Experimental Gonococcal Vaccine

摘要 生殖道淋病奈瑟菌感染不会诱导特异性保护性免疫状态， 可以重复获得。尽管采取了公共卫生措施， 频率;没有针对它的疫苗，甚至对最新一代抗生素的耐药性也在继续 出现。我们的SBIR I期工作建立了原则证明， 缓释白细胞介素-12微球制剂加专有淋球菌（GC）外膜 囊泡（NGoXIM，以前的GvaX 12）诱导持久的Th 1驱动的适应性免疫应答， 小鼠生殖道感染N.淋病这些研究表明：（i）诱导GC特异性 Th 1细胞，（ii）血清和生殖道分泌物中抗GC抗体的产生，（iii） 不同的N.淋病，（iv）特异性抗体的回忆和激发后T细胞的再活化 感染，和（v）针对感染的保护持续时间至少6个月。保护取决于 抗体和IFNγ产生。在SBIR II期，我们确定了鼻内（i.n.）免疫 小鼠，更重要的是，在非人类灵长类动物中。我们证实了类似的IFNγ产生和GC的产生， 特异性抗体，并通过该途径证明了对另外的抗原性不同的N. 淋病，包括临床分离株，并显示出功能性抗体活性，对GC的杀菌 测定。最后，我们结束了与FDA的C类IND前会议，获得了FDA的同意， 我们的单一物种灵长类毒理学计划此IIb期申请的具体目标部分基于 关于该会议期间传达的机构建议以及优化人类NGoXIM的必要性， 应用程序.在目标1中，将使用i.n.准备路线 用于人体试验目标2研究将总结符合FDA的药品质量和开发活动， 疫苗成分。成功完成目标1和2后，Therapyx将要求召开B类会议 与FDA确认已完成的非临床IND启用项目，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）。在目标4中，遵循FDA 指南和我们的B类会议的结果，我们将使用目标2中生成的经确认产品进行评价 食蟹猴中NGoXIM的初始血清药代动力学（PK）和毒性特征。总目标 该项目的主要目标是生产世界上第一种预防性疫苗， 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.