Chlamydial Immunity and Vaccine Development

衣原体免疫和疫苗开发

• 批准号: 9354727
• 负责人: HARLAN D CALDWELL
• 金额: $ 114.35万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9354727
• 关键词: Attenuated; Attenuated Live Virus Vaccine; CD4 Positive T Lymphocytes; CD8B1 gene; Chlamydia; Chlamydia Infections; Chlamydia trachomatis; Collaborations; Complex; Contracts; Cyclic GMP; Developmental Biology; Disease; Epidemic; Eye; Eye Infections; Female; Future; Genitourinary system; Goals; HIV; Human; Immunity; Infection; Infertility; Life; Life Style; Macaca; Malignant neoplasm of cervix uteri; Mediating; Modeling; Monkeys; National Institute of Allergy and Infectious Disease; Natural Immunity; Phase; Plasmids; Protocols documentation; Recombinants; Research Personnel; Risk Factors; Rodent Model; Sexually Transmitted Diseases; Solid; Structure; Subunit Vaccines; T-Lymphocyte; Trachoma; Vaccines; Virulent; Washington; Woman; Work; attenuation; human disease; immunogenic; immunogenicity; neglect; nonhuman primate; pre-clinical research; prevent; protective efficacy; transmission process; vaccine development; vaccine safety

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.

沙眼衣原体血清vas a-l3是高流行性盲虫的病因，是发展中国家的一种很大程度上被忽视的疾病，以及全球流行病的性传播感染（STI）。衣原体性传播疾病是HIV和宫颈癌共同因素的危险因素。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活衰减疫苗，以防止这些疾病。 衣原体的强制性细胞内生活方式，复杂的发育生物学和抗原结构已严重阻碍疫苗发育的进展。实时销售的疫苗（LAV）将有益于避免这些困难。我们已经制造了质粒缺乏沙眼菌株，并发现它对猴子的眼睛高度衰减。 通过LAV的眼部感染具有免疫原性，可诱导固体保护性免疫，以挑战有毒的沙丘瘤器官，有趣的是，LAV免疫被证明优于自然感染介导的免疫。在矛盾的是，疫苗介导的保护性免疫依赖于CD8 T细胞，这与由毒性衣原体引起的自然免疫再次感染与CD4 T细胞依赖性的抗性危机形成鲜明对比。 这些有前途的发现导致了NIAID支持，为疫苗，收缩CGMP疫苗产品以及提交I期临床方案以进行疫苗安全性和免疫原性研究。 使用女性猕猴衣原体性病模型与华盛顿研究人员的大学合作采用了类似的疫苗方法。

项目成果

A Chlamydia trachomatis strain with a chemically generated amino acid substitution (P370L) in the cthtrA gene shows reduced elementary body production.

• DOI: 10.1186/s12866-015-0533-2
• 发表时间: 2015-09-30
• 期刊: BMC microbiology
• 影响因子: 4.2
• 作者: Marsh JW;Wee BA;Tyndall JD;Lott WB;Bastidas RJ;Caldwell HD;Valdivia RH;Kari L;Huston WM
• 通讯作者: Huston WM

Chlamydial Lytic Exit from Host Cells Is Plasmid Regulated.

衣原体从宿主细胞中裂解退出受质粒调节。

• DOI: 10.1128/mbio.01648-15
• 发表时间: 2015
• 期刊: mBio
• 影响因子: 6.4
• 作者: Yang,Chunfu;Starr,Tregei;Song,Lihua;Carlson,JohnH;Sturdevant,GailL;Beare,PaulA;Whitmire,WilliamM;Caldwell,HarlanD
• 通讯作者: Caldwell,HarlanD