Combination Vaccines: Development, Clinical Research and Approval

612 Pages·1999·1.74 MB·English

by  Ronald W. Ellis

Combination Vaccines : Development,
title:
Clinical Research, and Approval
author: Ellis, Ronald W.
publisher: Humana Press
isbn10 | asin: 0896037177
print isbn13: 9780896037175
ebook isbn13: 9780585262291
language: English
subject Combined vaccines, Vaccines, Combined.
publication date: 1999
lcc: RM281.C65 1999eb
ddc: 615/.372
subject: Combined vaccines, Vaccines, Combined.
Page iii
Combination Vaccines
Development, Clinical Research, And Approval
Edited by
Ronald W. Ellis
BioChem Pharma, Inc., Northborough, MA
H P
UMANA RESS
T N J
OTOWA, EW ERSEY
© 1999 Humana Press Inc.
999 Riverview Drive, Suite 208
Totowa, New Jersey 07512
All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or
transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming,
recording, or otherwise without written permission from the Publisher.
All articles, comments, opinions, conclusions, or recommendations are those of the author(s),
and do not necessarily reflect the views of the publisher.
This publication is printed on acid-free paper.
ANSI Z39.48-1984 (American National Standards Institute)
Permanence of Paper for Printed Library Materials.
Cover design by Patricia F. Cleary.
For additional copies, pricing for bulk purchases, and/or information about other Humana titles,
contact Humana at the above address or at any of the following numbers: Tel: [phone];
Fax: [phone]; E-mail: [email protected] or visit our website at
http://humanapress.com
Photocopy Authorization Policy:
Authorization to photocopy items for internal or personal use, or the internal or personal use of
specific clients, is granted by Humana Press Inc., provided that the base fee of US $10.00 per
copy, plus US $00.25 per page, is paid directly to the Copyright Clearance Center at 222
Rosewood Drive, Danvers, MA 01923. For those organizations that have been granted a
photocopy license from the CCC, a separate system of payment has been arranged and is
acceptable to Humana Press Inc. The fee code for users of the Transactional Reporting Service
is: [0-89603-717-7/99 $10.00 + $00.25].
Printed in the United States of America. 10 9 8 7 6 5 4 3 2 1
Combination vaccines: development, clinical research, and approval / edited by Ronald W. Ellis.
p. cm.
Includes index.
ISBN 0-89603-717-7 (alk. paper)
1. Combined vaccines.I. Ellis, Ronald W.
[DNLM: 1. Vaccines, Combined. QW 805 C7308 1999]
RM281.C65 1999
615'.372-dc21
DNLM/DLC
for Library of Congress 98-55262
CIP
Page v
To my wife, Danielle, and children, Jacob and Miriam,
for their love, patience, and support.
Page vii
Preface
Breakthroughs in immunology, molecular biology, biochemistry, and
other related fields coupled with a greater understanding of
pathogenesis have resulted in the research and development (R&D) of
many new vaccines as well as improvements in several existing ones.
If such vaccines are widely used in at-risk populations, then it should
be possible to prevent much morbidity and mortality. Combination
vaccines (defined as two or more vaccines in a physically mixed
preparation) provide a way in which to encourage increased use of a
wide range of vaccines in a broad population. The combination
vaccine usually is mixed at the time of manufacture, but also may be
mixed immediately before being given to the subject.
The schedule for routine pediatric immunization used to be relatively
simple, consisting of four doses of diphtheria-tetanus-pertussis (DTP)
and one of measles-mumps-rubella (MMR) as injected vaccines as
well as oral polio vaccine (OPV). This schedule had remained
unchanged until about the last 10 years. During the 1990s, several
new vaccines have been introduced into the routine immunization
schedule for the first two years of life and are becoming more widely
used. Conjugated polysaccharide vaccines for Haemophilus influenzae
type b (Hib), given in three to four doses, were demonstrated effective
for preventing disease in young infants. Immunization with
recombinant hepatitis B (HB) vaccines (three doses) also became
recommended during the first year of life, since immunization of
high-risk adult populations had failed to reduce the rate of new HB
infections. More recently inactivated polio vaccine (IPV), another
injected vaccine, has been recommended in the US to replace the first
two doses of OPV in order to reduce the incidence of already rare
cases of vaccine-associated polio following the initial dose(s) of OPV.
Finally, varicella (V) vaccine, now given as a single dose in the
second year of life, was introduced to prevent chickenpox. As a
consequence, what started as five injections in the first two years of
life has become as high as 15, leading parents and health-care
practitioners to become concerned that young children could become
like pincushions! This plethora of vaccines creates increased needs for
recordkeeping and storage that could discourage health-care providers
from administering the full range of indicated vaccines. These issues
