Vaccinology E-Book

Gregg N. Milligan

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 1083

Veröffentlichungsjahr: 2014

Beschreibung

Vaccinology: An Essential Guide outlines in a clear, practical format the entire vaccine development process, from conceptualization and basic immunological principles through to clinical testing and licensing of vaccines.  With an outstanding introduction to the history and practice of vaccinology, it also guides the reader through the basic science relating to host immune responses to pathogens.

Covering the safety, regulatory, ethical, and economic and geographical issues that drive vaccine development and trials, it also presents vaccine delivery strategies, novel vaccine platforms (including experimental vaccines and pathogens), antigen development and selection, vaccine modelling, and the development of vaccines against emerging pathogens and agents of bioterror. There are also sections devoted to veterinary vaccines and associated regulatory processes.

Vaccinology: An Essential Guide is a perfect tool for designed for undergraduate and graduate microbiologists and immunologists, as well as residents, fellows and trainees of infectious disease and vaccinology. It is also suitable for all those involved in designing and conducting clinical vaccine trials, and is the ideal companion to the larger reference book Vaccinology: Principles and Practice.

Leseprobe

Table of Contents

Title page

Copyright page

Contributors

Preface

1: The History of Vaccine Development and the Diseases Vaccines Prevent

The 18th Century: Vaccines for Smallpox

The 19th Century: New Understanding of Infectious Diseases and Immunity

The 20th Century: The Control of Diseases Using Vaccines

Vaccines

Influenza

Rotavirus Vaccines

Further reading

2: The vaccine Development Pathway

Introduction

Regulation and Approval of Vaccines

Investigational New Drug Application: The “IND”

The Biologics License Application

Further reading

3: Control and Eradication of Human and Animal Diseases by Vaccination

The Control of Diseases by Vaccination

Further reading

4: Pathogenesis of Infectious Diseases and Mechanisms of Immunity

Introduction

Definitions: Colonization, Infection, Disease, Signs, Symptoms

Transmission and Portal of Entry

Routes of Spread in the Body

Target Organs and Cells

Mechanisms of Tissue Injury and Disease

Pathogen Evasion of Host Defenses

Vaccines for Infectious Diseases and Mechanisms of Vaccine-Induced Immunity

Toxin-Mediated Diseases

Diseases for Which Killed Pathogen Vaccines Were Developed

Live Attenuated Pathogen Vaccines

Subunit Vaccines

Further reading

5: The Host Immune Response, Protective Immunity, and Correlates of Protection

Introduction

Induction of Innate Immunity

Bridging Innate and Adaptive Immunity

Development of Adaptive Immune Responses

T Lymphocyte Immunity

B Lymphocyte Immunity

T Cell-Dependent B-Cell Responses

Persistent Production of Vaccine-Specific Antibody and B-cell Memory

T Cell-Independent B-Cell Responses

Mechanisms of Antibody-Mediated Protection

Development of Immunity at Mucosal Sites

Correlates of Protection

Benefits of Identifying a Vaccine Correlate of Protection

Mechanisms of Vaccine-Induced Protection

Further Reading

6: Adjuvants: Making Vaccines Immunogenic

What Is an Adjuvant and Why Are They Added to Certain Vaccines?

Characteristics of a Good Adjuvant

Safety

Types of Vaccine Adjuvants

Combination Adjuvants

Adjuvants for Veterinary Vaccines

Future Challenges

Further reading

7: Discovery and the Basic Science Phase of Vaccine Development

Basic Science and Translational Research

Mechanisms of Disease and Comparative Pathogenesis

Molecular Biology and Recombinant Vaccines

Therapeutic Vaccines and Vaccines Against Noninfectious Agents

Immunology of Protection and Adjuvants

High-Throughput Methods and Systems Biology

Bioinformatics and Reverse Vaccinology

Additional Roles for Basic Science in Vaccine Development

Conclusions

Further reading

8: Microbial-Based and Material-Based Vaccine Delivery Systems

Virus Vectors as Vaccine Platforms

DNA Viruses

RNA Viruses

Other Vaccine Vectors

Bacterial Vectors as Vaccine Platforms

Novel Tuberculosis Vaccines

Novel Delivery Systems

Plant Vectors

Biomaterials: a New Generation of Vaccine Adjuvants and Vaccine Platforms

Strategies for Antigen Encapsulation and Presentation

Strategies for Antigen Delivery

Strategies for Activating Innate Immunity

Conclusions and Future Directions for Biomaterials

Further reading

9: Licensed Vaccines for Humans

Introduction

Immunization Strategies

Specific Vaccine Types

Further reading

10: Veterinary Vaccines

Vaccine Selection for Companion and Food-Producing Animals

Status of Veterinary Vaccines for Infectious and Noninfectious Diseases in Companion and Food-producing Animals

