Immunopotentiators in Modern Vaccines

Immunopotentiators in Modern Vaccines, Second Edition, provides in-depth insights and overviews of the most successful adjuvants, those that have been included in licensed products, also covering the most promising technologies that have emerged in recent years. In contrast to existing books on the subject, the chapters here provide summaries of key data on the mechanisms of action of the individual vaccine adjuvants.

In addition, the book covers key aspects of how the technologies might be further developed and what might be their limitations, while also giving an overview of what made the most advanced adjuvant technologies successful.

• Provides contributions from leading international authorities in the field
• Features immunopotentiators classified by function, with well-illustrated, informative figures presenting the interaction between the immunopotentiators and the host immune system
• Lists advantages and potential hurdles for achieving a practical application for each specific immunopotentiator
• Offers US FDA perspectives which highlight how future adjuvants will be approved for new generation vaccines

Immunologists, virologists, microbiologists, oncologists, neuroscientists, and academics working in vaccinology. professionals and academics working in vaccinology who want up-to-date information about the mechanisms of modern immunopotentiators and their potential use in future rational vaccine design, decision makers and researchers in the field of vaccinology, policy makers, registration officers, marketing managers and students in the biomedical field

Chapter 1. Vaccine Adjuvants' Mode of Action: Unraveling ‘‘the Immunologist's Dirty Little Secret”

• Introduction
• Adjuvants Provide Start Signals for Immune Reactivity and Guide the Response to an Acceptable Magnitude
• Regulation of Immune Responses by Antigen Delivery (Signal 1)
• Facilitation of Signal 1
• Regulation of Signal 2
• Facilitation of Signal 2
• Release of Immune Brakes
• Signal 3: Regulating the Quality of Induced Immune Pathways and Immunity
• Facilitation of Signal 3
• Outlook

Chapter 2. The Role of Inflammasomes in Adjuvant-Driven Humoral and Cellular Immune Responses

• Introduction

Chapter 3. Dendritic Cells as Targets of Vaccines and Adjuvants

• Introduction
• General Characteristics of Dendritic Cells
• Dendritic Cells and T-Cell Activation
• The Role of Dendritic Cells in Prophylactic Vaccination
• The Role of Dendritic Cells in Therapeutic Vaccination
• Conclusions

Chapter 4. Host-Derived Cytokines and Chemokines as Vaccine Adjuvants

• Introduction
• Interleukin-1
• Interleukin-2
• Interleukin-6
• Interleukin-12
• Granulocyte-Macrophage Colony-Stimulating Factor
• Chemokines
• Interferon
• Concluding Remarks

Chapter 5. Discovery of Immune Potentiators as Vaccine Adjuvants

• Introduction
• Mode of Action of Empirically Derived Adjuvants: Aluminum Salts and Oil-In-Water Emulsions
• Pattern Recognition Receptor Agonists as Vaccine Immune Potentiators
• Toll-Like Receptors
• NOD-Like Receptors
• Combination of Immune Potentiators and Delivery Systems
• Small Molecule Immune Potentiators as New Adjuvants
• Design of Adjuvants Targeting Toll-Like Receptors
• Concluding Remarks

Chapter 6. Current Status of Toll-Like Receptor 4 Ligand Vaccine Adjuvants

• Introduction
• History
• Development Status of Clinical Toll-Like Receptor 4 Ligands
• Development Status of Selected Preclinical Toll-Like Receptor 4 Ligands
• Physicochemical Characterization
• Future Outlook

Chapter 7. Flagellins as Adjuvants of Vaccines

• List of Abbreviations
• Flagellins Are the Main Component of Bacterial Flagella
• Flagellin Is Recognized by Innate Receptors
• TLR5 Signaling Triggers the Transient Production of Immune Mediators by Myeloid and Epithelial Cells
• Direct Activation of Dendritic Cells by Flagellin
• Flagellin Also Activates Dendritic Cells by Indirect Signaling Through Structural Cells
• Flagellin Is a Potent Adjuvant for Vaccination
• Flagellin Potentiates Innate Antiinfectious and Tissue Repair Immune Effectors
• Concluding Remarks

