Development of Vaccines E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 938

Veröffentlichungsjahr: 2011

Beschreibung

Development of Vaccines: From Discovery to Clinical Testing outlines the critical steps, and analytical tools and techniques, needed to take a vaccine from discovery through a successful clinical trial. Contributions from leading experts in the critical areas of vaccine expression, purification, formulation, pre-clinical testing and regulatory submissions make this book an authoritative collection of issues, challenges and solutions for progressing a biologic drug formulation from its early stage of discovery into its final clinical testing. A section with details and real-life experiences of toxicology testing and regulatory filing for vaccines is also included.

Leseprobe

Table of Contents

Title Page

Copyright

Preface

Contributors

Part 1: Immunogen Design

Chapter 1: Microbial vaccine design: the Reverse Vaccinology approach

1.1 Introduction

1.2 Historical View of “Classical” Vaccinology

1.3 Reverse Vaccinology

1.4 Vaccine Design: From Conventional Vaccinology to the Postgenomic Era Through Reverse Vaccinology

1.5 Conclusions

References

Chapter 2: Design and Development of Recombinant Vaccines with Viral Properties

2.1 Introduction

2.2 Viral Properties and Immune Responses

2.3 Translating Immunogenic Viral Properties into Rationally Designed Vaccines

2.4 Conclusion

References

Chapter 3: Tools for Vaccine Design: Prediction and Validation of Highly Immunogenic and Conserved Class II Epitopes and Development of Epitope-driven Vaccines

3.1 Introduction

3.2 Applying Immunoinformatics Tools to the Problem of Vaccine Design

3.3 Epitope-Driven Approach to Vaccine Development

3.4 Vaccine Design Tools

3.5 Immunogenic Consensus Sequence (ICS) Vaccines

3.6 ICS Protein-Based Vaccines

3.7 Potential Pitfalls: Advantages and Disadvantages of IDV

References

Part 2: Vaccine Platforms

Chapter 4: Virus-Like Particle Vaccines: Advantages and Challenges

4.1 Introduction

4.2 Human Papillomavirus

4.3 HIV/AIDS

4.4 Norovirus

4.5 Influenza

4.6 Flaviviruses

4.7 Rift Valley Fever Virus

4.8 Conclusions

References

Chapter 5: Design platforms of nanocapsules for human therapeutics or vaccines

5.1 Application of Virus-Like Particles for Vaccination

5.2 Innate and Adaptive Cellular Immune Responses Against Virus-Like Particles

5.3 Tailoring Virus-Like Particles by Altering the Capsid Surface for Vaccine Development

5.4 Use of Fluorescent-Labeled Virus-Like Particles to Isolate Rotavirus-Specific B-Cell Clones for Human Monoclonal Antibody Production

5.5 VLP Application as a Delivery Carrier

5.6 Conclusion

References

Chapter 6: Designing Immunogens for Vaccine Development in reference to HIV

6.1 Summary

6.2 Introduction

6.3 HIV-1 Neutralizing Antibodies

6.4 Challenges in Inducing Broadly Neutralizing Antibodies

6.5 Current Strategies in Designing Immunogens to Induce Broadly Neutralizing Antibodies

References

Chapter 7: Expression and Purification of Recombinant Proteins for Vaccine Applications