Viruses

Bacteria

Parasites

Fungi

Status of Vaccines for Aquaculture

Future Challenges

Further Reading

11: Development of Vaccines for Microbial Diseases

Introduction

Principles of Vaccine Design

Examples of Vaccine Development and Production

Inactivated Virus Vaccine Development (Yellow Fever)

Animal Models

Good Laboratory Practices

Further Reading

12: The regulatory Path to Vaccine Licensure

Introduction

Regulation of Biologics

The Biological IND

The US FDA CBER IND Review Process

Alternate Licensure Strategies

Environmental Risk Assessment

New Drug Application and Common Technical Document

Worldwide Regulatory Authorities

Further Reading

13: Veterinary Vaccines: Regulations and Impact on Emerging Infectious Diseases

Global Veterinary Vaccine Market

Veterinary versus Human Vaccine Development

Veterinary Vaccine Regulations: an Overview

Veterinary Vaccine Regulations: USA, European Union, and Australia

Animal Testing During Vaccine Development

Impact of Veterinary Vaccines in Public Health

Response of National Authorities to Animal Disease Threats

Future Challenges

Further Reading

14: Vaccine Manufacturing

Introduction

Manufacturing Principles

Analytical Aspects

Good Manufacturing Practices

Future Outlook

Note

Further reading

15: Clinical Evaluation of Vaccines

Introduction

Phases of Clinical Trials

Government Jurisdiction

The Investigational New Drug Process

Good Clinical Practice (GCP)

The Sponsor

The Investigator

Institutional Review Boards and Independent Ethics Committees

Conclusion

Further reading

16: Vaccine Recommendations and Special Populations

What Happens After a Vaccine Is Licensed?

What Are Vaccination Schedules?

Are There Any Exceptions for Certain People (Special Populations)?

Conclusion

Further reading

17: Vaccine Safety

Introduction

Vaccine Safety in Vaccine Development

Vaccine Safety Post-Approval

Causality Assessment

Examples of Vaccine Fears

Communication Perspective in Vaccine Safety

Further reading

18: Understanding and Measuring the Dynamics of Infectious Disease Transmission

Concepts of Infectious Disease Transmission

Measures of Disease Transmission

Introduction to Infectious Disease Modeling

Further Reading

19: Vaccines from a Global Perspective

The Global Perspective

Diseases

Infrastructure

Regulatory

Future Challenges

Further Reading

20: Political, Ethical, Social, and Psychological Aspects of Vaccinology

Introduction

Politics in Vaccinology

Cognitive Biases, Distortions, and Preferred Cognitive Styles in Vaccine Decision Making

Ethical Issues in Vaccination

Further Reading

Index

End User License Agreement

List of Tables

Table 1.1  Vaccine-Preventable Illnesses Before and Since Routine Childhood Vaccination in the USA

Table 1.2  Properties of Infectious Disease Preventive Vaccines

Table 1.3  The Impact of Tetanus Toxoid Among US Soldiers

Table 1.4  Rubella, Netherlands, September 2004–2005.

Table 1.5  Direct and Indirect Effects of 7-Valent Pneumococcal Conjugate Vaccine

Table 4.1  Portals of Entry for Bacterial and Viral Pathogens

Table 4.2  Host Defense Subversion Strategies by Pathogenic Bacteria and Viruses

Table 5.1  Pattern Recognition Receptors

Table 5.2  Characteristics of Human Immunoglobulins

Table 6.1  Examples of Licensed and Developmental Adjuvants

Table 6.2  Utilization of Adjuvants in Vaccines for Veterinary Use

Table 7.1  Potential Roles of Cytokine and Chemokine Adjuvants

Table 7.2  Overview of “-Omics” Technologies

Table 7.3  Commonly Used Bioinformatics/Systems Biology Analysis Software Applications and Databases

Table 9.1  Definitions of Different Types of Vaccines

Table 9.2  Examples of Licensed Vaccines

Table 9.3  Examples of Immunoglobulins Available for Passive Immunization

Table 9.4  Number of Doses and Route of Administration for Commonly Used Vaccines

Table 9.5  Characteristics of an Ideal Vaccine

Table 9.6  Different Types of Vaccines

Table 9.7  Conditions That May Affect Whether or Not to Receive a Live Vaccine

Table 9.8  Examples of Multiple Vaccines Given on the Same Day

Table 9.9  Impact of Childhood Vaccines in the USA in the 20th Century

Table 9.10  Infectious Diseases That Can Be Eradicated…We Have Vaccines

Table 10.1  Partial Listing of Viruses That Are of Global Importance in Veterinary Medicine, Listed by Target Animal

a

Table 10.2  Second- and Third-Generation Licensed/Commercialized Veterinary Viral Vaccines, Listed by Target Animal