have stimulated major efforts toward the development of multidisease
combination vaccines that could reduce the number of injections in
children.
Page viii
The foregoing individual vaccines are monovalent, i.e., each one is
directed against a viral or bacterial pathogen that has a single
antigenic type, meaning that its major antigenic determinants are
group-common. However, there are many significant pathogens that
have multiple serotypes or serogroups. There are multivalent
combination vaccines available for several such pathogens, including
poliovirus (3 types), influenza virus (3 types), Streptococcus
pneumoniae (pneumococcal; 23 types), and rotavirus (4 types).
Ongoing R&D efforts are directed toward the development of
additional multivalent combination vaccines against pathogens such
as Neiserria meningitidis (meningococcal), Streptococcus agalactiae
(Group B Streptococcus or GBS), and dengue virus. The development
of such multivalent vaccines avoids the use of multiple injections for
individual serotypes. Thus, multivalent combination vaccines
typically are developed as such from the outset rather than developing
and licensing each individual serotype vaccine on its own.
Furthermore, multivalent vaccines themselves may become part of
multidisease combination vaccines, as already has happened for IPV.
The concept of combination vaccines has been developed and
exploited throughout most of the 20th century. DTP vaccines have
been available as multidisease combinations for about half a century,
while pneumococcal, influenza, and polio vaccines have been
available as multivalent combinations for several decades.
Combination vaccines can be both live (e.g., MMR, polio) or
inactivated/nonlive/killed subunit (e.g., DTP, HB, Hib). The main
thrust in the development of new combination vaccines has been
DTP-based multidisease combinations for pediatric use, with the
prospect of reducing (up to) 13 shots down to 4. There is also interest
in a combined MMRV vaccine for use during the second year of life
and eventually a booster dose in childhood. At the same time, new
pediatric multivalent combination vaccines are being developed, the
newest being rotavirus vaccine, which was approved in the US in
1998. There also is interest in developing new multidisease
combination vaccines (such as hepatitis A-hepatitis B) for adolescents
and adults, groups that ordinarily are less approachable for routine
immunizations, such that combining vaccines may increase the
immunization rates for these general age groups.
There are many challenges in the development of new combination
vaccines, as are discussed in Combination Vaccines: Development,
Clinical Research, and Approval. These include technical, clinical,
regulatory, manufacturing, marketing, and clinical-use issues. The key
to the successful development of combination vaccines lay in
identifying all such issues for each proposed combination and
developing a comprehensive integrated plan that addresses all these
challenges toward the beginning of the program.
Page ix
There are a large number of combination vaccines both in current use
as well as in development (Chapter 1). For combination-inactivated
vaccines based on DTP, the pertussis component has been the whole-
cell vaccine until recently. However, with the recent licensures of
acellular pertussis vaccines, this new component has become the basis
of future DTP combinations. DTP vaccine is not used for the
immunization of adults (due to reactogenicity of the P component).
Nevertheless, there has been a wide range of other combination
vaccines for adults and adolescents (Chapter 2). Some of these
vaccines are used in infants and children, whereas others are used
exclusively in the older age groups. Immunization schedules have
been developed for both adults and adolescents.
A key challenge for combination vaccines is that vaccine antigens,
which have been developed and licensed separately as vaccines, are
brought together into physical mixtures that are not always stable and
potent. Thus, pharmaceutical and technical developments of
combinations must be performed in a way that an immunogenic and
stable mixture in appropriate containers is developed according to
accepted regulatory standards (Chapter 3). The available combination
vaccines and the schedules for routine pediatric immunization are
listed, which reinforce the complexity of the technical task involved in
their development. Similarly, there are many clinical challenges in
developing combinations (Chapter 4). More specifically, the
immunogenicity of a particular component when given individually
often is not the same as in a combination; when diminished in
combination, this phenomenon is known as interference. There are
key statistical considerations in determining the appropriate size of
consistency trials for proving that the combination is as immunogenic
as its components given individually. Since it is not usually possible
or ethically acceptable to test the clinical efficacy of a combination
vaccine in terms of some or all of its components, it is very useful to