Experimental Gonococcal Vaccine

实验性淋球菌疫苗

• 批准号: 10217037
• 负责人: DOMINICK AUCI
• 金额: $ 100万
• 依托单位: THERAPYX, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10217037
• 关键词: Activities of Daily Living; Agreement; Antibiotics; Antibodies; Bacteria; Biological; Biological Assay; Biological Sciences; Biotechnology; Blood; Body Fluids; Centers for Disease Control and Prevention (U.S.); Clinical; Clinical Research; Collaborations; Communicable Diseases; Development; Development Plans; Disease; Dose; Dose-Limiting; Drug Kinetics; Encapsulated; Formulation; Frequencies; Future; Generations; Genital; Genitalia; Goals; Gonorrhea; Human; Human Development; Immune response; Immunity; Immunization; Incidence; Infection; Interferon Type II; Interleukin-12; Macaca fascicularis; Maximum Tolerated Dose; Measures; Membrane; Methods; Microspheres; Monkeys; Multi-Drug Resistance; Mus; NOEL; Nature; Neisseria gonorrhoeae; No-Observed-Adverse-Effect Level; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Preparation; Preventative vaccination; Prevention; Preventive vaccine; Primates; Process; Production; Program Development; Property; Public Health; Readiness; Recombinants; Recommendation; Reporting; Research Design; Resistance; Route; Safety; Science; Serum; Small Business Innovation Research Grant; T-Lymphocyte; Testing; Th1 Cells; Toxic effect; Toxicology; United States; Vaccines; Vesicle; Work; adaptive immune response; bactericide; base; clinical development; comparative; cross reactivity; design; healthy volunteer; improved; meetings; men; mouse model; nonhuman primate; novel strategies; novel therapeutics; particle; programs; public health relevance; reproductive tract; resistant strain

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.

抽象的 淋病奈瑟菌的生殖道感染不会引起特异性保护性免疫状态，并且 可以重复获取。尽管采取了公共卫生措施，该疾病的发病率仍然高得令人无法接受 频率;没有针对它的疫苗，甚至对最新一代抗生素的耐药性仍在继续 出现。我们的 SBIR 第一阶段工作建立了原理验证，即阴道内免疫 缓释白细胞介素 12 微球配方加上专有的淋球菌 (GC) 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 小鼠抵抗淋病奈瑟菌生殖道感染。这些研究表明：(i) GC 特异性的诱导 Th1 细胞，(ii) 在血清和生殖道分泌物中产生抗 GC 抗体，(iii) 预防 淋病奈瑟菌的不同菌株，(iv) 攻击后特定抗体的回忆和 T 细胞的重新激活 感染，以及 (v) 防止感染的持续时间至少 6 个月。保护取决于两者 抗体和 IFNγ 的产生。在 SBIR II 期中，我们确定了鼻内 (i.n.) 免疫的功效 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，并通过这种途径，证明了针对其他抗原多样化菌株的活性。 淋病，包括临床分离株，并在杀菌中表现出针对 GC 的功能性抗体活性 化验。最后，我们与 FDA 结束了 C 类 IND 前会议，并获得了 FDA 的同意 我们的单一物种灵长类动物毒理学计划。该 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 NGoXIM 以促进人类健康的必要性 应用。在目标 1 中，NGoXIM 将使用 i.n. 在非人类灵长类动物中进一步优化。路线准备中 用于人体试验。目标 2 研究将总结符合 FDA 规定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 将请求召开 B 类会议 与 FDA 确认已完成的非临床 IND 启用计划，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）。在目标 4 中，遵循 FDA 指导和 B 类会议的结果，我们将使用目标 2 中生成的经过验证的产品来评估 NGoXIM 在食蟹猴中的初始血清药代动力学 (PK) 和毒性特征。总体目标 该项目的目的是生产世界上第一种针对奈瑟菌生殖道感染的预防性疫苗 淋病。