Immunological Adjuvants and Vaccines

244 Pages·1990·7.6 MB·English

by  Anthony C. Allison (auth.), Gregory Gregoriadis, Anthony C. Allison, George Poste (eds.)

Immunological
Adjuvants and
Vaccines
NATO ASI Series
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Series A: Life Sciences
Immunological
Adjuvants and
Vaccines
Edited by
Gregory Gregoriadis
Royal Free Hospital School of Medicine
London, United Kingdom
Anthony C. Allison
Syntex Research
Palo Alto, California
and
George Poste
Smith Kline French Laboratories
Philadelphia, Pennsylvania
Plenum Press
New York and London
Published in cooperation with NATO Scientific Affairs Division
Proceedings of a NATO Advanced Study Institute on
Immunological Adjuvants and Vaccines,
held June 24-July 5, 1988,
in Cape Sounion Beach, Greece
Library of Congress Cataloging in Publication Data
NATO Advanced Study Institute on Immunological Adjuvants and Vaccines
(1988: Ajra Sounion, Greece)
Immunological adjuvants and vaccines I edited by Gregory Gregoriadis, An
thony C. Allison, and George Poste.
p. cm.-(NATO ASI series. Series A, Life sciences; v. 179)
"Proceedings of a NATO Advanced Study Institute on Immunological Ad
juvants and Vaccines, held June 24-July 5, 1988, in Capa Sounion Beach,
Greece" - T.p. verso.
"Published in cooperation with NATO Scientific Affairs Division."
Includes bibliographical references.
ISBN 978-1-4757-0285-9 ISBN 978-1-4757-0283-5 (eBook)
DOI10.1007/978-1-4757-0283-5
1. Immunological adjuvants-Congresses. 2. Vaccines-Congresses. I.
Gregoriadis, Gregory. II. Allison, Anthony C. (Anthony Clifford), 1925- III.
Poste, George. IV. North Atlantic Treaty Organization. Scientific Affairs Division.
V. Title. VI. Series.
IDNLM: 1. Adjuvants, Immunologic-congresses. 2. Vaccines-congresses.
OW 800 N279i 19881
ORI87.3.N37 1988
615'.372-dc20
DNLMCDLC 89-25561
for Library of Congress CIP
© 1989 Plenum Press, New York
Softcover reprint of the hardcover 1st edition 1989
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PREFACE
Vaccination, chiefly responsible for the eradication of smallpox and
the control of poliomyelitis and German measles in man and of foot-and
mouth, Marek's and Newcastle disease in domestic animals, remains the best
answer to infectious diseases. Early vaccines were live wild type organ
isms but these have been largely replaced by attenuated or killed organisms
or by purified components (subunits) thereof. More recently, developments
in recombinant DNA techniques, the advent of monoclonal antibodies and
progress in our understanding of the immunological structure of proteins,
have laid the foundations for a new generation of vaccines. For instance,
subuni t vaccines have been produced through gene cloning and a number of
peptides mimicking small regions of proteins on the outer coat of viruses
and capable of eliciting virus neutralizing antibodies, have been synthes
ized. Such vaccines are defined at the molecular level, can elicit immune
responses controlling specific infectious organisms and are, thus, potent
ially free of the problems inherent in conventional ones. However, because
subunit and peptide vaccines are only weakly or non-immunogenic, they re
quire the presence of immunological adjuvants. These are a diverse array of
agents that promote specific humoural and/or cell-mediated immunity
responses to antigens.
This book contains the proceedings of the 1st NATO Advanced Studies
Institute "Immunological Adjuvants and Vaccines" held in Cape Sounion Beach,
Greece during 24 June-5 July, 1988. It deals with traditional and modern
immunological adjuvants as applied to a variety of conventional and new
generation vaCCines, mechanisms of adjuvanticity and related immune res
ponses as well as optimization of such responses by the use of appropriate
adjuvant formulations. We express appreciation to Professors Ruth Arnon and
J.H.L. Playfair for their advice in the planning of the ASI, to Dr. G.
