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 New Generation
vaccznes
Third Edition, Revised and Expanded

edited by
Myron M. Levine
University of Maryland School of Medicine
Baltimore, Maryland, U.S.A.

James B. Kaper
University of Marylnnd School of Medicine
Baltimore, Muryland, U.S.A.

Rino Rappuoli
Chiron Vaccines
Siena, Italy

Margaret A. Liu
Transgene, S.A.
Strasbourg, France
and Karolinska Institute
Stockholm, Sweden

Michael I;: Good

Queensland Institute of Medical Research
Brisbane, Queensland, Australia

MARCEL

MARCELDEKKER,
INC. NEWYORK BASEL
DEKKER
The previous edition was published as New Generation Vaccines: Second Edition, Revised and Expanded
Myron M. Levine, Graeme C. Woodrow, James B. Kaper, Gary S. Cobon, eds., 1997

Although great care has been taken to provide accurate and current information, neither the author(s) nor the publisher, nor
anyone else associated with this publication, shall be liable for any loss, damage, or liability directly or indirectly caused or
alleged to be caused by this book. The material contained herein is not intended to provide specific advice or recommendations
for any specific situation.

Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for identification
and explanation without intent to infringe.

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ISBN: 0-8247-4071-8

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Foreword

The fact that this welcome third edition of New Generation Vaccines comes so hard on the heels of the second edition is just
one sign of the great vigor and momentum of vaccinology, now universally acknowledged as a discipline in its own right.
During the first golden age of immunology, the era of Louis Pasteur, Robert Koch, Emil von Behring, and Paul Ehrlich, the
nexus between medical microbiology and immunology was very close: vaccines were the practical goal of nearly all
investigations of the immune system. But before the end of the 19th century, Ehrlich was to show that one could produce
antibodies to the plant toxin ricin, derived from the castor bean, and Bordet discovered antibodies to red blood cells. The
observation that nonmicrobial materials could act as antigens was vastly extended by Landsteiner, who showed that specific
antibodies could be made against small organic chemicals that had never before existed in nature. Suddenly immunology had
burst out of the confines of medical microbiology. Scientists became fascinated with the puzzle of antibody diversity—how
one animal could make such a vast array of different antibodies—and the medical side of the discipline soon encountered
clinical problems such as autoimmunity, allergy, transplant rejection, and even cancer control. During the second golden age
of immunology, around 1955–1975, when nature’s broad strategy was revealed, the divorce between immunology and
vaccinology was almost complete.
Several forces fostered a remarriage. HIV/AIDS clearly demanded new thinking for an effective vaccine. Also, from the
mid-’70s on, the efforts of the World Health Organization and of private foundations such as the Rockefeller Foundation, the
Wellcome Trust, and the MacArthur Foundation tempted more academics into vaccinology by a combination of persuasion
(publicizing the parlous state of research into vaccines chiefly of interest to developing nations) and substantial grants. Gene
cloning was a major catalyst, as in so many other fields, and soon candidate antigens aplenty were produced by recombinant
DNA technology. This in turn showed most subunit vaccines to be only weakly immunogenic, and immunologists interested in
immune regulation entered the fray, exploring both the nature of adjuvanticity and the possible role of cytokines in enhancing
and guiding responses to vaccines. As a result, this third edition carries many contributions from card-carrying immunologists.
At the same time, the editors have realized that scientific breakthroughs alone cannot lead to the protection of the 130 million
infants born each year worldwide. Therefore, economic, logistic, regulatory, financial, ethical, and political aspects of global
vaccinology are also addressed.
The volume begins with a brief historical perspective and then introduces the many high technologies involved in the
creation of the new generation of vaccines. These include not only the most advanced platform technologies of the
biotechnology revolution but also the equally elaborate methods of assessment: toxicological studies, phased clinical trials,
preliminary and definitive evaluation of efficacy, cataloguing of adverse events, and measurement of eventual impact. Some of
the major international programs supporting more widespread use of vaccines are also described and the central, not sufficiently
appreciated, role of regulatory authorities is outlined.
Eradication of smallpox was a true public health triumph and global eradication of wild poliomyelitis virus is within sight as
a fitting encore. It is therefore particularly valuable and timely to get an ‘‘insider’s’’ view of the status of the global polio
eradication initiative.
The way that basic immunology can impinge on vaccinology is explored next. Then, a very important series of chapters
examines the once arcane but now increasingly scientific field of adjuvants, construing that term in the widest sense to include
not only physicochemical immunopotentiation but also novel delivery systems. A special category of the latter is described in
depth, namely, live viruses or bacteria as vectors for genetic vaccine constructs, a field that appears promising for the very
difficult vaccines such as for HIV/AIDS and malaria. The surprising delivery potential of the mucosal and transcutaneous
routes is also reviewed. DNA vaccines and ‘‘prime-boost’’ strategies receive chapters of their own.

