51 patents. His areas of interest include formulation optimization, nanoformulation, targeted drug delivery, localized drug delivery, and characterization of natural polymers as pharmaceutical excipients. Ranjit Sah, MD is a Research Coordinator at BMC South, Boston Medical Centre Health System, MA, USA. He has made significant contributions to research and clinical practice, notably as the Head of COVID-19 testing facilities in Nepal during the pandemic.

• Preface xxiPart 1: Introduction and Genetic Insights 11 Introduction to Viral Storms: Infectious Disease 3Shivaprasad Sirimalla, Sanjit Sah, Uday Venkat Mateti and Allen Pinto1.1 Introduction to Infectious Disease 41.2 Virology: Overview of Virus, Virus Structure, Classification, Replication, and Transmission 61.2.1 Overview of the Virus 61.2.2 Virus Structure 71.2.3 Classification of Viruses 81.2.4 Viral Replication 141.2.5 Viral Transmission 151.3 Viral Storms (Major Pandemics) 171.3.1 The Spanish Flu (1918–1919) 171.3.2 HIV/AIDS Pandemic (1980s–Present) 181.3.3 Sars (2002–2003) 191.3.4 H1N1 Influenza (2009) 191.3.5 COVID-19 Pandemic (2019–Present) 201.4 Factors Contributing to Viral Storms 211.4.1 Environmental Factors, Climate Change, and Urbanization 211.4.2 Social Factors: Global Travel, Population Density, and Healthcare Access 221.4.3 Biological Factors: Viral Mutations and Host Immune Response 241.5 Norovirus 251.5.1 Introduction to Norovirus: Overview of the Virus and Its Significance 251.5.2 Epidemiology: Global Impact and Spread of Norovirus 261.5.3 Clinical Presentation: Symptoms, Severity, and Complications 271.5.4 Transmission and Prevention: Modes of Transmission and Strategies to Prevent Outbreaks 281.6 Summary of Key Points 291.7 Conclusion 30References 312 Norovirus: Its Role in Gastroenteritis Outbreaks 39Ranjana Rohilla and Shriyansh Srivastava2.1 Infectious Etiology of Gastroenteritis 402.2 Introduction to Norovirus Gastroenteritis 412.3 History of Norovirus and Outbreaks 422.4 Epidemiology and Common Settings of Norovirus Outbreaks 442.4.1 Healthcare Facilities 462.4.2 Restaurants and Other Food Establishments 462.4.3 School and Child Day Care 482.4.4 Cruise Ships 482.5 Clinical Features 482.6 Gastroenteritis in Immunocompromised Individuals 492.7 Gastroenteritis in Immunocompetent Individuals 502.8 Economic Burden of Infection 512.9 Preparedness for Outbreaks 512.10 Conclusion 52References 533 The Genetics of Norovirus: Understanding Its Genome and Genogroups 61Naga Rani Kagithala, Rahul Sharma, Sasikanth Kothamasu, Shriyansh Srivastava and Ismail A. Ibrahim3.1 Introduction 623.2 Norovirus Genome 643.2.1 Structure and Organizational Forms of the Norovirus Genome 643.2.2 RNA Genome Characteristics 643.2.3 Open Reading Frames (ORFs) 653.2.4 Non-Structural Proteins (ORF1) 653.2.5 Principal Capsid Protein (VP1): ORF 2 663.2.6 ORF3: VP2 or Minor Capsid Protein 663.3 Genetic Diversity in Norovirus 663.3.1 Genogroups and Genotypes 663.3.2 Mechanisms of Genetic Variation 673.3.3 Mutation Rates and Hotspots 683.3.4 Recombination Events 703.3.5 Evolutionary Dynamics of Norovirus 703.4 Norovirus Genogroups 713.4.1 Classification and Characteristics of Norovirus Genogroups 713.4.2 Classification of VP1 Sequences 723.4.3 RdRp Designations 723.4.4 Genogroup I (GI) 723.4.5 Genogroup II (GII) 733.4.6 Genogroup III (GIII) 733.4.7 Epidemiology of Norovirus Genogroups 743.5 Molecular Techniques for Norovirus Genetic Analysis 753.5.1 Sequencing Technologies 753.5.2 Next-Generation Sequencing (NGS) 763.5.3 Whole-Genome Sequencing (WGS) 803.5.4 Phylogenetic Analysis 803.5.5 Genotyping and Molecular Epidemiology 813.6 Implications of Norovirus Genetic Variability 823.6.1 Impact on Vaccine Development 823.6.1.1 Monovalent Vaccines 823.6.1.2 Bivalent Vaccines 833.6.2 Antiviral Drug Resistance 833.6.3 Public Health Challenges 843.7 Recent Advances in Norovirus Genetics 853.7.1 New Discoveries in Norovirus Genomic Research 853.7.2 Emerging Genogroups and Strains 863.7.3 Future Directions in Norovirus Genetics 863.8 Conclusion 87Abbreviations 87References 884 Environmental Factors in Norovirus Outbreaks: Temperature and Rainfall 99Neeraj Kumar, Akanksha, Shriyansh Srivastava and Mohd Mujeeb4.1 Introduction 1004.2 Evolution of Norovirus 1034.2.1 Antigenic Drift 1034.2.2 Antigenic Shift 1034.2.3 Recombination Events 1044.2.4 Genetic Diversity 1044.2.5 Mutation Rates 1044.2.6 Pandemic Strains 1054.2.7 Geographic Differences 1054.2.8 Temporal Trends 1054.3 Fatal Details Regarding the Norovirus 1054.4 Mode of Transmission of Norovirus 1064.4.1 Environmental Source 1074.4.2 Influence of Temperature on Norovirus Outbreaks 1084.5 Correlation Between Temperature Fluctuations and Outbreaks 1094.6 Effect of Norovirus on Humidity 1104.7 The Impact of Rainfall on the Spread of the Norovirus 1104.8 The Impact of Water on the Spread of the Norovirus 1114.9 Norovirus Combined Effects of Temperature and Rainfall 1124.10 Stability of Norovirus 1124.11 Case Study 1134.12 Global Patterns in Temperature- and Rainfall-Related Outbreaks 1204.13 Mitigation Strategies and Public Health Interventions 1214.14 Conclusion 123References 1245 Zoonotic Transmission of Norovirus: Current Understanding and Future Implications 129Vini Mehta, Sapna Negi, Snehasish Tripathy, Sarvesh Rastogi and Ankita Mathur5.1 Brief Overview of Norovirus 1305.2 Epidemiology of Norovirus 1315.3 Symptoms of Norovirus-Associated Gastroenteritis 1325.4 Mode of Transmission of Norovirus 1325.4.1 Vomitus or Stool 1325.4.2 Through Contaminated Food and Water 1335.5 Zoonotic Transmission 1345.5.1 Animal Reservoirs 1355.5.2 Wild Animals 1385.6 Zoonotic Transmission Mechanisms of Norovirus 1395.6.1 Animal-to-Human Transmission 1395.6.2 Human-to-Animal Transmission 1405.7 Zoonotic Transmission Mechanism 1415.8 Future Implications and Research Directions 1425.9 Conclusion 143Abbreviations 144References 144Part 2: Transmission, Dynamics and Environmental Impacts 1516 Genetic Changes in Norovirus and Their Impact on Infectivity/Virulence 153Soumya Patil, Vijayalaxmi Bangra Manjeshwara, Uday Venkat Mateti and Raushan Kumar Chaudhary6.1 Introduction 1546.2 Classification of NoV 1556.3 Genomic Structure and Functions 1566.3.1 ORF1: The Replication Engine 1566.3.2 ORF2: The Master Builder 1596.3.3 ORF3: The Stabilizer 1596.3.4 ORF4: Murine Norovirus 1596.4 NoV Life Cycle: Molecular Mechanism of NoV Genome Replication 1596.5 Transmission 1616.6 Molecular Diversity 1626.7 Evolutionary Mechanisms and Dominance 1636.7.1 