7.1 Protein Expression

7.2 Prokaryotic Protein Expression Systems and Expression Vectors

7.3 Escherichiacoli( E. Coli )

7.4 Autoinduction

7.5 Eukaryotic Expression Systems Yeasts

7.6 Insect Cells

7.7 Mammalian Cells

7.8 Baby Hamster Kidney (BHK) Cells

7.9 Human Cells

7.10 Cell-Free Expression Systems

7.11 Protein Refolding

7.12 Protein Purification

References

Chapter 8: DNA Vaccines for infectious diesase

8.1 Introduction

8.2 Humoral Immune Responses

8.3 Cytotoxic T-Cell Responses

8.4 Protection by DNA Vaccines in Preclinical Disease Models

8.5 Vector and Gene Optimization

8.6 Adjuvants for DNA Vaccines

8.7 Immunostimulatory Activity of DNA Vaccines

8.8 DNA Vaccine Delivery Systems

8.9 Physical Methods

8.10 Particle-Mediated Delivery of DNA Vaccines

8.11 Use of Live Viral and Bacterial Vectors for Vaccine Delivery

8.12 Summary

References

Chapter 9: Developing Stable Cell Lines for the Production of Vaccine Antigens

9.1 Introduction

9.2 Background, Methods, and Approaches—CHO Cell Recombinant Proteins

9.3 Generation of Stable Cell Lines for the Production of Replication-Defective Viral Vaccines

9.4 Conclusions

References

Part 3: Characterization of Immunogens

Chapter 10: Spectroscopy of Vaccines

10.1 Introduction

10.2 Spectroscopic Analyses

10.3 Circular Dichroism

10.4 Fourier Transform Infrared Spectroscopy

10.5 Raman Spectroscopy

10.6 Tertiary Structure

10.7 Ultraviolet/Visible Absorption Spectroscopy

10.8 Fluorescence Spectroscopy

10.9 Other Methods to Detect Changes in Tertiary Structures

10.10 Measurement of Dynamic Aspects of Vaccine Structure

10.11 Analysis of Spectral Data

10.12 Spectroscopy in the Presence of Adjuvants

10.13 New Spectroscopic Approaches

10.14 Conclusions

References

Chapter 11: Biophysical Characterization of Protein Antigens within Vaccine Formulations

11.1 Introduction

11.2 Chromatography-Based Methods

11.3 Light-Based Methods

11.4 Differential Scanning Calorimetry

11.5 X-Ray Powder Diffractometry

11.6 Summary

References

Part 4: Formulation Optimization and Stability Evaluation

Chapter 12: Structural characteristics predict the stability of HIV

12.1 Introduction

12.2 Results

12.3 Discussion

12.4 Materials and Methods

12.5 Circular Dichroism

12.6 HPLC CD4 Binding Assay

12.7 Differential Scanning Calorimetric Analysis of Proteins

12.8 Hydrodynamic Radius Measurement

12.9 Surface Plasmon Resonance Assay

References

Chapter 13: Selection of optimal adjuvants and product factors that affect vaccine immunogenicity

13.1 Introduction

13.2 Vaccine-Induced Immunological Responses

13.3 Aluminum Salts

13.4 Nonaluminum Adjuvants

13.5 Other Product-Related Factors

13.6 Summary

References

Chapter 14: Lyophilization and Stabilization of Vaccines

14.1 Introduction

14.2 Lyophilization Process

14.3 Examples of Progress in Creating Lyophilized Vaccines

14.4 Current Research and Future Trends in Vaccine Lyophilization and Stabilization

14.5 Conclusions

References

Chapter 15: Effect of buffers and stabilizers on Vaccine stability and efficacy

15.1 Mechanisms of Stabilization of Vaccines by Buffers/Stabilizers

15.2 Effect of Excipients on Vaccine Efficacy

15.3 Surfactant Effects

15.4 Antioxidant Effects

15.5 Preservative Effects

15.6 Sugars

15.7 Amino and Nucleic Acids

15.8 Chelating Agent

15.9 Polymeric Zwitterionic Buffers

15.10 Abbreviations

References

Part 5: Clinical and Manufacturing Issues

Chapter 16: Selection of Final Product Containers

16.1 Introduction

16.2 Container Systems

16.3 Guidance and Recommendations from Industry and Regulatory Agencies

16.4 Container Design and Selection

16.5 Critical to Quality Attributes of the Product

16.6 Prescreening or Developmental Studies

16.7 Quality Throughout the Process

16.8 Container System Components, Suppliers, and the Raw Material Network

16.9 Container Development and Integrity Evaluation

References

Chapter 17: From the Lab to the Clinic: Filing a Phase I IND for an Investigational Vaccine

17.1 Introduction

17.2 The Pre-IND Meeting

17.3 Request Letter for a Pre-IND Meeting

17.4 Pre-IND Meeting Package (Background Package)

17.5 Conduct of the Pre-IND Meeting

17.6 Filing the IND

17.7 General Investigational Plan

17.8 Investigator's Brochure

17.9 Chemistry, Manufacturing, and Control (CMC) Information

17.10 Pharmacology and Toxicology Information

17.11 Other Information

17.12 After Filing the IND

Index

Color Plates

Copyright © 2010 by John Wiley & Sons, Inc. All rights reserved.

Published by John Wiley & Sons, Inc., Hoboken, New Jersey.

Published simultaneously in Canada.

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Library of Congress Cataloging-in-Publication Data:

Development of vaccines : from discovery to clinical testing / edited by Manmohan Singh, Indresh K. Srivasta.

p. ; cm.

Includes bibliographical references and index.