iii
iv Foreword

Following these chapters, which deal with generic issues, we come to a series of sections dealing with specific diseases. These
are grouped in a logical progression. A first set of chapters looks at diseases for which licensed vaccines are in place, exploring
issues such as impact, future potential, and, where appropriate, reasons for the need for further improvements, citing relevant
examples.
Next come chapters concerning diseases for which licensed vaccines do not yet exist, or, in the case of rotavirus, for which a
licensed vaccine was withdrawn. This extraordinary series of examples shows how far the subject has come, even since the
second edition. Nevertheless, the chapters do not attempt to hide what a distance there is still to travel. At the same time, it is
hard to contain a sense of excitement when contemplating the long-range potential here. Should the next 10 to 20 years prove as
successful as they appear from our present perspective, increased attention will have to be given to combinations and alternative
delivery systems lest our babies become pincushions! Equally, serious thought will have to be given to financing, even in the
industrialized countries. Currently, vaccines account for 2–3% of the sales of the pharmaceutical industry, and public health
taken as an ensemble for about 5% of all health expenditures. Surely both figures will have to rise substantially if the full promise
of vaccinology is to be realized.
Peering a little further into the future, it is not unreasonable to suggest that vaccines will extend their power into areas of
medicine beyond communicable diseases, and multiple chapters explore this issue. Anticancer vaccines have been the subject of
research for several decades, although the most clear-cut success area is that of vaccines against infections that can cause cancer.
The next probable ‘‘cab off the rank’’ here—a vaccine against human papilloma virus for the prevention of cervical cancer—
bids fair to become as important as the prototype, namely, the hepatitis B vaccine. Vaccines against autoimmune diseases,
atherosclerosis, Alzheimer’s disease, and drug addiction are more speculative, but the relevant chapters make fascinating
reading.
It is saddening to record that vaccines against agents of bioterrorism now constitute a new, but obligate, area of
study and concern. It is reassuring to note that the very large budget that has been made available in the United States
for such research will also benefit vaccinology more broadly as the National Institutes of Health is looking for bright
ideas as well as developmental research.
Can a work be monumental on the one hand and accessible on the other? Can it be both theoretically satisfying and
practically useful? Can it contribute meaningfully to the described remarriage of immunology and infectious disease science?
The answer is that it can if the editors have an Olympian overview of the field and the authors chosen are authoritative and
committed experts in their specialty. This comprehensive third edition of New Generation Vaccines is a rare triumph, a
vindication of the dedication of all concerned, a ‘‘must have’’ acquisition for any library, institutional or personal, purporting
to be serious about supporting vaccine science.
We are living in exciting times in global vaccinology. The Global Alliance for Vaccines and Immunization is spearheading a
new global thrust. Individual countries (or groupings like the European Union) are investing more heavily than ever before in
research. Vaccine manufacturers in both industrialized and developing countries are raising their game as far as Third World
diseases are concerned. Very new initiatives such as the Global Fund to fight HIV/AIDS, tuberculosis, and malaria constitute
potential sources for the mass-purchase of vaccines, should effective ones become available. A multitude of public sector–
private sector partnerships are springing up as if a post–September 11, 2001, world is at last recognizing that the gross global
inequities must be addressed, and that health is not a bad place to begin. As the 21st century unfolds, New Generation Vaccines
will be a precious guide to many seeking to create a better world.

Gustav J.V. Nossal, Ph.D, Hon. M.D., Hon. Dr.Sc.