Point Mutation 1646.7.2 Recombination 1676.7.2.1 Mechanisms of Recombination 1686.8 Recent Epidemiological Trends 1706.9 Global Impact and Challenges 1746.10 Conclusion 176Abbreviations 177References 1777 Bridging the Gap: One Health Approach in Norovirus 187Sasikanth Kothamasu, Naga Rani Kagithala, Dheeraj Sharma, Shriyansh Srivastava, Aroop Mohanty and Rakesh Sahu7.1 Overview of Norovirus: Structure and Epidemiology 1887.2 Understanding the One Health Approach 1907.2.1 Definition and Principles of One Health 1907.2.2 Historical Context and Evolution of the One Health Concept 1907.2.3 Relevance of One Health to Norovirus Control 1917.2.3.1 Environmental Transmission Pathways 1917.3 Transmission Pathways of Norovirus 1947.3.1 Human-to-Human Transmission 1947.3.2 Environmental Contamination and Spread 1947.3.3 Zoonotic Potential and Animal Reservoirs 1957.3.4 Role of Food and Water in Norovirus Outbreaks 1957.4 Epidemiology of Norovirus: A Global Perspective 1967.4.1 Geographic Distribution and Prevalence 1967.4.2 Risk Factors for Infection 1967.4.3 Seasonal and Regional Variations in Norovirus Incidence 1977.5 The One Health Approach to Norovirus Surveillance 1987.5.1 Integrating Human, Animal, and Environmental Surveillance Systems 1987.5.2 Advances in Diagnostic Techniques for Norovirus Detection 1997.5.3 Case Studies: Successful Implementation of One Health Surveillance 1997.6 Prevention and Control Strategies 2007.6.1 Hygiene and Sanitation Practices 2007.6.2 Vaccination Development and Challenges 2017.6.3 Environmental Management and Water Safety 2017.6.4 Role of Policy and Legislation in Norovirus Prevention 2027.7 Interdisciplinary Collaboration in One Health 2027.7.1 Building Effective Partnerships Between Health Sectors 2027.7.2 Case Studies of Multidisciplinary Efforts in Controlling Norovirus 2037.7.3 Challenges and Opportunities in Collaborative Approaches 2047.8 Case Studies: One Health Success Stories 2057.8.1 Outbreak Response in Different Regions 2057.8.2 Lessons Learned from Norovirus Control Efforts 2067.8.3 Scaling Up One Health Strategies Globally 2067.9 Future Directions in Norovirus Research and Control 2077.9.1 Emerging Trends in Norovirus Epidemiology 2077.9.2 Innovations in Vaccination and Treatment 2077.9.3 The Role of Technology in Enhancing One Health Approaches 2087.10 Conclusion 2087.10.1 Summarizing the Impact of the One Health Approach on Norovirus Control 2087.10.2 Recommendations for Future Action and Research 209References 2108 Recent Insights into the Dynamics of Norovirus Outbreak 221Sejal Porwal, Sonali Sundram, Rishabha Malviya and Shriyansh Srivastava8.1 Introduction 2228.2 Symptoms Related to Norovirus 2238.3 Epidemiology of Norovirus Outbreak 2258.4 Norovirus Genome and Structure 2268.5 Virion Morphology 2278.6 Transmission Mechanism 2278.6.1 Pattern of Viral Invasion into Host 2298.7 Administration of Pharmaceuticals and Challenges in Vaccination 2308.8 Immunity to Norovirus Infection 2338.9 Public Health Measures to Avoid Being Infected with Norovirus 2358.10 Conclusion 236References 2379 Norovirus Excretion Patterns and their Role in Spread 249Cynthia Lizzie Lobo, Soumya Patil, Raushan Kumar Chaudhary and Pukar Khanal9.1 Introduction 2509.2 Routes of Norovirus Excretion 2519.2.1 Fecal Shedding 2519.2.2 Vomitus 2539.2.3 Saliva 2549.3 Duration of Noroviral Shedding 2559.3.1 Factors Influencing Noroviral Shedding Patterns 2559.3.1.1 Host Factors 2559.3.1.2 Viral Factors 2569.3.1.3 Environmental Factors 2569.3.2 Asymptomatic Excretion of Norovirus 2579.4 Quantitative Analysis of Noroviral Load 2589.4.1 Measurement Techniques 2589.4.1.1 Reverse Transcriptase–Polymerase Chain Reaction (RT-PCR) 2589.4.1.2 Quantitative PCR (qPCR) 2599.4.1.3 Immune Electron Microscopy (IEM) 2599.4.1.4 Antigen Detection Immunoassays 2599.4.1.5 Biosensors 2609.4.2 Noroviral Load Decay Rates 2619.5 Transmission Modes of Norovirus 2619.5.1 Direct Person-to-Person Contact 2619.5.2 Aerosolized Norovirus Particles 2629.5.3 Contaminated Food or Water 2639.5.4 Contaminated Surfaces 2639.6 Role of Excretion Patterns in Norovirus Spread 2649.6.1 Contribution to Disease Transmission 2649.6.2 Environmental Contamination 2649.7 Public Health Implications of Excretion Patterns 2669.8 Research Gaps and Future Directions 267Abbreviations 268References 26810 The Role of Rainfall in the Control of Norovirus Outbreaks 275Sandhya Chaudhary, Rahul Kumar, Kalpana Rahate, Shriyansh Srivastava and Sathvik Belagodu Sridhar10.1 Introduction 27610.2 Characteristics of Norovirus 27610.2.1 Classification 27610.2.2 Structure of Norovirus 27810.2.3 Characteristics of Virus 27810.2.4 Viral Shedding and Transmission Potential 27910.2.5 Duration of Development and Manifestations 28010.3 Possible Environmental Markers for Outbreaks of the Human Norovirus 28110.3.1 Temperature 28110.3.2 Humidity 28210.3.3 Rainfall 28210.4 Relationship Between Rainfall and Norovirus Outbreaks 28310.5 Public Health and Infrastructure Challenges 28410.5.1 Water and Foodborne Transmission 28510.5.2 Transmission Between Individuals 28510.6 Prevention and Mitigation Strategies 28510.6.1 Controlling the Occurrence 28510.6.2 Sanitation 28710.6.3 Cleaning and Sanitization 28710.6.4 Colonization and Isolation 28710.7 Future Directions and Research Needs 28710.8 Conclusion 288Abbreviations 288References 28911 The Impact of COVID-19 on Norovirus Circulation and Research 295Laxmi, Shriyansh Srivastava, Sanjita Das, Malakapogu Ravindra Babu, Rishabha Malviya and S.K. Abdul Rahaman11.1 Introduction 29611.2 Norovirus: Characteristics and Epidemiology 29711.2.1 Virology and Pathogenesis 29811.2.2 Transmission Routes 29911.2.3 Global Epidemiology of Norovirus 30011.2.4 Seasonal Patterns and Outbreaks 30011.3 The COVID-19 Pandemic: An Overview 30211.3.1 Timeline of COVID-19 Spread 30211.3.2 Public Health Interventions and Their Impact 30311.3.3 Changes in Healthcare Systems 30411.4 Effects of COVID-19 on Norovirus Circulation 30411.4.1 Changes in Reporting and Surveillance 30411.4.2 Impact of Non-Pharmaceutical Interventions (NPIs) 30511.4.3 Predictions for Norovirus Resurgence Post-Pandemic 30511.5 Research Trends and Findings 30611.5.1 Changes in Norovirus Research Focus During Covid- 19 30611.5.2 Advances in Norovirus Vaccine Development 30711.5.2.1 Vaccine in Human Clinical Trials 30711.5.2.2 Vaccines in Pre-Clinical Trials 31011.5.3 Comparative Studies of Norovirus and Other Viruses 31111.5.3.1 Sapoviruses 31111.5.3.2 Lagovirus 31111.5.3.3 