IMMUNOCHEMISTRY OF CHLAMYDIAL SURFACE ANTIGENS

该项目的总体目标是开发一种疫苗， 控制沙眼衣原体引起的失明和不育。 的 衣原体主要外膜蛋白（MOMP）是主要靶点 用于衣原体疫苗开发的抗原。 在过去的工作中，我们 进行了广泛的研究，旨在确定抗原结构， 分子水平上的MOMP。 我们的目标是找出 在结构和功能上帮助T细胞（TH）和保护性B细胞 MOMP的表位，我们认为是关键的抗原靶点， 合成或重组亚单位衣原体疫苗的开发。 从 这项工作中，我们鉴定了一个抗原性共同的TH细胞MOMP表位， 为中和抗体的产生提供同源帮助 靶向血清型和保守的物种特异性MOMP B细胞表位。 共- 对应于MOMP序列的线性合成的嵌合T：B肽 含有保守的TH细胞表位和血清型， B细胞表位诱导的功能性衣原体中和抗体 同种小鼠品系中所需血清特异性的反应 在H-2上不同。 嵌合肽也能够引发 在用亚甲基蓝进行二次攻击后的中和抗体应答 免疫原性数量的完整衣原体。 这些免疫原性 表明合成的T：B肽免疫原可能具有相当大的 衣原体疫苗开发的潜力。 为了直接获得嵌合肽免疫原的效用， 我们研究了候选疫苗的免疫原性和疫苗效力， 一个C.沙眼性眼部感染 食蟹 用合成肽免疫原胃肠外免疫猴 产生血清中和抗体，但未能产生可检测的 泪液抗体 接种疫苗的猴子在以下情况下得到部分保护： 用C.沙眼衣原体，因为它们脱落的衣原体较少， 患病率显著降低。 部分保护与 在接种疫苗的受试者泪液中迅速出现中和IgG抗体 可能是通过渗出而局限于眼睛的猴子。 这些 这些发现首次证明了胃肠外给药的有益作用， 接种抗C.使用抗原性的沙眼眼部感染 确定的免疫原。 未来的工作将集中在结合胃肠外和口服 刺激粘膜和全身免疫的免疫方案， 试图产生一种更坚固的保护性免疫力。

The overall goal of this project is the development of a vaccine to prevent of control blindness and infertility caused by Chlamydia trachomatis. The chlamydial major outer membrane protein (MOMP) is the principle target antigen for the development of a chlamydia vaccine. In past work, we have undertaken extensive studies aimed at defining the antigenic structure of the MOMP at the molecular level. Our objective was to identify structurally and functionally both help-T (TH) and protective B-cell epitopes of the MOMP that we believe to be key antigenic targets for the development of a synthetic or recombinant subunit chlamydial vaccine. From this work we identified an antigenically common TH-cell MOMP epitope, that provides cognate help for the production of neutralizing antibodies targeted serovar and conserved species-specific MOMP B-cell epitopes. Co- linearly synthesized chimeric T:B peptides corresponding to MOMP sequences containing the conserved TH-cell epitope and serovar and species-specific B-cell epitopes induced functional chlamydial neutralizing antibody responses of the desired sero-specificity in strains of congenic mice differing at H-2. The chimeric peptides were also able to prime for neutralizing antibody responses following secondary challenge with sub- immunogenic quantities of intact chlamydiae. These immunogenic properties suggest that the synthetic T:B peptide immunogens my have considerable potential in chlamydial vaccine development. To directly access the utility of the chimeric peptide immunogens as vaccine candidates we studied their immunogenicity and vaccine efficacy in a sub-human primate model of C. trachomatis ocular infection. Cynomolgus monkeys immunized parenterally with the synthetic peptide immunogens produced serum neutralizing antibodies but failed to produce detectable tear antibodies. Vaccinated monkeys were partially protected following ocular challenge with C. trachomatis in that they shed fewer chlamydiae and had significantly less disease. Partial protection was associated with a rapid appearance of neutralizing IgG antibodies in the tears of vaccinated monkeys which was likely localized to the eye by transudation. These findings are the first to demonstrate a beneficial effect of parenteral vaccination against C. trachomatis ocular infection using an antigenically defined immunogen. Future work will focus on combining parenteral and oral immunization protocols to stimulate both mucosal and systemic immunity in attempts to produce a more solid protective immunity.