Chlamydial Immunity and Vaccine Development

沙眼衣原体血清型a - l3是高地方性致盲性沙眼（一种在发展中国家基本上被忽视的疾病）和全球流行的性传播感染（STI）的病原体。衣原体性传播感染是艾滋病毒的危险因素，也是宫颈癌的辅助因素。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。衣原体的专性细胞内生活方式、复杂的发育生物学和抗原结构阻碍了疫苗开发的进展。减毒活疫苗（LAV）将有助于克服这些困难。我们已经制造了一种质粒缺陷沙眼菌株，并发现它对猴眼具有高度减毒作用。眼部感染LAV具有免疫原性，可诱导固体保护性免疫来对抗强毒性沙眼，有趣的是，LAV免疫被证明优于自然感染介导的免疫。矛盾的是，疫苗介导的保护性免疫被证明依赖于CD8 T细胞，这与对毒性衣原体引起的感染的自然免疫形成鲜明对比，后者依赖于CD4 T细胞。这些有希望的发现促使NIAID支持为该疫苗申请IND，签订cGMP疫苗产品合同，并提交I期临床方案，进行疫苗安全性和人体免疫原性研究。与华盛顿大学的研究人员合作，正在利用雌性猕猴衣原体性病模型研究类似的疫苗方法。

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.