Table Of ContentCurrent Topics in
Microbiology
146 and Immunology
Editors
R. W. Com pans, Birmingham/Alabama . M. Cooper,
Birmingham/Alabama . H. Koprowski, Philadelphia
I. McConell, Edinburgh . F. Melchers, Basel
M. Oldstone, La Jolla/California . S. Olsnes, Oslo
H. Saedler, Cologne P. K. Vogt, Los Angeles
H. Wagner, Munich . I. Wilson, La Jolla/California
New Strategies for
Oral Immunization
International Symposium
at the University of Alabama at Birmingham
and Molecular Engineering Associates, Inc.
Birmingham, AL, USA, March 21-22, 1988
Organized and Edited by
1. Mestecky, and 1. R. McGhee
With 22 Figures
Springer-Verlag
Berlin Heidelberg NewY ork
London Paris Tokyo
JIRI MESTECKY, M.D.
Professor of Microbiology
Medicine and Oral Biology
JERRY R. MCGHEE, PH. D.
Professor of Microbiology
Department of Microbiology,
University of Alabama at Birmingham
UAB Station, Birmingham, Alabama 35 294, USA
ISBN-13: 978-3-642-74531-7 e-ISBN-13: 978-3-642-74529-4
DOl: 10.1007/978-3-642-74529-4
This work is subject to copyright. All rights are reserved, whetherthewholeorpartof
the material is concerned, specifically the rights oftranlation, reprinting, re-use of
illustrations, recitation, broadcasting, reproduction on microfilms orin other ways,
and storage in data banks. Duplication of this publication orpartsthereofisonly per
mitted under the provisions of the German Copyright Law ofSeptember9, 1965, in
its version of June 24,1985, and a copyright fee must always be paid. Violations fall
under the prosecution act of the German Copyright Law.
© Springer-Verlag Berlin Heidelberg 1989
Library of Congress Catalog Card Number 15-12910
Softcover reprint of the hardcover 1st edition 1989
The use of registered names, trademarks, etc. in this publication does not imply,
even in the absence ofa specific statement, that such names are exempt from the rele
vant protective laws and regulations and therefore free for general use.
Product Liability: The publishers can give no guarantee for information about drug
dosage and application thereof contained in this book. In every individual case the
respective user must check its accuracy by consulting other pharmaceutical
literature.
Offsetprinting: Color-Druck Dorfi GmbH, Berlin
2123/3020-543210 - Printed on acid-free paper
Preface
Environmental antigens, particularly those from ingested food and endogenous
gastrointestinal microorganisms, are important stimulants of the hosts immune
system. Thus, both humoral and cell-mediated arms of the systemic and mucosal
immune compartments are profoundly influenced by the constant exposure to such
environmental stimuli. It might be surprising to some to realize that the idea of
stimulating protective immunity by oral immunization was actually discovered by a
pioneering scientist and forebearer of modern immunology. Paul Ehrlich showed in
two largely neglected papers published in 1891, that the oral route of immunization has
distinct advantages over systemic immunization for protective immunity to the plant
poisons abrin and ricin. Even more remarkable was his demonstration that such
immunization protected guinea pigs to not only a systemic but also to a mucosal
challenge. He found that oral immunization with increasing doses of toxin protected
animals from conjunctival challenge, while control animals developed massive
necrotic lesions in the challenged eye. It should be stressed that these results were
reported only a few years after the discovery of antibodies and decades before it was
realized that different immunoglobulin isotypes occur and are found in characteristic
distribution in various external secretions. Since Ehrlich induced protective immune
responses at distant mucosal sites following oral immunization, he should be credited
as the first to discover the common mucosal immune system.
Oral immunization has continued to have a fascinating history. It is difficult to select
an antigen which has not been used by the oral route for immunization. In spite of the
frequently successful use of this route to induce immunity, it is most often
overshadowed by reports stressing other, usually systemic, routes for immunization.
Thus, only a few of the numerous vaccines in current use are given by the oral route.
We, therefore, felt that this neglect is not deserved and that oral immunization has
much to contribute, particularly, in light of recent methodological and technical
advances in antigen delivery systems, to modern human and veterinary preventive
medicine.
Realization of this meeting was possible due to the support provided by numerous
contributors: Molecular Engineering Associates, Birmingham, Alabama; the Procter
and Gamble Company, Cincinnati, Ohio; and numerous colleagues at The University of
Alabama at Birmingham, namely, Drs. J. Claude Bennett, e.O. Elson, G.H. Cassell, and
Deans J. Pittman and RR Ranney from the Schools of Medicine and Dentistry.
It gives us a great deal of pleasure to acknowledge the help of Ms. Maria Bethune for the
organization of this meeting as well as the typing and assembly of all manuscripts.
Jiri Mestecky, Jerry R McGhee
VI
Ehrlich P (1891) VI. Experimentelle Untersuchungen tiber Immunitiit. I. Ueber Ricin.
Deutsche Medicinische Wochenschrift 17:976-979.