Chapter 8. Toll-Like Receptor 7 and 8 Agonists for Vaccine Adjuvant Use

• Introduction
• Cellular Expression of Toll-Like Receptors 7 and 8 and Cross-Species Expression
• Toll-Like Receptor 7/8 Ligands
• Adjuvant Action of Toll-Like Receptor 7/8 Agonists
• Topical Application of Toll-Like Receptor 7/8 Agonists for Use as Vaccine Adjuvants
• Approaches to Optimizing Toll-Like Receptor 7/8 Adjuvant Effects
• Use of Toll-Like Receptor 7/8 Agonists in Combination With Other Adjuvants
• Conclusions

Chapter 9. CpG Oligodeoxynucleotides as Adjuvants for Clinical Use

• Toll-Like Receptor Agonists as Vaccine Adjuvants
• CpG Oligodeoxynucleotides
• A Brief History of CpG DNA and Toll-Like Receptor 9
• Recognition of CpG Motifs
• The Signaling Pathway Utilized by Toll-Like Receptor 9
• TLR9 Expression by B Cells and Plasmacytoid Dendritic Cells
• Classes of CpG Oligodeoxynucleotides
• Next-Generation CpG Oligodeoxynucleotides
• CpG Oligodeoxynucleotides as Adjuvants for Vaccines Targeting Infectious Pathogens
• CpG Oligodeoxynucleotide–Adjuvanted Hepatitis B Virus Vaccine, HEPLISAV
• CpG Oligodeoxynucleotide–Adjuvanted Anthrax Vaccine, NuThrax
• CpG Oligodeoxynucleotide–Adjuvanted Malaria Vaccines
• CpG Oligodeoxynucleotide–Adjuvanted Influenza Vaccines
• CpG Oligodeoxynucleotides as Stand-Alone Therapy for Infection
• CpG Oligodeoxynucleotides as Adjuvants for Vaccines Targeting Allergy
• CpG Oligodeoxynucleotides Coupled to Ragweed Allergen
• QbG10 Coadministration With Allergen
• QbG10 Without Allergen
• CpG Oligodeoxynucleotides as Adjuvants for Vaccines Targeting Cancer
• CpG Oligodeoxynucleotides in Cancer Immunotherapy
• CpG Oligodeoxynucleotides in Cancer Monotherapy
• CpG Oligodeoxynucleotides and Chemotherapy for Cancer
• CpG Oligodeoxynucleotides and Radiation Therapy for Cancer
• CpG Oligodeoxynucleotides and Therapeutic Monoclonal Antibodies for Cancer
• Adverse Events in Clinical Trials
• Limitations to the Interpretation of Clinical Data Involving CpG Oligodeoxynucleotides
• Conclusion and Perspectives

Chapter 10. Advax Adjuvant: A Potent and Safe Immunopotentiator Composed of Delta Inulin

• Delta Inulin Background
• Manufacture of Delta Inulin
• Advax-Adjuvanted Hepatitis B Vaccine
• Advax-Adjuvanted Influenza Vaccines
• Other Advax-Adjuvanted Vaccines
• Mechanism of Action
• Preclinical Safety and Toxicology
• Conclusions

Chapter 11. Natural Vaccine Adjuvants and Immunopotentiators Derived From Plants, Fungi, Marine Organisms, and Insects

• Introduction
• Plant-Derived Immunopotentiators
• Potential Adjuvants Derived From Fungi
• Marine Organism–Derived Immunopotentiators
• Insect-Derived Immunopotentiators
• Challenges Faced With Natural Product Research
• Methods Used for Screening Vaccine Adjuvants From Natural Products
• Conclusions

Chapter 12. Polymeric Particles as Vaccine Delivery Systems

• Introduction
• Use of PLG for Drug Delivery
• Use of PLG for Vaccine Delivery
• Conclusions

Chapter 13. MF59: A Safe and Potent Adjuvant for Human Use

• Introduction
• Initial Development of MF59 Adjuvant
• Composition of MF59
• Manufacturing of MF59
• The Mechanism of Action of MF59
• MF59 Safety Profile
• MF59-Adjuvanted Influenza Vaccine
• MF59 With Other Noninfluenza Vaccines
• Future Perspectives on the Use of MF59

Chapter 14. The Development of the Adjuvant System AS01: A Combination of Two Immunostimulants MPL and QS-21 in Liposomes