Vesivirus 31211.5.3.4 Nebovirus 31211.6 Public Health Implications 31211.6.1 Preparedness for Future Outbreaks 31211.6.2 Strategies for Mitigating Norovirus Spread 31311.6.3 Lesson Learned from COVID- 19 314Conclusion 315Abbreviations 315References 317Part 3: Cross-Species Studies and Therapeutic Development 32712 Norovirus in Animals: Bovine, Murine, and Other Hosts 329Aritra Banerjee, K.V. Leela, Shriyansh Srivastava, Pranav Gupta, Malakapogu Ravindra Babu and Ranjit Sah12.1 Introduction 33012.2 Genomic Organization and Virus 33112.3 Interactions Between Viruses and Cells 33212.4 Norovirus in Bovines 33312.5 Bovine Norovirus Distribution 33412.6 The Pathophysiology and Clinical Characteristics of Bovine Norovirus 33512.7 Diagnosis of the Bovine Norovirus 33712.7.1 Electron Microscopy 33712.7.2 Molecular Methods 33712.7.3 Antigen ELISAs 33712.7.4 Antibody ELISAs 33812.8 Norovirus in Murine 33812.8.1 Murine Norovirus Identification 33812.8.2 Structural Features of MNV 33912.8.3 MNV Infection in Wild-Type Mice 34012.8.4 To Control Norovirus Infection, Innate Immunity is Necessary 34012.8.5 To Eradicate a Norovirus Infection, Adaptive Immunity is Required 34112.9 Porcine Norovirus 34112.10 In Lions, Norovirus 34212.11 Conclusion 343References 34313 The Challenges of Developing Norovirus Vaccines and Therapies 359Gita Chawla, Tathagata Pradhan and Ojasvi Gupta13.1 Overview of Norovirus Epidemiology 35913.2 Classification and Molecular Biology of Norovirus 36113.3 Current Approaches to Norovirus Therapy 36313.3.1 Symptomatic Treatment 36313.3.2 Antiviral Drug Development 36413.3.3 Passive Immunization Strategies 36413.3.4 Vaccine Candidates 36513.3.4.1 Virus-Like Particle (VLP) Vaccines 36513.3.4.2 P Particle-Based Vaccines 36713.3.4.3 Recombinant Protein Vaccines 36713.3.4.4 Bivalent and Multivalent VLP Vaccines 36713.3.4.5 Oral Vaccines 36813.3.4.6 Plant-Derived Vaccines 36813.3.5 Monoclonal Antibody-Based Passive Immunization 36913.4 Challenges in Norovirus Vaccine Development 36913.4.1 Genetic Diversity and Rapid Evolution 36913.4.2 Lack of Long-Lasting Immunity 37213.4.3 Absence of Reliable In Vitro Culture System 37213.4.4 Unclear Correlates of Protection 37213.4.5 Variation in Host Susceptibility 37313.4.6 High Cost and Complexity of Clinical Trials 37313.5 Conclusion and Future Perspectives 374References 37514 The Importance of Animal Models and In Vitro Cultivation for Norovirus Research 379Prarambh S.R. Dwivedi, Masmarika Mohan, Pukar Khanal, Sanjit Sah and C.S. Shastry14.1 Introduction 38014.2 Importance of Animal and Cell Culture Models for Human Norovirus 38114.2.1 Importance of Cell Culture Models 38114.2.2 Importance of Animal Models 38214.3 Animal Models of HuNoV Infection 38314.3.1 Mice Model 38414.3.2 Chimpanzee Model 38814.3.3 Macaques Model 38914.3.4 Gnotobiotic Calves and Pigs as Model 39014.3.5 Zebrafish Model 39114.3.6 Recovirus Model 39214.4 Advancement of In Vitro Models for Norovirus 39314.4.1 Early Attempts to Cultivate HuNoVs 39314.4.2 Key Discoveries That Helped to Cultivate the Human Epithelial System 39514.4.3 Reverse Genetic Systems 39814.4.4 Human Norovirus Strains 39914.5 Conclusion 402Abbreviations 403References 40415 The Role of Human Intestinal Enteroids in Norovirus Research 413Apeksha Shetty, Anushree Deshpande, Raushan Kumar Chaudhary and Prakash Patil15.1 Introduction to Human Intestinal Enteroids (HIEs) 41415.1.1 Definition and Significance of HIEs 41415.1.2 The Components of HIEs: Enterocytes, Goblet Cells, Paneth Cells, and Germ Cells 41615.1.3 Activity of HIEs: Ion Transport and Immune Function 41715.2 Components Required for Norovirus Activation 41915.2.1 Receptors and Ligands Involved in Norovirus Binding and Entry 41915.2.2 Enzymes that are Required for Norovirus Replication 42315.2.3 Cellular Factors Which Help in Regulating Norovirus Replication and Tropism 42515.3 Pathophysiology of Norovirus Infection 42515.3.1 Mechanism of Infection of Norovirus Into the Gut: Attachment, Internalization, and Replication 42515.3.2 Immune Response to Norovirus Infection: Cellular and Humoral Immunity 42815.3.3 Few Clinical Symptoms of Norovirus Infection: Diarrhea, Vomiting, and Dehydration 42915.4 Norovirus Cell Tropism 43015.4.1 Viral Tropism: Process of Norovirus Targeting Specific Cell Types in the Gut 43015.4.2 Factors That Influence Norovirus Tropism: Age, Genetics, and Environment 43115.5 Role of Additional Gastrointestinal Components in Norovirus Infection 43215.5.1 Mechanisms Through Which Bile Acids Enhance Norovirus Replication 43215.5.2 How the Bile Acids and the Ceramides Deal with the Entry Restriction for Norovirus 43315.5.3 Potential Therapeutic Applications of Bile Acids and Ceramide in Treating Norovirus 43415.6 Antiviral Compound Screening Using HIEs 43515.6.1 Screening Methods of Antiviral Compounds Using HIEs 43515.6.2 Examples of Antiviral Compounds Discovered by Using HIEs 43615.6.3 Future Directions for Antiviral Compound Screening Using HIEs 43715.7 Future Perspectives 43815.8 Conclusion 439Abbreviations 439References 440Index 447

Sachin Kumar, PhD is an Assistant Professor in the Department of Pharmacology, Delhi Pharmaceutical Sciences and Research University, New Delhi, India. He has published more than 60 peer-reviewed papers in national and international journals and six book chapters. His research interests include diagnosis, biomarkers, meta-analysis, and pharmacoeconomic analysis. Shriyansh Srivastava is a PhD Research Scholar in the Department of Pharmacology at Delhi Pharmaceutical Sciences and Research University, New Delhi India. He has published more than 60 research articles in prestigious international journals, ten book chapters, five books, and two patents. Rishabha Malviya, PhD is an Associate Professor in the Department of Pharmacy in the School of Medical and Allied Sciences at Galgotias University, Greater Noida, India, with more than 13 years of experience. He has authored more than 150 research papers for national and international journals of repute, 102 books, and 51 patents. His areas of interest include formulation optimization, nanoformulation, targeted drug delivery, localized drug delivery, and characterization of natural polymers as pharmaceutical excipients. Ranjit Sah, MD is a Research Coordinator at BMC South, Boston Medical Centre Health System, MA, USA. He has made significant contributions to research and clinical practice, notably as the Head of COVID-19 testing facilities in Nepal during the pandemic.

