Investigation of novel chlamydia vaccines in male infection models and sexual transmission challenges

项目摘要 沙眼衣原体（Ct）是导致世界上最常见的细菌性性传播疾病的病原体 感染，2020年超过1.29亿例。未经治疗的泌尿生殖道Ct可能有严重的后遗症，包括 盆腔炎、宫外孕、输卵管因素不孕、附睾炎、尿道炎、前列腺炎。 未经治疗的肛门直肠Ct可导致直肠炎、溃疡、脓肿、裂隙和瘘管。肛门直肠感染 也可能作为细菌的储存库，通过自身接种发生泌尿生殖道感染。最大Ct 研究集中在女性泌尿生殖道感染，因为这些感染更常见地导致严重的 后遗症然而，有一个很大的差距，迫切需要研究Ct感染的男性。虽然男性 泌尿生殖道感染不太可能导致严重的后遗症，男性可以将感染传播给女性 生殖道，更容易出现并发症。此外，肛门直肠感染发生在男性 与男性发生性关系的人，与女性发生性关系的男性和女性。目前的治疗方法是治愈性抗生素， 但是这些不能防止再感染，不能有力地清除所有解剖部位的感染， 患者依从性。确定减少和预防Ct传播以及限制感染的策略， 非常紧急。我们的实验室已经开发出了针对衣原体的疫苗，使用高免疫原性的噬菌体病毒- 类颗粒（VLP）作为展示免疫原性免疫原性细胞中Ct粘附因子的短肽表位的平台， 方式特别地，我们的靶向Ct粘附因子主要外膜蛋白的Qb-VD 4-MOMP疫苗， 在雌性小鼠中提供保护。然而，肛门直肠道和男性泌尿生殖道具有不同的 免疫环境和Ct感染在这些网站没有得到很好的研究。F31的目标是 研究我们的Qb-VD 4-MOMP疫苗在雄性小鼠中保护免受衣原体感染的能力。的 这项研究的总体目标是确定这些疫苗的免疫原性和保护能力 在雄性小鼠中，利用泌尿生殖器、肛门直肠和性传播感染模型。这场 研究将突出强调通过预防感染和 传输目的1将研究疫苗在雄性小鼠泌尿生殖道或肛门直肠感染 衣原体此外，在免疫的情况下，疫苗的效力的一方或双方的合作伙伴将是 在衣原体的小鼠性传播模型中进行了研究（目的2）。这些疫苗可能会或可能不会引起 对雄性和雌性的保护相同，使用佐剂、混合疫苗或替代疫苗 在雄性中提供保护可能需要靶点。总的来说，这项研究将揭示重要方面， 疫苗介导的保护，并推动这些疫苗更接近人类临床试验。

PROJECT SUMMARY Chlamydia trachomatis (Ct) is the pathogen that causes the world’s most common bacterial sexually transmitted infection, with over 129 million cases in 2020. Untreated urogenital Ct can have severe sequelae, including pelvic inflammatory disease, ectopic pregnancy, tubal factor infertility, epididymitis, urethritis, and prostatitis. Untreated anorectal Ct can lead to proctitis, ulcerations, abscesses, fissures, and fistulas. Anorectal infections likely also act as a reservoir for the bacterium, in which urogenital infection occurs via autoinoculation. Most Ct research has focused on female urogenital infections, as these infections more commonly cause severe sequelae. However, there is a large gap and an urgent need to study Ct infections in males. Although male urogenital tract infections are less likely to lead to severe sequelae, males can transmit infection to the female reproductive tract, which is more vulnerable to complications. Additionally, anorectal infections occur in men who have sex with men, men who have sex with women and in women. Current treatment is curative antibiotics, but these do not prevent reinfection, do not robustly clear infection at all anatomic sites, and can have poor patient compliance. Identifying strategies to reduce and prevent transmission of Ct, as well as limit infection, is very urgent. Our lab has developed vaccines against Chlamydia using highly immunogenic bacteriophage virus- like particles (VLPs) as a platform displaying short peptide epitopes of Ct adhesion factors in an immunogenic manner. In particular, our Qb-VD4-MOMP vaccine, targeting Ct adhesion factor Major Outer Membrane Protein, provides protection in female mice. However, the anorectal tract and male urogenital tract have distinct immunological environments, and Ct infections at these sites are not well studied. This F31 proposal aims to investigate the ability of our Qb-VD4-MOMP vaccine to protect against Chlamydia infection in male mice. The overall goal of this proposed research is to determine the immunogenicity and protective ability of these vaccines in male mice, utilizing urogenital, anorectal, and sexual transmission infection models. The outcome of this research will highlight the populations that will benefit from vaccination by preventing both infection and transmission. Aim 1 will investigate vaccine efficacy in male mice urogenitally or anorectally infected with Chlamydia. Additionally, vaccine efficacy in the context of immunization of either or both partners will be investigated in mouse sexual transmission models of Chlamydia (Aim 2). These vaccines may or may not elicit the same protection in males as in females, and the use of adjuvants, mixed vaccines, or alternative vaccine targets may be necessary to provide protection in males. Overall, this research will reveal important aspects of vaccine-mediated protection and advance these vaccines closer to human clinical trials.