Vaccines: From Concept to Clinic A Guide to the Development and Clinical Testing of Vaccines for Human Use Edited by Lawrence C. Paoletti and Pamela M. McInnes Copyright © 1999 by CRC Press Library of Congress Cataloging-in-Publication Data Vaccines, from concept to clinic : a guide to the development and clinical testing of vaccines for human use / edited by Lawrence C. Paoletti and Pamela M. McInnes. p. cm. Includes bibliographical references and index. ISBN 0-8493-1168-3 (alk. paper) 1. Vaccines. 2. Vaccines–Testing. I. Paoletti, Lawrence C. II. McInnes, Pamela M. [DNLM: 1. Vaccines, Synthetic. 2. Research Design. 3. Clinical Trials. QW 805V11644 1998] QR189.V275 1998. 65’.372—dc21 DNLM/DLC 98-21739 CIP This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. 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Paoletti Dr. Paoletti graduated in 1988 from the University of New Hampshire at Durham with a doctoral degree in Microbiology. He joined the Channing Labo- ratory, Brigham and Women’s Hospital, Boston, to pursue postdoctoral studies on the development of oligosaccharide-protein conjugate vaccines against group B streptococcal disease. In 1991, Dr. Paoletti became part of a team, which in- cluded members of the NIH’s NIAID, developing the first group B streptococcal capsular polysaccharide-protein conjugate vaccines for use in clinical trials. Sev- eral other group B streptococcal conjugate vaccines are now in various stages of clinical evaluation. His experiences in the academic pursuit of producing vac- cines for clinical trials provided the inspiration for this book. Pamela M. McInnes Dr. McInnes is currently Chief of the Respiratory Diseases Branch, Division of Microbiology and Infectious Diseases, National Institute of Allergy and In- fectious Diseases, National Institutes of Health. Before taking this position, she served as the Neonatal Pathogens and Maternal Immunization Program Officer in the Respiratory Diseases Branch, having joined the Respiratory Diseases Branch in 1990, after a year as an NIH Grants Associate. Previously, Dr. McInnes was Associate Professor of Orthodontics at LSU School of Dentistry, in New Or- leans, Louisiana. She received her dental degree and advanced degree in biomaterials from the University of the Witwatersrand in Johannesburg, South Africa. Dr. McInnes is actively involved with the NIH extramural research commu- nity in the mission of reducing the morbidity and mortality attributable to respi- ratory diseases. She has a particular interest in vaccine development and clinical evaluation. Copyright © 1999 by CRC Press Foreword The field of vaccinology has expanded exponentially during the past 20 years. It is no longer merely a small branch of microbiology, immunology, or clinical infectious diseases but a complex and substantive discipline in its own right. A number of high-profile events—the HIV epidemic, the increase in antimi- crobial resistance of bacterial pathogens, the emergence and reemergence of in- fections from Ebola virus to diphtheria—all have underscored, for scientists and the public, the critical role that immunization must play if infectious diseases are to be successfully controlled over the long term. This is truly an exciting time for this fledgling field as vaccinologists extend their scope from the prevention of the classic infections of childhood such as diphtheria, whooping cough, and measles, to the prevention of infections in all age groups and all over the world. For example, vaccines are being developed against sexually transmitted dis- eases targeted for adolescents and adults, against respiratory viruses targeted to high-risk adults and the elderly, and against group B Streptococcus targeted to mothers for the protection of their babies. In addition to these vaccines for uni- versal use, numerous agents are being developed for more specialized uses in particular geographic areas (e.g., dengue, malaria), in travelers or in high-risk groups such as surgical patients and the immunocompromised. With the ad- vent of more powerful adjuvants and lymphokines which may allow us to both enhance and modulate the immune response, it may soon become possible to develop therapeutic vaccines to treat chronic or recurring infections such as hepa- titis B, hepatitis C, and genital herpes. These technologies may ultimately allow vaccinologists to design vaccines for the immunotherapy of cancer, or for the control of autoimmune diseases and allergies. There are numerous manifestations of the expanding interest in vaccine re- search. National and international meetings occur not on an annual but on a monthly or even weekly basis. Many medical schools and public health schools offer courses in vaccine development and evaluation. A number of academic institutions have founded vaccine research and/or clinical evaluation centers that are supported by national institutes of health and by industry. Several na- tional and international institutes devoted to vaccine research and development have recently been created. Vaccine literature is burgeoning with numerous