Gonococcal Vaccine Evaluation in a Humanized Mouse Model

人源化小鼠模型中的淋球菌疫苗评估

• 批准号: 9389653
• 负责人: LEE Mark WETZLER
• 金额: $ 72.82万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-17 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9389653
• 关键词: Adhesions; Animal Model; Antibiotic Resistance; Antibiotics; Antigens; Bacterial Adhesins; Bacterial Infections; Biological; CEACAM1; CEACAM5 gene; Ceftriaxone; Cell model; Cervical; Data; Defect; Development; Diestrus; Disease; Ectopic Pregnancy; Epithelium; Estradiol; Estrus; Ethics; Event; Exposure to; Female; Fibrosis; Future; Genes; Genetic; Genitourinary system; Goals; Gonorrhea; Grant; Gray unit of radiation dose; HIV; Human; Immune; Immune response; Immunity; Immunological Models; Incidence; Infection; Infertility; Inflammation; Inflammatory Response; Investigation; Laboratories; Life; Modeling; Molecular Models; Mus; Natural Immunity; Neisseria gonorrhoeae; Neisseria meningitidis; Pan Genus; Pattern; Pelvic Inflammatory Disease; Phase; Predisposition; Public Health; Publishing; Quinolones; Receptor Cell; Research; Role; Sister; Solid; Specificity; Symbiosis; Time; Transgenic Mice; Tube; VDAC1 gene; Vaccination; Vaccine Design; Vaccines; Vagina; Virulence Factors; Virus Shedding; Work; acquired immunity; cytokine; fitness; gonococcal porin; human data; humanized mouse; in vivo; insight; microbial; molecular modeling; mouse model; neutrophil; nonhuman primate; pathogen; reproductive; reproductive tract; response; success; tool; transcriptome sequencing; transcriptomics; transmission process; vaccine candidate; vaccine development; vaccine evaluation

PROJECT SUMMARY Efforts to develop a gonococcal vaccine have continued for over three decades without notable progress. While the significant sequelae of infection in females and solid evidence that concurrent gonococcal (GC) infection can enhance HIV transmission have spurred these investigations, this goal has become more urgent given the recent increase in GC antibiotic resistance, especially to ceftriaxone. Two major issues associated with this absence of success have been 1) the lack of an animal model that appreciates the human specificity of gonococcal adhesins and other virulence factors, and 2) the lack of correlates of immunity that can inform vaccine design. The overall objective of this proposal is to evaluate potential gonococcal vaccine candidates in a recently developed GC both transcervical induced upper genital tract (UGT) and intravaginal induced lower genital tract (LGT) infection models utilizing humanized transgenic mice expressing CEACAM 1 or CEACAM5 respectively. The aims of this grant are to 1) Evaluate the ability of high priority gonococcal vaccine candidates (porin, OMV and LOS derived mimotopes) to protect humanized TG mice from LGT or UGT GC infection, 2) Determine which immune defects may allow for enhanced infection in WT mice (to aid in discerning potential correlates of immunity) and 3) Examine pattern of in vivo expressed GC genes by RNAseq transcriptomics and Compare to similar data from humans. If the aims are fulfilled, a new model for gonococcal vaccine evaluation will be established and validated by comparison to human infection, correlates of gonococcal immunity will be discerned, and the relative utility of gonococcal vaccine candidates will be determined in order to prioritize and guide their future development towards their ultimate use in humans.

项目总结 开发淋病疫苗的努力已持续了三十多年，但没有取得显著进展。 虽然女性感染的重大后遗症和确凿证据表明并发淋球菌(GC) 感染会增加艾滋病毒的传播已经刺激了这些研究，这一目标变得更加紧迫 鉴于最近GC抗生素耐药性的增加，特别是对头孢曲松的耐药性。与此相关的两个主要问题 由于缺乏成功，1)缺乏一种能够理解人类特异性的动物模型 淋球菌粘附素和其他毒力因子的相关性，以及2)缺乏可告知 疫苗设计。这项提案的总体目标是评估潜在的淋病疫苗候选疫苗。 新近发展起来的经宫颈诱导上生殖道(UGT)和经阴道诱导下生殖道(UGT)GC 表达CEACAM1或CEACAM5的人源化转基因小鼠生殖道感染模型的建立 分别进行了分析。这笔赠款的目的是：1)评估高度优先的淋病疫苗候选疫苗的能力 (Porin、OMV和LOS衍生的模拟表位)保护人源化TG小鼠免受LGT或UGT GC感染，2) 确定哪些免疫缺陷可能导致WT小鼠感染增强(以帮助识别潜力 免疫相关性)和3)通过RNAseq转录和检测体内表达的GC基因的模式 与来自人类的类似数据进行比较。如果目标实现，淋球菌疫苗评估的新模型 将通过与人类感染的比较来确定和验证，淋球菌免疫的相关因素将是 将确定淋球菌候选疫苗的相对效用，以便确定优先顺序和 引导它们未来的发展，使其最终用于人类。