ISBN 978-0-470-25637-4 (cloth)

1. Vaccines. 2. Drug development. 3. Drug stability. I. Manmohan Singh, 1964 Nov. 8- II. Srivasta, Indresh K.

[DNLM: 1. Vaccines–pharmacology. 2. Drug Discovery–methods. 3. Drug Stability. QW 805] QR189.D48 2011

615'.372–dc22

2010048282

Preface

Rapid advances have been made in the last two decades toward understanding the disease biology and developing preventive and therapeutic vaccines against infectious and parasitic diseases, cancer, allergies, fertility and immune disorders by both academia and the pharmaceutical industry. The journey has been punctuated by successes and challenges. But there is hope that with development of new technologies and better understanding of the disease biology, most if not all debilitating diseases will be prevented, or at the very least, cure serious infectious diseases, reduce pain and suffering of mankind, and improve the quality of life.

For development of a successful vaccine, we need to: 1. identify a target, 2. design an immunogen, 3. develop strategies for expression and purification of the immunogen in an appropriate structure and conformation, and 4. select an adjuvant and delivery system for inducing long-lasting T and B cell immune responses. Each of these aspects is critical for the successful development of a vaccine, and has its own challenges. This book provides conceptual ideas, case studies, and examples to understand these challenges and how to address them.

Immunogen design could be a rate-limiting step in the development of vaccines. Significant technological advances have been made in identification and design of novel immunogens through the genome sequencing of pathogens and identification of a plethora of antigens through reverse vaccinology. Similarly, advances in crystallization techniques have allowed for availability of structural information for viral and bacterial immunogen used to rational design of vaccines.

Once an immunogen has been identified/designed, then the next big question is: How do we use these immunogen(s) for inducing appropriate immune responses? Several platforms could be used to induce a potent immune response, such as DNA delivery, recombinant protein, VLP, and vector. Many variables exist within each platform, for example in the recombinant subunit vaccine platform, the challenges are to select which system to use for the expression of proteins or VLPs, and how to purify them efficiently and in correct conformation. Each of these platforms has its own advantages and challenges, and not every platform may be relevant or appropriate for every target; therefore platform selection for vaccine development needs to be clearly thought through. The success or failure of a vaccine depends on the quality of the immune responses induced and, to a certain extent, the quality of the immune response is platform dependent. Combination of different platforms, also known as prime-boost regimen, allows overcoming some of these challenges and broadening immune responses. This concept is more effective for difficult targets, such as HIV.

Another aspect critical for vaccine development is characterization of vaccines; better characterization increases the possibility of inducing better responses. In addition to immunogen, an integral component of a successful and effective vaccine is adjuvant. It is important to mention that to-date, aluminum mineral salts remain the most common adjuvant approved for use in vaccine products in humans. Apart from its safety profile, use had expanded due to the lack of availability of a suitable alternative. However, over the last few years, awareness about how some of these vaccine adjuvants work has led to a dramatic increase of focus in this area. Whether it is through activation of the innate immune responses or delivery to the targeted site, these novel adjuvant formulations can now be more well-characterized and optimized for their function. Formulations can now be designed to induce both cellular and humoral responses. Local responses in nasal and oral routes can now be generated using selective mucosal adjuvants. Evaluation of synergistic effects and repeated use are also being explored. However these new technologies will have to demonstrate a safety profile that is acceptable for mass immunization and prophylactic use. After a vaccine is designed, expressed, purified, characterized, and formulated, vialing the vaccine is not a trivial task and does involve significant efforts in selecting appropriate vials, quality control, and final fill-finish of the vaccine for clinical evaluation. The final step in the Phase I clinical evaluation of a prototype vaccine is regulatory compliance and filing the IND.

This book covers all the critical aspects for developing a successful vaccine, and highlights some of emerging vaccine technologies which will be a part of licensed products in the future. The book provides in-depth evaluation of all factors that govern the induction of an optimal immune response. Chapters on immunogen design, such as reverse vaccinology, and structure-based rational design of vaccines provide conceptual insights and application of concepts and tools for immunogen design. Chapters on vaccine technology platforms are organized to provide in-depth review of each platform, and its application for production and purification of immunogens. Chapters on vaccine characterization summarize beautifully the available technologies for characterizing vaccines and their applications.

Adjuvant history, antigen presentation, mechanism of action, and safety profile build a sound base for addressing some specific vaccine formulation issues. Detailed descriptions of all leading vaccine technologies with their limitations should greatly help researchers and students enhance their understanding of these technologies, and how to apply them for developing successful vaccines. The book also has chapters on clinical and nonclinical safety evaluation of vaccine formulations, which serve as a guideline for moving vaccines from research to clinic. Overall, the book highlights the most recent and up-to-date advances in the field of vaccines development.

