Mucosal Vaccines: Innovation for Preventing Infectious Diseases

Cover
Mucosal Vaccines: Innovation for Preventing
Infectious Diseases
Copyright
Dedication
List of Contributors
Preface
Part I: Introduction
1 Historical Perspectives on Mucosal Vaccines
	I Introduction
	II Existing Mucosal Vaccines
	III Strategies for Enhancing Mucosal Vaccines
	IV Oral Tolerance
	V Concluding Remarks and Future Perspectives
	References
Part II: Principles of Mucosal Vaccine
2 Anatomical Uniqueness of the Mucosal Immune System (GALT, NALT, iBALT) for the Induction and Regulation of Mucosal Immuni...
	I Introduction
	II Evolutionary Requirement for Mucosal Lymphoid Organs
	III Gut-Associated Lymphoid Tissue
		A Cryptopatches
		B Isolated Lymphoid Follicles
		C Peyer’s Patches, Cecal Patches, and Colonic Patches
	IV Development of Gut-Associated Lymphoid Tissue
	V M Cell Differentiation in Gut-Associated Lymphoid Tissue
	VI Lymphoid Tissues of the Respiratory Tract
		A Nasopharyngeal-Associated Lymphoid Tissue
		B Bronchus-Associated Lymphoid Tissue
	VII Concluding Remarks
	References
3 Mucosal Antigen Sampling Across the Villus Epithelium by Epithelial and Myeloid Cells
	I Introduction
	II Basic Components of the Mucosal Barrier and Lymphoid Tissues
	III Antigen Uptake Across the Villus Epithelium
		A Paracellular and Transcellular Transport Across Villus Epithelial Cells
		B Myeloid Cell Uptake of Antigens and Bacteria in the Lamina Propria
		C Summary and Future Perspectives
	References
4 Protective Activities of Mucosal Antibodies
	I Introduction
	II Properties of Antibodies of Various Ig Isotypes in External Secretions
	III Origin of Antibodies in External Secretions
	IV Protective Effect of Mucosal Antibodies
	V The Role of IgG in Mucosal Immunity
	VI Mechanisms of Protection Mediated by Mucosal IgA Antibodies
		A Inhibition of Antigen Absorption
		B Inhibition of Bacterial Adherence
		C Polyreactivity
		D Ig Glycan–Dependent Reactivity With Microorganisms
		E Neutralization of Biologically Active Antigens
		F Interactions of Mucosal Ig With Innate Antimicrobial Components of Mucosal Defense
	VII Concluding Remarks
	References
	Further Reading
5 Mucosal Immunity for Inflammation: Regulation of Gut-Specific Lymphocyte Migration by Integrins
	I Introduction
	II Molecular Mechanisms for the Recruitment of Circulating Lymphocytes to Tissues
	III Integrin Deactivation as a Regulatory Mechanism for Efficient Cell Migration
	IV Interstitial Migration
	V Immunological Synapse
	VI Imprinting of Homing Specificity by Dendritic Cells
	VII Integrin α4β7–MAdCAM-1 Interactions
	VIII Therapeutic Integrin Inhibition for Inflammatory Bowel Diseases
	IX Iatrogenic and Genetic Immune-Deficiencies Involving Integrins
	X Therapeutic Integrin Inhibition for HIV Infection
	References
6 Innate Immunity at Mucosal Surfaces
	I Introduction
	II Innate Mucosal Barriers in the Gut
		A Structures of the Mucosal Barriers
		B Innate Barrier Dysfunction and Disease Pathogenesis
	III Innate Immune Regulation in the Gut
		A Pattern Recognition Receptors
		B Associations Between Individual TLRs and Intestinal Inflammation
		C Association Between CLRs and Intestinal Inflammation
		D Association Between RLRs and Intestinal Inflammation
		E Association Between NLRs and Intestinal Inflammation
	IV Concluding Remarks
	References
7 Induction and Regulation of Mucosal Memory B Cell Responses
	I Introduction
	II Mucosal Vaccine Induction of Memory B Cells
	III The Inductive Site for Gut Memory B Cell Responses Is the Peyer’s Patches
	IV A Model System to Study Mucosal Memory B Cell Development
	V The Germinal Center Reaction in Peripheral Lymph Nodes and Peyer’s Patches
	VI Respiratory Tract Infections and Mucosal Memory B Cells
	VII Mucosal Memory B Cells and Homing Markers
	VIII Are Mucosal Memory B Cells Sessile or Recirculating?
