A Sexual Transmission-Blocking Vaccine Against Chlamydia infections

项目摘要 沙眼衣原体是最常见的性传播细菌病原体， 全世界大约有1亿人。根据所研究的人口，约有5-20% 妇女在生育年龄期间对衣原体呈阳性。由于50%的感染是无症状的， 很难识别和治疗这群人。如果衣原体感染没有得到诊断或治疗， 在怀孕期间，70%受感染母亲所生的婴儿从母亲那里感染。 许多生殖器感染的临床前动物模型是使用设定数量的衣原体建立的， 接种剂量。然而，很少有研究表明，动物是通过性行为感染的。 性交最近，我们建立了一个衣原体性传播的小鼠模型。 鼠伤寒沙门氏菌通过感染的雄性小鼠经性传播给雌性小鼠， 新生小鼠这项提案的目标是开发一种阻断传播的疫苗， 衣原体不仅可以从雄性小鼠传播到雌性小鼠，也可以从性感染的雌性小鼠传播到 新生的小狗作为候选疫苗，我们将使用衣原体外膜蛋白复合物（COMC）， 早先已经表明，COMC能够在小鼠中引起针对生殖器感染的保护， 不孕此外，COMC有几种免疫显性膜蛋白，包括主要的外膜蛋白， 膜蛋白、60 kDa富含半胱氨酸的蛋白、12-15 kDa富含半胱氨酸的蛋白和推定的 外膜蛋白，以其天然构象形式。COMC可以大规模生产， 小实验室操作。到目前为止，还没有研究来检查COMC预防 雌性和新生小鼠的性传播。本研究假设COMC特异性Th 1+细胞 雌性小鼠中的Th 2特异性免疫将阻断衣原体从受感染的雄性小鼠向雌性小鼠的性传播。 雌性小鼠和从雌性小鼠到幼崽。将研究两个具体目标。具体目标1将确定 潜在的人佐剂和COMC递送途径，用于引发传播阻断免疫， 雌性小鼠对衣原体的传播。具体目标2将确定COMC的推进战略， 哺乳母鼠，使母鼠能够提供保护性免疫成分，特别是抗体和Th 1 细胞因子，通过乳汁传给幼崽这将是第一个专注于预防性传播疾病的疫苗研究。 衣原体在两个宿主中的传播。这种性传播模式与人类感染相似， 研究将采用免疫分子方法鉴定人类佐剂。这项研究的结果将有助于 我们将设计一种针对人类生殖器衣原体感染的传播阻断疫苗。

PROJECT SUMMARY Chlamydia trachomatis, the most common sexually transmitted bacterial pathogen, annually infects approximately 100 million men and women worldwide. Depending on the population studied, about 5-20% women are positive for Chlamydia during their reproductive age. Since 50% of infections are asymptomatic, it is very difficult to identify and treat this group of people. If a Chlamydia infection is not diagnosed or treated properly during pregnancy, 70% of babies born from infected mothers acquire the infection from their mothers. Many preclinical animal models of genital infections were established using set numbers of Chlamydia as inoculation doses. However, very few studies were performed in which animals were infected by sexual intercourse. Recently, we have developed a mouse model of sexual transmission of Chlamydia in which C. muridarum was transmitted sexually from infected male mice to female mice and from sexually infected female mice to newborn mice. The goal of this proposal is to develop a transmission-blocking vaccine that will prevent Chlamydia transmission not only from male mice to female mice but also from sexually infected female mice to newborn pups. As a vaccine candidate we will use Chlamydia outer membrane protein complex (COMC) since it has been shown earlier that COMC was able to elicit protection in mice against a genital infection and infertility. In addition, COMC has several immunodominant membrane proteins including the major outer membrane protein, the 60 kDa cysteine rich protein, the 12-15 kDa cysteine rich proteins, and the putative outer membrane proteins, in their native conformational forms. COMC can be produced in large scale with a little laboratory manipulations. So far no studies have been performed to examine COMC's ability to prevent sexual transmission in female and newborn mice. The hypothesis of the study is that COMC-specific Th1 plus Th2-specific immunity in female mice will block sexual transmission of Chlamydia from infected male mice to female mice and from female mice to pups. Two specific aims will be studied. Specific Aim 1 will identify potential human adjuvant(s) and the route of COMC delivery for eliciting a transmission-blocking immunity in female mice against chlamydial transmission. Specific Aim 2 will identify the boosting strategies of COMC on nursing dams so that dams can supply protective immune components, especially antibodies and Th1 cytokines, to pups through milk. This will be the first vaccine study focusing on the prevention of sexual transmission of Chlamydia in two hosts. This sexual transmission model parallels human infections and this study will adopt an immuno-molecular approach to identify human adjuvants. The results of this study will help us to design a transmission-blocking vaccine for humans against genital chlamydial infections.