Manmohan Singh

Indresh K. Srivastava

Contributors

SHIREESH P. APTE, Mansfield, Texas

MATTHEW ARDITO, Epivax, Inc., Providence, Rhode Island

MARTIN F. BACHMANN, Cytos Biotechnology AG, Zürich-Schlieren, Switzerland

LUIS BAEZ, Amgen, Thousand Oaks, California

SUSAN BARNETT, Novartis Vaccines, Cambridge Massachusetts

MICHÈLE A. BAROCCHI, Novartis Vaccines, Siena, Italy

NITIN BHARDWAJ, University of Pittsburgh, Pittsburgh, Pennsylvania

ZOHAR BIRON-SOREK, Weizmann Institute of Science, Rehovot, Israel

EMILY BRAUNSTEIN, Pfizer Vaccines Research, Pearl River, New York

R. HOLLAND CHENG, University of California at Davis, Davis, California

JAMES CHESKO, Infectious Disease Research Institute, Seattle, Washington

ANNE S. DE GROOT, Epivax, Inc., Providence, Rhode Island

JOE DESROSIERS, Epivax, Inc., Providence, Rhode Island

ADRIAN DISTLER, Amgen, Thousand Oaks, California

TIM DUTILL, Infectious Disease Research Institute, Seattle, Washington

HERMANCIA S. EUGENE, University of Pittsburgh, Pittsburgh, Pennsylvania

JEANNE FLANDEZ, Novartis Vaccines, Cambridge, Massachusetts

CHRIS FOX, Infectious Disease Research Institute, Seattle, Washington

MICHAEL FRANTI, Novartis Vaccines, Cambridge, Massachusetts

BRENDAN M. GILES, University of Pittsburgh, Pittsburgh, Pennsylvania

HIROSHI HANDA, National Institute of Infectious Diseases, Tokyo, Japan

SANGEETA B. JOSHI, University of Kansas, Lawrence, Kansas

NARENDER KALYAN, Pfizer Vaccines Research, Pearl River, New York

ELAINE KAN, Novartis Vaccines and Diagnostics, Emeryville, California

AEMRO KASSA, Novartis Vaccines, Cambridge, Massachusetts

MASAAKI KAWANO, University of California at Davis, Davis, California

PAUL KNOPF, Epivax, Inc., Providence, Rhode Island

KIT S. LAM, University of California at Davis Cancer Center, Sacramento, California

GERD LIPOWSKY, Glycovxyn AG, Schlieren, Switzerland

ZHIJIAN LU, Pfizer Biotherapeutics Research, Cambridge, Massachusetts

PADMA MALYALA, Novartis Vaccines, Cambridge, Massachusetts

WILLIAM MARTIN, Epivax, Inc., Providence, Rhode Island

DEEANN MARTINEZ-GUZMANN, Novartis Vaccines and Diagnostics, Emeryville, California