	IX Memory B Cells Show Poor Clonal Relatedness to Long-Lived Plasma Cells Following Oral Priming Immunizations
	X Considerations for Mucosal Subcomponent Vaccine Development
	XI Concluding Remarks
	References
8 Induction and Regulation of Mucosal Memory T Cell Responses
	I Introduction
	II Mucosal Compartmentalization That Causes Inflammatory Responses in the Airway
		A Preference of Tissue-Resident Memory T Cells for Mucosal Tissues
		B Presence of Heterogenic Memory Th2 Cells in Different Mucosal Organs
		C Epithelial Cytokines as Key Mediators for Mucosal Immune Responses: IL-25, IL-33, and TSLP
		D Innate and Adaptive Immunity Involvement in IL-33-Induced Inflammation at Mucosal Sites
	III Mucosal Inflammation and Inducible Bronchus-Associated Lymphoid Tissue
		A Induction of Inducible Bronchus-Associated Lymphoid Tissue During Inflammation at Mucosal Tissue Sites
		B Maintenance of Memory T Cells Within the Inducible Bronchus-Associated Lymphoid Tissue in the Mucosal Site
	IV Model of Disease Induction by Tpath Cells
	V Concluding Remarks
	References
9 Influence of Commensal Microbiota and Metabolite for Mucosal Immunity
	I Introduction
	II Microbiota
	III Mucosal Immunity
		A Gut Microbiota and Mucosal Immunity
			1 Gut Mucosal Surface
			2 Cell-Mediated Immunity
			3 Humoral Immunity
		B Microbiota and Extraintestinal Immunity
			1 Oral Immunity
			2 Respiratory Tract Immunity
			3 Other Mucosal Immune Sites
	IV Skin Immunity
	V Microbiota and Vaccines
	VI Concluding Remarks
	Financial Support
	References
Part III: Mucosal Modulations for Induction of Effective Immunity
10 Innate Immunity-Based Mucosal Modulators and Adjuvants
	I Introduction
	II Innate Immune System Activators as Adjuvants for Mucosally Administered Subunit Vaccines
	III Cytokines as Mucosal Vaccine Adjuvants
		A Interferon Alpha
		B Interleukin-1 Family
	IV Nanoemulsions as Mucosal Vaccine Adjuvants
	V Mast-Cell-Activating Compounds With Adjuvant Activity
		A Compound 48/80
		B Other Mast Cell Activators With Mucosal Adjuvant Activity
	VI Cationic Polyethyleneimine Used as a Mucosal Vaccine Adjuvant
	VII Mucosal Adjuvant Activity of Toll-Like Receptor Ligands
		A CpG Mucosal Adjuvant and Modulator Activity
		B Monophosphoryl Lipid A Mucosal Adjuvant and Modulator Activity
	VIII Concluding Remarks and Future Perspective
	References
11 Toxin-Based Modulators for Regulation of Mucosal Immune Responses
	I Introduction
	II Toxins Used For Modulation of Immune Responses
	III Toxin-Derivative Adjuvants for Mucosal Vaccines
		A ADP-Ribosylation of Defective Mutants of Cholera Toxin and Labile Toxin
		B Other Cholera Toxin and Labile Toxin Derivatives
		C Derivatives of Other Toxin Adjuvant
		D Delivery Systems for Toxin-Based Adjuvant
	IV Innate Mechanisms Regulated by Toxin-Based Adjuvants for Induction of Mucosal Immunity
	V Induction of Tolerance by Toxin-Based Adjuvants
	VI Concluding Remarks and Future Perspectives
	References
12 Influence of Dietary Components and Commensal Bacteria on the Control of Mucosal Immunity
	I Introduction
	II Vitamins
		A Vitamin A
		B Vitamin B Complex
			1 Vitamin B1
			2 Vitamin B3
			3 Vitamin B9
		C Vitamin D
	III Lipids
	IV Commensal Bacteria and Their Metabolites
	V Concluding Remarks
	References
13 Mast Cells for the Control of Mucosal Immunity
	I Introduction
	II Exocytosis of Biologically Active Modulators
	III Peripheral Location
	IV Multipronged Activation at Infection Sites
		A Direct Recognition of Pathogens or Their Products
		B Indirect Recognition of Pathogens
		C Activation by Endogenous Danger Signals
	V Initiation of Local Innate Immune Responses
		A Direct Bactericidal Activity
		B Proteolytic Degradation of Toxins
		C Induction of Immune Cell Trafficking to Sites of Infection
	VI Contributions to Adaptive Immune Responses
		A Enhancing Influx of Immune Cells Into Draining Lymph Nodes
		B Antigen Presentation
		C Effectors of Adaptive Immunity
		D Adjuvant Activity of Mast Cell Activators and Products
	VII Dysregulated or Impaired Mast Cell Activity During Infection
	VIII Concluding Remarks and Future Perspectives
	References
14 Innate Lymphoid Cells for the Control of Mucosal Immunity
	I Introduction
	II Innate Lymphoid Cell Development and Tissue Heterogeneity
	III Organizing and Initiating Innate Lymphoid Cell–Dependent Barrier Immunity
		A Cellular Regulation of Mucosal ILCs
		B. Enteric Nervous System Regulates Mucosal Innate Lymphoid Cells
		C Microbial and Metabolic Regulation of Mucosal Innate Lymphoid Cells
	IV Mucosal Innate Lymphoid Cells in Pathogen Defense
	V Innate Lymphoid Cells in Mucosal Tissue Repair