Honorary Governor and Patron
Walter and Eliza Hall Institute of Medical Research
Professor Emeritus
The University of Melbourne
Melbourne, Victoria, Australia
Preface to the Third Edition

In the intervening years since the publication of the second edition of New Generation Vaccines, extraordinary advances have
occurred in the field of vaccines and immunization. These encompass not only breakthroughs in research and development
but also advances in assuring vaccine safety, standardizing the way clinical trials are performed (and how data are
monitored and validated), manufacture of vaccines, and the public health use of vaccines. The third edition of New
Generation Vaccines highlights these and many other relevant changes in the field of vaccinology and puts them in a
historical perspective.
At the time of publication of the last edition, clinical trials with DNA vaccines were just beginning and there was great
expectation that this technology might revolutionize vaccinology. The results of these clinical trials, now available, reveal
that DNA vaccines used alone do not meet expectations. On the other hand, fundamental improvements in DNA vaccines
and the advent of ‘‘heterologous prime-boost’’ strategies have rekindled interest in their use in focused ways. DNA vaccines
appear able to prime subjects so that they can respond to the same antigens when presented in another formulation as a
boosting regimen, for example, by means of a viral live vector.
Since the last edition, the Bill and Melinda Gates Foundation has completely revolutionized the funding of research and
development and the performance of clinical trials of candidate vaccines against neglected diseases, such as malaria, AIDS,
tuberculosis, leishmaniasis, Dengue fever, Group A Neisseria menigitidis, and shigellosis.
Another seminal event since the publication of the second edition has been the formation of the Global Alliance for
Vaccines and Immunization (GAVI) and its financial instrument, the Vaccine Fund. Working in unison through GAVI, major
global partners in immunization (e.g., the World Health Organization, UNICEF, the World Bank, the Gates Foundation, etc.)
are raising immunization coverage and introducing new vaccines to infants residing in the world’s 74 poorest countries. A
chapter in this edition describes GAVI and the Vaccine Fund, including their research objectives.
Since the last edition, two new conjugate vaccines have been licensed, including a seven-valent pneumococcal conjugate
that is now used widely in the United States and a Group C meningococcal conjugate that is used extensively in the United
Kingdom. Programmatic use of these vaccines has had a profound impact in diminishing the respective disease burdens.
Since the last edition was published, a major dichotomy has appeared between the industrialized world and developing
countries with respect to the vaccines administered to infants and children, their site of manufacture, the formulations and
combinations of vaccine antigens, and immunization schedules. A vibrant vaccine industry is emerging in developing countries
(e.g., India, Indonesia, Brazil, Cuba) that now supplies most of the vaccine utilized in developing countries; these vaccines are
becoming increasingly distinct from those used in industrialized countries. Vaccine safety is increasingly becoming a focus of
public concern in industrialized countries, where many pediatric infectious diseases (e.g., diphtheria, measles, pertussis) have
largely disappeared and populations do not feel threatened by these infections. In industrialized countries, the switch from live
oral polio vaccine to inactivated polio vaccine, the introduction of less reactogenic acellular pertussis vaccine, the discontinua-
tion of use of thimerosal as a preservative in multidose vials, and the withdrawal of a live rotavirus vaccine after it was
incriminated as a rare cause of intussusception within one week following immunization of infants are all examples of this trend
as regulatory and public health actions are taken to enhance vaccine safety. These topics are all covered in a series of chapters on
regulatory issues and vaccine safety. In contrast, in developing countries where infections such as measles, pertussis, and
diphtheria still pose notable risks of severe disease and death, and financial resources are constrained, the emphasis is to achieve
the highest coverage possible with the most potent vaccines, even at the cost of some reactogenicity.
Another trend in industrialized countries is the search for vaccines to prevent or treat (‘‘vaccine therapy’’) various chronic
infections that afflict these populations and create an enormous economic burden. Accordingly, chapters that describe strategies