• Preface xxiPart 1: Introduction and Genetic Insights 11 Introduction to Viral Storms: Infectious Disease 3Shivaprasad Sirimalla, Sanjit Sah, Uday Venkat Mateti and Allen Pinto1.1 Introduction to Infectious Disease 41.2 Virology: Overview of Virus, Virus Structure, Classification, Replication, and Transmission 61.2.1 Overview of the Virus 61.2.2 Virus Structure 71.2.3 Classification of Viruses 81.2.4 Viral Replication 141.2.5 Viral Transmission 151.3 Viral Storms (Major Pandemics) 171.3.1 The Spanish Flu (1918–1919) 171.3.2 HIV/AIDS Pandemic (1980s–Present) 181.3.3 Sars (2002–2003) 191.3.4 H1N1 Influenza (2009) 191.3.5 COVID-19 Pandemic (2019–Present) 201.4 Factors Contributing to Viral Storms 211.4.1 Environmental Factors, Climate Change, and Urbanization 211.4.2 Social Factors: Global Travel, Population Density, and Healthcare Access 221.4.3 Biological Factors: Viral Mutations and Host Immune Response 241.5 Norovirus 251.5.1 Introduction to Norovirus: Overview of the Virus and Its Significance 251.5.2 Epidemiology: Global Impact and Spread of Norovirus 261.5.3 Clinical Presentation: Symptoms, Severity, and Complications 271.5.4 Transmission and Prevention: Modes of Transmission and Strategies to Prevent Outbreaks 281.6 Summary of Key Points 291.7 Conclusion 30References 312 Norovirus: Its Role in Gastroenteritis Outbreaks 39Ranjana Rohilla and Shriyansh Srivastava2.1 Infectious Etiology of Gastroenteritis 402.2 Introduction to Norovirus Gastroenteritis 412.3 History of Norovirus and Outbreaks 422.4 Epidemiology and Common Settings of Norovirus Outbreaks 442.4.1 Healthcare Facilities 462.4.2 Restaurants and Other Food Establishments 462.4.3 School and Child Day Care 482.4.4 Cruise Ships 482.5 Clinical Features 482.6 Gastroenteritis in Immunocompromised Individuals 492.7 Gastroenteritis in Immunocompetent Individuals 502.8 Economic Burden of Infection 512.9 Preparedness for Outbreaks 512.10 Conclusion 52References 533 The Genetics of Norovirus: Understanding Its Genome and Genogroups 61Naga Rani Kagithala, Rahul Sharma, Sasikanth Kothamasu, Shriyansh Srivastava and Ismail A. Ibrahim3.1 Introduction 623.2 Norovirus Genome 643.2.1 Structure and Organizational Forms of the Norovirus Genome 643.2.2 RNA Genome Characteristics 643.2.3 Open Reading Frames (ORFs) 653.2.4 Non-Structural Proteins (ORF1) 653.2.5 Principal Capsid Protein (VP1): ORF 2 663.2.6 ORF3: VP2 or Minor Capsid Protein 663.3 Genetic Diversity in Norovirus 663.3.1 Genogroups and Genotypes 663.3.2 Mechanisms of Genetic Variation 673.3.3 Mutation Rates and Hotspots 683.3.4 Recombination Events 703.3.5 Evolutionary Dynamics of Norovirus 703.4 Norovirus Genogroups 713.4.1 Classification and Characteristics of Norovirus Genogroups 713.4.2 Classification of VP1 Sequences 723.4.3 RdRp Designations 723.4.4 Genogroup I (GI) 723.4.5 Genogroup II (GII) 733.4.6 Genogroup III (GIII) 733.4.7 Epidemiology of Norovirus Genogroups 743.5 Molecular Techniques for Norovirus Genetic Analysis 753.5.1 Sequencing Technologies 753.5.2 Next-Generation Sequencing (NGS) 763.5.3 Whole-Genome Sequencing (WGS) 803.5.4 Phylogenetic Analysis 803.5.5 Genotyping and Molecular Epidemiology 813.6 Implications of Norovirus Genetic Variability 823.6.1 Impact on Vaccine Development 823.6.1.1 Monovalent Vaccines 823.6.1.2 Bivalent Vaccines 833.6.2 Antiviral Drug Resistance 833.6.3 Public Health Challenges 843.7 Recent Advances in Norovirus Genetics 853.7.1 New Discoveries in Norovirus Genomic Research 853.7.2 Emerging Genogroups and Strains 863.7.3 Future Directions in Norovirus Genetics 863.8 Conclusion 87Abbreviations 87References 884 Environmental Factors in Norovirus Outbreaks: Temperature and Rainfall 99Neeraj Kumar, Akanksha, Shriyansh Srivastava and Mohd Mujeeb4.1 Introduction 1004.2 Evolution of Norovirus 1034.2.1 Antigenic Drift 1034.2.2 Antigenic Shift 1034.2.3 Recombination Events 1044.2.4 Genetic Diversity 1044.2.5 Mutation Rates 1044.2.6 Pandemic Strains 1054.2.7 Geographic Differences 1054.2.8 Temporal Trends 1054.3 Fatal Details Regarding the Norovirus 1054.4 Mode of Transmission of Norovirus 1064.4.1 Environmental Source 1074.4.2 Influence of Temperature on Norovirus Outbreaks 1084.5 Correlation Between Temperature Fluctuations and Outbreaks 1094.6 Effect of Norovirus on Humidity 1104.7 The Impact of Rainfall on the Spread of the Norovirus 1104.8 The Impact of Water on the Spread of the Norovirus 1114.9 Norovirus Combined Effects of Temperature and Rainfall 1124.10 Stability of Norovirus 1124.11 Case Study 1134.12 Global Patterns in Temperature- and Rainfall-Related Outbreaks 1204.13 Mitigation Strategies and Public Health Interventions 1214.14 Conclusion 123References 1245 Zoonotic Transmission of Norovirus: Current Understanding and Future Implications 129Vini Mehta, Sapna Negi, Snehasish Tripathy, Sarvesh Rastogi and Ankita Mathur5.1 Brief Overview of Norovirus 1305.2 Epidemiology of Norovirus 1315.3 Symptoms of Norovirus-Associated Gastroenteritis 1325.4 Mode of Transmission of Norovirus 1325.4.1 Vomitus or Stool 1325.4.2 Through Contaminated Food and Water 1335.5 Zoonotic Transmission 1345.5.1 Animal Reservoirs 1355.5.2 Wild Animals 1385.6 Zoonotic Transmission Mechanisms of Norovirus 1395.6.1 Animal-to-Human Transmission 1395.6.2 Human-to-Animal Transmission 1405.7 Zoonotic Transmission Mechanism 1415.8 Future Implications and Research Directions 1425.9 Conclusion 143Abbreviations 144References 144Part 2: Transmission, Dynamics and Environmental Impacts 1516 Genetic Changes in Norovirus and Their Impact on Infectivity/Virulence 153Soumya Patil, Vijayalaxmi Bangra Manjeshwara, Uday Venkat Mateti and Raushan Kumar Chaudhary6.1 Introduction 1546.2 Classification of NoV 1556.3 Genomic Structure and Functions 1566.3.1 ORF1: The Replication Engine 1566.3.2 ORF2: The Master Builder 1596.3.3 ORF3: The Stabilizer 1596.3.4 ORF4: Murine Norovirus 1596.4 NoV Life Cycle: Molecular Mechanism of NoV Genome Replication 1596.5 Transmission 1616.6 Molecular Diversity 1626.7 Evolutionary Mechanisms and Dominance 1636.7.1 Point Mutation 1646.7.2 Recombination 1676.7.2.1 Mechanisms of Recombination 1686.8 Recent Epidemiological Trends 1706.9 Global Impact and Challenges 1746.10 Conclusion 176Abbreviations 177References 1777 Bridging the Gap: One Health Approach in Norovirus 187Sasikanth Kothamasu, Naga Rani Kagithala, Dheeraj Sharma, Shriyansh Srivastava, Aroop Mohanty and Rakesh Sahu7.1 Overview of Norovirus: Structure and Epidemiology 1887.2 Understanding the One Health Approach 1907.2.1 Definition and Principles of One Health 1907.2.2 Historical Context and Evolution of the One Health Concept 1907.2.3 Relevance of One Health to Norovirus Control 1917.2.3.1 Environmental Transmission Pathways 1917.3 Transmission Pathways of Norovirus 1947.3.1 Human-to-Human Transmission 1947.3.2 Environmental Contamination and Spread 1947.3.3 Zoonotic Potential and Animal Reservoirs 1957.3.4 Role of Food and Water in Norovirus Outbreaks 1957.4 Epidemiology of Norovirus: A Global Perspective 1967.4.1 Geographic Distribution and Prevalence 1967.4.2 Risk Factors for Infection 1967.4.3 Seasonal and Regional Variations in Norovirus Incidence 1977.5 The One Health Approach to Norovirus Surveillance 1987.5.1 Integrating Human, Animal, and Environmental Surveillance Systems 1987.5.2 Advances in Diagnostic