Emerging Pathways of Vaccine Adjuvants

Vivek P. Chavda is an assistant professor in the Department of Pharmaceutics and Pharmaceutical Technology, L.M. College of Pharmacy, Gujarat, India with over eight years of teaching and biologics industry experience. He has more than 200 national and international publications, four edited books, an authored book, and 28 book chapters and is working on three patents. His research interests include the development of biologics processes and formulations, medical device development, nanodiagnostics and non-carrier formulations, long-acting parenteral formulations, and nanovaccines. Vasso Apostolopoulos, PhD, is a Vice-Chancellor Distinguished Fellow and Director of the Immunology and Translational Research Group at Victoria University, Australia and the Immunology Program Director at the Australian Institute for Musculoskeletal Science, Australia. She is a world-renowned researcher with over 100 awards, 510 research publications, and 22 patents to her credit. Her interests include vaccine and drug development for cancer, chronic, infectious, and autoimmune diseases.

• Preface xv1 Adjuvants Boosting Vaccine Effectiveness 1Vasso Apostolopoulos1.1 Vaccines Over the Years 11.2 Adjuvants in the Modern Era 21.3 Conventional Adjuvants 31.4 Particulate Adjuvants 51.5 Immunostimulatory Adjuvants 71.6 Approved Adjuvants for Human Use 81.7 Conclusion 9References 102 In Silico Adjuvant Design and Validation for Vaccines 15Vivek P. Chavda, Anjali P. Bedse, Pankti C. Balar, Bedanta Bhattacharjee, Shilpa S. Raut and Vasso Apostolopoulos2.1 Introduction 162.1.1 Importance of Vaccines and Adjuvants in Immunology 162.1.2 Limitations of Traditional Adjuvant Discovery Methods 162.1.3 Introduction to In Silico Approaches for Adjuvant Design 172.2 In Silico Techniques for Adjuvant Discovery 172.2.1 Immunoinformatics Tools for Epitope Prediction 182.2.1.1 Identification of B-Cell and T-Cell Epitopes 182.2.1.2 Tools Used for MHC and B-Cell Receptor Binding Prediction Tools 192.2.2 Molecular Docking Simulation 202.2.2.1 Application of Molecular Docking in Adjuvant Design 212.2.3 Artificial Intelligence and Machine Learning for Adjuvant Design 212.2.3.1 Leveraging Large Datasets for Adjuvant Discovery 222.2.3.2 Types of Machine Learning Algorithms Used 222.2.3.3 Case Study 232.2.4 In Silico Toxicology Prediction 232.2.4.1 Minimizing Safety Concerns During Adjuvant Design 242.2.4.2 Software Tools for Virtual Toxicity Assessment 242.3 Case Studies: Successful Applications of In Silico Adjuvant Design 252.3.1 Designing Adjuvants Targeting Specific Immune Pathways (e.g., TLR Agonists) 252.3.2 Development of Multi-Epitope Vaccines with In Silico Adjuvant Selection 272.3.3 Repurposing Existing Drugs as Vaccine Adjuvants Through In Silico Analysis 282.4 Challenges and Future Directions of In Silico Adjuvant Design 292.5 Conclusion 31References 323 Adjuvant and Immunity 39Himel Mondal, Shaikat Mondal, Bairong Shen and Rajeev K. Singla3.1 Introduction 403.2 Immune Response to Vaccines 423.2.1 Immune Response to Pathogens 423.2.2 Immune Response to Vaccines 443.3 Mechanisms of Adjuvants in Modulating Immunity 453.3.1 Sustained Release of Antigen 453.3.2 Upregulation of Cytokines and Chemokines 463.3.3 Cellular Recruitment at the Site of Injection 473.3.4 Increased Antigen Uptake and Presentation 473.3.5 Activation and Maturation of APCs 483.3.6 Activation of Inflammasomes 483.4 Immunogenicity According to the Types of Adjuvants 493.4.1 Minerals 493.4.2 Emulsions 503.4.3 Polymers 503.4.4 Saponins 513.4.5 Complement Components and