SEAN P. MCBURNEY, University of Pittsburgh, Pittsburgh, Pennsylvania

JULIE A. MCMURRY, Epivax, Inc., Providence, Rhode Island

C. RUSSELL MIDDAUGH, University of Kansas, Lawrence, Kansas

TATSUO MIYAMURA, Tokyo Institute of Technology, Yokohama, Japan

LEONARD MOISE, Epivax, Inc., Providence, Rhode Island

DEREK O'HAGAN, Novartis Vaccines, Cambridge, Massachusetts

RINO RAPPUOLI, Novartis Vaccines, Siena, Italy

STEVE REED, Infectious Disease Research Institute, Seattle, Washington

ROBERTO ROSINI, Novartis Vaccines, Siena, Italy

TED M. ROSS, University of Pittsburgh, Pittsburgh, Pennsylvania

SHANNAN L. ROSSI, University of Pittsburgh, Pittsburgh, Pennsylvania

PAMPI SARKAR, Novartis Vaccines, Cambridge, Massachusetts

KIRSTEN SCHNEIDER-OHRUM, University of Pittsburgh, Pittsburgh, Pennsylvania

MANINDER SIDHU, Pfizer Vaccines Research, Pearl River, New York

MANMOHAN SINGH, Novartis Vaccines, Cambridge, Massachusetts

INDRESH K. SRIVASTAVA, Novartis Vaccines, Cambridge, Massachusetts

SAMUEL STEPENSON, Novartis Vaccines, Siena, Italy

YIDE SUN, Novartis Vaccines and Diagnostics, Emeryville, California

KENNETH G. SUROWITZ, Merck Research Laboratories, North Wales, Pennsylvania

XIAN-CHUN TANG, University of Pittsburgh, Pittsburgh, Pennsylvania

RYAN TASSONE, Epivax, Inc., Providence, Rhode Island

SYDNEY O. UGWU, Pfizer Vaccine Research, Pearl River, New York

JEFFREY ULMER, Novartis Vaccines, Cambridge, Massachusetts

THOMAS VEDVICK, Infectious Disease Research Institute, Seattle, Washington

WEI WANG, Pfizer, Inc., Chesterfield, Missouri

LI XING, University of California at Davis, Davis, California

CARLO ZAMBONELLI, Novartis Vaccines and Diagnostics, Cambridge, Massachusetts

JIMIN ZHANG, Pfizer Biotherapeutics Research, Cambridge, Massachusetts

XIAOTIAN ZHONG, Pfizer Biotherapeutics Research, Cambridge, Massachusetts

RICHARD ZOLLNER, Pfizer Biotherapeutics Research, Cambridge, Massachusetts

Part 1

IMMUNOGEN DESIGN

Chapter 1

Microbial vaccine design: the Reverse Vaccinology approach

Roberto Rosini, Michèle A. Barocchi, and Rino Rappuoli

1.1 Introduction

Infectious diseases are the greatest cause of morbidity and mortality worldwide; pathogenic bacteria are responsible for approximately 50% of this burden. From a public health standpoint, prevention of diseases has a greater impact and is more cost effective than treating the infection. Vaccines are the most cost-effective methods to control infectious diseases and at the same time one of the most complex products of the pharmaceutical industry. There are several infectious diseases for which traditional approaches for vaccine discovery have failed. With the advent of whole-genome sequencing and advances in bioinformatics, the vaccinology field has radically changed, providing the opportunity for developing novel and improved vaccines. Overall, the combination of different approaches (“-omics” approaches)—genomics, transcriptomics, metabolomics, structural genomics, proteomics, and immunomics—are being exploited to design new vaccines.

1.2 Historical View of “Classical” Vaccinology

The history of vaccination is traditionally dated to the publication, in 1798, of Edward Jenner's landmark experiments with cowpox in which he inoculated a neighbor's boy with purulent material from a milkmaid's hand lesion in the United Kingdom. The boy, 8 years old, was subsequently shown to be protected against a smallpox challenge. For more than 80 years, little more was done with respect to immunization, until Louis Pasteur discovered the attenuating effect of exposing pathogens to air or to chemicals. This discovery was achieved as the result of leaving cultures on the laboratory bench during a summer holiday. Thus, Pasteur developed the first vaccine made in the laboratory and also founded the terminology of vaccination (1, 2). Since the time of Pasteur until recently, there have been two paths of vaccine development: attenuation or inactivation and the production of recombinant subunits. With regard to attenuation, heat, oxygenation, chemical agents, or aging were the first methods used, notably by Pasteur for rabies and anthrax vaccines. Passage in an animal host, such as the embryonated hen's egg, was the next method, as practiced by Theiler for the yellow fever vaccine. After the development of in vitro cell culture in the 1940s, attenuation was accomplished by a variety of means, including selection of random mutants, adaptation to growth at low temperatures, chemical mutation to induce inability to grow at high temperature (temperature sensitivity), or induction of auxotrophy in bacteria. The second set of strategies are represented by the inactivation of the microorganism or by purifying small subunits derived from the pathogen of interest.

Late in the nineteenth century, Theobald Smith in the United States and Pasteur's colleagues independently showed that whole organisms could be killed without losing immunogenicity. This new strategy soon became the basis of vaccines for typhoid and cholera and later for pertussis, influenza, and hepatitis A. Other approaches consisted in isolation of virulence factors from the microorganisms, such as toxins or capsular polysaccharides. In the 1920s, the exotoxins of Corynebacterium diphtheriae and Clostridium tetani were inactivated by formalin, to provide antigens for immunization against diphtheria and tetanus (1). Extracted type-b polysaccharide capsule of Haemophilus influenzae was shown attractive as a vaccine antigen since the invasive disease was almost exclusively restricted to type-b organisms, and antipolysaccharide antibodies had an important role in natural immunity. However, early observations with Hib demonstrated the limitations of plain polysaccharide as a vaccine antigen. When given, during the first 2 years of life, purified polysaccharide induced relatively low levels of serum antibodies, typically insufficient to protect against invasive disease. Following further studies with a variety of bacterial polysaccharides, and in the light of the limitations of plain polysaccharide as vaccine antigens, the Hib polysaccharide was shown to be more immunogenic when covalently linked to a protein carrier, giving additionally boosted responses characteristic of T-dependent memory (3, 4). Overall, with the classical vaccinology approaches many infectious diseases can be prevented. Table 1.1 reports a list of vaccines licensed for immunization in the United States Food and Drug Administration (FDA) (5).