v
vi Preface to the Third Edition

to develop vaccines against Alzheimer’s disease, rheumatoid arthritis, insulin-dependent diabetes, multiple sclerosis, and
various forms of cancer are included in this edition.
The science of immunology continues to blaze new trails for vaccinology, and multiple chapters in this edition review this
work. Practical ways of immunizing without the use of needles are also covered, including mucosal immunization, trans-
cutaneous immunization, and the use of needle-free injection devices.
The tragedy of September 11, 2001, when terrorists hijacked airliners and flew them into the World Trade Center towers in
New York City resulting in thousands of deaths, and the bioterrorist dissemination of anthrax spores through the postal system
that followed shortly thereafter and resulted in two dozen cases and six deaths (and in major disruption of civil society) had a
perceptible impact on vaccinology. Following these events, governments in the United States and many other countries
encouraged the development of new or improved vaccines against several potential bioterror agents and diverted resources
toward that end. Chapters covering this subject are also found in this edition.
The pace and extent of modern vaccine development make it impossible to include within a single volume all the notable
research advances on all vaccines. Accordingly, as before, there are gaps. For example, progress on the development of vaccines
to prevent Pseudomonas aeruginosa pulmonary disease in cystic fibrosis patients is omitted, as are updates on progress in
administering attenuated measles vaccine by aerosol and the development of new measles vaccines that aim to immunize infants
in the developing world who are too young to get the current parenteral vaccine.
Assembling the third edition of New Generation Vaccines has been a formidable undertaking that required input and help
from many individuals. We heartily thank all the authors who contributed the diverse chapters that comprise the fundamental
strength of the volume. We also express our indebtedness to Sandra Beberman and Barbara Mathieu of Marcel Dekker, Inc.,
who provided invaluable assistance and guidance. Special thanks and appreciation go to our families and friends who gave
encouragement and showed patience during the many evening and weekend hours consumed in the preparation and editing of
the book. Finally, this volume could not have been completed without the organizational prowess, fastidious attention to detail,
tenacity, technical competence, and diplomatic skills of Mrs. Dottie Small, Assistant to Myron M. Levine.

Myron M. Levine
James B. Kaper
Rino Rappuoli
Margaret A. Liu
Michael F. Good
Preface to the Second Edition

The second edition of New Generation Vaccines appears at a propitious time, two centuries after Edward Jenner initiated the
dawn of vaccination in 1796 by demonstrating that inoculation with material from cowpox lesions induced protection against
smallpox. Indeed, as the 20th century comes to an end, vaccines are now recognized as among the most cost-effective preventive
measures available in modern medicine’s armamentarium. With aggressive use of vaccines, smallpox has been eradicated
globally, poliomyelitis regionally, and measles has been brought under control worldwide. Moreover, the tools of modern
biotechnology make it within the realm of possibility to prepare candidate vaccines against almost any infectious disease, as
long as sufficient resources are committed. In this second edition, we acknowledge the arrival of vaccinology as a discipline that
has come of age.
A global picture of public health interventions with vaccines is depicted in two chapters in this second edition, one
documenting the triumphs of the Expanded Programme on Immunization and the other describing international disease
eradication and disease control efforts. In other chapters, the painstaking stepwise process by which candidate vaccines move
progressively from Phase 1 and 2 clinical trials to Phase 3 and 4 trials is discussed.
We have attempted to provide reviews of the fundamentals advances in immunology and biotechnology that constitute the
underpinnings to vaccine development. Many chapters offer illustrative examples of vaccine candidates representing the
application of state-of-the-art biotechnology. However, it is also clear that technologies gain and lose popularity, with some
succeeding and others disappearing. For instance, notably absent are examples based on the use of antiidiotypic antibodies, and
there are few examples of synthetic peptide vaccines, indicating how enthusiasm for these technologies has dissipated since the
first edition. In contrast, live-vector vaccine technology has matured, and therefore considerable attention is paid to the use of
vaccinia and attenuated Salmonella live vectors. Multiple examples of antigen delivery systems such as polylactide/poly-
glycolide microspheres, liposomes, cochleates, and viruslike particles are contained in this edition, A very popular new
technology, ‘‘DNA vaccines,’’ did not exist in 1990, when the first edition was published; this revolutionary approach has gained
extraordinary momentum in the time between the planning of this edition and its publication. Results of clinical trials being
carried out with DNA vaccines in the late 1990s should indicate whether this approach will flourish.
In many chapters, considerable attention is paid to mucosal immunization, not only to achieve SIgA responses to protect
mucosal surfaces but as a way of eliciting serum antibodies and cell-mediated immune responses. An ultimate form of mucosal
immunization might be with ‘‘edible vaccines,’’ as explained in the chapter that describes the engineering of transgenic plants
expressing vaccine antigens.
With contributions from leaders in their respective fields, we have tried to provide many examples of improves vaccines for
diseases against which licensed vaccines already exist and of new vaccines against diseases that were previously unassailable by
immunoprophylaxis. Unfortunately, it was impossible to be completely inclusive. Examples of specific material not covered in
this edition include the excellent recent progress made by teams in Vienna, Boston, and Berne working on vaccines against
Pseudomonas aeruginosa, and update on maternal immunization, and progress in vaccines against leprosy, cytomegalovirus,
and group B streptococcal infections.
Several new vaccines have become licensed in many countries since the first edition. Haemophilus influenzae type b
conjugate vaccines, for example, have had an extraordinary impact in industrialized countries where they have been used in a
programmatic way. These vaccines have been found to interfere with respiratory tract colonization by H. influenzae type b. As a
consequence, there has been an interruption of transmission, and a herd immunity effect has been observed. Vaccines against
hepatitis A, varicella, typhoid fever (Ty21a and Vi polysaccharide), cholera (CVD 103-HgR live vaccine and B subunit-killed
whole-cell combination vaccine) and Japanese B encephalitis, and acellular pertussis vaccines have been licensed in various