Cytokines 523.4.6 Bacterial Components 523.5 Adjuvants and Humoral Immunity 533.5.1 B-Cell Activation and Antibody Production 533.5.2 Enhanced Germinal Center Formation 533.5.3 Isotype Switching 543.5.4 Long-Lasting Antibody Responses 543.5.5 Antibody Affinity Maturation 543.5.6 Enhanced IgG Subclass Responses 553.5.7 Increased Antibody Titers 553.6 Adjuvants and Cellular Immunity 563.6.1 Activation of Antigen-Presenting Cells (APCs) 563.6.2 Cytokine Production and T-Cell Differentiation 563.6.3 Cytotoxic T-Cell Activation 573.6.4 Cross-Presentation of Exogenous Antigens 573.6.5 Inflammation and Immune Cell Recruitment 573.6.6 Memory T-Cell Generation 573.6.7 Enhancement of Antigen Persistence 583.6.8 Antigen Depot Formation 583.6.9 Induction of Th1 Responses 583.7 Adjuvants and Innate Immunity 583.7.1 Phagocytosis and Antigen Processing 593.7.2 Complement Activation 593.7.3 Induction of Local Inflammation 593.7.4 Pattern Recognition Receptor Activation 603.7.5 Natural Killer (NK) Cell Activation 603.7.6 Activation of Epithelial Cells 603.8 Adjuvants and Mucosal Immunity 613.8.1 Enhanced Mucosal Antigen Uptake 613.8.2 Secretory IgA Production 623.8.3 Induction of Tolerance 623.8.4 Activation of Dendritic Cells 623.8.5 Recruitment of Effector Cells 623.8.6 Cross-Presentation at Mucosal Sites 633.8.7 Improvement of Oral and Nasal Vaccines 633.9 Adjuvants and Vaccine Efficacy in Specific Populations 633.9.1 Infant 643.9.2 Elderly 643.9.3 Immunocompromised Individuals 643.10 Conclusion 653.10.1 Enhanced Vaccine Efficacy 653.10.2 Tailored Immune Responses 663.10.3 Protection in Vulnerable Populations 663.10.4 Reduction in Antigen Doses 663.10.5 Development of Universal Vaccines 663.10.6 Management of Emerging Diseases 663.10.7 Prevention of Epidemics and Pandemics 663.10.8 Public Health Impact 67References 674 Antigen Selection and Design 73Pankti C. Balar, Anjali P. Bedse, Vivek P. Chavda, Chukwuebuka E. Umeyor, Prafull Kolekar, Brian O. Ogbonna, Ankita Anure, Daniel U. Eze, Payal Dodiya and Vandana B. Patravale4.1 Introduction 744.2 Types of Antigens Used in Vaccines 754.2.1 Whole Inactivated Pathogens 754.2.2 Live Attenuated Vaccine 764.2.3 Viral Subunit Vaccines 764.2.4 Conjugate Vaccines 774.2.5 DNA Vaccines 774.2.6 Other Antigen Types 784.2.7 Considerations for Antigen Selection 784.2.7.1 Specificity and Immunogenicity 784.2.7.2 Target Pathogen Life Cycle Stage 794.2.7.3 Safety and Stability 804.3 Antigen Design Strategies 804.3.1 Recombinant Protein Engineering (RPE) 804.3.1.1 Selection of Antigenic Regions 814.3.1.2 Gene Cloning 814.3.1.3 Vector Selection 814.3.1.4 Codon Optimization 814.3.1.5 Fusion Tags 814.3.1.6 Protein Refolding 814.3.1.7 Post-Translational Modifications 824.3.1.8 Structural Stabilization 824.3.1.9 Multimerization 824.3.2 Peptide Optimization 834.3.2.1 Identification of Immunogenic Epitopes 834.3.2.2 Selection of Conserved Regions 834.3.2.3 Length Optimization 834.3.2.4 Modification of Amino Acid Residues 834.3.2.5 Conjugation to Carrier Proteins 834.3.3 Reverse Vaccinology 844.3.3.1 Genome Sequencing 844.3.3.2 General Process Followed for Reverse Vaccinology Platform-Based Modification 844.4 Adjuvants: Mechanism of Action and Types 854.4.1 The Rationale for Using Adjuvants 854.4.2 Mechanisms of Adjuvant Action 864.4.3 Types of Adjuvants 864.4.3.1 Aluminum Salts (Alum) 864.4.3.2 Toll-Like Receptor (TLR) Agonists 874.4.3.3 Saponins 884.4.3.4 Liposomes and Lipid-Based Nanoparticles (LNPs) 884.4.3.5 Polymer-Based Adjuvants 894.5 Novel Formulation Strategies for Improved Vaccine Efficacy 904.5.1 Biological Adjuvants 