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Comment. 

Previous attempts at chlamydial vaccine development have been ‘close ended’, making assumptions about the limited number of candidate antigens to be explored. New vaccine approaches are likely to be ‘open ended’, using modern techniques of ‘functional genomics’ to systematically explore chlamydial ORFs that might have vaccine potential. Clearly, this approach is only feasible because of the availability of complete genome sequences. At present, it is unlikely that DNA itself would be acceptable as a practical immunogen; there are concerns about the safety of DNA constructs based on eukaryotic expression vectors for use against non-lethal diseases. Such concerns may diminish, as DNA vaccines become better understood. The strength of functional genomics is its ability to reveal hitherto unknown vaccine candidates among open reading frames [ORFs] whose function is poorly understood. The Aventis Pasteur project, in which over 200 open reading frames have been explored for their suitability, produced several surprises. Firstly, C. pneumoniae MOMP and the 60KDa cysteine rich proteins were identified as vaccine candidates, even though there has been doubt about whether they are surface exposed on C. pneumoniae because of the presence of the polymorphic outer membrane proteins. Surface accessibility of the target antigen is required for protection mediated by neutralising antibody but not by cell mediated immunity. Secondly, the protective role of the ADP / ATP translocase suggests the hitherto unsuspected existence of a whole new set of vaccine candidates based on molecules which are metabolically or physiologically important. Although the protective effect was relatively modest, it was reproducible and statistically significant. Combinations of several different protective ORFs might enhance protection at least additively. This is the approach which Antex Biologics appear to have taken in choosing a mix of C. trachomatis putative membrane proteins. 

At the present time the role of CD8+ cytotoxic T lymphocytes against chlamydial infected cells is unclear and somewhat controversial. Experimental infection in knock out mice tends to be consistent with the importance of CD4+ helper T cells, rather than CD8+ cytotoxic T cells. However Michael Starnbach's group at Harvard, have observed during infection with C. trachomatis, CD8(+) T cells are primed despite the fact that the bacteria remain confined to a host cell vacuole throughout their developmental cycle. This suggested that chlamydial antigens recognized by these CD8(+) T cells must have access to the host cell cytoplasm. Working in collaboration with the Corixa corporation in Seattle, a retroviral expression system was used which identified Cap1, a 31-kDa protein from C. trachomatis, as a protein  recognized by protective, ifng secreting CD8(+) T cells. Cap1 contains no strong homology to any known protein and it is localized to the inclusion membrane and is virtually identical across human C. trachomatis serovars. It was suggested that inclusion proteins like Cap1 are potential vaccine candidates and may also give new insight into chlamydial intravacuolar biology [Fling et al., 2001]. 

Given that there is now a conjunction of powerful new technology plus at least three interested vaccine companies, the prospects for progress on chlamydial vaccines are good.

[MEW] November 2002

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Reference

Fling, S. P., Sutherland, R. A., Steele, L. N., Hess, B., D'Orazio, S. E., Maisonneuve, J., Lampe, M. F., Probst, P. & Starnbach, M. N. (2001). CD8+ T cells recognize an inclusion membrane-associated protein from the vacuolar pathogen Chlamydia trachomatis. Proceeding of the National Academy of Sciences U S A. 98, 1160 - 1165. Full article