Table 10.3  Recently Commercialized Veterinary Bacterial Vaccines, Listed by Target Animal

Table 10.4  Veterinary Protozoal Vaccines, Listed by Target Animal

Table 11.1  Key Considerations for Vaccine Development

Table 11.2  Quality Control Testing of a Viral Vaccine Product from Harvest to Filled Drug Product

Table 11.3  Vaccine Potency Assays with Recommended Human Vaccine Dose

Table 11.4  Examples of Vaccine Manufacturing Processes (Source: Vaccine package insert)

Table 12.1  Environmental Risk Analysis for Release of a Genetically Modified Organism (GMO) Vaccine

Table 13.1  Overview of the Research and Development Phases for a Veterinary Vaccine

a

Table 14.1  Historic Dates and Events Related to Vaccines, Licensing, and Events

Table 14.2  Manufacturing Process and Examples of Vaccines

Table 14.3  Some Definitions in the Manufacturing Process

Table 14.4  Some examples of Assays Used in Quality Control of Vaccines

Table 15.1  Vaccine Clinical Trial Phases

Table 15.2  GCP Sponsor Responsibilities

Table 15.3  GCP Investigator Responsibilities

Table 15.4  Common Mistakes Leading to Noncompliance

Table 15.5  Institutional Review Board Responsibilities

Table 16.1  Factors Considered in Making Universal Vaccine Recommendations

Table 16.2  Typical Travel-Related Vaccines

Table 17.1  Summary of Efficacy Trials of Two Rotavirus Vaccine Candidates

Table 17.2  Summary of Vaccine Safety Trials With an Emphasis on Intussusception, With the Relative Risk of the Condition Following Receipt of the Rotavirus Vaccine Candidate or Control

Table 18.1  Values of

R

0

for Well-Known Infectious Diseases

Table 18.2  Values of the Herd Immunity Threshold for Well-known Infectious Diseases

Table 19.1  Diseases for Vaccine Research and Development

a

Table 19.2  Priority Areas for Research and Development of New or Improved Vaccines

Table 19.3  Characteristics of a Vaccine

Table 19.4  Examples of Combination Vaccines

Table 19.5  Major Diseases Caused by Infectious Agents in 2010

Table 19.6  Components of Vaccine Implementation

Table 19.7  Catalog of Available Immunization Policy Recommendations

Table 20.1  The Basis for Population-Based Vaccination Programs

Table 20.2  Political Issues Relevant to Mass Vaccination

Table 20.3  Stages of Change Applied to Vaccine Decision Making

Table 20.4  The Effect of Ecological Systems on Vaccine Decision Making

Table 20.5  Common Biases and Heuristics Applied to Vaccine Decision Making

Table 20.6  Preferred Cognitive Styles Applied to Vaccine Decision Making

List of Illustrations

Figure 1.1  “Baby” Ruth Cleveland, first child of President and Mrs. Grover Cleveland, who died of diphtheria in 1904, aged 12 years. The former president and the remainder of the family were treated with diphtheria antitoxin and remained symptom free.

Figure 1.2  Cases of diphtheria in the Russian Federation per 100,000 population 1992–2006. The bars demonstrate the immunization coverage rate for children as measured by the Department of Sanitation, Russian Federation. Data provided by Dr. Olga Shamshava, 2007.

Figure 1.3  A 7-day-old infant with neonatal tetanus. Intense spasmodic muscle contractions shown as clenching of the feet (left) and of the facial muscles causing risus sardonicus, literally a “sardonic grin” (right). The child's mother had not previously been immunized. © Martin G. Myers

Figure 1.4  Pertussis attack rate in England and Wales (1940–1982). Reprinted from Cherry JD. (1984). The epidemiology of pertussis and pertussis immunization in the United Kingdom and the United States: a comparative study. Current Probl Pediatr 14(2), 80.

Figure 1.5  One of the last wild-type poliomyelitis cases in the USA, a 12-year-old girl in 1979, shown here with paralysis of her right leg and arm, the “tripod sign” when trying to sit up, and the epidemiologic link, her Amish cap. Poliovirus, type 1, was recovered from her. © Martin G. Myers

Figure 1.6  Serum and secretory antibody responses to orally administered, live attenuated polio vaccine and to intramuscular inoculation of inactivated polio vaccine. From Ogra PL, Fishant M, Gallagher MR (1980). Viral vaccination via mucosal routes. Review of Infectious Diseases 2(3); 352–369.

