Chlamydial Immunity and Vaccine Development

沙眼衣原体血清型A-L3是高流行性致盲性沙眼（一种在发展中国家被严重忽视的疾病）和性传播感染（STI）的病原体，在世界范围内流行。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。 衣原体特有的细胞内生活方式、复杂的发育生物学和抗原结构阻碍了疫苗的发展。减毒活疫苗（LAV）将有助于规避这些困难。我们已经制造了质粒缺陷型沙眼菌株，发现其对猴眼高度减毒。 LAV的眼部感染具有免疫原性，并诱导对强毒沙眼器官攻击的固体保护性免疫。有趣的是，LAV免疫显示出比天然感染介导的免疫更上级。与此相反，疫苗介导的保护性免疫显示出依赖于CD 8 T细胞，这与针对由强毒衣原体引起的感染的依赖于CD 4 T细胞的天然免疫形成鲜明对比。 这些有希望的发现导致NIAID支持为疫苗寻求IND，合同cGMP疫苗产品，并提交I期临床方案，以进行人体疫苗安全性和免疫原性研究。 与华盛顿大学的研究人员合作，正在使用雌性猕猴衣原体STD模型进行类似的疫苗研究。

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.