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New approaches to vaccination.

Almost 40 years of chlamydial vaccine research has basically not produced the desired vaccine. Cynics might be forgiven for regarding chlamydial vaccines as dream vaccines. However technical and conceptual advances made in the last decade hold real promise for the development of useful vaccines against chlamydial infection. Some of these are summarised in the thumbnail slide below: 

[Thumbnail: Possible new approaches to chlamydial vaccine development].

Firstly, it is now clear that the T-helper 1 cell mediated immune response plays a key role in the protective immune response to chlamydial infection. This has only truly been appreciated since the classic paper of Morrison et al., 1995 and has been paralleled generally by recognition of the key role of the dendritic cell as an antigen presenting cell. The finding that  bone marrow derived mouse dendritic cells, pulsed ex vivo with chlamydiae, promote protective Th1-type cell mediated immune responses comparable to those obtained by infection with live organisms [Su et al., 1998] offers a cellular method in the laboratory whereby chlamydial components capable of causing the production of IL-12 and of stimulating T-helper 1 responses can be identified. Unfortunately good ex vivo results are not always accompanied by in vivo successes [Shaw et al., 2002].

Secondly, mice intramuscularly or intranasally immunized with C. muridarum DNA (genetic material) coding for the genetically engineered expression of chlamydial major outer membrane protein were protected from fatal experimental lung infection with this organism [Zhang et al., 1997; Brunham & Zhang, 1999; Zhang et al., 1999; 2000]. Effective induction of protective cell mediated immune responses to chlamydiae has also been achieved with DNA vaccines in turkeys [Vanrompay et al., 1999; 2001a; b]. However a similar approach did not protect against genital, as opposed to respiratory, C. muridae infection in the mouse. The power of this DNA-based approach (see later) is that it can be used to explore known whole chlamydial genomes for protective open reading frames (coding regions of DNA).

Thirdly, there are improved technical methods of producing genital tract mucosal antibody responses now available that offer potential for chlamydial vaccine development. In mice intranasal vaccination with whole organisms protects against intra-vaginal infection with C. trachomatis. Eldexomer gel, a sticky gel, can be used to coat the cervix, slowly releasing chlamydial antigen so as to achieve a sustained, mucosal immune response [Wassen et al., 1996]. New gene constructs designed to elicit mucosal immunity are at the experimental stage. This includes the expression of chlamydial components capable of inducing a protective immune response, using the normal flora, harmless vaginal bacterium, Lactobacillus [Turner et al., 1999]. One of the most effective stimulators of mucosal immune response and of neutralizing antibody is cholera toxin.  De-toxified constructs of cholera toxin can be linked to protective bacterial antigens, targeting the mucosal immune response against them [Agren et al., 1998]. 

Fourthly, chlamydial genome sequencing and other approaches has lead to potential new vaccine candidates. Among these are the chlamydial polymorphic membrane proteins, constituents of the experimental Antex Biologics TRACVAX^® 

Finally, research into gene therapy has lead to new carrier viruses into which chlamydial vaccine constructs can be genetically engineered to take advantage of the viral  capability of eliciting Th1 type responses to the insert. 

The ultimate goal of current chlamydial vaccine efforts is an acceptable immunisation regimen capable of inducing a sterilising, long-lived, protective immunity at mucosal sites of infection (C. trachomatis) or in the lungs or blood vessels (C. pneumoniae). This lofty goal poses tremendous challenges, but we have new techniques and information to meet them. These challenges are  compounded by the biological complexity of chlamydia, the existence of multiple variants, the capacity to induce both protective and deleterious immune effectors, and the occurrence of asymptomatic and persistent infections. Vaccination still represents the best approach to protect the greatest number of people against the complications of chlamydial infections. Considering the urgency and the enormity of these challenges, a partially protective vaccine capable of preventing some of the severe complications of infection might be an acceptable short-term goal.

For more detailed information, readers are referred to the excellent and comprehensive review by Igietseme et al., 2002.

NEXT: Chlamydophila pneumoniae vaccines.

References

Agren L, Lowenadler B, Lycke N. (1998). A novel concept in mucosal adjuvanticity: the CTA1-DD adjuvant is a B cell-targeted fusion protein that incorporates the enzymatically active cholera toxin A1 subunit. Immunology and Cell Biology 76, 280 - 287.

Brunham RC, Zhang D-J. (1999). Transgene as vaccine for chlamydia. American Heart Journal 138, S519 - 522.

Igietseme, J. U., Black, C. M. & Caldwell, H. D. (2002). Chlamydia vaccines: strategies and status. BioDrugs 16, 19 - 35. [Excellent and comprehensive review].

Morrison, R. P., Feilzer, K. & Tumas, D. B. (1995). Gene knockout mice establish a primary protective role for major histocompatibility complex class II-restricted responses in Chlamydia trachomatis genital tract infection. Infection and Immunity 63, 4661 - 4668. Full article  [Milestone paper which established the key importance of class II restricted responses in cell mediated immunity to chlamydial infection].

Shaw, J., Grund, V., Durling, L., Crane, D., Caldwell, H. D. (2002). Dendritic cells pulsed with a recombinant chlamydial major outer membrane protein antigen elicit a CD4(+) type 2 rather than type 1 immune response that is not protective. Infection and Immunity 70, 1097 - 1105.

Turner, M. S. & Giffard, P. M. (1999). Expression of Chlamydia psittaci- and human immunodeficiency virus-derived antigens on the cell surface of Lactobacillus fermentum BR11 as fusions to bspA. Infection and Immunity 67, 5486 - 5489. Full article   

Vanrompay, D., Cox, E., Volckaert, G. & Goddeeris, B. (1999). Turkeys are protected from infection with Chlamydia psittaci by plasmid DNA vaccination against the major outer membrane protein. Clinical and Experimental Immunology 118, 49 - 55. [Innovative work].

Vanrompay, D., Vanloock, M., Cox, E., Goddeeris, B. M. & Volckaert, G. (2001a). Genetic immunization for Chlamydia psittaci. Verh K Acad Geneeskd Belg. 63, 177 - 188.

Vanrompay, D., Cox, E., Kaiser, P., Lawson, S., Van Loock, M., Volckaert, G. &  Goddeeris, B. (2001b). Protection of turkeys against Chlamydophila psittaci challenge by parenteral and mucosal inoculations and the effect of turkey interferon-gamma on genetic immunization. Immunology 103, 106 - 112.

Wassen L., Schon, K., Holmgren, J., Jertborn, M. & Lycke, N. (1996). Local intravaginal vaccination of the female genital tract.  Scandinavian Journal of Immunology  44: 408 - 414.

Zhang, D-J., Yang, X., Berry, J., Shen, C., McClarty, G. & Brunham, R. C. (1997). DNA vaccination with the major outer-membrane protein gene induces acquired immunity to Chlamydia trachomatis (mouse pneumonitis) infection. Journal of Infectious Diseases 176, 1035 - 1040. [Excellent innovative work by this group opening up new approaches to chlamydial vaccine development]

Zhang, D. J., Yang, X., Shen, C. & Brunham, R. C. (1999). Characterization of immune responses following intramuscular DNA immunization with the MOMP gene of Chlamydia trachomatis mouse pneumonitis strain. Immunology 96, 314 - 321.

Zhang, D-J., Yang, X., Shen, C., Lu, H., Murdin, A. & Brunham, R. C. (2000). Priming with Chlamydia trachomatis major outer membrane protein (MOMP) DNA followed by MOMP ISCOM boosting enhances protection and is associated with increased immunoglobulin A and Th1 cellular immune responses. Infection and Immunity 68, 3074 - 3078. Full article