Deliconstantinos Wl10, as Chairman of the local committee, contributed most
effectively to its success, and to Mrs. A. Massaro for her help with prac
tical aspects of the ASI. We are particularly grateful to Hrs. Susan
Gregoriadis for her invaluable input in the editing of the book. The ASI
was held under the sponsorship of NATO Scientific Affairs Division and co
sponsored and generously financed by Smith Kline and French Laboratories
(Philadelphia). Financial assistance was also provided by Syntex (Palo
Alto), Biophor (College Station), Sclavo (Sienna), Institut Merieux (Lyons),
Hoffmann-La-Roche (Easle), Boehringer (Mannhetll), Merck Sharp and Dohme
(West POint), Organon (Oss), Connaught Laboratories (Willowdale), Schering
(W. Berlin), Ciba Geigy (Horsham), Merz and Dade (Dudingen), Johnson and
Johnson (La Jolla) and Northumbria Biologicals (Cramlington).
June 1989 Gregory Gregoriadis
Anthony C. Allison
George Poste
v
CONTENTS
Antigens and Adjuvants for a New Generation of Vaccines
A.C. Allison 1
Structural and Functional Studies on MHC-Peptide Antigen
Interactions 13
H.B. Grey, S. Buus and A. Sette
Role of Interferon Gamma in the Priming of Human Accessory
Cells for Autocrine Secretion of Monokines (IL-l and
TNF) and HLA Class II Gene Expression 21
J.L. Virelizier, F. Arenzana-Seisdedos and S.C. Mogensen
Chemical Events in Immune Induction: Evidence for a Covalent
Intercellular Reaction Essential in Antigen-specific
T-cell Activation 27
J. Rhodes
Aluminium Salts: Perspectives in their Use as Adjuvants 35
R. Bomford
Saponins as Immunoadjuvants 43
R. Bomford
The Immunoadjuvant Dimethyldioctadecylammonium Bromide 47
H. Snippe and C.A. Kraaijeveld
Bacterial Endotoxins: Relationships between Chemical
Structure and Biological Activity 61
E.T. Rietschel, L. Brade, U. Schade, U. Seydel,
U. Zahringer, H. Loppnow, H-D. Flad and H. Brade
Recombinant Gamma Interferon as an Immunologic~l Adjuvant 75
J.H.L. Playfair, A.W. Heath and J.B. De Souza
The Immunoadjuvant Action of Liposomes: Role of Structural
Characteristics 79
G. Gregoriadis, L. Tan and Q. Xiao
Immunoadjuvant Action of Liposomes: Mechanisms 95
N. van Rooijen and D. Su
Liposomal Vaccine to Streptococcus Pneumoniae Type 3 and 14 107
H. Snippe, A.F.B. Verheul and J.E.G. van Dam
vii
Liposomes as Carriers of Vaccines: Development of a
Liposomal Malaria Vaccine 123
C.R. Alving, R.L. Richards, M.D. Hayre, W.T. Hockmeyer
and R.A. Wirtz
Nonionic Block Copolymer Surfactants as Immunological
Adjuvants: Mechanisms of Action and Novel Formulations 133
R.L. Hunter, B. Bennett, D. Howerton, S. Buynitzky and
LJ. Check
Use of Syntex Adjuvant Formulation to Augment Humoral
Responses to Hepatitis B Virus Surface Antigen and
to Influenza Virus Hemagglutinin 145
N.E. Byars, G. Nakano, M. Welch and A.C. Allison
Immunostimulating Complex (Iscom) 153
B. Morein, K. Lovgren and S. Hoglund
Recombinant Sub-unit and Peptide Viral Vaccines 163
F. Brown
Synthetic Antigens and Vaccines 175
R. Arnon
The Development and Preliminary Clinical Evaluation of an
Antifertility Vaccine 187
P.D. Griffin
Recent Progress with Vaccines against Epstein-Barr Virus
Infection 195
M.A. Epstein
Measurement of Antibody Affinity, Concentration and Isotype
to Evaluate Antigens, Adjuvants, and Inmrunization
Regimens in Vaccine Research 203
B.W. Hughes, J.S. Kenney and A.C. Allison
Recommendations for the Assessment of Adjuvants
(Inmrunopotentiators) 213
D.E.S. Stewart-Tull
Interaction between Industry and the Basic Researcher in the
University during Vaccine Development 227
D.E.S. Stewart-Tull
Contributors 233
Index 237
viii
ANTIGENS AND AlilllVANTS FOR A NEW GENERATION OF VACCINES
Anthony C. Allison
Syntex Research
Palo Alto
California, USA
INTRODUCTION
More than a decade has passed since vaccination made possible the
global eradication of smallpox. Vaccination has also been remarkably suc
cessful in reducing morbidity and mortality due to yellow fever virus in
Africa as well as Central and South America. These vaccines, as well as the
vaccines developed after the last World War against measles and rubella,
contain live attenuated viruses. While there is no question about the
efficacy of such vaccines and their safety in the great majority of recip
ients, they can produce encephalitis or other complications in humans with
immunodeficiency. Many persons in developing countries are immuno-deficient
because of infections and poor nutrition (Dowd and Heatley, 1984). The high
prevalence of human immunodeficiency virus (HIV) in parts of Africa is now
recognized. Live bacterial vaccines, e.g. Mycobacterium bovis BCG, can also
produce generalized infections in immunocompromised persons. Hence the
desirability of developing vaccines based on inactivated viruses or bac
teria, or purified antigens, is generally recognized. The question is
whether such development is feasible: there is still a widespread belief
that only living vaccines can elicit cell-mediated immunity and protection
against some infections.
