Therapeutic Vaccines against Chlamydial Diseases
Type of DegreeDissertation
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Subclinical infections with intracellular bacteria of the family Chlamydiaceae cause substantial losses in animal agriculture. To validate the feasibility of therapeutic vaccination against chlamydial infection and disease, a prospective cohort study was conducted in a herd of 147 dairy cows to investigate the influence of chlamydial infection on subclinical inflammation of the bovine mammary gland. Vaccination against Chlamydophila spp. with an inactivated whole-organism vaccine of C. abortus/C. pecorum elementary bodies produced a highly significant decrease in milk somatic cell numbers, thus reducing bovine mastitis. It also increased antibody levels against Chlamydophila spp., but did not eliminate shedding of C. abortus in milk as detected by PCR. These results show an etiological involvement of the widespread Chlamydophila spp. infections in bovine mastitis, a herd disease of critical importance for the dairy industry. More importantly, this investigation shows the potential for improvement of chlamydial disease by therapeutic vaccination. To validate the concept of unbiased selection of vaccine candidate genes from the genome of a chlamydial species, we then tested 18 C. pneumoniae candidate genes for immune protection. Twelve of these genes had been previously identified by expression library immunization (ELI) and C. pneumoniae challenge in mice. Six additional genes had been previously reported in the literature as presumptive vaccine candidates after selection by surface location of the encoded protein T cell epitopes that were identified by computer algorithms. These 18 genes were used individually to immunize mice, which were then challenged with a high-dose C. pneumoniae inoculum. The protective effect was evaluated by the criteria of survival, lung disease and pathogen clearance. C. pneumoniae genes cutE and Cpn0420 identified by ELI protected mice from C. pneumoniae-induced death, increased elimination of C. pneumoniae, and alleviated lung disease. Gene oppA_2 was protective by dual criteria (disease reduction and C. pneumoniae elimination), whereas ssb (disease reduction), ide and Cpn0095 (C. pneumoniae elimination), and Cpn0020 (survival) were protective by a single criterion. Among the previously reported genes identified by other criteria, npt1, Momp and gatA protected partially by increasing survival, but none mediated further protection. Therefore, unbiased genome-wide screening by ELI proved to be the better method for identification of vaccine candidates. Given the high protection mediated by genes cutE, Cpn0420, and oppA_2, their combined use in a recombinant vaccine may mediate protection equal to that induced by previous natural infection. This may merit further investigations for use in human populations.