Techniques for Norovirus Detection 1997.5.3 Case Studies: Successful Implementation of One Health Surveillance 1997.6 Prevention and Control Strategies 2007.6.1 Hygiene and Sanitation Practices 2007.6.2 Vaccination Development and Challenges 2017.6.3 Environmental Management and Water Safety 2017.6.4 Role of Policy and Legislation in Norovirus Prevention 2027.7 Interdisciplinary Collaboration in One Health 2027.7.1 Building Effective Partnerships Between Health Sectors 2027.7.2 Case Studies of Multidisciplinary Efforts in Controlling Norovirus 2037.7.3 Challenges and Opportunities in Collaborative Approaches 2047.8 Case Studies: One Health Success Stories 2057.8.1 Outbreak Response in Different Regions 2057.8.2 Lessons Learned from Norovirus Control Efforts 2067.8.3 Scaling Up One Health Strategies Globally 2067.9 Future Directions in Norovirus Research and Control 2077.9.1 Emerging Trends in Norovirus Epidemiology 2077.9.2 Innovations in Vaccination and Treatment 2077.9.3 The Role of Technology in Enhancing One Health Approaches 2087.10 Conclusion 2087.10.1 Summarizing the Impact of the One Health Approach on Norovirus Control 2087.10.2 Recommendations for Future Action and Research 209References 2108 Recent Insights into the Dynamics of Norovirus Outbreak 221Sejal Porwal, Sonali Sundram, Rishabha Malviya and Shriyansh Srivastava8.1 Introduction 2228.2 Symptoms Related to Norovirus 2238.3 Epidemiology of Norovirus Outbreak 2258.4 Norovirus Genome and Structure 2268.5 Virion Morphology 2278.6 Transmission Mechanism 2278.6.1 Pattern of Viral Invasion into Host 2298.7 Administration of Pharmaceuticals and Challenges in Vaccination 2308.8 Immunity to Norovirus Infection 2338.9 Public Health Measures to Avoid Being Infected with Norovirus 2358.10 Conclusion 236References 2379 Norovirus Excretion Patterns and their Role in Spread 249Cynthia Lizzie Lobo, Soumya Patil, Raushan Kumar Chaudhary and Pukar Khanal9.1 Introduction 2509.2 Routes of Norovirus Excretion 2519.2.1 Fecal Shedding 2519.2.2 Vomitus 2539.2.3 Saliva 2549.3 Duration of Noroviral Shedding 2559.3.1 Factors Influencing Noroviral Shedding Patterns 2559.3.1.1 Host Factors 2559.3.1.2 Viral Factors 2569.3.1.3 Environmental Factors 2569.3.2 Asymptomatic Excretion of Norovirus 2579.4 Quantitative Analysis of Noroviral Load 2589.4.1 Measurement Techniques 2589.4.1.1 Reverse Transcriptase–Polymerase Chain Reaction (RT-PCR) 2589.4.1.2 Quantitative PCR (qPCR) 2599.4.1.3 Immune Electron Microscopy (IEM) 2599.4.1.4 Antigen Detection Immunoassays 2599.4.1.5 Biosensors 2609.4.2 Noroviral Load Decay Rates 2619.5 Transmission Modes of Norovirus 2619.5.1 Direct Person-to-Person Contact 2619.5.2 Aerosolized Norovirus Particles 2629.5.3 Contaminated Food or Water 2639.5.4 Contaminated Surfaces 2639.6 Role of Excretion Patterns in Norovirus Spread 2649.6.1 Contribution to Disease Transmission 2649.6.2 Environmental Contamination 2649.7 Public Health Implications of Excretion Patterns 2669.8 Research Gaps and Future Directions 267Abbreviations 268References 26810 The Role of Rainfall in the Control of Norovirus Outbreaks 275Sandhya Chaudhary, Rahul Kumar, Kalpana Rahate, Shriyansh Srivastava and Sathvik Belagodu Sridhar10.1 Introduction 27610.2 Characteristics of Norovirus 27610.2.1 Classification 27610.2.2 Structure of Norovirus 27810.2.3 Characteristics of Virus 27810.2.4 Viral Shedding and Transmission Potential 27910.2.5 Duration of Development and Manifestations 28010.3 Possible Environmental Markers for Outbreaks of the Human Norovirus 28110.3.1 Temperature 28110.3.2 Humidity 28210.3.3 Rainfall 28210.4 Relationship Between Rainfall and Norovirus Outbreaks 28310.5 Public Health and Infrastructure Challenges 28410.5.1 Water and Foodborne Transmission 28510.5.2 Transmission Between Individuals 28510.6 Prevention and Mitigation Strategies 28510.6.1 Controlling the Occurrence 28510.6.2 Sanitation 28710.6.3 Cleaning and Sanitization 28710.6.4 Colonization and Isolation 28710.7 Future Directions and Research Needs 28710.8 Conclusion 288Abbreviations 288References 28911 The Impact of COVID-19 on Norovirus Circulation and Research 295Laxmi, Shriyansh Srivastava, Sanjita Das, Malakapogu Ravindra Babu, Rishabha Malviya and S.K. Abdul Rahaman11.1 Introduction 29611.2 Norovirus: Characteristics and Epidemiology 29711.2.1 Virology and Pathogenesis 29811.2.2 Transmission Routes 29911.2.3 Global Epidemiology of Norovirus 30011.2.4 Seasonal Patterns and Outbreaks 30011.3 The COVID-19 Pandemic: An Overview 30211.3.1 Timeline of COVID-19 Spread 30211.3.2 Public Health Interventions and Their Impact 30311.3.3 Changes in Healthcare Systems 30411.4 Effects of COVID-19 on Norovirus Circulation 30411.4.1 Changes in Reporting and Surveillance 30411.4.2 Impact of Non-Pharmaceutical Interventions (NPIs) 30511.4.3 Predictions for Norovirus Resurgence Post-Pandemic 30511.5 Research Trends and Findings 30611.5.1 Changes in Norovirus Research Focus During Covid- 19 30611.5.2 Advances in Norovirus Vaccine Development 30711.5.2.1 Vaccine in Human Clinical Trials 30711.5.2.2 Vaccines in Pre-Clinical Trials 31011.5.3 Comparative Studies of Norovirus and Other Viruses 31111.5.3.1 Sapoviruses 31111.5.3.2 Lagovirus 31111.5.3.3 Vesivirus 31211.5.3.4 Nebovirus 31211.6 Public Health Implications 31211.6.1 Preparedness for Future Outbreaks 31211.6.2 Strategies for Mitigating Norovirus Spread 31311.6.3 Lesson Learned from COVID- 19 314Conclusion 315Abbreviations 315References 317Part 3: Cross-Species Studies and Therapeutic Development 32712 Norovirus in Animals: Bovine, Murine, and Other Hosts 329Aritra Banerjee, K.V. Leela, Shriyansh Srivastava, Pranav Gupta, Malakapogu Ravindra Babu and Ranjit Sah12.1 Introduction 33012.2 Genomic Organization and Virus 33112.3 Interactions Between Viruses and Cells 33212.4 Norovirus in Bovines 33312.5 Bovine Norovirus Distribution 33412.6 The Pathophysiology and Clinical Characteristics of Bovine Norovirus 33512.7 Diagnosis of the Bovine Norovirus 33712.7.1 Electron Microscopy 33712.7.2 Molecular Methods 33712.7.3 Antigen ELISAs 33712.7.4 Antibody ELISAs 33812.8 Norovirus in Murine 33812.8.1 Murine Norovirus Identification 33812.8.2 Structural Features of MNV 33912.8.3 MNV Infection in Wild-Type Mice 34012.8.4 To Control Norovirus Infection, Innate Immunity is Necessary 34012.8.5 To Eradicate a Norovirus Infection, Adaptive Immunity is Required 34112.9 Porcine Norovirus 34112.10 In Lions, Norovirus 34212.11 Conclusion 343References 34313 The Challenges of Developing Norovirus Vaccines and Therapies 359Gita Chawla, Tathagata Pradhan and Ojasvi Gupta13.1 Overview of Norovirus Epidemiology 35913.2 Classification and Molecular Biology of Norovirus 36113.3 Current Approaches to Norovirus Therapy 36313.3.1 Symptomatic Treatment 36313.3.2 Antiviral Drug Development 36413.3.3 Passive Immunization Strategies 36413.3.4 Vaccine Candidates 36513.3.4.1 Virus-Like Particle (VLP) Vaccines 36513.3.4.2 P Particle-Based Vaccines 36713.3.4.3 Recombinant Protein Vaccines 36713.3.4.4 Bivalent and Multivalent VLP Vaccines 36713.3.4.5 Oral Vaccines 36813.3.4.6 Plant-Derived Vaccines 36813.3.5 Monoclonal Antibody-Based Passive Immunization 36913.4 Challenges in Norovirus Vaccine Development 36913.4.1 Genetic Diversity and Rapid Evolution 36913.4.2 Lack of Long-Lasting Immunity 37213.4.3 Absence of