Figure 1.7  Measles in a boy demonstrating the typical rash of measles. © Martin G. Myers

Figure 1.8  Measles in (A) the USA (Centers for Disease Control and Prevention, 1995) and (B) Iowa (Iowa Department of Health, 2007, www.idph.state.is.us/adper/pdf/cade/decades/pdf) 1960–1989. Measles vaccine was licensed in 1963, and mandatory immunization laws were enacted widely by states in the late 1960s and 1970s. Iowa enacted its immunization law in 1977 (Iowa Administrative Code, 1977). From chapter 17 in Myers & Pineda in Barrett & Stanberry (Elsevier).

Figure 1.9  Newborn with congenial rubella syndrome, including hepatosplenomagly, cataracts, purpura, and microcephaly. © Martin G. Myers

Figure 1.10  Early vesicle formation following VZV infection. © Martin G. Myers

Figure 1.11  Group A streptococcal fasciitis in a previously normal child with varicella. © Martin G. Myers

Figure 1.12  Age-specific incidence of herpes zoster as a function of age. From figure 39.2 in Levin M in Plotkin et al. (eds) Vaccines, 6th edition (with permission from J. Pellissier and M. Brisson, Merck & Co, Inc.).

Figure 1.13  Age-related cellular immune response to varicella zoster virus. From figure 39.3 in Levin M in Plotkin et al (eds) Vaccines, 6th edition. Data from Burke et al.

Figure 1.14  A child with leukemia and herpes zoster with the characteristic distribution of rash in the distribution of a dermatome. © Martin G. Myers

Figure 1.15  The relation of age incidence of influenzal meningitis to the bactericidal power of human blood at different ages against a smooth meningeal strain or

H. influenzae

. From Fothergill LD and Wright J (1933). Journal of Immunology 24, 273–284.

Figure 1.16  Incidence of

Haemophilus influenzae

invasive disease, United States, 1987–1997. From Centers for Disease Control and Prevention. (1998). Progress towards eliminating Haemophilus influenzae Type b disease among infants and children—United States, 1987–1997. Morbidity and Mortality Weekly Report 47(46), 993–998.

Figure 1.17  Incidence of invasive pneumococcal disease (IPD)/100,000 in children younger than 5 years of age. From Centers for Disease Control and Prevention. (2008). Invasive pneumococcal disease in children 5 years after conjugate vaccine introduction—Eight States, 1998–2005. Morbidity and Mortality Weekly Report 57(6), 144–148.

Figure 1.18  Purpura fulminans in a young child with shock due to meningococcal bacteremia. © Martin G. Myers

Figure 1.19  Rate of hepatitis A by county in the USA, 1987–1997 and 2004, per 100,000 population.. From Centers for Disease Control and Prevention. (2006). Prevention of Hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). Morbidity and Mortality Weekly Report 55 (No. RR-7), 1–23.

Figure 1.20  Host (avian, human and swine) origins for the gene segments of the 2009 A(H1N1) virus: PB2, polymerase basic 2; PB1, polymerase basic 1; PA, polymerase acidic; HA, hemagglutinin; NP, nucleoprotein; NA, neuraminidase; M, matrix gene; NS, nonstructural gene. Color of gene segment in circle indicates host. From Garten RJ, Davis CT, Russell CA, et al. (2009). Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans. Science 325(5937), 197–201.

Figure 1.21  Percentage of positive rotavirus tests by week and year: USA 2000–2010. From panel A of figure 1, Tate JE, Mutuc JD, Panozzo CA, et al. (2011). Sustained decline in rotavirus detection in the United States following the introduction of rotavirus vaccine in 2006. Pediatric Infectious Diseases 30; S30–S34.

Figure 1.22  Number of children with mild/moderate and severe rotavirus diarrhea in Aracaju, 2006–2008. From Gurgel RG et al. (2009). Gastroenterology 137:1970–1975.

Figure 2.1  A schematic of the typical phases of vaccine development and approval.

Figure 3.1  Photograph showing a young girl with severe rash characteristic of smallpox. Photograph from James Hicks/ Center for Disease Control and Prevention.

Figure 3.2  Introduction of rinderpest into Africa resulted in a massive pandemic with huge livestock losses due to the disease and associated “stamping-out” policy initiated to stop its spread as shown in this photograph. Photograph from Agricultural Research Council: Onderstepoort Veterinary Institute.