vii
viii Preface to the Second Edition

countries since the first edition. The development of vaccines against several infectious diseases of importance solely (or mainly)
in developing countries, such as malaria, has been lagging, compared to the extraordinary progress made in vaccines considered
to be priorities for the industrialized countries (e.g., H. Influenzae type b conjugates and accellular pertussis vaccines).
Moreover, where new vaccines against infections important in developing countries have become licensed (e.g., Ty21a, Vi
polysaccharide, and the live and nonliving oral cholera vaccines), they have not been introduced for routine use; rather, these are
largely vaccines used by travelers from industrialized countries who visit developing countries. Finding ways to help developing
countries introduce programmatic use of new vaccines poses a challenge that must be addressed by the vaccinology and public
health communities.
Even as the technology for vaccine development has burgeoned and clinical vaccine testing has become more sophisticated,
so have public perceptions and the views of regulatory agencies changed with time, For this reason, chapters on regulatory issues
have been included to further broaden the perspective of the book.
The editors would like to thank the many contributors who have provided outstanding chapters for this edition. Special
thanks go to family and friends whose support and patience sustained us during the many evening and weekend hours required
to plan and edit this edition. This book could not have been completed without the competent assistance of Dottie Small and
Brenda Lown at the Center for Vaccine Development and Henry Boehm at Marcel Dekker, Inc.

Myron M. Levine
Graeme C. Woodrow
James B. Kaper
Gary S. Cobon
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Contents

Foreword Gustav J. V. Nossal iii 7. Development and Supply of Vaccines:

Preface to the Third Edition v An Industry Perspective 75
Preface to the Second Edition vii Michel Greco
8. Reaching Every Child—Achieving Equity
in Global Immunization 89
R. Bruce Aylward, M. Birmingham,
J. Lloyd, and B. Melgaard

Introduction to Vaccinology 9. A Paradigm for International

Cooperation: The Global Alliance for
1. Vaccines and Vaccination in Historical Vaccines and Immunization (GAVI) and
Perspective 1 the Vaccine Fund 101
Myron M. Levine and Rosanna Lagos Lisa Jacobs, Jacques-Francois Martin,
and Tore Godal
2. An Overview of Biotechnology in Vaccine
Development 11 10. Economic Analyses of Vaccines and
James B. Kaper and Rino Rappuoli Vaccination Programs 107
Benjamin Schwartz and
3. Initial Clinical Evaluation of New Vaccine Ismael Ortega-Sanchez
Candidates: Investigators’ Perspective of
Phase I and II Clinical Trials of Safety,
Immunogenicity, and Preliminary Efficacy 19 Regulatory Issues
Carol O. Tacket, Karen L. Kotloff,
and Margaret B. Rennels 11. The Role of the Food and Drug
Administration in Vaccine Testing and
4. Long-Term Evaluation of Vaccine Licensure 117
Protection: Methodological Issues for Norman Baylor, Lydia A. Falk,
Phase III and IV Studies 29 and Karen Midthun
John D. Clemens, Abdollah Naficy,
Malla R. Rao, and Hye-won Koo 12. Developing Safe Vaccines 127
Leslie K. Ball, Robert Ball,
5. Ethical Considerations in the Conduct of and Bruce G. Gellin
Vaccine Trials in Developing Countries 49
Charles Weijer and Claudio F. Lanata
Eradication and Elimination Programs
6. Vaccine Economics: From Candidates to
Commercialized Products in the 13. Polio Eradication: Capturing the Full
Developing World 57 Potential of a Vaccine 145
Amie Batson, Piers Whitehead, R. Bruce Aylward, Rudolph Tangermann,
and Sarah Glass Roland Sutter, and Stephen L. Cochi