904.5.2 Biodegradable Polymers 934.5.3 Designer Adjuvants with Specific Immunomodulatory Properties 944.5.4 Adjuvanted Mucosal Vaccines 954.6 Future Directions and Challenges 964.6.1 Personalized Vaccines and Adjuvant Selection 964.6.2 Novel Adjuvant Discovery Platforms 974.6.3 Addressing Safety Concerns of New Adjuvants 974.7 Conclusion 97References 985 Adjuvants in Licensed Vaccines 107Kaushika Patel, Nandita Chawla, Yashvi Mehta and Sachin Patel5.1 Introduction 1085.2 Adjuvants Included in Vaccines 1095.3 Cellular and Molecular Targets for Adjuvant 1105.3.1 Depot Formation at the Injection Site 1115.3.2 Induction and Upregulation of Cytokines and Chemokines 1125.3.3 Antigen Presentation 1125.3.4 Activation and Maturation of DCs 1125.3.5 Activation of Inflammasomes 1135.4 Endogenous Adjuvants in Live Vaccines 1135.4.1 Alum 1145.4.2 Aluminum-Based Adjuvants 1155.4.3 Mf 59 1175.4.4 Combination of Immune Stimulants: Adjuvant System (AS) 1175.4.4.1 AS04 1185.4.4.2 AS03 1185.4.4.3 AS01 1195.4.4.4 AS15 1195.4.5 Cytosine Phosphoguanosine 1018 (CpG 1018) 1205.4.5.1 Saponin-Based Adjuvants 1205.4.5.2 Liposomal Adjuvants 1215.4.6 Adjuvants for Coronavirus Vaccines 1225.4.7 Cancer Vaccine Adjuvants 1235.5 Vaccine Adjuvants in COVID-19 Vaccines 1245.5.1 Reasons and the Advantages of Adjuvant Incorporation Into Vaccines Against COVID- 19 1255.5.2 Current Adjuvanted COVID-19 Vaccines 1255.6 Adjuvant-Related Toxicities 1275.6.1 Adjuvant-Associated Local Toxicity 1275.6.2 Adjuvant-Associated Systemic Toxicity 1275.7 Conclusion 128References 1286 Nanomaterial-Based Vaccine Adjuvants 137Tanvi, Philips Kumar, Rajat Goyal, Kashish Wilson, Hitesh Chopra and Rajeev K. Singla6.1 Introduction 1386.1.1 Unveiling the Essence: Navigating Vaccine Definition and Conceptualizing Vaccines 1386.1.1.1 Nanomaterials as Immune Modulators 1396.1.1.2 Enhancing Efficacy and Safety 1396.1.1.3 Personalized Vaccinology 1396.1.2 Importance in Preventing Infectious Diseases 1406.2 Vaccine Adjuvants and Their Role in Enhancing Immune Responses 1416.2.1 Mechanism of Action 1426.2.2 Types of Adjuvants 1426.2.3 Need for Novel Adjuvants to Improve Vaccine Effectiveness and Safety 1446.3 Overview of Nanotechnology and Introduction to Innovative Applications in Medicines 1456.3.1 Nanomaterials in Vaccines: Enhancing Immunity with Precision 1476.4 Exploring the Nano Realm: Properties and Varied Types of Nanomaterials in Vaccines or Exploring Nanomaterials in Vaccines: Properties, Types, and Implications for Immunization 1486.4.1 Lipid Nanoparticles 1486.4.2 Polymer Nanoparticles 1486.4.3 Nanoparticles 1486.4.4 Nanotubes 1496.5 Engineered Nanomaterials as Vaccine Adjuvants 1496.5.1 Metal and Metal Oxide Based Vaccine Adjuvant 1506.5.1.1 Aluminum-Based Vaccine Adjuvant 1506.5.1.2 Gold Nanoparticles 1506.5.2 Polymeric Nanoparticles 1516.5.2.1 Poly (Lactic-Co-Glycolic Acid) (PLGA) 1516.5.2.2 Poly (γ-Glutamic Acid) (PGA) 1526.5.2.3 Chitosan 1526.5.2.4 Polyethyleneimine (PEI) 1526.5.2.5 pH-Responsive Polymer 1526.5.3 Liposome 1536.5.4 Immune Activation Mechanism by ENMs 1536.6 Challenges in the Development of ENM-Based Adjuvants 1556.7 Mechanism of Action and Data 1566.7.1 Interactions of Nanomaterial-Based Adjuvants with the Immune System for Enhanced Vaccine Response 1576.8 Case Studies: Examples of Nanomaterial-Based Adjuvants 1586.8.1 Nanomaterial-Enhanced Vaccines: Insights from Preclinical and Clinical Studies 1596.8.2 Advantages and Challenges Associated with Each Nanomaterial 1606.9 Design and Development Considerations 1606.9.1 Navigating Nanomaterial-Based Adjuvant Design: