Chlamydia is the most prevalent sexually transmitted bacterial infection in many developed countries, including Canada. Untreated infections in women can lead to a number of complications including pelvic inflammatory disease, tubal factor infertility, and ectopic pregnancy. Public health programs, including screening for at-risk individuals, partner identification, and antibiotic treatment, have had limited success in controlling the rising incidence of chlamydial infections over the past two decades. A chlamydia vaccine that prevents infection and its pathological sequelae is the next essential step to control this persistent public health problem. Chlamydia spp. utilize the highly conserved type III secretion (T3S) system as an essential virulence factor for infection and intracellular replication. Here, we evaluated a novel chimeric antigen (BD584) consisting of three T3S proteins from C. trachomatis (CopB, CopD, and CT584) as a potential chlamydia vaccine candidate. Intranasal immunization with BD584 elicited strong humoral responses that neutralized infection in vitro. Following intravaginal challenge with C. muridarum, immunized mice had a 95% reduction in chlamydial shedding and a 87.5% reduction in incidence of upper genital tract pathology compared to control mice. BD584 immunization generated strong cell-mediated and mucosal antibody responses in mice with different genetic backgrounds, and conferred protection against an intravaginal C. trachomatis infection in two out of three strains of mice. BD584 formulated with NE01, a mucosal adjuvant known to be safe and effective in humans, was shown to be highly immunogenic and efficacious against C. trachomatis infection in mice. These results suggest that BD584 may represent a promising antigen for use in a chlamydia vaccine. / Thesis / Doctor of Philosophy (PhD) / Chlamydia is the most common sexually transmitted bacterial infection in the world. The goal of this thesis is to evaluate a novel chlamydia vaccine in a mouse model of genital chlamydia infection. We engineered a fusion protein, BD584, made up of three highly conserved type III secretion (T3S) proteins CopB, CopD, and CT584. We show that vaccination with BD584 generated strong immune responses and protected mice from chlamydia infection and the associated reproductive tract disease. Interestingly, the level of protection afforded by BD584 vaccination is dependent upon the genetic background of the animal. Furthermore, we have identified particular antibody subtypes directed against BD584 as markers of BD584-mediated protective immunity. Lastly, we show that vaccination with BD584 formulated with a clinically safe and effective mucosal adjuvant generates robust immune responses and confers protection against chlamydia in mice. Together, these results provide support for the use of T3S proteins in a chlamydia vaccine.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/24583 |
| Date | January 2019 |
| Creators | Liang, Steven |
| Contributors | Mahony, James, Medical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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