	VI Innate Lymphoid Cells in Allergy, Autoimmunity, and Persistent Inflammation
	VII Cross-Regulation of Innate and Adaptive Immunity by Mucosal Innate Lymphoid Cells
	VIII Concluding Remarks
	References
15 Mucosal Regulatory System for Balanced Immunity in the Gut
	I Introduction
	II Induction of Intestinal Immune Tolerance by CD103+ Dendritic Cells
	III Regulation of Immune Homeostasis by Intestinal Resident CX3CR1high Macrophages
	IV Roles of Human Intestinal Myeloid Cells in the Maintenance of Gut Homeostasis and Inflammatory Bowel Disease
	V Concluding Remarks
	References
16 Regulation of Mucosal Immunity in the Genital Tract: Balancing Reproduction and Protective Immunity
	I Introduction
	II Immunology of the Female Genital Tract
		A Innate Immune Cells in the Upper Female Genital Tract
		B Adaptive Immune Cells in the Upper Female Genital Tract
		C Innate Immune Cells in the Lower Female Genital Tract
		D Adaptive Immune Cells in the Lower Female Genital Tract
		E Soluble Mediators in the Female Genital Tract
		F Toll-Like Receptor Expression in the Female Genital Tract
		G Hormone Effects on Genital Tract Infections
		H Contraceptive-Driven Susceptibility to Sexually Transmitted Diseases in the Female Genital Tract
		I Hormone Receptors and Signaling
	III Immunology of the Male Reproductive Tract
	IV Chlamydia
		A Pathogenesis of C. trachomatis Genital Tract Infections
		B Natural Immunity and Vaccines
		C Protective Immunity Against Chlamydia
		D Choice of Antigen
		E Adjuvant Selection and Route of Immunization
	V Chlamydia as a Gastrointestinal Commensal: The Elephant in the Room?
	VI Genital Herpes
		A HSV-2 Vaccine Development
		B Future Perspectives
	VII Concluding Remarks and Future Perspectives
	VIII Key Points
	References
17 Mucosal Regulatory System for Balanced Ocular Immunity
	I Introduction
	II Organization of the Ocular Surface Mucosa
	III Immunology of the Ocular Surface Mucosa
	IV Targets and Strategies for Vaccine Development
		A Common Ocular Pathogens
		B Strategies for Ocular Vaccine Development
	References
	Further Reading
18 Mucosal Regulatory System for the Balanced Immunity in the Middle Ear and Nasopharynx
	I Introduction
	II Innate and Acquired Immunity of Middle Ear and Nasopharynx
		A Distribution of Toll-Like Receptors in Human Epithelial Cells in the Middle Ear and Changes That Result From the Ensuing ...
		B Distribution of Toll-Like Receptors in Human Epithelial Cells in Nasopharyngeal Mucosae and Its Modification of Type I Al...
	III Immunomodulation of Middle Ear and Nasopharyngeal Mucosae and Its Clinical Impact
	IV Innovative Immunotherapy for Attenuating Nasal Symptoms of Cedar Pollinosis via the Mucosal Route With Transgenic Rice S...
	V Concluding Remarks and Future Perspectives
	References
Part IV: Current and New Approaches for Mucosal Vaccine Delivery
19 Current and New Approaches for Mucosal Vaccine Delivery
	I Introduction
	II Nano/Microscale Carriers as Promising Delivery Tools for Vaccines
	III Mucosal Vaccine Delivery: Past, Present and Future
		A Oral Vaccine Delivery
			1 Advantages and Limitations of Oral Vaccines
			2 Oral Vaccine Delivery Systems
				a Emulsions and Micelles
	IV Liposomes
	V Immunostimulating Complexes
	VI Virus-Like Particles
	VII Polymeric Particle-Based Oral Delivery
	VIII Oral Delivery of Vaccines Using Food Materials
		A Tablets and Capsules
		B Nasal Vaccine Delivery
			1 Advantages and Limitations of Nasal Vaccines
			2 Nasal Vaccine Delivery Systems
				a Nanoemulsions
	IX Liposomes
	X Chitosan
	XI Starch Nanoparticles
	XII Polymer Nanoparticles
	XIII Nanogels
	XIV Concluding Remarks and Future Perspectives
	References
	Further Reading
20 Plant-Based Mucosal Vaccine Delivery Systems
	I Introduction
	II Transgenic Technologies for Vaccine Production in Plants
		A Biolistic Method for Stable Transformation
		B Agrobacterium-Mediated Transformation
		C MucoRice System
	III Plant-Based Vaccines for the Prevention and Control of Infectious Diseases
		A Enterotoxigenic Escherichia coli
		B Norovirus
		C Hepatitis B Virus
		D Rabies
		E Influenza Virus
		F Diarrhea Caused by Vibrio cholerae
	IV Concluding Remarks
	References
21 Plant-Based Mucosal Immunotherapy: Challenges for Commercialization
	I INTRODUCTION
	II Advances in Developing Plant-Based Mucosal Immunotherapy Products: A Quarter of a Century Later
	III A Lack of Recent Human Clinical Trials Testing the Safety and/or Efficacy of Plant-Based Mucosal Immunotherapy
	IV Cost of Production for Plant-Based Mucosal Immunotherapeutics: Is This a Realistic Advantage?