• Introduction
• AS01 Formulation Development
• Rational for AS01 Selection
• Clinical Experience
• AS01 Mode of Action
• Regulatory Considerations
• Conclusions

Chapter 15. Development and Evaluation of AS04, a Novel and Improved Adjuvant System Containing 3-O-Desacyl-4′- Monophosphoryl Lipid A and Aluminum Salt

• Introduction
• AS04 Adjuvant System
• AS04 Formulation Process
• 3-O-Desacyl-4′- Monophosphoryl Lipid A Dose Selection
• Safety Aspects of Adjuvants for Use in Vaccines
• Examples of AS04-Based Vaccines
• Summary

Chapter 16. ISCOMATRIX Adjuvant in the Development of Prophylactic and Therapeutic Vaccines

• Introduction
• Induction of T-Cell Responses by ISCOMATRIX Vaccines
• Induction of Antibody Responses by ISCOMATRIX Vaccines
• ISCOMATRIX Adjuvant Promotes Antigen Dose Sparing
• Clinical Studies Involving ISCOMATRIX Vaccines
• Use of ISCOMATRIX Adjuvant in Infectious Disease Vaccine Development
• Evaluation for Use in Hepatitis B Vaccine
• Evaluation for Use in Human Immunodeficiency Virus Vaccines
• Evaluation for Use in Rabies Vaccines
• Evaluation for Use in Dengue Vaccines
• Evaluation for Use in Respiratory Syncitial Virus Vaccines
• Evaluation for Use in Pandemic Influenza Vaccines
• Evaluation for Use in Herpes Simplex Virus 2 Vaccines
• Evaluation for Bacterial and Parasitic Vaccines
• Combining ISCOMATRIX Adjuvant With Other Immune Stimulators for Cancer Therapy
• Conclusion

Chapter 17. Development and Evaluation of CAF01

• Introduction
• CAF01 Adjuvant Formulation
• Preclinical Immunogenicity Assessment
• Safety Evaluation
• Clinical Immunogenicity Assessment
• Adjuvant Mechanism
• Combination With Other Adjuvants
• Future Perspectives

Chapter 18. Mineral Adjuvants

• Introduction
• Preparation and Crystalline Structure of Mineral Adjuvants
• Application of Mineral Adjuvants
• Vaccine Stability and Metallic Ions
• Dosing Mineral Adjuvants
• Mechanisms of Adjuvant Activity
• In Vivo Clearing of Aluminum and Calcium Adjuvants
• Side Effect Profile of Mineral Adjuvants
• Concluding Remarks

Chapter 19. Toxin-Based Mucosal Adjuvants

• Preface
• Cholera Toxin and Attempts to Separate Toxicity From Adjuvant Functions
• Efforts to Develop Safe and Potent LT-Based Mucosal Adjuvants for Human Use
• Pertussis Toxin–Derived Adjuvants
• Rational Design of Novel CT-Based Adjuvants With Maintained ADP-Ribosylating Property
• Concluding Remarks

Chapter 20. Adjuvants for Skin Vaccination

• Introduction
• Skin as a Vaccination Site
• Routes of Skin Vaccination
• Adjuvants for Skin Immunization
• Skin Adjuvants in Clinical Trials
• Conclusions

Chapter 21. Vaccination to Treat Noninfectious Diseases: Surveying the Opportunities

• Introduction
• The Immune System
• Induction of an Immune Response by Vaccination: General Considerations
• Adjuvants in Immunotherapy Based on Induction of Antibodies
• Potential and Actual Problems With Active Vaccination
• Adjuvants to Stimulate T-Cell Immunity
• Adjuvants and Vaccines to Enhance Innate Immunity
• Adjuvants and Vaccines Based on Humoral Immunity
• Adjuvants and Vaccine Strategies to Enhance the Immunogenicity of Tumor Antigens
• Vaccination Against Allergies
• Summary and Conclusions

Chapter 22. A Framework for Evaluating Nonclinical Safety of Novel Adjuvants and Adjuvanted Preventive Vaccines

• Introduction
• Current Status of Relevant, Global Regulatory Guidance and Initiatives
• Foundation of a Good Preclinical Safety Package
• Adjuvants, Adjuvanted Vaccines, and the Potential for Immune-Mediated Disease
• Conclusions

Conclusions—“Getting Better”