ix
x Contents

Basic Immunology Applied to Vaccine Development Live Vector Vaccines

14. Recent Advances in Immunology that 27. Vaccinia Virus and Other Poxviruses as
Impact Vaccine Development 159 Live Vectors 313
Marcelo B. Sztein Bernard Moss
15. High-Throughput Informatics and 28. Live Adenovirus Recombinants as
In Vitro Assays for T-Cell Epitope Vaccine Vectors 325
Determination: Application to the Design L. Jean Patterson, Bo Peng, Xinli Nan,
of Epitope-Driven Vaccines 179 and Marjorie Robert-Guroff
Anne S. DeGroot, Hakima Sbai, William
Martin, John Sidney, Alessandro Sette, 29. RNA Virus Replicon Vaccines 337
and Jay A. Berzofsky Nancy L. Davis and Robert E. Johnston

16. The Challenge of Inducing Protection in 30. Attenuated Salmonella and Shigella as
Very Young Infants 197 Live Vectors Carrying Either Prokaryotic
Claire-Anne Siegrist or Eukaryotic Expression Systems 353
James E. Galen, Marcela F. Pasetti,
17. Vaccination and Autoimmunity 203 Marcelo B. Sztein, Eileen M. Barry,
Paul-Henri Lambert and Michel Goldman and Myron M. Levine

Adjuvants, Immunopotentiation, and Nonliving Improving DNA Vaccines

Antigen Delivery Systems
31. DNA Vaccines 367
18. Adjuvants for the Future 213 Indresh K. Srivastava, Margaret A. Liu,
Richard T. Kenney and Robert Edelman
and Jeffrey B. Ulmer
19. MF59 Adjuvant Emulsion 225 32. DNA-Modified Virus Ankara and Other
Audino Podda and Giuseppe Del Giudice Heterologous Prime-Boost Immunization
20. Immune-Enhancing Sequences (CpG Strategies for Effector T Cell Induction 381
Motifs), Cytokines, and Other Adrian V. S. Hill, Joerg Schneider, and
Immunomodulatory Moieties 237 Andrew J. McMichael
Sanjay Gurunathan, Dennis M. Klinman,
and Robert A. Seder
Nonparenteral Delivery of Vaccines and
21. Use of Genetically Detoxified Mutants of Infant Combination Vaccines
Cholera and Escherichia coli Heat-Labile
Enterotoxins as Mucosal Adjuvants 251 33. Mucosal Immunization and Needle-Free
Gordon Dougan and Gill Douce Injection Devices 393
Myron M. Levine and James D. Campbell
22. Recent Developments in Vaccine Delivery
Systems 259 34. Transcutaneous Immunization 401
Derek T. O’Hagan Gregory M. Glenn and Richard T. Kenney
23. Proteosomek Technology for Vaccines 35. Combination Vaccines for Routine Infant
and Adjuvants 271 Immunization 413
George H. Lowell, David Burt, Margaret B. Rennels, Rosanna M. Lagos,
Greg White, and Louis Fries and Kathryn M. Edwards
24. Viruslike Particle (VLP) Vaccines 283
Margaret E. Conner and Mary K. Estes
New and Improved Vaccines Against Diseases for
25. Immunostimulating Reconstituted Which There Already Exist Licensed Vaccines
Influenza Virosomes 295
Reinhard Glueck 36. Meningococcal Conjugate and Protein-
Based Vaccines 421
26. Plants as a Production and Delivery Rino Rappuoli, Andrew J. Pollard, and
Vehicle for Orally Delivered Subunit E. Richard Moxon
Vaccines 305
Tsafrir S. Mor, Hugh S. Mason, 37. The Postlicensure Impact of
Dwayne D. Kirk, Charles J. Arntzen, Haemophilus influenzae Type b and
and Guy A. Cardineau Serogroup C Neisseria meningitides
Contents xi

