Gonococcal Vaccine Evaluation in a Humanized Mouse Model

描述（由申请人提供）：开发淋球菌疫苗的努力已经持续了30多年，但没有取得显著进展。尽管女性感染的显著后遗症以及同时感染胃癌可增强HIV传播的确凿证据刺激了这些研究，但鉴于最近胃癌抗生素耐药性的增加，特别是对头孢曲松的耐药性增加，这一目标变得更加紧迫。与这种不成功相关的两个主要问题是：1)缺乏能够理解淋球菌黏附素和其他毒力因子的人类特异性的动物模型；2)缺乏可为疫苗设计提供信息的免疫相关因素。本提案的总体目标是利用人源化转基因小鼠NeMo-8在最近开发的GC阴道感染模型中评估潜在的淋球菌候选疫苗。该资助的目的是：1)评估人源化TG小鼠对阴道淋球菌感染的免疫反应；2)确定活生物体感染或死生物体免疫是否能在该小鼠模型中提供任何保护；3)评估淋球菌候选疫苗的功效，包括淋球菌孔蛋白、淋球菌外膜囊泡和诺华疫苗定义的其他外膜成分。如果目标实现，将建立一个新的淋球菌疫苗评价模型，识别淋球菌免疫的相关因素，并确定淋球菌候选疫苗的相对效用，以便优先考虑和指导其未来的发展，最终用于人类。

DESCRIPTION (provided by applicant): 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 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 vaginal infection model utilizing humanized transgenic mice termed NeMo-8. The aims of this grant are to 1) Evaluate the immune response to vaginal gonococcal infection of the humanized TG mice, 2) Determine if infection with live organisms or immunization with killed organisms affords any protection in this mouse model, and 3) Evaluate the efficacy of gonococcal vaccine candidates, including gonococcal porin, gonococcal outer membrane vesicles, and other outer membrane components defined by Novartis Vaccines (see letter). If the aims are fulfilled, a new model for gonococcal vaccine evaluation will be established, 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.