Viral nucleic acids or their DNA homologues can become incorporated
into host cell DNA, and are known to trans-activate protooncogenes, which
could have undesirable long-term effects. Hence antigens lacking nucleic
acids are preferred for the new generation of vaccines. Some viral subunit
antigens are readily prepared from the viruses themselves, e.g. influenza
virus haemagglutinin (RA), or from naturally occurring materials, e.g.
hepatitis B virus surface antigen (HBsAg) from the serum of carriers.
However, two procedures have revolutionized antigen production during the
past decade.
Recombinant Antigens
One is production by recombinant DNA technology. The prototype is the
surface antigen of hepatitis B virus (HBsAg) cloned and expressed in yeast
in a form physically and antigenically resembling the 22 nm particles in
serum (Valenzuela et aI, 1983; Murray et aI, 1984). Recombinant HBsAg has
been shown to have immunogenicity in humans comparable to that of HBsAg de
rived from serum (Scolnick et aI, 1984), and it is now authorized for human
use in the USA and several other countries. In principle it is possible to
produce a wide range of antigens by recombinant DNA technology, although
optimal expression systems vary with different antigens. For example, HBsAg
is not readily produced in Escherichia coli, which is however a good expres
sion system for the nucleocapsid antigen (HBcAg) of the same virus (Murray
et aI, 1984). HBcAg from E. coli is in the form of particles physically and
antigenically resembling those produced during natural infection; conversion
of this p21 polypeptide to a non-particulate form in detergent changes its
antigenicity to that of HBeAg (MacKay et aI, 1981), illustrating the import
ance of conformation for antigenicity. When the three-dimensional structure
of antigens is known from X-ray crystallography and monoclonal antibodies
defining protective epitopes, many are found to be conformational rather
than linear. This is true of influenza virus haemagglutinin (Wiley et aI,
1981) and poliovirus (Hogle et aI, 1985), for example. Using suitable ex
pression systems, e.g. E. coli, yeast, baculovirus or mammalian cells, it is
possible to produce protein antigens with conformations similar to those
naturally occurring in many infectious agents. For example, herpes simplex
virus (HSV-2) glycoproteins B and D expressed in mammalian cells are typic
ally glycosylated and, inoculated with suitable adjuvants, efficiently pro
tect guinea pigs from genital HSV-2 infections (Berman et aI, 1985).
Many microbial antigens are being expressed by recombinant technology,
including pertussis and tetanus toxoids, bacterial fimbriae, respiratory
syncytial virus fusion protein and HIV surface and nucleocapsid antigens.
Recombinant technology can also be used to express peptides as fusion pro
teins with bacterial flagella, fimbriae, outer membrane proteins and other
potential carriers. All of these recombinant antigens are candidates for
inclusion in a new generation of vaccines.