	V Infrastructure and Protocols for Plant-Based Mucosal Immunotherapeutic Manufacturing
	VI Regulatory Approval for Plant-Based Mucosal Immunotherapy
	VII Safety of Plant-Made Biologics and Plant-Specific Glycosylation
	VIII Mucosal Tolerance Therapy Using Plant-Made Proteins
	IX Global Contamination From Food-Crop-Made Vaccines or Tolerogens
	X Safety of Consumable Formulations From Food-Crop-Made Vaccines or Tolerogens
	XI Separating Expression From Finishing the Product Geographically and Over Extended Periods of Time Using Seed-Based Platforms
	XII Plant-Based Mucosal Immunotherapy: Challenges for Commercialization
	References
22 Attenuated Salmonella for Oral Immunization
	I Introduction
	II Approaches for Attenuation
		A Serial passage
		B Deletion mutants
		C Mutations in Salmonellapathogenicity islands
		D Vectoring guest antigens
		E Antigen delivery —location
		F Regulated delayed attenuation
		G Regulated delayed antigen synthesis
		H Regulated delayed vaccine lysis
		I Strategies for reducing lipid A toxicity
		J Sugar-inducible acid resistance
		K Modification of fimbriae
	III Vaccines against nontyphoidal Salmonella
	IV Concluding remarks
	References
23 Recombinant Bacillus Calmette-Guérin for Mucosal Immunity
	I Introduction
	II Oral Immunization
		A Mycobacterium tuberculosis
		B HIV
	III Intravesical Immunotherapy
		A Bladder Cancer
	IV Stimulation of Pulmonary Immune Responses
		A Tuberculosis
		B Coccidiosis, Schistosoma, and Borrelia
	References
	Further Reading
24 Recombinant Adenovirus Vectors as Mucosal Vaccines
	I Introduction
	II Adenoviruses
	III Immune Responses to Adenoviruses
	IV Types of Adenovirus Vectors
	V Construction, Purification, and Titration of Adenovirus Vectors
	VI Quality Control of Adenovirus Vectors
	VII Thermostability of Adenovirus Vectors
	VIII Immunogenicity of Adenovirus Vectors
	IX The Mucosal Immune System
	X Mucosal Vaccines
	XI Adenovirus Vectors as Oral Vaccines
	XII Adenovirus Vectors as Intranasal Vaccines
	XIII Immunizations Through the Rectal or Genital Mucosa
	XIV Use of Adjuvants for Mucosal Adenovirus Vector Vaccines
	XV Concluding Remarks and Future Perspectives
	References
25 Mucosal Approaches for Systemic Immunity to Anthrax, Brucellosis, and Plague
	I Introduction
	II Origins of Vaccination
	III Anthrax
		A The Disease and Historical Perspective
		B Development of First Anthrax Vaccines
		C Live Vaccines for Anthrax
	IV Brucellosis
		A Etiological Agents and Disease
		B Protection to Brucella Infections Is Th1 Cell-Dependent
		C Current Vaccines
		D Mucosal Vaccination Approaches for Brucellosis
	V Plague
		A The Disease and Historical Perspective
		B Antibody-Dependence for Immune Protection to Plague
		C Th1- and Th17-Mediated Immunity Against Plague
		D Attempt to Develop Plague Mucosal Vaccine
	References
26 Nanodelivery Vehicles for Mucosal Vaccines
	I Introduction
	II Characteristics of the Nasal Immune System
		A Structure and Function of Nasopharyngeal-Associated Lymphoid Tissue
		B Mechanism for the Induction of Antigen-Specific Nasal Immune Responses
		C Lymphocyte Imprinting and Homing Mechanisms in the Nasal Immune System
	III Drug-Delivery Systems for Nasal Vaccines
	IV cCHP Nanogel as a Drug-Delivery System for Nasal Vaccines
	V Development of a Nanogel-Based Nasal Vaccine Against Pneumonia
	VI Application of cCHP Nasal Vaccines Against Noninfectious Diseases
	VII Concluding Remarks and Future Perspectives
	Abbreviations
	References
27 Effectiveness of Sublingual Immunization: Innovation for Preventing Infectious Diseases
	I Introduction
	II Localization of Antigen-Presenting Cells in the Sublingual Mucosa