Reliable In Vitro Culture System 37213.4.4 Unclear Correlates of Protection 37213.4.5 Variation in Host Susceptibility 37313.4.6 High Cost and Complexity of Clinical Trials 37313.5 Conclusion and Future Perspectives 374References 37514 The Importance of Animal Models and In Vitro Cultivation for Norovirus Research 379Prarambh S.R. Dwivedi, Masmarika Mohan, Pukar Khanal, Sanjit Sah and C.S. Shastry14.1 Introduction 38014.2 Importance of Animal and Cell Culture Models for Human Norovirus 38114.2.1 Importance of Cell Culture Models 38114.2.2 Importance of Animal Models 38214.3 Animal Models of HuNoV Infection 38314.3.1 Mice Model 38414.3.2 Chimpanzee Model 38814.3.3 Macaques Model 38914.3.4 Gnotobiotic Calves and Pigs as Model 39014.3.5 Zebrafish Model 39114.3.6 Recovirus Model 39214.4 Advancement of In Vitro Models for Norovirus 39314.4.1 Early Attempts to Cultivate HuNoVs 39314.4.2 Key Discoveries That Helped to Cultivate the Human Epithelial System 39514.4.3 Reverse Genetic Systems 39814.4.4 Human Norovirus Strains 39914.5 Conclusion 402Abbreviations 403References 40415 The Role of Human Intestinal Enteroids in Norovirus Research 413Apeksha Shetty, Anushree Deshpande, Raushan Kumar Chaudhary and Prakash Patil15.1 Introduction to Human Intestinal Enteroids (HIEs) 41415.1.1 Definition and Significance of HIEs 41415.1.2 The Components of HIEs: Enterocytes, Goblet Cells, Paneth Cells, and Germ Cells 41615.1.3 Activity of HIEs: Ion Transport and Immune Function 41715.2 Components Required for Norovirus Activation 41915.2.1 Receptors and Ligands Involved in Norovirus Binding and Entry 41915.2.2 Enzymes that are Required for Norovirus Replication 42315.2.3 Cellular Factors Which Help in Regulating Norovirus Replication and Tropism 42515.3 Pathophysiology of Norovirus Infection 42515.3.1 Mechanism of Infection of Norovirus Into the Gut: Attachment, Internalization, and Replication 42515.3.2 Immune Response to Norovirus Infection: Cellular and Humoral Immunity 42815.3.3 Few Clinical Symptoms of Norovirus Infection: Diarrhea, Vomiting, and Dehydration 42915.4 Norovirus Cell Tropism 43015.4.1 Viral Tropism: Process of Norovirus Targeting Specific Cell Types in the Gut 43015.4.2 Factors That Influence Norovirus Tropism: Age, Genetics, and Environment 43115.5 Role of Additional Gastrointestinal Components in Norovirus Infection 43215.5.1 Mechanisms Through Which Bile Acids Enhance Norovirus Replication 43215.5.2 How the Bile Acids and the Ceramides Deal with the Entry Restriction for Norovirus 43315.5.3 Potential Therapeutic Applications of Bile Acids and Ceramide in Treating Norovirus 43415.6 Antiviral Compound Screening Using HIEs 43515.6.1 Screening Methods of Antiviral Compounds Using HIEs 43515.6.2 Examples of Antiviral Compounds Discovered by Using HIEs 43615.6.3 Future Directions for Antiviral Compound Screening Using HIEs 43715.7 Future Perspectives 43815.8 Conclusion 439Abbreviations 439References 440Index 447

Sachin Kumar, PhD is an Assistant Professor in the Department of Pharmacology, Delhi Pharmaceutical Sciences and Research University, New Delhi, India. He has published more than 60 peer-reviewed papers in national and international journals and six book chapters. His research interests include diagnosis, biomarkers, meta-analysis, and pharmacoeconomic analysis. Shriyansh Srivastava is a PhD Research Scholar in the Department of Pharmacology at Delhi Pharmaceutical Sciences and Research University, New Delhi India. He has published more than 60 research articles in prestigious international journals, ten book chapters, five books, and two patents. Rishabha Malviya, PhD is an Associate Professor in the Department of Pharmacy in the School of Medical and Allied Sciences at Galgotias University, Greater Noida, India, with more than 13 years of experience. He has authored more than 150 research papers for national and international journals of repute, 102 books, and 51 patents. His areas of interest include formulation optimization, nanoformulation, targeted drug delivery, localized drug delivery, and characterization of natural polymers as pharmaceutical excipients. Ranjit Sah, MD is a Research Coordinator at BMC South, Boston Medical Centre Health System, MA, USA. He has made significant contributions to research and clinical practice, notably as the Head of COVID-19 testing facilities in Nepal during the pandemic.

• Preface xxiPart 1: Introduction and Genetic Insights 11 Introduction to Viral Storms: Infectious Disease 3Shivaprasad Sirimalla, Sanjit Sah, Uday Venkat Mateti and Allen Pinto1.1 Introduction to Infectious Disease 41.2 Virology: Overview of Virus, Virus Structure, Classification, Replication, and Transmission 61.2.1 Overview of the Virus 61.2.2 Virus Structure 71.2.3 Classification of Viruses 81.2.4 Viral Replication 141.2.5 Viral Transmission 151.3 Viral Storms (Major Pandemics) 171.3.1 The Spanish Flu (1918–1919) 171.3.2 HIV/AIDS Pandemic (1980s–Present) 181.3.3 Sars (2002–2003) 191.3.4 H1N1 Influenza (2009) 191.3.5 COVID-19 Pandemic (2019–Present) 201.4 Factors Contributing to Viral Storms 211.4.1 Environmental Factors, Climate Change, and Urbanization 211.4.2 Social Factors: Global Travel, Population Density, and Healthcare Access 221.4.3 Biological Factors: Viral Mutations and Host Immune Response 241.5 Norovirus 251.5.1 Introduction to Norovirus: Overview of the Virus and Its Significance 251.5.2 Epidemiology: Global Impact and Spread of Norovirus 261.5.3 Clinical Presentation: Symptoms, Severity, and Complications 271.5.4 Transmission and Prevention: Modes of Transmission and Strategies to Prevent Outbreaks 281.6 Summary of Key Points 291.7 Conclusion 30References 312 Norovirus: Its Role in Gastroenteritis Outbreaks 39Ranjana Rohilla and Shriyansh Srivastava2.1 Infectious Etiology of Gastroenteritis 402.2 Introduction to Norovirus Gastroenteritis 412.3 History of Norovirus and Outbreaks 422.4 Epidemiology and Common Settings of Norovirus Outbreaks 442.4.1 Healthcare Facilities 462.4.2 Restaurants and Other Food Establishments 462.4.3 School and Child Day Care 482.4.4 Cruise Ships 482.5 Clinical Features 482.6 Gastroenteritis in Immunocompromised Individuals 492.7 Gastroenteritis in Immunocompetent Individuals 502.8 Economic Burden of Infection 512.9 Preparedness for Outbreaks 512.10 Conclusion 52References 533 The Genetics of Norovirus: Understanding Its Genome and Genogroups 61Naga Rani Kagithala, Rahul Sharma, Sasikanth Kothamasu, Shriyansh Srivastava and Ismail A. Ibrahim3.1 Introduction 623.2 Norovirus Genome 643.2.1 Structure and Organizational Forms of the Norovirus Genome 643.2.2 RNA Genome Characteristics 643.2.3 Open Reading Frames (ORFs) 653.2.4 Non-Structural Proteins (ORF1) 653.2.5 Principal Capsid Protein (VP1): ORF 2 663.2.6 ORF3: VP2 or Minor Capsid Protein 663.3 Genetic Diversity in Norovirus 663.3.1 Genogroups and Genotypes 663.3.2 Mechanisms of Genetic Variation 673.3.3 Mutation Rates and Hotspots 683.3.4 Recombination Events 703.3.5 Evolutionary Dynamics of Norovirus 703.4 Norovirus Genogroups 713.4.1 Classification and Characteristics of Norovirus Genogroups 713.4.2 Classification of VP1 Sequences 723.4.3 RdRp Designations 723.4.4 Genogroup I (GI) 723.4.5 Genogroup II (GII) 733.4.6 Genogroup III (GIII) 733.4.7 Epidemiology of Norovirus Genogroups 743.5 Molecular Techniques