Ehrlich P (1891) Experimentelle Untersuchungen tiber Immunitiit. II. Ueber Abrin.
Deutsche Medicinische Wochenschrift 17:1218-1219.
Contents
Oral Immunization and Mucosal Immune System
J. Mestccky, and 1.R. McGhee: Oral Immunization: Past and Present. With 2 Figures. . 3
P. Brandtzaeg: Overview of the Mucosal Immune System. With 4 Figures. . . . . . . . .. 13
Antigen Delivery Systems
C.O. Elson: Cholera Toxin and its Subunits as Potential Oral Adjuvants. . . . . . . . . . .. 29
R. Curtiss III, S.M. Kelly, P.A. Gulig, and K. Nakayama: Selective Delivery of Antigens
by Recombinant Bacteria.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 35
S.M. Michalek, N .K. Childers, 1. Katz, F .R. Denys, A.K. Berry, 1.H. Eldridge, J .R. McGhee,
and R. Curtis III: Liposomes as Oral Adjuvants. With 1 Figure. . . . . . . . . . . . . . . .. 51
J .H. Eldridge, R .M. Gilley, J.K. Staas, Z. Moldoveanu, J .A. Meulbroek, and T.R. Tice:
Biodegradable Micropheres: Vaccine Delivery System for Oral Immunization.. . . . . .. 59
Viral Vaccines
R.H. Waldman, and K.-C. Bergmann: Introduction to Oral Immunization Against Viral
Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 69
P.L. Ogra, E.E. Leibovitz, and G. Zhao-Ri: Oral Immunization and Secretory Immunity
to Viruses. . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 73
K.-C. Bergmann, and R.H. Waldman: Oral Immunization with Influenza Virus: Experimental
and Clinical Studies.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 83
Z. Moldoveanu, 1.K. Staas, R.M. Gilley, R. Ray, R.W. Compans, J.H. Eldridge, T.R. Tice,
and J. Mestecky: Immune Responses to Influenza Virus in Orally and Systemically
Immune Mice. With 6 Figures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 91
K .-S. Chen, and G.V. Quinnan Jr.: Efficacy of Inactived Influenza Vaccine Delivered by
Oral Administration. With 1 Figure .................................... 101
B.R. Murphy, and M.L. Clements: The Systemic and Mucosal Immune Response of Humans
to Influenza A Virus .............................................. 107
J.G. N edrud, X .-P. Liang, and M.E. Lamm: Oral Immunization with Sendai Virus in Mice.
With 1 Figure ................................................... 117
R. Edelman, J. Flores, and A.Z. Kapikian: Immunity to Rotaviruses. With 1 Figure .... 123
H. Koprowski: Rabies Oral Immunization. With 1 Figures ............. ' ...... 137
Bacterial Vaccines
U. Dahlgren, B. Carlsson, F. Jalil, R. MacDonald, F. Mascart-Lemone, K. Nilsson,
D. Roberton, F. Sennhauser, A. Wold, and L.A. Hanson: Induction of the Mucosal Immune
Response ..................................................... 155
A. Tarkowski, C. Lue, Z. Moldoveanu, H. Kiyono, J.R. McGhee, J.T. Prchal, N.B. Halpern,
and J. Mestecky: Systemic Immunization for the Induction of IgA Responses. With
I Figure ...................................................... 161
J.B. Robbins, R. Schneerson, S.C. Szu, A. Fattom, Y. Yang, T. Lagergard, C. Chu, and
U.S. Sorensen: Prevention of Invasive Bacterial Diseases by Immunization with
Polysaccharide-Protein Conjugates ..................................... 169
R.L. Clancy, F.J. Wallace, A.W. Cripps, and G.T. Pang: Protection Induced Against Acute
Bronchitis - The Use of Human and Rat Models to Determine Mechanisms of Action of
Oral Immunization with Haemophilus influenzae . .......................... 181
M.A. Taubman, and D.J. Smith: Oral Immunization for the Prevention of Dental
Diseases ...................................................... 187
J. Holmgren, J. Clemens, D.A. Sack, J. Sanchez, and A.-M. Svennerholm: Oral Immunization
Against Cholera ................................................. 197
T.L. Hale, and S.B. Formal: Oral Shigella Vaccines .......................... 205
D.F. Keren, R.A. McDonald, J.S. Wassef, L.R. Armstrong, and J.E. Brown: The Enteric
Immune Response to Shigella Antigens. With 4 Figures ....................... 213
A. Tagliabue: Immune Response to Oral Salmonella Vaccines. With I Figure ......... 225
J.R. McGhee, and J. Mestecky: Oral Immunization: A Summary ................. 233
List of Contributors
You will find the adresses at the beginning of the respective contribution
Armstrong, L.R. 213 Lue,C.
