Chlamydial Immunity and Vaccine Development

沙眼衣原体A-L3血清型是高度地方性致盲沙眼的病原体，沙眼是发展中国家普遍被忽视的一种疾病，性传播感染(STI)在全世界流行。衣原体感染是HIV的危险因素，也是宫颈癌的共同因素。控制这些重要的人类疾病是该项目的长期目标。为此，我们的目标是开发一种安全有效的减毒活疫苗来预防这些疾病。衣原体固有的细胞内生活方式、复杂的发育生物学和抗原结构分别阻碍了疫苗开发的进展。一种减毒活疫苗(LAV)将有助于绕过这些困难。我们已经制作了一株缺乏质粒的沙眼病毒株，并发现它对猴眼具有高度的减毒作用。眼部感染LAV具有免疫原性，可诱导对沙眼衣原体攻击的固体保护性免疫，有趣的是，LAV免疫优于自然感染介导的免疫。疫苗介导的保护性免疫依赖于CD8T细胞，而天然免疫则依赖于依赖于CD4T细胞的强毒衣原体。这些有希望的发现导致了NIAID的支持，以资助IND用于疫苗，合同cGMP疫苗产品，并提交了第一阶段临床方案，以在人类身上进行疫苗安全性和免疫原性研究。一种类似的疫苗方法正在与华盛顿大学的研究人员合作，使用雌性猕猴衣原体性病模型。

Chlamydia trachomatis serovars A-L3 are the causative agents of hyperendemic blinding trachoma, a largely neglected disease of the developing world, and sexually transmitted infections (STI) that are epidemic worldwide. Chlamydial STI are risk factors for HIV and a cervical cancer co-factor. Control of these important human diseases is the long term goal of this project. Towards this end our goal is to develop a safe and efficacious live attenuated vaccine to prevent these diseases. The obligate intracellular life style, complex developmental biology, and antigenic structure of chlamydiae have severally hindered progress in vaccine development. A live-attenuated vaccine (LAV) will be beneficial in circumventing these difficulties. We have made a plasmid deficient trachoma strain and found it to be highly attenuated for the monkey eye. Ocular infection with the LAV is immunogenic and induces solid protective immunity to challenge with virulent trachoma organsims, Interestingly, LAV immunity was shown to be superior to natural infection mediated immunity. Paradoxially, vaccine mediated protective immunity was shown to be dependent of CD8 T cells which was in sharp contrast to natural immunity againt infection caused by virulent chlamydiae which is CD4 T cell dependent. These promising finding have led to NIAID support to purse an IND for the vaccine, contract a cGMP vaccine product, and the submission of phase I clinica protocol to conduct vaccine safety and immunogenicity studies in humans. A similar vaccine approach is being pursued in collaboration with Univeristy of Washington investigators using a female macaque chlamydial STD model.