papers appearing in major scientific journals; two journals devoted exclusively to vaccines have appeared; and there are countless books and monographs on specific vaccines, vaccine technologies, adjuvants, vaccine delivery devices, and the like. Vaccines: From Concept to Clinical Testing fills an important gap in this exten- sive vaccine literature. Designed with academic vaccine researchers in mind, it provides a road map of how a vaccine is taken from an idea in a researcher’s imagination to the lab bench through preclinical evaluation, into the clinic for Copyright © 1999 by CRC Press safety immunogenicity and efficacy, and ultimately to commercialization as a licensed product. Those who have traveled down this complex path during the past 20 years, and the editors Lawrence Paoletti and Pamela McInnes are among them, realize how much they would have benefited if this book had been on their shelf when they began. The first portion of this book is devoted to the preclinical stages of vaccine development. The first chapter by Rino Rappuoli and Giuseppe Del Giudice provides a lucid and thoughtful description of how vaccine targets are identi- fied and prioritized from both a public health and a commercial vantage and how approaches are selected rationally, from the many available, to develop a vaccine against a particular infectious disease. In Chapter 2, Andrew Onderdonk and Ronald Kennedy review the use of animal models in the preclinical evaluation of vaccines, with special emphasis on primates. At the least, every candidate vaccine must be evaluated for safety, toxicity, and immunogenicity in appropriate animals before human studies are initiated. At best, animal models of infection can provide valuable insights into a vaccine’s protective activity and its mechanism and thereby enhance the like- lihood of its success in preventing human disease. The third chapter, by Dace Madore, Nancy Strong, and Sally Quataert, thor- oughly reviews the validation, standardization, and calibration of serologic as- says, a critical issue in the preclinical and clinical evaluation of vaccine immunogenicity and ultimately in the development of serologic correlates of protection. A practical guide for the academic researcher who wishes to prepare a vac- cine for initial Phase I human evaluation is provided in the fourth chapter, by Lawrence Paoletti. Although it is personally rewarding for the academic inves- tigator to take a vaccine idea into human trials, the regulatory requirements have become increasingly stringent, and thus the personal commitment and resource requirements have become truly daunting. Consequently, most aca- demic scientists now link up with an established public or private sector vaccine development laboratory to accomplish this task. The middle portion of the book deals with rules of the road in the process of clinical vaccine investigation from the vantages of both the driver (Chapter 5) and the traffic cop (Chapter 6). Martha Mattheis and Pamela McInnes provide a practical investigator’s guide to writing an Investigational New Drug applica- tion, based on their own extensive experience at NIAID in writing such docu- ments. In Chapter 6, Donna Chandler, Loris McVitty, and Jeanne Novack give the regulator’s perspective of the IND process, including a valuable list of com- mon pitfalls. Jane Biddle describes the ins and outs of patenting technology, interpreting material transfer agreements, and negotiating licensing agreements in Chapter 7. Like physicians practicing under managed care systems, vaccine researchers also have had to become businesspersons in order to succeed in getting their vaccines developed. Familiarity with the technical details and rules of the road Copyright © 1999 by CRC Press for this transition from the academic laboratory to the commercial laboratory is absolutely essential for academic vaccine researchers. The final two chapters of the book are both entertaining and inspiring sagas of the development of two vaccines, a malaria vaccine in David Kaslow’s Chap- ter 8 that is still a “work in progress,” and the Oka strain varicella vaccine in Michiaki Takahashi’s Chapter 9 that is now marketed globally. The common thread in both stories is that they amply illustrate the three most important character traits of the successful vaccine developer—persistence, persistence, and persistence. George R. Siber, M.D. Pearl River, New York Copyright © 1999 by CRC Press Preface The scientific literature today is replete with books on vaccines, written and edited by experts active in the field. Recently published books review the state of research on vaccines against the most common, as well as the most rarely encountered, diseases of humans and animals. Instructive books and manuals describe new methods of vaccine preparation, delivery, handling, and storage. Monographs from domestic and international vaccine meetings, information originating from several academic sources, and audiovisual lectures from meet- ings are readily accessible via the Internet. An international peer-reviewed jour- nal dedicated