Conjugate Vaccines 427 49. Vaccine Strategies to Prevent

Jay Wenger, Helen Campbell, Elizabeth Dengue Fever 583
Miller, and David Salisbury Niranjan Kanesa-thasan, J. Robert Putnak,
and David W. Vaughn
38. Pneumococcal Protein–Polysaccharide
Conjugate Vaccines 443 50. Vaccination Against the Hepatitis C
Orin S. Levine, David L. Klein, and Viruses 593
Jay C. Butler Michael Houghton and Sergio Abrignani
39. Pneumococcal Common Proteins and 51. Live Vaccine Strategies to Prevent
Other Vaccine Strategies 459 Rotavirus Disease 607
David E. Briles, James C. Paton, and Richard L. Ward, H. Fred Clark,
Susan K. Hollingshead Paul A. Offit, and Roger I. Glass
40. Polysaccharide-Based Conjugate 52. Vaccines Against Respiratory
Vaccines for Enteric Bacterial Syncytial Virus and Parainfluenza
Infections: Typhoid Fever, Virus Types 1–3 621
Nontyphoidal Salmonellosis, James E. Crowe, Jr., Peter L. Collins,
Shigellosis, Cholera, and and Brian R. Murphy
Escherichia coli 0157 471
Shousun C. Szu, John B. Robbins, 53. Developing a Vaccine Against
Rachel Schneerson, Vince Pozsgay, Epstein–Barr Virus 641
and Chiayung Chu Denis Moss and Mandvi Bharadwaj
41. Attenuated Strains of Salmonella 54. Cytomegalovirus Vaccines 649
enterica serovar Typhi as Live Oral David I. Bernstein and
Vaccines Against Typhoid Fever 479 Stanley A. Plotkin
Myron M. Levine, James Galen,
Carol O. Tacket, Eileen M. Barry, 55. Herpes Simplex Vaccines 661
Marcela F. Pasetti, and Marcelo B. Sztein Richard J. Whitley
42. Vaccines Against Lyme Disease 487 56. Vaccines for Hantaviruses, Lassa
Mark S. Hanson and Robert Edelman Virus, and Filoviruses 679
Connie Schmaljohn, Joseph B.
43. Oral B Subunit–Killed Whole-Cell McCormick, Gary J. Nabel, and
Cholera Vaccine 499 Alan Schmaljohn
Jan Holmgren and Charlotta Bergquist
57. Development of a Vaccine to Prevent
44. Attenuated Vibrio cholerae Strains as Live
Infection with Group A Streptococci
Oral Cholera Vaccines and Vectors 511
and Rheumatic Fever 695
James B. Kaper and Carol O. Tacket
Michael F. Good, P. J. Cleary, James
45. Novel Vaccines Against Tuberculosis 519 Dale, Vincent Fischetti, K. Fuchs,
Robert J. Wilkinson and Douglas B. Young H. Sabharwal, and J. Zabriskie

46. New Approaches to Influenza Vaccine 537 58. Vaccines Against Group B
John J. Treanor, James C. King, and Streptococcus 711
Kenneth M. Zangwill Morven S. Edwards, Lawrence C.
Paoletti, and Carol J. Baker
47. Chimeric Vaccines Against Japanese
Encephalitis, Dengue, and West Nile 559 59. Overview of Live Vaccine Strategies
Konstantin V. Pugachev, Against Shigella 723
Thomas P. Monath, and Farshad Guirakhoo Karen L. Kotloff, Thomas L. Hale,
Eileen M. Barry, and Philippe Sansonetti

60. Oral Inactivated Whole Cell B Subunit

Vaccines Against Diseases for Which Licensed Vaccines Combination Vaccine Against
Do Not Currently Exist (or That Have Not Been Enterotoxigenic Escherichia coli 737
Widely Used) Ann-Mari L. Svennerholm and
Stephen J. Savarino
48. Challenges and Current Strategies in the
Development of HIV/AIDS Vaccines 573 61. Multivalent Shigella/Enterotoxigenic
Chad A. Womack, Margaret A. Liu, Escherichia coli Vaccine 751
and Barney S. Graham Eileen M. Barry and Myron M. Levine
xii Contents