	III Role of Draining Lymph Nodes in Sublingual Vaccination
	IV Mechanism for Induction of CD4+ T Cell Activation Following Sublingual Vaccination
	V Sublingual Vaccination Induces Both Systemic and Mucosal Antibody Responses
	VI Sublingual Administration Is Useful for Induction of Antibody Against Viral Infection
	VII Sublingual Administration Does Not Redirect Antigens to the Central Nervous System
	VIII Sublingual Vaccination Induces T and B Cell Activation in Female Mouse Genital Tissues
	IX Concluding Remarks and Future Perspectives
	References
28 M Cell-Targeted Vaccines
	I Introduction
	II M Cell Differentiation
	III Candidate Molecules for M Cell Targeting and Their Ligands
		A α(1,2)-Linked Fucose
		B GP2
		C PrPC
		D Integrins
		E Uromodulin (Umod)
		F C5aR
		G Claudin 4
		H Secretory IgA (SIgA) Receptors
		I α2-3-Linked Sialic Acid
	IV Contribution of M Cells for the Development of Oral Tolerance
	V Enhancement of M Cell Number and Function
	VI Concluding Remarks and Future Perspectives
	References
Part V: Mucosal Vaccines for Bacterial Diseases
29 Induction of Local and Systemic Immunity by Salmonella Typhi in Humans
	I Introduction
	II Current Vaccines and Models to Study Immunogenicity to Salmonella Typhi
	III Live Attenuated Oral Vaccine and Human Challenge Model of Typhoid Fever
	IV Systemic T Cell Immunity Induced by Oral Salmonella Typhi
	V Humoral and Systemic B Cell Immunity Induced by Oral Salmonella Typhi
	VI Changes in Innate and Mucosal-Associate Invariant T Cells Induced by Oral Salmonella Typhi
	VII Gut-Homing Memory T Cells: A Window Into Mucosal Immunity
	VIII Accumulation and Retention of Gut-Homing Memory T Cells in the Mucosa
	IX Mucosal Immunity to Salmonella Typhi
	X Relationship Between Systemic and Mucosal Immunity to Salmonella Typhi
	XI Concluding Remarks
	References
30 Oral Shigella Vaccines
	I Introduction
	II Shigella Infection: Burden of Disease and Vulnerable Groups
	III Shigella Pathogenesis and Virulence Factors
	IV Naturally Acquired Immunity Against Shigella
	V Immune Responses to Shigella in Children
	VI Animal Models of Mucosal Shigella Infection
	VII History of Oral Shigella Vaccine Candidates
	VIII Immunity Induced by Oral Shigella Vaccines
	IX Multivalent Oral Shigella Vaccines
		A Shigella–Typhoid
		B Escherichia coli–Shigella
		C Shigella–ETEC
	X Parenteral Shigella Vaccine Candidates
	XI An Ideal Oral Shigella Vaccine: Features and Implementation
	XII Concluding Remarks
	References
31 Cholera Immunity and Development and Use of Oral Cholera Vaccines for Disease Control
	I Introduction
	II Susceptibility and Innate Immunity in Cholera
	III Oral Cholera Vaccines
	IV Adaptive Mucosal Immune Responses in Cholera
		A Mucosal IgA Antibody and Antibody-Secreting Cell Responses
		B Intestine-Derived Gut-Homing Circulating Antibody-Secreting Cells
		C Intestinal Mucosal T Cells
	V Systemic Antibody and Memory B Cell Responses
		A Vibriocidal Antibody Responses
		B Serum Antibody Responses to Defined Antigens
			1 IgA Responses
			2 IgG Responses
			3 Immunoglobulin M
		C Memory B Cell Responses in Cholera
	VI Modifiers of Immune Responses
	VII Public Health Use of Oral Cholera Vaccines
	VIII WHO Recommendations and a “Global RoadMap to End Cholera by 2030”
	IX Concluding Remarks and Future Perspectives
	References
32 Oral Vaccines for Enterotoxigenic Escherichia coli
	I Introduction
	II Enterotoxigenic Escherichia coli Vaccine Candidates
		A Fimbrial Antigens and Heat-Labile Enterotoxin Are Major Protective Antigens
			1 Studies in Animals
			2 Studies in Humans
		B Structure of the Major Putative Protective Enterotoxigenic Escherichia coli Antigens: Colonization Factor Antigens and En...