Bergmann, K.-C. 67,83 MacDonald, R. 155
Berry,A.K. 51 McDonald, R.A. 213
Brandtzaeg, P. 13 Mascart-Lemone, F. 155
Brown, J.E. 213 McGhee, J.R. 3,51,161
Carlsson, B. 155 Mestecky, J. 3, 91, 161
Chen, K.S. 101 Meulbroeck, J.A. 59
Childers, N.K. 51 Michalek, S.M. 5 1
Chu, C. 169 Moldoveanu, Z. 59,91, 161
Clancy, R.L. 181 Murphy, B.R. 107
Clemens, J. 197 Nakayama, K. 35
Clements, M.L. 107 Nedrud,J.G. 117
Com pans, R.W. 91 Nilsson,K. 155
Cripps, A.W. 181 Ogra, P.L. 73
CurtissIII,R. 35,51 Pang, G.T. 181
Dahlgren, U. 155 Prchal, J .T. 161
Denys, F .R. 51 Quinnan, Jr., G.Y. 101
Edelman, R. 123 Ray,R.
Eldridge,J.H.51,59,91 Robbins, J.B. 169
Elson, C.O. 29 Roberton, O. 155
Fattom, A Sack, D.A. 197
Flores, J. 123 Sanchez, J. 197
Formal, S.B. 59,205 Schneerson, R. 169
Gilley, R.M. 91 Sennhauser, F. 155
Gulig,P.A. 35 Smith, OJ. 187
Hale, T.L. 205 Sorensen, U.S. 169
Halpern, N.B. 161 Staas, J.K. 59,91
Hanson, L.A. 155 Svennerholm, A.-M. 197
Holmgren, J. 197 Szu, S.C. 169
Jalil, F. 155 TagJiabue, A. 225
Kapikian, A.Z. 123 Tarkowski, A. 161
Katz, J. 51 Taubman, M.A. 187
Kelly, S.M. 35 Tice, T.R. 59,91
Keren, D.F. 213 Waldman, R.H. 67,83
Kiyono, H. 161 Wallace, F.J. 181
Koprowski, H. 137 Wassef, J.S. 213
Lagergard, T. 169 Wold, A. 155
Lamm, M.E. 117 Yang, Y. 169
Leibovitz, E.E. 73 Zhao-Ri, G. 73
Liang, X.-P. 117
Oral Immunization
and Mucosal Immune System
Oral Immunization: Past and Present
J. Mestecky, and J.R McGhee
Departments of Microbiology and Medicine, University of Alabama at Birmingham,
Birmingham, AL 35294, USA
INTRODUCTION
Diverse environmental antigens of microbial and food origin constantly stimulate the
entire immune system. Mucosal membranes which represent a vast area of contact
with the environment, are exposed daily to antigenic substances that induce specific
humoral as well as cell-mediated immune responses not only at the site of the
stimulation - mucosa-associated lymphoid tissues - but also in the draining lymph
nodes, spleen, and the bone marrow (Fig. 1). Therefore, it should not be surprising that
mucosa-associated organs, especially the intestines, contain the largest accumulation of
lymphoid cells, including Band T lymphocytes and plasma cells, as well as accessory
and antigen- processing and-presenting cells (Brandtzaeg this volume). Quantitatively,
the intestinal tract is the most active organ engaged in immunoglobulin production
and antibodies, particularly those of the IgA isotype, are selectively transported into the
gut lumen (Conley and Delacroix 1987; Mestecky and McGhee 1987).
Mucosal surfaces are the most frequent portals of entry of common viral, bacterial, and
parasitic infectious diseases and of potentially harmful antigenic substances from'the
environment. It has been convincingly demonstrated that secretory antibodies are able
to limit the absorption of protein antigens through the mucosal membranes, inhibit
the attachment of bacteria to the epithelial cells, and neutralize a broad spectrum of
viruses that infect epithelial cells, or cause more generalized diseases (Kilian et al. 1988).
Because the currently used systemic immunization may not be effective in the
induction of antibodies in external secretions, especially in individuals who had not
been previously exposed to a given microorganism or environmental antigen through
mucosal membranes, numerous attempts have been made to induce an immune
response in external secretions (for review see Mestecky 1987). Thus, mucosal surfaces
of the upper respiratory tract, conjunctiva, vagina, or intestinal tract have been exposed
to killed or attenuated viruses or bacteria in many attempts to induce, frequently with
success, a local immune response and protection of mucosal areas restricted to the site
of antigen application. Subsequent extensive studies that addressed the questions
concerning the origin of IgA-producing plasma cells and effective routes of
immunization revealed that gut- and bronchus-associated-Iymphoid tissues function as
sources of antigen-sensitized and IgA-committed plasma cell precursors that populate
remote mucosal tissues and glands and led to the formulation of the concept of a
common mucosal immune system (for reviews see Lamm 1976; Mestecky and McGhee
1987).
In addition to humoral responses manifested by secretory antibodies, antigen ingestion
profoundly influences systemic immunity (Fig. 1). Of particular interest for the
prevention of sensitization by environmental allergens is the state of oral tolerance
(Tomasi 1980) that appears to be predominately mediated by a subset of T cells and their
Current Topics in Microbiology and Immunology, Yol. 146
© Springer·Yerlag Berlin· Heidelberg 1989
