Background: Mycobacterium tuberculosis, the causative agent of
tuberculosis (TB), infects ~8 million annually culminating in ~2 million
deaths. Moreover, about one third of the population is latently
infected, 10% of which develop disease during lifetime. Current approved
prophylactic TB vaccines (BCG and derivatives thereof) are of variable
efficiency in adult protection against pulmonary TB (0%–80%), and
directed essentially against early phase infection.
Methods: A genome-scale dataset was constructed by analyzing published
data of: (1) global gene expression studies under conditions which
simulate intra-macrophage stress, dormancy, persistence and/or
reactivation; (2) cellular and humoral immunity, and vaccine potential.
This information was compiled along with revised
annotation/bioinformatic characterization of selected gene products and
in silico mapping of T-cell epitopes. Protocols for scoring, ranking and
prioritization of the antigens were developed and applied.
Results: Cross-matching of literature and in silico-derived data, in
conjunction with the prioritization scheme and biological rationale,
allowed for selection of 189 putative vaccine candidates from the entire
genome. Within the 189 set, the relative distribution of antigens in 3
functional categories differs significantly from their distribution in
the whole genome, with reduction in the Conserved hypothetical category
(due to improved annotation) and enrichment in Lipid and in Virulence
categories. Other prominent representatives in the 189 set are the
PE/PPE proteins; iron sequestration, nitroreductases and proteases, all
within the Intermediary metabolism and respiration category; ESX
secretion systems, resuscitation promoting factors and lipoproteins, all
within the Cell wall category. Application of a ranking scheme based on
qualitative and quantitative scores, resulted in a list of 45
best-scoring antigens, of which: 74% belong to the
dormancy/reactivation/resuscitation classes; 30% belong to the Cell wall
category; 13% are classical vaccine candidates; 9% are categorized
Conserved hypotheticals, all potentially very potent T-cell antigens.
Conclusion: The comprehensive literature and in silico-based analyses
allowed for the selection of a repertoire of 189 vaccine candidates, out
of the whole-genome 3989 ORF products. This repertoire, which was ranked
to generate a list of 45 top-hits antigens, is a platform for selection
of genes covering all stages of M. tuberculosis infection, to be
incorporated in rBCG or subunit-based vaccines.
Zvi, A.; Ariel, N.; Fulkerson, J.; Sadoff, J.C.; Shafferman, A. Whole genome identification of Mycobacterium tuberculosis vaccine candidates by comprehensive data mining and bioinformatic analyses. BMC Medical Genomics (2008) 1 (1) 18. [DOI: 10.1186/1755-8794-1-18]
Whole genome identification of Mycobacterium tuberculosis vaccine candidates by comprehensive data mining and bioinformatic analyses.