			1 Colonization Factors
			2 Heat-Labile Enterotoxin (LT)
			3 ST Heat-Stable enterotoxin
			4 O Antigens
	III Evaluation of Optimal Administration Routes of an Enterotoxigenic Escherichia coli Vaccine
		A Passive Protection Trials in Humans to Get Proof of Concept
		B Candidate Vaccines in Preclinical Phase
			1 Recombinant Attenuated Bacteria
			2 Purified Antigens
		C Multiepitope Protein Antigens
	IV Oral Mucosal Adjuvants
	V Methods for Assessing Mucosal Immune Responses Against Enterotoxigenic Escherichia coli Candidate Vaccines in Humans
	VI Candidate Vaccines in Clinical Development
		A ACE527
		B Tip Adhesins
		C LT patch
		D Oral Inactivated Whole Cell Enterotoxigenic Escherichia coli Vaccines
			1 rCTB-CF Enterotoxigenic Escherichia coli Vaccine
			2 Multivalent ETEC vaccine(ETVAX)
	VII Concluding Remarks
		A Preclinical Vaccine Candidates
		B Vaccine Candidates in Clinical Development
	References
33 A Future for a Vaccine Against the Cancer-Inducing Bacterium Helicobacter pylori?
	I Introduction
	II The Therapeutic Tool Box of Helicobacter pylori Infections
	III The Unheeded Role of Epithelial Cells in the Execution of Mucosal Defense
	IV Vaccines as Stimulators of Mucosal Immunity
	V Natural Immunity Against Helicobacter pylori
	VI The Failure of Past Vaccination Attempts
	VII Unmasking Helicobacter pylori’s Immune Evasion Strategy
	VIII Concluding Remarks and Future Perspectives
	References
34 Mucosal Vaccines for Streptococcus pneumoniae
	I Introduction
	II Host Immune Responses to Pneumococci During Nasopharyngeal Colonization
		A The Role of Innate Immunity Against Pneumococci
		B The Role of Acquired Immunity Against Pneumococci
	III Immunization Against Streptococcus pneumoniae at Mucosal Surfaces
	IV Current and Future Status of Human Mucosal Vaccine Trials
	V Concluding Remarks
	References
35 Development of a Mucosal TB Vaccine Using Human Parainfluenza Type 2 Virus
	I Introduction
	II Mucosal Immune Responses in TB Infection
	III Vaccine Delivery Systems for Induction of Mucosal Immunity
	IV Novel Vaccine Candidate, rHPIV2, in TB Protection
	V Protective Effects of an rHPIV2 Vaccine in Mice With TB
	VI Possibilities of rHPIV2 as a Next-Generation Vaccine Candidate
	VII Future Study Using the HPIV2 Vaccine
	Abbreviations
	References
36 Sexually Transmitted Infections and the Urgent Need for Vaccines: A Review of Four Major Bacterial STI Pathogens
	I Introduction
	II Chlamydia
		A Microbiology
		B Clinical Manifestations
		C Epidemiology
		D Current Treatment Options
		E Immune Responses Associated With Pathology
		F Vaccine-Related Research
		G Preclinical Vaccine Studies and Vaccine Trials in Progress
		H Challenges to the Development of a Vaccine
	III Gonorrhea
		A Microbiology
		B Clinical Manifestations
		C Epidemiology
		D Current Treatment Options
		E Immune Responses Associated With Pathology
		F Vaccine-Related Research
		G Future Vaccine Implications
	IV Syphilis
		A Microbiology
		B Epidemiology
		C Clinical Manifestations
		D Current Treatment Options
		E Immune Responses Associated With Pathology
		F Vaccine-Related Research
		G Conclusions
	V Mycoplasma
		A Microbiology
		B Epidemiology
		C Clinical Manifestations
		D Current Treatment Options
		E Immune Responses Associated With Pathology
		F Vaccination Research
		G Conclusions
	VI Concluding Remarks
	References
37 Mucosal Vaccines for Oral Disease
	I Introduction
	II Mucosal Vaccines for Caries Prevention
	III Mucosal Vaccines for Periodontal Disease
	IV Protein Based Mucosal Vaccine
	V DNA-Based Vaccine
	VI Nasal Administration of Periodontal Vaccine
	VII Sublingual Vaccine for Periodontal Diseases
	VIII Concluding Remarks
	References
Part VI: Mucosal Vaccines for Viral Diseases
38 Vaccination Against Respiratory Syncytial Virus
	I Introduction
	II Global Impact and Clinical Disease
	III Correlates of Protection
	IV Maternal Immunization to Protect Vulnerable Infants
	V RSV Immunity and Vaccination in Infants and Young Children
	VI RSV Immunity and Vaccination in Older Adults
	VII Concluding Remarks
	References
39 Nasal Influenza Vaccines
	I Introduction
	II Humoral Immune Responses to Influenza Virus Infection
	III Development of the Nasal Influenza Vaccines
		A Live Attenuated Influenza Vaccines
		B Intranasal Inactivated Influenza Vaccines
	References
40 The Role of Innate Immunity in Regulating Rotavirus Replication, Pathogenesis, and Host Range Restriction and the Implic...