for Norovirus Genetic Analysis 753.5.1 Sequencing Technologies 753.5.2 Next-Generation Sequencing (NGS) 763.5.3 Whole-Genome Sequencing (WGS) 803.5.4 Phylogenetic Analysis 803.5.5 Genotyping and Molecular Epidemiology 813.6 Implications of Norovirus Genetic Variability 823.6.1 Impact on Vaccine Development 823.6.1.1 Monovalent Vaccines 823.6.1.2 Bivalent Vaccines 833.6.2 Antiviral Drug Resistance 833.6.3 Public Health Challenges 843.7 Recent Advances in Norovirus Genetics 853.7.1 New Discoveries in Norovirus Genomic Research 853.7.2 Emerging Genogroups and Strains 863.7.3 Future Directions in Norovirus Genetics 863.8 Conclusion 87Abbreviations 87References 884 Environmental Factors in Norovirus Outbreaks: Temperature and Rainfall 99Neeraj Kumar, Akanksha, Shriyansh Srivastava and Mohd Mujeeb4.1 Introduction 1004.2 Evolution of Norovirus 1034.2.1 Antigenic Drift 1034.2.2 Antigenic Shift 1034.2.3 Recombination Events 1044.2.4 Genetic Diversity 1044.2.5 Mutation Rates 1044.2.6 Pandemic Strains 1054.2.7 Geographic Differences 1054.2.8 Temporal Trends 1054.3 Fatal Details Regarding the Norovirus 1054.4 Mode of Transmission of Norovirus 1064.4.1 Environmental Source 1074.4.2 Influence of Temperature on Norovirus Outbreaks 1084.5 Correlation Between Temperature Fluctuations and Outbreaks 1094.6 Effect of Norovirus on Humidity 1104.7 The Impact of Rainfall on the Spread of the Norovirus 1104.8 The Impact of Water on the Spread of the Norovirus 1114.9 Norovirus Combined Effects of Temperature and Rainfall 1124.10 Stability of Norovirus 1124.11 Case Study 1134.12 Global Patterns in Temperature- and Rainfall-Related Outbreaks 1204.13 Mitigation Strategies and Public Health Interventions 1214.14 Conclusion 123References 1245 Zoonotic Transmission of Norovirus: Current Understanding and Future Implications 129Vini Mehta, Sapna Negi, Snehasish Tripathy, Sarvesh Rastogi and Ankita Mathur5.1 Brief Overview of Norovirus 1305.2 Epidemiology of Norovirus 1315.3 Symptoms of Norovirus-Associated Gastroenteritis 1325.4 Mode of Transmission of Norovirus 1325.4.1 Vomitus or Stool 1325.4.2 Through Contaminated Food and Water 1335.5 Zoonotic Transmission 1345.5.1 Animal Reservoirs 1355.5.2 Wild Animals 1385.6 Zoonotic Transmission Mechanisms of Norovirus 1395.6.1 Animal-to-Human Transmission 1395.6.2 Human-to-Animal Transmission 1405.7 Zoonotic Transmission Mechanism 1415.8 Future Implications and Research Directions 1425.9 Conclusion 143Abbreviations 144References 144Part 2: Transmission, Dynamics and Environmental Impacts 1516 Genetic Changes in Norovirus and Their Impact on Infectivity/Virulence 153Soumya Patil, Vijayalaxmi Bangra Manjeshwara, Uday Venkat Mateti and Raushan Kumar Chaudhary6.1 Introduction 1546.2 Classification of NoV 1556.3 Genomic Structure and Functions 1566.3.1 ORF1: The Replication Engine 1566.3.2 ORF2: The Master Builder 1596.3.3 ORF3: The Stabilizer 1596.3.4 ORF4: Murine Norovirus 1596.4 NoV Life Cycle: Molecular Mechanism of NoV Genome Replication 1596.5 Transmission 1616.6 Molecular Diversity 1626.7 Evolutionary Mechanisms and Dominance 1636.7.1 Point Mutation 1646.7.2 Recombination 1676.7.2.1 Mechanisms of Recombination 1686.8 Recent Epidemiological Trends 1706.9 Global Impact and Challenges 1746.10 Conclusion 176Abbreviations 177References 1777 Bridging the Gap: One Health Approach in Norovirus 187Sasikanth Kothamasu, Naga Rani Kagithala, Dheeraj Sharma, Shriyansh Srivastava, Aroop Mohanty and Rakesh Sahu7.1 Overview of Norovirus: Structure and Epidemiology 1887.2 Understanding the One Health Approach 1907.2.1 Definition and Principles of One Health 1907.2.2 Historical Context and Evolution of the One Health Concept 1907.2.3 Relevance of One Health to Norovirus Control 1917.2.3.1 Environmental Transmission Pathways 1917.3 Transmission Pathways of Norovirus 1947.3.1 Human-to-Human Transmission 1947.3.2 Environmental Contamination and Spread 1947.3.3 Zoonotic Potential and Animal Reservoirs 1957.3.4 Role of Food and Water in Norovirus Outbreaks 1957.4 Epidemiology of Norovirus: A Global Perspective 1967.4.1 Geographic Distribution and Prevalence 1967.4.2 Risk Factors for Infection 1967.4.3 Seasonal and Regional Variations in Norovirus Incidence 1977.5 The One Health Approach to Norovirus Surveillance 1987.5.1 Integrating Human, Animal, and Environmental Surveillance Systems 1987.5.2 Advances in Diagnostic Techniques for Norovirus Detection 1997.5.3 Case Studies: Successful Implementation of One Health Surveillance 1997.6 Prevention and Control Strategies 2007.6.1 Hygiene and Sanitation Practices 2007.6.2 Vaccination Development and Challenges 2017.6.3 Environmental Management and Water Safety 2017.6.4 Role of Policy and Legislation in Norovirus Prevention 2027.7 Interdisciplinary Collaboration in One Health 2027.7.1 Building Effective Partnerships Between Health Sectors 2027.7.2 Case Studies of Multidisciplinary Efforts in Controlling Norovirus 2037.7.3 Challenges and Opportunities in Collaborative Approaches 2047.8 Case Studies: One Health Success Stories 2057.8.1 Outbreak Response in Different Regions 2057.8.2 Lessons Learned from Norovirus Control Efforts 2067.8.3 Scaling Up One Health Strategies Globally 2067.9 Future Directions in Norovirus Research and Control 2077.9.1 Emerging Trends in Norovirus Epidemiology 2077.9.2 Innovations in Vaccination and Treatment 2077.9.3 The Role of Technology in Enhancing One Health Approaches 2087.10 Conclusion 2087.10.1 Summarizing the Impact of the One Health Approach on Norovirus Control 2087.10.2 Recommendations for Future Action and Research 209References 2108 Recent Insights into the Dynamics of Norovirus Outbreak 221Sejal Porwal, Sonali Sundram, Rishabha Malviya and Shriyansh Srivastava8.1 Introduction 2228.2 Symptoms Related to Norovirus 2238.3 Epidemiology of Norovirus Outbreak 2258.4 Norovirus Genome and Structure 2268.5 Virion Morphology 2278.6 Transmission Mechanism 2278.6.1 Pattern of Viral Invasion into Host 2298.7 Administration of Pharmaceuticals and Challenges in Vaccination 2308.8 Immunity to Norovirus Infection 2338.9 Public Health Measures to Avoid Being Infected with Norovirus 2358.10 Conclusion 236References 2379 Norovirus Excretion Patterns and their Role in Spread 249Cynthia Lizzie Lobo, Soumya Patil, Raushan Kumar Chaudhary and Pukar Khanal9.1 Introduction 2509.2 Routes of Norovirus Excretion 2519.2.1 Fecal Shedding 2519.2.2 Vomitus 2539.2.3 Saliva 2549.3 Duration of Noroviral Shedding 2559.3.1 Factors Influencing Noroviral Shedding Patterns 2559.3.1.1 Host Factors 2559.3.1.2 Viral Factors 2569.3.1.3 Environmental Factors 2569.3.2 Asymptomatic Excretion of Norovirus 2579.4 Quantitative Analysis of Noroviral Load 2589.4.1 Measurement Techniques 2589.4.1.1 Reverse Transcriptase–Polymerase Chain Reaction (RT-PCR) 2589.4.1.2 Quantitative PCR (qPCR) 2599.4.1.3 Immune Electron Microscopy (IEM) 2599.4.1.4 Antigen Detection Immunoassays 2599.4.1.5 Biosensors 2609.4.2 Noroviral Load Decay Rates 2619.5 Transmission Modes of Norovirus 2619.5.1 Direct Person-to-Person Contact 2619.5.2 Aerosolized Norovirus Particles 2629.5.3 Contaminated Food or Water 2639.5.4 Contaminated Surfaces 2639.6 Role of Excretion Patterns in Norovirus Spread 2649.6.1 Contribution to Disease Transmission 2649.6.2 Environmental Contamination 2649.7 Public Health Implications of