62. Vaccines Against Gonococcal Infection 755 75. Vaccines Against Schistosomiasis 915
Timothy A. Mietzner, Christopher E. Andre´ Capron, Gilles J. Riveau,
Thomas, Marcia M. Hobbs, and Paul B. Bartley, and Donald P.
Myron S. Cohen McManus
63. Vaccines Against Campylobacter jejuni 775 76. Vaccines Against Entamoeba histolytica 927
David R. Tribble, Shahida Baqar, and Christopher D. Huston and
Daniel A. Scott William A. Petri, Jr.
64. Vaccines Against Uropathogenic 77. Vaccines Against Human Hookworm
Escherichia coli 787 Disease 937
Solomon Langermann and W. Ripley Peter J. Hotez, Zhan Bin,
Ballou, Jr. Alex Loukas, Jeff M. Bethony,
James Ashcom, Kashinath Ghosh,
65. Vaccine Strategies Against John M. Hawdon, Walter Brandt,
Helicobacter pylori 795 and Philip K. Russell
Karen L. Kotloff, Cynthia K. Lee,
and Giuseppe Del Giudice
66. Vaccines for Staphylococcus aureus Vaccines Against Cancer and Other Chronic Diseases
Infections 807 and Vaccine Therapy
Ali I. Fattom, Gary Horwith, and
Robert Naso 78. Principles of Therapeutic Vaccination
for Viral and Nonviral Malignancies 953
67. Moraxella catarrhalis and Nontypable
Drew M. Pardoll
Haemophilus influenzae Vaccines to
Prevent Otitis Media 817 79. Vaccines Against Human
Philippe A. Denoel, Fabrice Godfroid, Papillomavirus Infection 977
Joelle Thonnard, Ce´cile Neyt, David W. John Boslego, Xiaosong Liu, and
Dyer, and Jan T. Poolman Ian H. Frazer
68. Vaccines for Chlamydia trachomatis 80. Active Immunization with Dendritic
and Chlamydia pneumoniae 835 Cells Bearing Melanoma Antigens 987
Andrew D. Murdin and Ralph M. Steinman, Karolina
Robert C. Brunham Palucka, Jacques Banchereau,
69. Overview of Vaccine Strategies Beatrice Schuler-Thurner, and
for Malaria 847 Gerold Schuler
Michael F. Good and David Kemp 81. Vaccine Against Alzheimer’s
70. Adjuvanted RTS,S and Other Disease 995
Protein-Based Pre-Erythrocytic Stage Roy M. Robins-Browne, Richard A.
Malaria Vaccines 851 Strugnell, and Colin L. Masters
D. Gray Heppner, Jr., James F. Cummings, 82. Vaccines Against Atherosclerosis 1003
Joe D. Cohen, W. Ripley Ballou, Jr., Carl R. Alving
Christian F. Ockenhouse, and Kent E. Kester
83. Vaccine Therapy 1011
71. Malaria: A Complex Disease that May Donald S. Burke
Require A Complex Vaccine 861
Stephen L. Hoffman, Denise L. Doolan, 84. Vaccination-Based Therapies in
and Thomas L. Richie Multiple Sclerosis 1025
Jacqueline Shukaliak-Quandt and
72. Plasmodium falciparum Asexual Blood Roland Martin
Stage Vaccine Candidates: Current Status 875
Danielle I. Stanisic, Laura B. Martin, 85. Vaccine Therapy for Autoimmune
Robin F. Anders, and Michael F. Good Diabetes 1041
Irun R. Cohen
73. Malaria Transmission-Blocking
Vaccines 887 86. Vaccines for the Treatment of
Allan Saul Autoimmune Diseases 1047
David C. Wraith
74. Vaccines Against Leishmania 903
Farrokh Modabber, Steven G. Reed, 87. Vaccines to Treat Drug Addiction 1057
and Antonio Campos-Neto Paul R. Pentel and Dan E. Keyler
Contents xiii

Vaccines Against Bioterror Agents Julie B. Milstien, Jean Ste´phenne, and

Lance Gordon
88. Vaccines Against Agents of Bioterrorism 1067
Theodore J. Cieslak, Mark G. Kortepeter, 90. Heterogeneity of Pediatric Immunization
and Edward M. Eitzen, Jr. Schedules in Industrialized Countries 1093
James D. Campbell and Margaret Burgess

89. A Primer on Large-Scale Manufacture of

Modern Vaccines 1081 Index 1097
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