	I Introduction
	II Host Innate Immune Sensors and Rotavirus Infection
		A Cytoplasmic Sensors
		B Membrane-Associated Sensors
		C Other Sensors
	III Host Innate Responses to Rotavirus and Their Effects on Viral Replication
	IV Regulation of the Interferon Induction Pathway by Rotavirus
		A Regulation of the Interferon Signaling Pathway by Rotavirus
		B Regulation of STAT1 by Rotavirus
		C Degradation of Different Types of Interferon Receptors
		D STAT1 Sequestration in the Cytoplasm
		E Regulation of IRF7 and IRF9
		F Rotavirus Regulation of Other Effector Antiviral Factors
	V Taking Advantage of Rotavirus Host Range Restriction to Reliably Attenuate Live Rotavirus Vaccine Candidates
	References
41 Development of Oral Rotavirus and Norovirus Vaccines
	I Introduction
	II Rotavirus Vaccine Development
		A Rotavirus Disease
		B Rotavirus Classification
		C Initial Vaccine Efforts Using Live Animal Rotavirus
		D RotaShield, the First Licensed Rotavirus Vaccine
		E RotaTeq and Rotarix, the Second Generation of Licensed Rotavirus Vaccines
		F Other Nationally Licensed Rotavirus Vaccines
		G Remaining Obstacles to Rotavirus Vaccination and Future Directions
	III Norovirus Vaccine Development
		A Norovirus Disease
		B Norovirus Structure
		C Norovirus Classification
		D Challenges in Norovirus Vaccine Development
		E Virus-Like Particle-Based Norovirus Vaccines
		F Alternative Norovirus Vaccines in the Pipeline
		G Future Directions in Norovirus Vaccine Development
	IV Concluding Remarks
	References
42 Mucosal Vaccines Against HIV/SIV Infection
	I Introduction
	II Mucosal Vaccines Inducing HIV-Specific Antibody Responses
		A Characterization of Anti-HIV Neutralizing Antibodies to Design a Mucosal HIV Vaccine
		B Passive Anti-HIV Antibody Administration as a Model of Mucosal Vaccines
		C Antibody-Related Correlates in HIV Vaccine Clinical Trials
		D Analysis of Mucosal Tissues and Ab Effector Function for Vaccine Design
	III Mucosal Vaccines Inducing HIV-Specific T Cell Responses
		A Mucosal HIV Infection in the Acute Phase Toward Systemic Infection
		B Viral Vectors for Mucosal Anti-HIV T Cell Responses
		C Mucosal T Cell Responses Effective Against HIV Infection
	References
43 Mucosal Vaccines for Genital Herpes
	I Introduction
	II HSV-1 and HSV-2 Virus Life Cycle
	III Pathogenesis of Genital Herpes
	IV Symptoms of Genital Herpes
	V Immune Protective Mechanisms Against HSV Infections
		A Innate Immune Response to HSV Infections
		B Protective Memory Responses Against Genital Herpes Infection
			1 Antibody-Mediated Protection
			2 T Cell-Mediated Protection
	VI Vaccine Approaches Against Genital Herpes
		A Past Prophylactic Vaccine Trials
		B Mucosal Vaccines Against HSV-2
			1 Intravaginal HSV-2 Vaccines
			2 Intranasal Vaccines
	VII Future Strategies for HSV-2 Vaccine
	VIII Concluding Remarks and Future Perspectives
	References
44 Maternal Vaccination for Protection Against Maternal and Infant Bacterial and Viral Pathogens
	I Introduction
	II Diphtheria, Pertussis, and Tetanus
	III Influenza Virus
	IV Measles, Mumps, and Rubella
	V The Next Frontier of Maternal Vaccines
		A Respiratory Syncytial Virus
		B Human Immunodeficiency Virus
		C Human Cytomegalovirus
		D Herpes Simplex Virus
		E Zika Virus
		F Group B Streptococcus
	VI Concluding Remarks
	VII Summary of Key Points
	Funding
	References
Part VII: New and Novel Approaches for Mucosal Vaccine Development
45 Systems Biological Approaches for Mucosal Vaccine Development
	I Introduction
	II Systems Vaccinology
		A Proof of Concept: Studies With the Yellow Fever Vaccine YF-17D
		B Extending Systems Vaccinology to Other Vaccines
		C Are Molecular Signatures of Immunogenicity Versus Efficacy the Same?
		D Beyond Blood: Systems Analysis of Gene Signatures in Lymphoid and Nonlymphoid Tissues
		E From Data to Knowledge to Understanding
	III Systems Biology of Vaccines Against Mucosal Infections
		Challenge 1: Discovering Correlates of Protection
			1 Controlled Human Infection Models
			2 Can Signatures in the Blood Predict Mucosal Immunity?
		Challenge 2: Discovering Fundamental Immunological Mechanisms of Mucosal Immunity
			1 How Can Vaccines and Adjuvants Imprint Mucosal Homing of Antigen-Specific T and B Cells?
			2 How do Antibodies Protect Against Infection at Mucosal Sites?
			3 What Roles Do T Cells Play in Protection Against Infection at Mucosal Sites?
		Challenge 3: How Can the Durability of Mucosal Responses Be Enhanced?