Figure 3.3  This photograph shows people waiting in line to receive polio vaccination in San Antonio, Texas (1962), illustrating the public demand for this vaccine. Photograph from Mr. Stafford Smith/ Centers for Disease Control and Prevention.

Figure 3.4  Slaughtered livestock are burned to prevent spread of foot-and-mouth disease during the outbreak in the United Kingdom in 2001. The large number of uninfected animals slaughtered during recent outbreaks had led to demands for changes in strategy to control outbreaks. Photograph by Murdo Macleod.

Figure 4.1  Portals of entry/shedding for pathogenic microbes.

Figure 4.2  Routes of spread and sites of replication for pathogenic microbes.

Figure 4.3  Inflammation at the site of infection initiated by complement activation.

Figure 4.4  During sepsis bacterial components trigger generation of inflammatory mediators and an inflammatory cascade.

Figure 4.5  Pathogen (direct) and host response (indirect) mediated tissue damage during infection.

Figure 4.6  Primary immune mechanisms against extracellular and intracellular pathogens.

Figure 4.7  Mechanisms of bacterial toxin mediated damage.

Figure 5.1  Primary and secondary immune responses to pathogens or vaccine antigens. Primary exposure of naïve T and B cells to pathogen or vaccine antigen results in a rapid increase in antigen-specific cell number. As the pathogen is cleared, a rapid contraction of the population due to cell death ensues. However, a portion of the antigen-specific population survives and is maintained for long periods of time as memory cells such that an increased frequency of antigen-specific cells is present in secondary lymphoid tissues and peripheral tissues. These populations rapidly expand following reexposure to antigen and are capable of providing protection and rapidly clearing the pathogen from the site of infection.

Figure 5.2  T cell-dependent B-cell responses. Antigen is presented to naïve T cells in the T-cell zone of secondary lymphoid tissue (A). Antigen also binds to the BCR of antigen-specific B cells, which then also migrate to the T-cell zone. Activated T cells provide help to the recently activated B cells (B). The B cells then either produce antibody outside of the B-cell follicle (C) or enter the follicle and cycle between an area of intense B cell proliferation and somatic hypermutation of BCR genes, the Dark zone (D), and an area where antigen selection and class switch occur, the Light zone (E). B cells that successfully compete for antigen depots on follicular dendritic cells and receive survival signals from follicular T cells (F) may undergo further rounds of proliferation and selection or exit the germinal center to become memory B cells (G) or antibody-secreting plasma cells (H).

Figure 5.3  Induction of antibody responses using polysaccharide-protein conjugate vaccines. (A) Cross-linking of BCR on polysaccharide-specific B cell results in activation, proliferation, and production of IgM antibody. In the absence of T-cell help, the class switch to IgG antibody production and differentiation of memory B cells is extremely limited. (B) Conjugation of a protein molecule such as diphtheria toxoid to the polysaccharide results in binding to polysaccharide-specific BCR on the B cell surface, internalization and processing of the toxoid molecule, and presentation on class II MHC molecules. Recognition of the complex by toxoid-specific helper T cells results in delivery of critical co-stimulatory signals (CD40–CD40 ligand) and cytokines necessary for induction of class switch and differentiation of polysaccharide-specific memory B cells.

Figure 5.4  Development and retention of adaptive immune responses in the gut mucosa (A). Macrophages and dendritic cells in the dome region take up antigen that has transcytosed from the gut lumen through M cells and deliver it to the T-cell area of the mucosal associated lymphoid tissue (B). Antigen is presented to T cells, which become activated and migrate to the germinal center (C) and provide help for antigen-specific B cells. Activated, antigen-specific B and T cells migrate to the lymph node (D) and ultimately enter the bloodstream. As these cells circulate and pass through mucosal capillaries in the lamina propria region (E), they bind to the endothelial cells by a mechanism involving a MadCAM-1/α4β7 integrin interaction. T cells may stay in the lamina propria or further migrate to sites between the gut epithelial cells. IgA antibody secreted by lamina propria plasma cells binds to the pIgR on mucosal epithelial cells (F), is internalized, and is transported to the gut lumen.

Figure 6.1  Local events following injection of vaccine formulated with an antigen delivery adjuvant. Antigen depots are deposited at the injection site and are maintained over time, resulting in a prolonged release of free antigen for activation of T and B lymphocytes in the lymph node. Inflammatory events from the injection result in local production of proinflammatory cytokines, which in turn attract tissue monocyte/macrophages or dendritic cells to the injection site. These cells take up and process antigen into antigenic peptides for association with MHC molecules and mature in the presence of the proinflammatory cytokines to express high levels of MHC molecules, co-stimulatory molecules, and the CCR7 molecule required for homing of the cells to the T-cell zone of the lymph node.

