Gonococcal Vaccine Evaluation in a Humanized Mouse Model

项目摘要 开发淋球菌疫苗的努力已经持续了三十多年，但没有取得显著进展。 虽然女性感染的严重后遗症和确凿的证据表明，并发淋球菌（GC） 感染能增强艾滋病病毒的传播促使了这些调查，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。两大问题相关 缺乏成功的原因是：1）缺乏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，以及2）缺乏免疫相关性，可以告知 疫苗设计该提案的总体目标是评估潜在的淋球菌候选疫苗， 最近开发的经宫颈诱导的上生殖道（UGT）和阴道内诱导的下生殖道（UGT）的GC 利用表达CEACAM1或CEACAM5的人源化转基因小鼠的生殖道（LGT）感染模型 分别该补助金的目的是：1）评估高优先级淋球菌疫苗候选人的能力 （孔蛋白、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（以帮助识别潜在的 3）通过RNAseq转录组学检查体内表达的GC基因的模式， 与人类的类似数据进行比较。如果目标实现，一种新的淋球菌疫苗评价模型 将通过与人类感染的比较来建立和验证淋球菌免疫的相关性， 将确定淋球菌候选疫苗的相对效用，以确定优先次序， 引导它们未来的发展，最终用于人类。

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.