Balancing Manufacturing Scalability, Stability, and Regulatory Compliance 1616.9.2 Importance of Balancing Immunostimulants with Safety to Avoid Adverse Reactions 1626.10 Future Perspectives and Challenge 1636.10.1 Advancing Nanomaterial-Based Adjuvants: Pioneering Personalized Vaccines and Synergistic Combination Strategies 1636.10.2 Navigating Nanomaterial-Based Adjuvant Development: Overcoming Toxicity Concerns and Regulatory Challenges 1646.11 Conclusion 165References 1667 Adjuvants for Non-Invasive Routes of Vaccine Delivery 171Shruti U. Rawal, Tosha Pandya, Mangesh Kulkarni, Riya Patel and Anjali Menon7.1 Introduction 1727.2 Vaccine Delivery Through Non-Invasive Routes: Scopes and Challenges 1757.2.1 Mucosal Delivery: Oral, Buccal, Sublingual, Intranasal, Pulmonary, Rectal, and Vaginal Delivery 1777.2.2 Intradermal and Transdermal Delivery 1797.2.3 Ocular Delivery 1807.3 Conventional and Novel Adjuvants 1817.3.1 Conventional Adjuvants 1827.3.2 Novel Adjuvants 1837.3.2.1 Liposomes and Niosomes 1877.3.2.2 Virus-Like Particles (VLPs) and Virosomes 1887.3.2.3 Lipid-Based Nanoparticles 1897.3.2.4 Nanoemulsions (NEs) 1907.3.2.5 Dendrimers 1907.3.2.6 Polymeric Nanoparticles 1917.3.2.7 Miscellaneous Novel Adjuvants 1917.3.3 Recent Novel Adjuvants 1927.3.3.1 Archaeosomes 1927.3.3.2 Proteosomes 1927.3.3.3 Carbonate Apatite Nanoparticles 1937.3.3.4 Hyaluronan Nanocarriers and Laser Adjuvant 1937.3.3.5 Nanoparticles Containing DNA Vaccine pRSC-gD-IL- 21 1947.3.3.6 Glucopyranosyl Lipid A (GLA) as Immune Adjuvant for Respirable HPV-L2 Dry Powder Vaccine 1947.4 Toxicity and Adverse Events 1957.4.1 Systemic Reactogenicity and Reactions 1957.5 Regulatory Approval for Adjuvants and Adjuvanted Vaccines 1967.5.1 Challenges for Safety Evaluation of Adjuvanated Vaccines 2007.5.2 Challenges During Pre-Clinical Phase 2007.6 Prospects 2007.7 Conclusion 201References 2028 Regulatory Guidelines for Vaccine Adjuvants 211Suneetha Vuppu, Vivek P. Chavda, Toshika Mishra, Nikita Sharma and Sathvika Kamaraj8.1 Introduction 2128.2 Vaccine Adjuvants 2148.3 Mechanism of Action 2158.3.1 Formation of Depot for Antigen Protection 2168.3.2 Enhanced Presentation of Antigen 2168.3.3 Modulation of Immune Response 2168.4 Adjuvant Platforms 2198.5 Regulatory Guidelines for Vaccine Adjuvants 2218.5.1 World Health Organization 2238.5.2 Food and Drug Administration 2248.5.3 European Medicines Agency 2258.5.4 Health Canada 2268.5.5 Australian Therapeutic Goods Administration (TGA) 2278.6 Conclusion 227Acknowledgments 227References 2289 Adjuvant and Vaccine Safety 235Shalini Bhattacharya, Jyoti Singh, Rupesh K. Gautam, Nadeem Farooqui, Nimita Manocha and Hitesh Malhotra9.1 Introduction 2359.1.1 Classification of Adjuvants 2379.1.1.1 Aluminum Salts 2379.1.1.2 Liposomal Adjuvants 2389.1.1.3 Emulsion-Based Adjuvants 2389.1.1.4 Virus-Like Particle Adjuvant 2389.1.1.5 Saponin-Based Adjuvant 2399.2 Method and Mechanism of Action 2459.3 Approaches and Perceptions of Adjuvant Safety in Public Health 2479.3.1 Preclinical Safety Evaluation of Adjuvants 2479.3.2 Adjuvants’ Clinical Safety Evaluation 2489.3.2.1 Phase I Clinical Trials 2489.3.2.2 II/III Phase Clinical Trials 2499.3.2.3 Post-Marketing Surveillance 2499.4 Guidelines and Regulatory Considerations 2499.5 Adjuvant Safety Testing With Emerging Technologies 2509.6 Conclusion 251References 25210 Shortcomings of Current Adjuvants and Future Prospects 255Pankti C. Balar, Vasso Apostolopoulos and Vivek P. Chavda10.1 Introduction 25610.2 Limitations 25610.3 Advancements 25710.4 This Book 25910.5 The Future 259References 260Index 263