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Prospects for Chlamydial Vaccine Development.

Introduction: History of chlamydial vaccine development.

Chlamydial infections tend to be insidious, with the individual frequently not aware they are infected. These infections tend to "grumble on" for a long time and, left untreated, may lead to severe problems such as blindness, infertility, pneumonia and perhaps, in the case of C. pneumoniae, enhanced coronary artery disease. In the poorest parts of the world where trachoma tends to be found, antibiotic treatment may be unavailable or difficult to sustain. Under these circumstances prevention would seem better than cure. Compared with antibiotic therapy, an effective vaccine offers a much more sustained, though indirect, anti-chlamydial effect. However the relative weakness of natural immunity to chlamydial infections suggests that developing a vaccine is not going to be easy. The hope must be that, by focusing on selected, potentially protective chlamydial components (antigens), and by carefully maximizing the host protective response it may be possible to improve on nature.

Empirical attempts were made in the 1960s and early 1970s by four major groups to prevent trachoma by vaccination. The vaccines used were whole, dead, C. trachomatis organisms, relatively crude by today's standards. The general impression is that, at best, these vaccines produced short term protection against natural infection with organisms related to the vaccine strain. Short term protection was also observed in blind volunteers experimentally inoculated with C. trachomatis. However in some instances it appeared that vaccination might have enhanced the severity of ocular disease when individuals became re-infected, particularly if a low strength vaccine preparation was used. This is consistent with the view that some of the severe damage associated with chronic chlamydial infection (e.g. scarring distortion of the eyelids or blockage of the fallopian tubes) may be caused in certain individuals by the immune response to the infection [see: immunopathology]. At around the same time, damaging responses against vaccines directed against other infectious agents, such as respiratory syncytial virus and measles, were also reported. Eventually, the trachoma vaccine trials were abandoned.

[Thumbnail slide: Progress on the way to a chlamydial vaccine.]

Renewed attempts to protect against C. trachomatis infection were made in the mid 1980s following the discovery that the major outer membrane protein (MOMP) of C. trachomatis was able to generate neutralising antibodies capable of blocking chlamydial infection of host cells [Caldwell & Perry, 1982]. It was possible to identify the precise regions of MOMP (so called B cell epitopes) that generated neutralizing antibody [Conlan et al., 1988, 1989; Stephens et al., 1988; Zhong & Brunham, 1991]. Unfortunately, despite sustained efforts over the next decade, it became clear that subunit vaccines against MOMP were not the answer. There were difficulties in preparing MOMP with the native 3-dimensional structure thought necessary to generate effective neutralising antibody. There were also fundamental immunological problems as to how best sustain adequate levels of secretory antibody at the superficial mucosal surfaces of the body that C. trachomatis infects; a problem which has yet to be solved.

[Thumbnail: It's not so easy to develop vaccines against chlamydiae!]

Fortunately, as this approach began to run out of steam, experiments in gene knock-out mice in the mid 1990s demonstrated the key role of cell mediated immunity, rather than of neutralizing antibody, in protective immunity to chlamydial infections [Cotter et al., 1997; Johannson et al., 1997, 1998; Morrison et al., 1995 and others]. This came together with a number of other things: realization of the key role of dendritic cells in the immune response [Stagg et al., 1993; Su et al., 1998]; availability of whole genomic sequences for Chlamydia [Stephens et al., 1998] and Chlamydophila [Kalman et al., 1999] species that, for the first time, indicated what chlamydiae are composed of. This in turn opened up systematic new methods using vaccines based on chlamydial genes (DNA vaccines) to identify chlamydial components involved with protective immunity. For the first time major vaccine companies (Antex, Aventis-Pasteur, Corixa) have entered chlamydial vaccine research, developing vaccines against both C. pneumoniae and C. trachomatis.

The following sections briefly describe the evidence for protective immunity in chlamydial infection, the basis of protective immunity,  the current approach to chlamydial vaccine development and C. pneumoniae vaccines. 

