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Conference Summary
Workshop on Carbohydrate Moieties
as Vaccine Candidates
Christopher E. Taylor*
*National Institutes Health, Bethesda, Maryland, USA
Suggested
citation for this article
Workshop on Carbohydrate Moieties as Vaccine Candidates
Bethesda, MD, USA
October 6-7, 2004
Whole microbes, microbial subunits and extracts, and peptide and protein
antigens have been the focus of much vaccine research and development.
While studies of peptide and protein antigens have been facilitated by
the rapid advances in genomics and proteomics, studies of sugar chains,
which are abundantly expressed on the outer surfaces of viral, bacterial,
protozoan, and fungal pathogens and on the membranes of mammalian cells,
have not kept pace with technologic advances. Polysaccharide-based vaccines
have demonstrated efficacy in disease-prevention strategies, e.g., Haemophilus
influenzae b and pneumococcal conjugate vaccines. However, our understanding
of several aspects of polysaccharide vaccines is limited, and more knowledge
is needed to allow greater development and deployment. The goals of this
workshop were to examine the mechanisms involved in generating an appropriate
immune response to selected carbohydrate antigens, highlight recent and
novel advances, and discuss how this information could be used in the
development of effective vaccines. The workshop participants included
national and international research scientists and clinicians from the
National Institutes of Health, the Food and Drug Administration, academia,
and industry.
The meeting was organized into 7 sessions on such topics as genetic and
cellular mechanisms of carbohydrate immunity, carbohydrate antigens for
vaccines, and new tools for studying carbohydrates. Understanding the
mechanistic aspects of the genetic control and the cellular pathways of
the immune response to bacterial carbohydrate antigens should provide
insights into ways to enhance the immune response and thus facilitate
vaccine development. Studies were also presented on novel molecules involved
in the recognition of carbohydrate antigens such as specific intercellular
adhesion molecule (ICAM)–grabbing nonintegrins, which are C-type lectins
that show substantial expression in many tissues, and toll-like receptors,
which function as pattern recognition receptors for conserved pathogen
structures and serve as key links between innate and adaptive immunity.
Investigations are ongoing to determine how these molecules function in
bacterial clearance and in signaling innate and adaptive responses. A
number of presentations were focused on the role of CD1 proteins, which
present lipid antigens (e.g., from mycobacteria or Francisella tularensis,
a potential weapon of bioterrorism) to T cells. The evidence that CD1-restricted
T cells contribute to immunity against microbial infection includes the
observation that CD1 is expressed at higher levels in lesions of tuberculoid
leprosy in comparison to lepromatous leprosy. The design of optimal vaccines
against such pathogens should include lipid and peptide antigens.
Presentations from several invited experts emphasized the current challenges
facing the development of vaccines for meningococcal meningitis. Given
that group B meningococcal capsular polysaccharide is similar to host
molecules, studies are ongoing to identify vaccine candidates that elicit
protective antibody without eliciting autoantibodies. A licensed outer
membrane vesicle vaccine was recently introduced for widespread use in
New Zealand to control an epidemic. Regarding groups A and C polysaccharides,
differences exist in age-related immune responses; for example, for unknown
reasons group A polysaccharide is uniquely immunogenic in infants as young
as 6 months of age and repeated doses elicit booster antibody responses,
whereas group C is poorly immunogenic and repeated doses do not induce
adequate responses.
A continuing problem in vaccine research is devising methods to enhance
the immune response and then ensuring that it is protective against disease;
for instance, the use of CD40 agonist antibody plus antigen showed remarkably
rapid immune response and protection in a murine model of anthrax. Equally
challenging are efforts to develop combined and multivalent vaccines;
several new approaches were discussed. For instance, a diphtheria, tetanus,
pertussis, hepatitis B, H. influenzae b, meningococcal A and C
combination vaccine has been tested in an open, randomized, controlled
study. It induces groups A and C bactericidal antibody responses in infants
and has reactogenicity profiles similar to meningococcal A and C conjugates
given separately. Recent efforts in HIV vaccine research indicate that
producing a multivalent envelope glycan conjugate vaccine to induce production
of broad neutralizing antibodies is possible.
New technologies such as carbohydrate microarrays, automated syntheses
of oligosaccharides, and biophysical and computational methods for studying
antigen-antibody interactions are now available for providing insight
into the structure of and immune response to carbohydrate antigens. Additionally,
peptide mimotopes may be used in carbohydrate technologies designed for
proteins. An oligosaccharide synthesizer is now being used in the development
of a number of vaccines, including those for malaria, leishmaniasis, HIV,
tuberculosis, and leprosy. A Consortium for Functional Genomics (Web site
available from http://www.functionalglycomics.org)
has been established at the Scripps Research Institute and has developed
a novel glycan array format that uses covalent coupling of glycans to
glass slides.
At the conclusion of the workshop, participants were asked to identify
gaps in knowledge and resource needs. The gaps include 1) elucidating
the mechanisms of immunity to and regulation of carbohydrate antigens
in adults, children, and neonates and using opportunities (e.g., computer
capacity) for modeling carbohydrate antigen-antibody interactions; 2)
defining the molecular basis of enhanced immunogenicity with glycoconjugate
vaccines and investigating the role of adjuvants; 3) examining the role
of CD1-reactive T cells in the immune response to capsular polysaccharides;
and 4) developing surrogates for in vivo immunity for the use of glycolipids
as CD1-based vaccines in humans. Resource needs include the following:
1) enhanced availability of carbohydrate microarrays; 2) development of
appropriate animal models and the availability of a transgenic mouse platform
that allows generation of human antibodies; 3) development of tetramers
and analytical chemistry to help in the identification of antigens, e.g.,
for the use of glycolipids as CD-1-based vaccines; and 4) enhanced good
laboratory practice (GLP) resources to produce synthetic carbohydrate
vaccines and GLP testing for vaccine candidate safety in animals and for
production of good manufacturing practice vaccine candidates. As a result
of the workshop, an open LISTSERV (GLYCOIMMUNOLOGY) has been established,
and the Journal of Clinical Infectious Diseases will publish a review
article. For additional information, contact ctaylor@niaid.nih.gov
The workshop was
sponsored by funds from the National Vaccine Program Office and the
National Institute of Allergy and Infectious Diseases.
Suggested citation
for this article:
Taylor CE. Workshop
on carbohydrate moieties as vaccine candidates [conference summary]. Emerg
Infect Dis [serial on the Internet]. 2005 Apr [date cited]. Available
from http://www.cdc.gov/ncidod/EID/vol11no04/04-1142.htm
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