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 This
review is intended to cover some recent advances in
identification of vaccine candidates and in methods of
delivery of vaccine antigens. Sequencing of bacterial genomes
has led to rapid utilization of the predicted open reading
frames to identify potential candidates for evaluation and,
with improvements in proteomics combined with microanalytical
sequencing techniques, to identify expressed proteins.
Expression of vaccine antigens in human food sources has been
greatly improved, opening the possibility of orally delivered
subunit vaccines, as has the ability to modify the immune
response with cytokines and chemokines. These techniques are
slowly making their way to human studies and show great
promise for future human use.
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Introduction
Informed decisions regarding the potential efficacy of
vaccine candidates can save considerable time and expense at
downstream development and clinical trials. Recent
developments in bioinformatics and in our understanding of the
pathogenicity, epidemiology and nature of the protective
immune response have dramatically changed vaccine research. As
a multidisciplinary field, advances in vaccinology parallel
many of the innovations made in a wide variety of other areas
of investigation (
Fig. 1). This review seeks to briefly summarize some of
these advances and how they have affected or may affect
vaccinology.
Genomics
One of the earlier published applications of genomics to
vaccinology has been to identify and clone open reading frames
(ORFs) that encode putative virulence factors and
surface-localized proteins of a particular bacterial pathogen
[1]. Using existing algorithms to predict surface
localization and comparisons to known vaccine candidates,
several hundred ORFs may be cloned into expression systems.
The relative binding properties of antibodies to ORF products
can be assayed using a whole-cell enzyme-linked immunosorbent
assay (ELISA) or fluorescent activated cell sorter (FACS)
analysis. Leading vaccine candidates are then tested in animal
models or in vitro assays designed to provide some
indication of the ability of the antigen to elicit a
protective immune response.
Although this process, sometimes referred to as reverse
vaccinology
[2], represents an enormous advance compared to
conventional methods, it still requires a considerable amount
of time and effort. Fortunately, as more genomes are being
sequenced and analyzed, additional criteria are rapidly being
developed that can be used to improve the in silico
screening process for identification of surface proteins
[3•]. Particularly useful in this regard is a
centralization of databases and tools that permits a variety
of analyses and comparisons to be made
[4•].
Information about the genome structure of microbial pathogens
lends valuable information regarding the juxtaposition of
potential vaccine targets relative to repeated regions, mobile
genetic elements or pathogenicity islands. Also, the rapidly
developing field of comparative genomics is beginning to
define specific sets of metabolic and pathogenic markers that
are likely to confer the selective advantages required for a
pathogen to infect specific hosts and occupy a particular
niche
[4•,5–7] . DNA microarrays have been used to define
specific genetic adaptations present in different endemic and
pandemic strains of Vibrio cholerae
[8] and indicate that a limited number of genes are
responsible for the enhanced fitness of pandemic strains.
Comparative genomics of Staphylococcus aureus
[9•] and other human pathogens show that more than 20% of
the genome can be devoted to strain-specific functions. Given
that this diversity can be disproportionately present in
cell-surface antigens, comparative genomics becomes an even
more important method for large-scale screening of conserved
vaccine targets. Alternatively, identification of genes unique
to pathogenic biotypes
[10,11] may provide specific vaccine targets and avoid
potential complications of inducing immunity to normal
commensal strains.
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BioMedNet Magazine
20th November - 3rd December 2002 |
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