Synthetic Peptide Antigens
The second strategy, which is becoming a major industry, is identific
ation of peptides in antigens recognized by T-Iymphocytes and by antibodies
and using the corresponding synthetic (or occasionally recombinant) peptides
in vaccines. The finding that quite small peptides bind to class II MHC
glycoproteins of antigen-presenting and stimulate T-lymphocytes (discussed
by Howard Gray; see below) has encouraged this approach. The concept of
synthetic peptide vaccines is of course appealing, and some interesting
candidates are emerging, including peptides of foot and mouth disease virus
and the connnon cold virus (discussed by Fred Brown, below). However, two
potential difficulties should not be overlooked. First, it is seldom poss
ible with synthetic peptides to reproduce conformational epitopes (although
disulphide-constrained loops and some other specific peptide conformations
can be synthesized). Second, innnune responses to peprides are frequently
genetically restricted. For example, mice of the H-2 haplotype do not
respond to S region peptides of HBV although they can respond to pre-S
peptides of the virus (Milich et aI, 1985). Hence it seems likely that in
outbred populations such as humans there will be a higher proportion of low
responders to peptides than to multi -epitope recombinant subunits. No syn
thetic peptide vaccine is yet in use; however, there is no shortage of ex
perimental work on the subject, and efficacious peptide vaccines may emerge
during the next few years.
IMPROVEMENT OF CURRENTLY USED VACCINES
To vaccinate against hepatitis B virus (HBV), three doses of HBsAg ad
juvanted with alum are given. It would be convenient to reduce the dose of
expensive HBsAg and to use two injections instead of three. It would also
be helpful to improve responses to HBV vaccine, espeCially in newborn child
ren in developing countries and in special groups, such as intravenous drug
2
users, in developed countries. Alum is the only adjuvant currently author
ized for human use. While it is a good adjuvant for bacterial toxins, it is
ineffective with some other antigens. Antibody responses to influenza virus
haernagglutinin are not increased by alum (Nicholson et aI, 1979). Influenza
vaccine is used mainly in humans aged 6S years or over, who are particularly
susceptible to the disease. In such individuals antibody responses to in
fluenza vaccine are inconsistent (Arden et aI, 1986) and an improved vaccine
is urgently needed. The currently used inactivated pertussis vaccine is
crude and occasionally produces neurological complications. It should be
possible to produce an efficacious vaccine without risk of such side ef
fects. Hence there is room for improvement of vaccines already in use.
VACCINES FOR THE FUTURE
The need for new vaccines is even greater: topping the list of those
urgently required are vaccines against the human immunodeficiency virus
(HIV-l) and malaria. However, other vaccines that may be more readily
developed within a few years include vaccines for hepatitis A virus, respir
atory syncytial virus and cornman bacterial infections of childhood. The
development of vaccines against herpesviruses also seems feasible.
How can existing vaccines be improved and new ones developed? To real
ize the full potential of recombinant and synthetic peptide antigens they
will have to be used with an adjuvant that elicits a protective immune
response. For vaccine design it is useful to know what type of immune
response is required for protection. Is the formation of antibodies suf
ficient or is cell-mediated immunity required? Is any antibody response
sufficient or are certain subclasses of antibodies, for example those able
to activate complement or mediate antibody-dependent cellular cytotoxicity,
required for optimal protection? Is secretory IgA required for protection
against mucosal infections?
As dicussed below, some adjuvants more consistently elicit cell
mediated immunity than others, and they can also favour the formation of
antibodies of protective isotypes. Adjuvants are therefore useful probes to
analyse immune responses. For a long time adjuvants such as alum and
Freund's complete adjuvant were used empirically without any knowledge of
how they exert their effects. With the great advances that have taken place
in immunology during the last decade, at least some of the effects of ad
juvants are being defined at the cellular and molecular levels. There is
widespread misunderstanding about the distinction between adjuvants and
inducers of non-specific resistance to infections, as there is about the
ambiguous uses of terms such as "carrier". It is therefore useful to begin
with a few relevant definitions.
DEFINITIONS
Elsewhere I have discussed the distinction between adjuvants, which
increase specific immune responses, and agents which non-specifically in
crease resistance to infections and tumors (Allison, 1978). This they do by
activating cells of the monocyte-macrophage lineage or natural killer cells.
Lipopolysaccharide endotoxins (LPS) and some murarnyl dipeptides (MDP) , or
related compounds such as murarnyl tripeptide phosphatidylethanol-arnine (MTP
PE), can have both activities. For reasons that will be discussed compounds
that are pure adjuvants, lacking capacity to increase non-specific resis
tance, are preferable for vaccine administration. Major differences between
the two effects are observed in timing and sensitivity to radiation. Non
specific resistance to infectious agents following administration of Myco
smarr
bacterium bovis BeG, Propionibacterium acnis, or active polymers or
3