to this field completes the information base. So why initiate another book on vaccines? What else can be added to the vaccine field that has not yet been covered? This book arose as we began to generate a clinical lot of polysaccharide-pro- tein conjugate vaccine against group B Streptococcus. For the group B streptococ- cal vaccine project, research conducted in the 1970s and 1980s told us what we needed to do technically in the laboratory to create the vaccines; however, infor- mation on the steps necessary to manufacture, bottle, and test clinical lots of this vaccine was not readily available. This information was gleaned primarily from conversations and correspondence with colleagues in industry and government. We realized that compiling the necessary information in one book might be use- ful to researchers who were on the verge of producing a lot of vaccine for Phase I clinical trials and who were asking these questions: Can I produce a clinical lot of vaccine in my laboratory? How should the vaccine be vialed? What are the expectations of the FDA? What is an IND application and how is it filed? What are CFRs? Which CFRs apply to the production of a vaccine? What is potency and how is it measured? We learned that the answers to these questions resided in publications from different regulatory agencies and in the minds and notebooks of those who had gone through the process of manufacturing a vaccine for clinical use, filing an IND application, and designing and performing clinical trials. Without access to such resources, the young vaccine developer could be bewildered and frustrated by the complexity of the endeavor. Through this book we seek to provide guid- ance in this process. The core issues around which the rest of the book was de- veloped are: considerations for the preparation of a clinical lot of vaccine, an understanding of each phase of clinical testing, knowledge of the organization and preparation of a manufacturer’s protocol and an IND application, and aware- ness of the concerns of those who review INDs. Areas considered critical to vac- cine development—identification of protective epitopes, development of animal models or test systems, appropriate design and performance of serological as- says—are at the front of the book. Because technology transfer has become a central concern of scientists whose discoveries may have not only a public health impact but also an economic impact, we include a chapter on this critical but Copyright © 1999 by CRC Press often confusing topic as a reference for both the novice and the experienced scientist. Students of vaccine research may gain invaluable insights into vaccine research and development by reading the final segment of the book, which de- scribes the personal trials and tribulations encountered in the development of two vaccines: one that has gained widespread acceptance for human use (vari- cella) and one that is still in its developmental stages (malaria). This book would not have been created without the commitment of the au- thors and the encouragement of our colleague, Dr. Arthur Tzianabos. We thank Jaylyn Olivo and Julie McCoy of the Brigham and Women’s Hospital Editorial Service for reviewing each chapter (their talents in this field are without equal). We also acknowledge with gratitude those at our respective institutions who have created and nurtured an environment that allows the pursuit of this kind of project. Lawrence C. Paoletti and Pamela M. McInnes Copyright © 1999 by CRC Press Contributors Jane A. Biddle, Ph.D. Dace V. Madore, Ph.D. Jane A Biddle Consultants Director 4209 West Bertona St. Immunobiological Services Seattle, WA 98199 Wyeth-Lederle Vaccines and Pediatrics Donna K.F. Chandler, Ph.D. 211 Bailey Road Division of Vaccines and West Henrietta, NY 14586-9728 Related Products Applications Office of Vaccines Research Martha J. Mattheis, M.S., and Review Chief Center for Biologics Evaluation Clinical and Regulatory and Research Affairs Branch Food and Drug Administration Division of Microbiology and 1401 Rockville Pike Infectious Diseases Rockville, MD 20852-1448 NIAID, NIH Solar Building Giuseppe Del Giudice, Ph.D. Room 3A01 IRIS, The Chiron-Vaccines Bethesda, MD 20892-7630 Immunobiological Research Institute in Siena Pamela M. McInnes, D.D.S., Via Fiorentina 1 M.Sc. (Dent.) 53100 Siena Chief Italy Respiratory Diseases Branch Division of Microbiology and David C. Kaslow, M.D. Infectious Diseases Head, Malaria Vaccines Section NIAID, NIH and Recombinant Protein Solar Building, Room 3B04 Expression Unit Laboratory of Parasitic Diseases Bethesda, MD 20892-7630 Building 4, Room B1-31 NIAID, NIH Loris D. McVittie, Ph.D. Bethesda, MD 20892-0425 Division of Vaccines and Related Products Applications Ronald C. Kennedy, Ph.D. Office of Vaccines Research Department of Microbiology and and Review Immunology Center for Biologics Evaluation The University of Oklahoma and Research Health Sciences Center Food and Drug Administration P.O. Box 26901 1401 Rockville Pike Oklahoma City, OK 73109 Rockville, MD 20852-1448 Copyright © 1999 by CRC Press