Figure 6.2  Local events following injection of antigen-loaded ISCOMs or liposomes. Inflammatory events following the injection result in recruitment of dendritic cells and monocyte/macrophages. Uptake of ISCOMs or liposomes may be accomplished through mechanisms such as phagocytosis, pinocytosis, or fusion with the plasma membrane such that the vehicles are delivered to endosomal or cytoplasmic compartments for degradation and presentation with cellular MHC proteins. Cell maturation events result in homing of the antigen presenting cell to T-cell zones in the lymph node. It is also possible that “free” liposomes or ISCOMs may reach the lymph node via the lymphatic system for activation of B lymphocytes or processing and presentation by lymphoid resident dendritic cells.

Figure 6.3  Immunogenicity of vaccine formulated with an immunostimulatory adjuvant. (A) Immunization with live attenuated vaccine results in maturation of dendritic cells and the production of co-stimulatory molecules (B7), proinflammatory cytokines, and type I IFNs. These cells provide all the antigen and co-stimulatory signals necessary to drive naïve T-cells to proliferate, produce cytokines and express cytotoxic activity and to differentiate into memory T cells. (B) Immunization with purified recombinant protein in the absence of any PAMP does not result in maturation of dendritic cells, and important co-stimulatory and cytokine signals are not provided so that the T-cell response is not maintained and T-cell memory is not induced. (C) Immunization of the same recombinant protein in the presence of an immunostimulatory adjuvant, in this case MPL, results in recognition of the adjuvant by cell-associated PRRs and subsequent maturation of dendritic cells. Again, appropriate cytokine and co-stimulatory signals are provided to drive proliferation of antigen-specific T cells with ultimate differentiation into memory T cells.

Figure 7.1  The “iceberg” of infection.

Figure 7.2  Virus reassortment.

Figure 7.3  Comparative pathogenesis by expression profiling.

Figure 7.4  The classical vaccine development pathway.

Figure 7.5  The reverse vaccinology pathway.

Figure 8.1  (A) Stylized depiction of poxvirus structure (from http://www.utmb.edu/virusimages/ with permission of Frederick Murphy, University of Texas Medical Branch [UTMB], Galveston, Texas). (B) A smallpox virion visualized by negative stain electron microscopy. Magnification about ×150,000. Micrograph from Frederick Murphy, UTMB, Galveston, Texas. (C) Plasmids encoding a vaccinia virus promoter and vaccine gene flanked by regions homologous to the insertion region of MVA genome are transfected into MVA-infected chick embryo fibroblasts. The promoter and vaccine gene are inserted into the MVA genome by homologous recombination. Recombinant MVA virions expressing the protein of interest are selected and plaque purified.

Figure 8.2  (A) Stylized depiction of adenovirus structure (from http://www.utmb.edu/virusimages/ with permission of Frederick Murphy, UTMB). (B) Colorized transmission electron micrograph of adenovirus. Micrograph from Dr. G. William Gary, Jr., Center for Disease Control and Prevention. (C) Genes encoding vaccine antigens can be inserted into expression cassettes located at the sites of adenovirus gene deletion. A first-generation replication defective adenovirus vector with deletions of E1 and E3 genes is shown.

Figure 8.3  (A) Stylized depiction of alphavirus structure (from http://www.utmb.edu/virusimages/ with permission of Frederick Murphy, UTMB). (B) Ultra-thin section of a Vero cell culture infected with Eastern equine encephalitis virus (24-hr infection) (from http://www.utmb.edu/virusimages/ with permission of Frederick Murphy). Magnification approximately ×70,000. Micrograph from F.A. Murphy, UTMB, Galveston, Texas. (C) Vector construction of three types of alphavirus vectors. The small green arrow indicates the site of the subgenomic promoter. (1) Layered DNA–RNA vector. (2) Virus-like particle vector. (3) Replication competent alphavirus vector.

Figure 8.4  (A) Stylized depiction of flavivirus structure (from http://www.utmb.edu/virusimages/ with permission of Frederick Murphy, UTMB, Galveston, Texas). (B) Transmission electron micrograph of dengue virus. Photo taken by Fredrick Murphy and provided by Frederick Murphy and Cynthia Goldsmith, Center for Disease Control and Prevention. (C) Electron micrograph of yellow fever virus (×234,000). Electron micrograph from Erskine Palmer, Center for Disease Control and Prevention. (C) Construction of the ChimeriVax dengue vaccine. The genes for the premembrane (prM) and envelope (E) proteins of yellow fever virus are deleted and replaced with the prM and E genes from dengue1, dengue 2, dengue 3, or dengue 4. Precise amounts of each vaccine virus must be mixed to provide protective immunity against all four dengue serotypes.