[MEW] June 2002

NEXT: Evidence for protective immunity

References

Caldwell, H. D. & Perry, L. J. (1982).  Neutralization of Chlamydia trachomatis infectivity with antibodies to the major outer membrane protein. Infection and Immunity 38, 745 - 754. [Established that MOMP generates neutralizing antibody]

Conlan, J. W., Clarke, I. N. & Ward, M. E. (1988). Epitope mapping with solid phase peptides: identification of type-, subspecies-, species- and genus-reactive antibody binding domains on the major outer membrane protein of Chlamydia trachomatis. Molecular Microbiology 2, 673 - 679. [Ultra high resolution mapping of epitopes on MOMP using a novel technique. Described the critical binding residues of these epitopes].

Conlan, J. W., Kajbaf, M., Clarke, I. N., Chantler, S. & Ward, M. E. (1989). The major outer membrane protein of Chlamydia trachomatis: critical binding site and conformation determine the specificity of antibody binding to viable chlamydiae. Molecular Microbiology 3, 311 - 318.

Cotter, T. W., Ramsey, K. H., Miranpuri, G. S. et al., (1997). Dissemination of Chlamydia trachomatis chronic genital tract infection in gamma interferon gene knockout mice. Infection and Immunity  65, 2145 - 2152. Full article   [Evidence of the importance of ifng as key effector in protective immunity. Complementary to Johansson et al findings].

Johansson, M., Schon, K., Ward, M. E & Lycke, N. (1997). Genital tract infection with Chlamydia trachomatis fails to induce protective immunity in gamma interferon receptor deficient mice despite a strong local immunoglobulin A response. Infection and Immunity  65, 1032 - 1044. Full article    [Established the importance of CD4+ Th1 response for the adaptive immune response to genital chlamydial infection with a human strain of C. trachomatis]

Johansson, M., Schon, K., Ward, M. & Lycke N. (1997). Front line: Studies in knockout mice reveal that anti-chlamydial protection requires TH1 cells producing IFN-gamma: is this true for humans? Scandinavian Journal of Immunology 46, 546 - 552. [An interesting summary of work by one group using a human C. trachomatis isolate and a wide range of knockout mice to determine the key factors for the protective adaptive immune response].

Kalman, S., Mitchell, W., Marathe, R., et al., (1999). Comparative genomes of Chlamydia pneumoniae and C. trachomatis. Nature Genetics 21, 385-389. Full article

Knight, S. C., Iqball, S., Woods, C., Stagg, A., Ward, M. E. & Tuffrey, M. (1995). A peptide of Chlamydia trachomatis shown to be a primary T-cell epitope in vitro induces cell-mediated immunity in vivo. Immunology 85, 8-15.

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].

Stagg, A. J., Elsley, W. A., Pickett, M. A., Ward, M. E. & Knight, S. C. (1993). Primary human T-cell responses to the major outer membrane protein of Chlamydia trachomatis. Immunology 79, 1 - 9. [First use of dendritic cells in vitro to explore the cell mediated response to chlamydiae]

Stephens, R. S., Wagar, E. A. & Schoolnik, G. K. (1988). High resolution mapping of serovar-specific and common antigenic determinants of the major outer membrane protein of Chlamydia trachomatis. Journal of Experimental Medicine 167, 817 - 831.

Stephens, R. S., Kalman, S., Lammel, C. et al., (1998). Genome sequence of an obligate intracellular pathogen of humans: Chlamydia trachomatis. Science 282, 754 - 759. + [The first genomic sequence, and high quality]

Su, H., Messer, R., Whitmire, W., Fischer, E., Portis, J. C. & Caldwell, H. D. (1998). Vaccination against chlamydial genital tract infection after immunization with dendritic cells pulsed ex vivo with nonviable Chlamydiae. Journal of Experimental Medicine 188, 809 - 818. Full article

Zhong, G. M. & Brunham, R. C. (1991) Antigenic determinants of the chlamydial major outer membrane protein resolved at a single amino acid level. Infection and Immunity 59, 1141 - 1147.