Gonococcal Vaccine Evaluation in a Humanized Mouse Model

描述(由申请人提供)：研制淋病疫苗的努力已持续了三十多年，但没有取得显著进展。虽然女性感染的严重后遗症和同时感染GC可增强HIV传播的确凿证据促使了这些研究，但鉴于最近GC抗生素耐药性的增加，特别是对头孢曲松的耐药性，这一目标变得更加紧迫。与这种缺乏成功相关的两个主要问题是：1)缺乏认识淋球菌粘附素和其他毒力因子的人类特异性的动物模型；2)缺乏能够指导疫苗设计的免疫相关因素。这项建议的总体目标是评估最近开发的GC阴道感染模型中潜在的淋球菌疫苗候选，该模型利用人源化的转基因小鼠NEMO-8。这笔赠款的目的是1)评估人源化转基因小鼠对阴道淋球菌感染的免疫反应，2)确定活体感染或灭活生物免疫在该小鼠模型中是否提供保护，以及3)评估候选淋球菌疫苗的效力，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(见信函)。如果实现了这些目标，将建立一个新的淋病疫苗评估模式，识别淋病免疫的相关性，并确定淋病候选疫苗的相对效用，以便优先考虑和指导它们未来的发展，使其最终用于人类。

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.