Figure 8.5  Examples of carrier outer membrane proteins (Omp or Porin) used to display the passenger amino acid sequence of a foreign antigen.

Figure 8.6  The AIDA-I autotransporter protein used in vaccine design to display the

Y. enterocolitica

heat shock protein Hsp60 (Hsp6074-86).

Figure 8.7  Bacterial ghosts are cell envelopes derived from Gram-negative bacteria devoid of all cytoplasmic content but preserving immunogenic cell surface structures.

Figure 8.8  A simplified view of antigen presentation by dendritic cells. Left, exogenous particles, proteins or pathogens can be taken into the cell through various pathways, including phagocytosis (for particles >1 μm), macropinocytosis (<1 μm), and endocytosis from caveolae (∼60 nm) or clathrin-coated pits (∼120 nm). Exogenous antigens are then processed in endocytic vesicles (phagosomes, endosomes, lysosomes and/or endolysosomes; dashed arrows represent multiple vesicular steps). Processed antigen (peptide) is subsequently loaded onto MHC class II molecules (which have been assembled in the endoplasmic reticulum, transported through the Golgi apparatus and targeted to endocytic compartments) in a lysosome or MHC class II compartment (MIIC). The peptide–MHC class II complexes then move through exocytic vesicles to the cell surface, where antigen presentation occurs. MHC class II loading of endogenous antigen provided by autophagy can also occur, particularly when the cell is under stress. Right, antigen can be loaded onto MHC class I molecules through two main pathways. In the classical pathway, endogenous or viral proteins in the cytosol are processed through the proteasome, transported into the endoplasmic reticulum through the molecule TAP (transporter associated with antigen processing), loaded onto MHC class I molecules, and then transported through the Golgi apparatus and exocytic vesicles to the cell surface for presentation. In addition, exogenous antigens that have been phagocytosed, macropinocytosed, or endocytosed can be cross-presented on MHC class I molecules by some subsets of the dendritic cell. In this pathway, antigen either may be loaded in endocytic compartments (not shown) or may escape endosomes and arrive in the cytosol, where it is processed through the proteasome as usual, loaded onto MHC class I molecules and transported to the surface. Finally, terminal degradation pathways can occur (for example, when apoptotic cells are internalized). Reprinted by permission from Macmillan Publishers Ltd: Hubbell JA, Thomas SN, Swartz MA (2009). Materials engineering for immunomodulation. Nature, 462:449–460.

Figure 9.1  Comparison of the mechanisms associated with different vaccination strategies. Whereas immunization with killed virus elicits mainly antibody-mediated immunity and delivery of conventional DNA vaccines confers primarily cell-mediated immunity, a “split-genome” DNA construct generates single-round infectious particles that generate both humoral and cell-mediated protection almost as potent as the response to a live attenuated virus. Single-round infectious particles eliminate concerns about the safety of infection with live attenuated viruses w, weak response. (From Barrett, AD [2008]. Flavivirus DNA vaccine with a kick. Nature Biotechnology 26, 525–526.)

Figure 9.2  The eight-plasmid reverse-genetics system. Generation of recombinant vaccines for pandemic influenza. (a) Six plasmids encoding the internal proteins of the high-growth influenza A/Puerto Rico/8/34 (PR8) donor virus or the attenuated, cold-adapted (ca) H2N2 A/Ann Arbor/6/60 (AA) donor virus are cotransfected with two plasmids encoding the avian influenza virus haemagglutinin (HA; modified to remove virulence motifs, if necessary) and neuraminidase (NA) glycoproteins into qualified mammalian cells and the recombinant virus is then isolated. Recombinant viruses containing internal protein genes from the PR8 virus are used to prepare inactivated influenza virus vaccines. Recombinant viruses containing internal protein genes from the attenuated, cold-adapted AA virus are used to prepare live attenuated influenza virus vaccines. (b) The generation of pandemic influenza vaccine viruses by classical reassortment. The reassortant viruses derive six internal protein genes from the vaccine donor virus and the HA and NA genes from the circulating avian influenza virus. The reassortant virus is selected using antisera specific for the HA and NA glycoproteins of the donor virus. M, matrix protein; NP, nucleoprotein; NS, nonstructural protein; PA, polymerase acidic protein; PB, polymerase basic protein. (From Subbarao K and Joseph T [2007]. Scientific barriers to developing vaccines against avian influenza viruses. Nature Reviews Immunology 7, 267–278.)

