Experimental Gonococcal Vaccine

摘要 生殖道感染淋病奈瑟菌不会诱导特定的保护性免疫状态 可以重复获得。尽管采取了公共卫生措施，但该病仍居高不下，令人无法接受 频率；没有针对它的疫苗，甚至对最新一代的抗生素的耐药性仍在继续 才能出现。我们的SBIR第一阶段工作建立了一项原则证明，即阴道内免疫 白细胞介素12缓释微球制剂加专有淋球菌外膜 囊泡(NGoXIM，以前的GvaX12)诱导持久的Th1驱动的适应性免疫反应，保护 抗淋病奈瑟菌感染小鼠。这些研究表明：(I)诱导GC特异性 Th1细胞，(2)在血清和生殖道分泌物中产生抗GC抗体，(3)保护 不同的淋病奈瑟氏菌株，(Iv)攻击后特异性抗体的召回和T细胞的重新激活 (V)至少6个月不受感染的保护期。保护取决于两者 抗体和干扰素γ的产生。在SBIR第二阶段，我们建立了鼻腔内(I.N.)的疗效。在中国进行免疫接种 老鼠，更重要的是，在非人类灵长类动物中。我们证实了类似的干扰素γ的产生和GC- 特异性抗体，并通过这一途径展示了对其他抗原性不同的N。 淋球菌，包括临床分离株，并在杀菌中显示出抗GC的功能性抗体活性 化验。最后，我们结束了与FDA的C型Pre-Pre-IND会议，获得了机构与 我们的单一物种灵长类毒理学计划。此阶段IIb应用程序的具体目标部分基于 关于在那次会议期间传达的机构建议以及为人类优化NGoXIM的必要性 申请。在目标1中，NGoXIM将在使用I.N.的非人类灵长类动物中进一步优化。准备中的路线 用于人体试验。AIM 2研究将总结符合FDA的药品质量和开发活动 疫苗成分。在成功完成AIMS 1和AIMS 2后，Treatyx将请求B类会议 与FDA确认完成的非临床IND使能计划，包括NHP毒理学研究 计划和初步临床研究设计，足以支持IND(目标3)。在AIM 4中，遵循FDA 指导和我们B类会议的结果，我们将使用在目标2中生成的经过验证的产品来评估 NGoXIM在食蟹猴体内的初始血清药代动力学(Pk)和毒性特征。总目标 该项目的目的是生产世界上第一个预防生殖道奈瑟氏菌感染的疫苗 淋病。

ABSTRACT Genital tract infection with Neisseria gonorrhoeae does not induce a state of specific protective immunity and it can be acquired repeatedly. Despite public health measures, the disease persists at an unacceptably high frequency; there is no vaccine against it, and resistance even to the latest generations of antibiotics continues to emerge. Our SBIR Phase I work established proof-of-principle that intra-vaginal immunization with a sustained-release interleukin-12 microsphere formulation plus proprietary gonococcal (GC) outer membrane vesicles (NGoXIM, previously GvaX12) induces durable Th1-driven adaptive immune responses that protect mice against genital tract infection with N. gonorrhoeae. Those studies demonstrated: (i) induction of GC-specific Th1 cells, (ii) generation of anti-GC antibodies in serum and genital tract secretions, (iii) protection against diverse strains of N. gonorrhoeae, (iv) recall of specific antibodies and reactivation of T cells after challenge infection, and (v) duration of protection against infection for at least 6 months. Protection depended upon both antibodies and IFNγ production. In SBIR Phase II, we established efficacy of intranasal (i.n.) immunization in mice and, importantly, in non-human primates. We confirmed similar IFNγ production and generation of GC- specific antibodies and by this route, demonstrated activity against additional antigenically diverse strains of N. gonorrhoeae, including clinical isolates, and showed functional antibody activity against GC in bactericidal assays. Finally, we concluded a type C pre-pre-IND meeting with the FDA, garnering Agency agreement with our single species primate toxicology plans. The specific aims of this Phase IIb application are partially based on Agency recommendations communicated during that meeting and the need to optimize NGoXIM for human application. In Aim 1 NGoXIM will be further optimized in non-human primates using the i.n. route in preparation for human trials. Aim 2 studies will conclude FDA-compliant pharmaceutical quality and development activity for the vaccine components. Upon successful completion of Aims 1 and 2, Therapyx will request a type B meeting with the FDA to confirm that the completed non-clinical IND-enabling program, including an NHP toxicology study plan and preliminary clinical study design, is sufficient to support an IND (Aim 3). In Aim 4, following FDA guidance and the results of our type B meeting, we will use validated products generated in Aim 2 to evaluate initial serum pharmacokinetics (PK) and toxicity profiles of NGoXIM in cynomolgus monkeys. The overall goal of this project is to produce the world's first prophylactic vaccine against genital tract infection with Neisseria gonorrhoeae.