Excretion Patterns 2669.8 Research Gaps and Future Directions 267Abbreviations 268References 26810 The Role of Rainfall in the Control of Norovirus Outbreaks 275Sandhya Chaudhary, Rahul Kumar, Kalpana Rahate, Shriyansh Srivastava and Sathvik Belagodu Sridhar10.1 Introduction 27610.2 Characteristics of Norovirus 27610.2.1 Classification 27610.2.2 Structure of Norovirus 27810.2.3 Characteristics of Virus 27810.2.4 Viral Shedding and Transmission Potential 27910.2.5 Duration of Development and Manifestations 28010.3 Possible Environmental Markers for Outbreaks of the Human Norovirus 28110.3.1 Temperature 28110.3.2 Humidity 28210.3.3 Rainfall 28210.4 Relationship Between Rainfall and Norovirus Outbreaks 28310.5 Public Health and Infrastructure Challenges 28410.5.1 Water and Foodborne Transmission 28510.5.2 Transmission Between Individuals 28510.6 Prevention and Mitigation Strategies 28510.6.1 Controlling the Occurrence 28510.6.2 Sanitation 28710.6.3 Cleaning and Sanitization 28710.6.4 Colonization and Isolation 28710.7 Future Directions and Research Needs 28710.8 Conclusion 288Abbreviations 288References 28911 The Impact of COVID-19 on Norovirus Circulation and Research 295Laxmi, Shriyansh Srivastava, Sanjita Das, Malakapogu Ravindra Babu, Rishabha Malviya and S.K. Abdul Rahaman11.1 Introduction 29611.2 Norovirus: Characteristics and Epidemiology 29711.2.1 Virology and Pathogenesis 29811.2.2 Transmission Routes 29911.2.3 Global Epidemiology of Norovirus 30011.2.4 Seasonal Patterns and Outbreaks 30011.3 The COVID-19 Pandemic: An Overview 30211.3.1 Timeline of COVID-19 Spread 30211.3.2 Public Health Interventions and Their Impact 30311.3.3 Changes in Healthcare Systems 30411.4 Effects of COVID-19 on Norovirus Circulation 30411.4.1 Changes in Reporting and Surveillance 30411.4.2 Impact of Non-Pharmaceutical Interventions (NPIs) 30511.4.3 Predictions for Norovirus Resurgence Post-Pandemic 30511.5 Research Trends and Findings 30611.5.1 Changes in Norovirus Research Focus During Covid- 19 30611.5.2 Advances in Norovirus Vaccine Development 30711.5.2.1 Vaccine in Human Clinical Trials 30711.5.2.2 Vaccines in Pre-Clinical Trials 31011.5.3 Comparative Studies of Norovirus and Other Viruses 31111.5.3.1 Sapoviruses 31111.5.3.2 Lagovirus 31111.5.3.3 Vesivirus 31211.5.3.4 Nebovirus 31211.6 Public Health Implications 31211.6.1 Preparedness for Future Outbreaks 31211.6.2 Strategies for Mitigating Norovirus Spread 31311.6.3 Lesson Learned from COVID- 19 314Conclusion 315Abbreviations 315References 317Part 3: Cross-Species Studies and Therapeutic Development 32712 Norovirus in Animals: Bovine, Murine, and Other Hosts 329Aritra Banerjee, K.V. Leela, Shriyansh Srivastava, Pranav Gupta, Malakapogu Ravindra Babu and Ranjit Sah12.1 Introduction 33012.2 Genomic Organization and Virus 33112.3 Interactions Between Viruses and Cells 33212.4 Norovirus in Bovines 33312.5 Bovine Norovirus Distribution 33412.6 The Pathophysiology and Clinical Characteristics of Bovine Norovirus 33512.7 Diagnosis of the Bovine Norovirus 33712.7.1 Electron Microscopy 33712.7.2 Molecular Methods 33712.7.3 Antigen ELISAs 33712.7.4 Antibody ELISAs 33812.8 Norovirus in Murine 33812.8.1 Murine Norovirus Identification 33812.8.2 Structural Features of MNV 33912.8.3 MNV Infection in Wild-Type Mice 34012.8.4 To Control Norovirus Infection, Innate Immunity is Necessary 34012.8.5 To Eradicate a Norovirus Infection, Adaptive Immunity is Required 34112.9 Porcine Norovirus 34112.10 In Lions, Norovirus 34212.11 Conclusion 343References 34313 The Challenges of Developing Norovirus Vaccines and Therapies 359Gita Chawla, Tathagata Pradhan and Ojasvi Gupta13.1 Overview of Norovirus Epidemiology 35913.2 Classification and Molecular Biology of Norovirus 36113.3 Current Approaches to Norovirus Therapy 36313.3.1 Symptomatic Treatment 36313.3.2 Antiviral Drug Development 36413.3.3 Passive Immunization Strategies 36413.3.4 Vaccine Candidates 36513.3.4.1 Virus-Like Particle (VLP) Vaccines 36513.3.4.2 P Particle-Based Vaccines 36713.3.4.3 Recombinant Protein Vaccines 36713.3.4.4 Bivalent and Multivalent VLP Vaccines 36713.3.4.5 Oral Vaccines 36813.3.4.6 Plant-Derived Vaccines 36813.3.5 Monoclonal Antibody-Based Passive Immunization 36913.4 Challenges in Norovirus Vaccine Development 36913.4.1 Genetic Diversity and Rapid Evolution 36913.4.2 Lack of Long-Lasting Immunity 37213.4.3 Absence of Reliable In Vitro Culture System 37213.4.4 Unclear Correlates of Protection 37213.4.5 Variation in Host Susceptibility 37313.4.6 High Cost and Complexity of Clinical Trials 37313.5 Conclusion and Future Perspectives 374References 37514 The Importance of Animal Models and In Vitro Cultivation for Norovirus Research 379Prarambh S.R. Dwivedi, Masmarika Mohan, Pukar Khanal, Sanjit Sah and C.S. Shastry14.1 Introduction 38014.2 Importance of Animal and Cell Culture Models for Human Norovirus 38114.2.1 Importance of Cell Culture Models 38114.2.2 Importance of Animal Models 38214.3 Animal Models of HuNoV Infection 38314.3.1 Mice Model 38414.3.2 Chimpanzee Model 38814.3.3 Macaques Model 38914.3.4 Gnotobiotic Calves and Pigs as Model 39014.3.5 Zebrafish Model 39114.3.6 Recovirus Model 39214.4 Advancement of In Vitro Models for Norovirus 39314.4.1 Early Attempts to Cultivate HuNoVs 39314.4.2 Key Discoveries That Helped to Cultivate the Human Epithelial System 39514.4.3 Reverse Genetic Systems 39814.4.4 Human Norovirus Strains 39914.5 Conclusion 402Abbreviations 403References 40415 The Role of Human Intestinal Enteroids in Norovirus Research 413Apeksha Shetty, Anushree Deshpande, Raushan Kumar Chaudhary and Prakash Patil15.1 Introduction to Human Intestinal Enteroids (HIEs) 41415.1.1 Definition and Significance of HIEs 41415.1.2 The Components of HIEs: Enterocytes, Goblet Cells, Paneth Cells, and Germ Cells 41615.1.3 Activity of HIEs: Ion Transport and Immune Function 41715.2 Components Required for Norovirus Activation 41915.2.1 Receptors and Ligands Involved in Norovirus Binding and Entry 41915.2.2 Enzymes that are Required for Norovirus Replication 42315.2.3 Cellular Factors Which Help in Regulating Norovirus Replication and Tropism 42515.3 Pathophysiology of Norovirus Infection 42515.3.1 Mechanism of Infection of Norovirus Into the Gut: Attachment, Internalization, and Replication 42515.3.2 Immune Response to Norovirus Infection: Cellular and Humoral Immunity 42815.3.3 Few Clinical Symptoms of Norovirus Infection: Diarrhea, Vomiting, and Dehydration 42915.4 Norovirus Cell Tropism 43015.4.1 Viral Tropism: Process of Norovirus Targeting Specific Cell Types in the Gut 43015.4.2 Factors That Influence Norovirus Tropism: Age, Genetics, and Environment 43115.5 Role of Additional Gastrointestinal Components in Norovirus Infection 43215.5.1 Mechanisms Through Which Bile Acids Enhance Norovirus Replication 43215.5.2 How the Bile Acids and the Ceramides Deal with the Entry Restriction for Norovirus 43315.5.3 Potential Therapeutic Applications of Bile Acids and Ceramide in Treating Norovirus 43415.6 Antiviral Compound Screening Using HIEs 43515.6.1 Screening Methods of Antiviral Compounds Using HIEs 43515.6.2 Examples of Antiviral Compounds Discovered by Using HIEs 43615.6.3 Future Directions for Antiviral Compound Screening Using HIEs 43715.7 Future Perspectives 43815.8 Conclusion 439Abbreviations 439References 440Index 447