A Sexual Transmission-Blocking Vaccine Against Chlamydia infections

一种针对衣原体感染的性传播阻断疫苗

• 批准号: 9334708
• 负责人: SUKUMAR PAL
• 金额: $ 19.31万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-20 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9334708
• 关键词: Adjuvant; Adopted; Age; Agonist; Animal Model; Animals; Antibodies; Chlamydia; Chlamydia Infections; Chlamydia trachomatis; Coitus; Discipline of Nursing; Dose; Female; Freund' s Adjuvant; Genital system; Goals; Health; Human; Immune; Immunity; Immunize; Incidence; Infection; Infertility; Inflammasome; Interferons; Laboratories; Membrane Proteins; Milk; Modeling; Molecular; Molecular Conformation; Mothers; Mus; Newborn Infant; Nurses; Population Study; Pregnancy; Prevalence; Prevention; Production; Recombinants; Route; Sexual Transmission; Technical Expertise; Vaccination; Vaccines; Woman; cysteine rich protein; cytokine; design; genital infection; major outer membrane protein; male; men; mouse model; pathogen; pre-clinical; prevent; protective efficacy; protein complex; pup; reproductive; transmission process; transmission-blocking vaccine; vaccine candidate; vaccine trial

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.

项目总结 沙眼衣原体是最常见的性传播细菌病原体，每年感染 全球约有1亿男性和女性。根据研究人群的不同，约有5%-20% 女性在她们的生育年龄衣原体呈阳性。由于50%的感染是无症状的，它 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%的受感染母亲所生的婴儿是从母亲那里感染的。 许多临床前生殖器感染的动物模型是使用固定数量的衣原体作为 接种剂量。然而，很少有研究表明动物是通过性传播感染的 性交。最近，我们建立了一种衣原体性传播的小鼠模型。 鼠疟原虫从感染的雄性小鼠通过性传播给雌性小鼠，从性感染的雌性小鼠传播 从小鼠到新生小鼠。这项提案的目标是开发一种传播阻断疫苗，以防止 衣原体不仅从雄性小鼠传播到雌性小鼠，而且从性感染的雌性小鼠传播到 刚出生的幼崽。作为候选疫苗，我们将使用衣原体外膜蛋白复合体(COMC)，因为 早些时候已经表明，Comc能够诱导小鼠免受生殖器感染的保护，并 不孕不育。此外，Comc还具有几种免疫优势膜蛋白，包括主要的外膜蛋白 膜蛋白、60 kDa的富含半胱氨酸的蛋白、12-15 kDa的富含半胱氨酸的蛋白以及推测的 外膜蛋白，以其天然构象形式。COMc可以用一种 实验室里的小把戏。到目前为止，还没有进行任何研究来检验COMC预防 雌性小鼠和新生小鼠的性传播。这项研究的假设是Comc特异性Th1+ 雌性小鼠的Th2特异性免疫将阻断衣原体从感染的雄性小鼠到 雌性老鼠和从雌性老鼠到幼崽。我们将研究两个具体目标。具体目标1将确定 潜在人佐剂(S)及其诱导小鼠传播阻断免疫的途径 雌性小鼠对抗衣原体传播。具体目标2将确定中国商飞的提振战略 护理水坝，使水坝能够提供保护性免疫成分，特别是抗体和Th1 细胞因子，通过牛奶给幼崽。这将是首个以预防性行为为重点的疫苗研究 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，而这 这项研究将采用免疫分子方法来鉴定人类佐剂。这项研究的结果将有助于 美国将为人类设计一种预防生殖器衣原体感染的传播阻断疫苗。