Figure 9.3  Construction of ChimeriVax-based vaccines. Chimeric flaviviruses vaccines are constructed by replacing the genes coding for premembrane (prM) and envelope (E) proteins from yellow fever virus (YFV) 17D-204 vaccine with those of heterologous flaviviruses (dengue [DENV], Japanese encephalitis virus [JEV] or West Nile virus [WNV]). After DNA cloning, RNA is transcribed and transfected into Vero cells to obtain chimeric viruses possessing the YFV 17D replication machinery and the external coat of the relevant heterologous flavivirus.

Figure 9.4  Development of a

Neisseria meningitidis

type B candidate vaccine by reverse vaccinology.

Figure 11.1  Generalized outline indicating the major steps involved in the vaccine research and development pathway.

Figure 11.2  Outline of the sequence of events involved in identification of vaccine antigens, manufacture of the vaccine, and overall clinical investigation plan through licensure of the vaccine with regulatory authorities.

Figure 11.3  Generalized process model for production, purification, and formulation of vaccines in culture initiated by fermentation, purification, characterization, formulation, and regulatory release.

Figure 11.4  Scheme for the purification of a candidate inactivated yellow fever 17D virus vaccine produced in suspension cultures of Vero cells.

Figure 12.1  Drug development process.

Figure 12.2  The Common Technical Document (CTD) triangle. The CTD is organized into five modules. Module 1 is region specific, and modules 2, 3, 4, and 5 are intended to be common for all regions.

Figure 13.1  Charts showing the relative contribution of zoonotic pathogens to human emerging infectious diseases. Emerging infectious diseases are dominated by zoonoses, where the majority of these zoonotic diseases originate from wildlife. Adapted from Jones et al. (2008).

Figure 14.1  Seasonal influenza vaccine manufacturing time line.

Figure 15.1  An overview of the vaccine development time line.

Figure 16.1  The 2014 WHO-recommended immunization chart for routine immunization. This table summarizes the WHO vaccination recommendations. It is designed to assist the development of country-specific schedules and is not intended for direct use by health care workers. Country specific schedules should be based on local epidemiologic, programmatic, resource, and policy considerations. While vaccines are universally recommended, some children may have contraindications to particular vaccines. Refer to http://www.who.int/immunization/documents/positionpapers/ for the footnotes and most recent version of this table. This version was updated February 26, 2014.

Figure 16.2  Recommended immunization schedule for persons aged 0 through 18 years—United States, 2014. This schedule includes recommendations in effect as of January 1, 2014. For those who fall behind or start late, see the catch-up schedule in Figure 16.4. The recommendations must be read along with the footnotes (found at: http://www.cdc.gov/vaccines/schedules/hcp/imz/child-adolescent.html).

Figure 16.3  Recommended Adult Immunization Schedule—United States, 2014. The figure below provides adult vaccination schedules according to age. Always use this table in conjunction with their respective footnotes (found at: http://www.cdc.gov/vaccines/schedules/downloads/adult/adult-schedule.pdf).

Figure 16.4  Catch-up immunization schedule for persons aged 4 months through 18 years who start late or who are more than 1 month behind—United States, 2014. This figure provides catch-up schedules and minimum intervals between doses for children whose vaccinations have been delayed. A vaccine series does not need to be restarted regardless of the time that has elapsed between doses. Use the section appropriate for the child's age. Always use this table in conjunction with the accompanying childhood and adolescent immunization schedule (Figure 16.2) and their respective footnotes (found at: http://www.cdc.gov/vaccines/schedules/downloads/child/0-18yrs-child-combined-schedule.pdf).

Figure 18.1  Epidemiologic triad of disease causation.

Figure 18.2  Natural history of disease.

Figure 18.3  Stages of infection and disease.

Figure 18.4  Schematic of the basic reproductive number.

Figure 18.5  Relationship between herd immunity threshold and

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Guide

Cover

Table of Contents

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Preface

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Library of Congress Cataloging-in-Publication Data

Vaccinology : an essential guide / edited by Gregg N. Milligan, Alan D.T. Barrett.

            p. ; cm.

    Includes bibliographical references and index.

    ISBN 978-0-470-65616-7 (pbk.)

    I.  Milligan, Gregg N., editor.    II.  Barrett, A. D. T. (Alan D. T.), editor.

    [DNLM: 1.  Vaccines–pharmacology.    2.  Vaccines–therapeutic use.    3.  Drug Discovery.    4.  Vaccination.    QW 805]

    RM281

    615.3'72–dc23

                                                                                        2014011447

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Cover design by Andy Meaden

Contributors

A. Paige Adams, DVM, PhD