		Challenge 4: Understanding the Basis of Population Differences in the Efficacy of Mucosal Vaccines
	IV Concluding Remarks
	References
46 Harnessing γδ T Cells as Natural Immune Modulators
	I Introduction
	II γδ T Cell Surface Receptors
	III Similarities of γδ T Cells to Myeloid and Macrophage Cells
	IV γδ T Cell-Mediated Cytotoxicity
	V γδ T Cell Cytokine Production
	VI Role of γδ  T Cells in Infectious Diseases
	VII Therapeutic Potential for Manipulation of γδ T Cells
	VIII Plant Polyphenols for the Activation of γδ T Cells
		A Plant Polysaccharides as γδ T Cell-Targeted Immunomodulator
		B Microbial Products for the Regulation of γδ T Cells
	IX Concluding Remarks
	Abbreviations
	References
47 Mucosal Vaccines for Aged: Challenges and Struggles in Immunosenescence
	I Introduction
	II Age-Associated Changes in the Gastrointestinal Tract Immune System
	III Potential Mechanisms in Gut Aging: Roles of M Cells
	IV Involvement of Mucosal CD4+ T Cells in Gut Aging
	V The Intestinal Microbiota Potentially Shapes Mucosal Immunosenescence
	VI Rejuvenation of Gut Immunity by Mesenchymal Stem Cell Transfer
	VII Nasopharygeal-Associated Lymphoid Tissue Versus Gut-Associated Lymphoid Tissue: Similarities and Gaps
	VIII Distinct Aging Process of Nasopharygeal-Associated Lymphoid Tissue Function
	IX Mucosal Vaccines and Therapies Fight for Immunosenescence
	X A Dentritic Cell-Targeting Mucosal Vaccines for Aged
	XI Next Generation of Potent Mucosal Vaccines for the Elderly
	References
Part VIII: Can Mucosal Vaccines be Applied to Other Infectious and Noninfectious Diseases?
48 Mucosal Vaccine Development for Veterinary and Aquatic Diseases
	I INTRODUCTION
		A Considerations for Mucosal Veterinary Vaccine
			1 Mass Delivery
			2 Differentiation of Infected From Vaccinated Animals Vaccines
			3 Economics and Trade
	II Exploration of Commercial and Experimental Mucosal Veterinary Vaccines
		A Mucosal Vaccines for Livestock
			1 Suidae
				a Porcine transmissible gastroenteriditis and porcine epidemic diarrhea virus
			2 Caprinae and Ovidae
				a Brucella ovis
			3 Bovinae
				a Bovine herpesvirus 1
				b Hemorrhagic septicemia
				c Bovine viral diarrhea virus
			4 Avian Species
				A Avian influenza
		B Companion Animals
			1 Leporidae
				a Rabbit hemmorrhagic disease
		C Wildlife
			1 Koala
				a Chlamydia pecorum
			2 Prairie Dogs
				a Plague
			3 Multispecies
				a Rabies
		D Mucosal Aquatic Vaccines
			1 Immersion Vaccines
			2 Oral and Intranasal Vaccines
			3 Injected Vaccine
		E Immunocontraceptive Vaccines
			1 Efficacy, Safety, and Economic Feasibility of Immunocontraceptive Vaccines
		F Mucosal Vaccines to Improve Fertility
	III Veterinary Vaccines and One Health
	IV Concluding Remarks
	References
49 Mucosal Vaccine for Malaria
	I Introduction
	II Malaria’s Effect on the Gastrointestinal System
	III Gastrointestinal system’s effect on malaria: a role for gut microbiata?
	IV Mucosal Vaccines Against Malaria
	V Concluding Remarks
	References
50 Mucosal Vaccine for Parasitic Infections
	I Introduction
	II Protozoan Infections
		A Amoebiasis
		B Giardiasis
		C Cryptosporidiosis
		D Toxoplasmosis
	III Helminth Infections
		A Schistosomiasis (Trematodiasis)
		B Cysticercosis (Cestodiasis)
		C Echinococcosis (Cestodiasis)
		D Trichinellosis (Nematodiasis)
	IV Concluding Remarks
	References
51 Mucosal Vaccines for Allergy and Tolerance
	I Introduction
	II Immunotherapy
		A Hypoallergenic Antigens
		B Anti-IgE
		C Adjuvants and Delivery
		D DNA Vaccines
	III Microbiota
	IV Concluding Remarks
	References
52 Novel Strategies for Targeting the Control of Mucosal Inflammation
	I Introduction
	II For Every Action, There Is an Equal and Opposite Reaction
	III Key Features of the Host Response in Homeostasis
	IV Microbial Communities, Microbial Pathogenesis, and Dysbiosis
	V The Concept of a Homeostatic Scar and Immunological Dysfunction
	VI The Impact of Immunization on Homeostasis
		A Passive Immunization
		B Active Immunization
	VII Future Perspectives
	VIII Concluding Remarks
	References
Index
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