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 生殖道感染了淋病奈瑟氏菌，不会诱导特定的受保护的免疫力，IT 可以反复获取。尽管采取了公共卫生措施，但这种疾病仍然存在着令人难以置信的高度 频率;没有疫苗，即使对最新一代的抗生素也有抵抗力继续 出现。我们的SBIR阶段工作确定了原理证明，即用A 持续释放的白介素12微球配方奶粉和专有淋球菌（GC）外膜 蔬菜（Ngoxim，以前的GVAX12）会影响耐用的Th1驱动的自适应免疫调查器 针对生殖道感染的小鼠淋病。这些研究表明：（i）GC特异性的诱导 Th1细胞，（ii）血清和生殖道分泌物中抗GC抗体的产生，（iii）保护 淋病猪笼草的潜水菌株，（iv）特异性抗体的回忆和挑战后T细胞的重新激活 感染和（v）至少6个月的保护持续时间。依赖两者的保护 抗体和IFNγ产生。在SBIR II期中，我们确定了鼻内（I.N.）免疫的有效性 老鼠，重要的是，在非人类的隐私中。我们证实了类似的IFNγ产生和GC的产生 特定的抗体，通过这种途径，表现出对氮的其他抗原多样性菌株的活性。 淋病，包括临床分离株，并在细菌中显示针对GC的功能抗体活性 测定。最后，我们得出了与FDA的C型预先批次会议，并获得了与FDA的同意 我们的单一物种私人毒理学计划。该阶段IIB应用程序的具体目的是部分基于的 在该会议期间传达的代理建议以及为人类优化NGOXIM的需求 应用。在AIM 1中，NGOXIM将在非人类隐私中进一步优化。准备中的路线 用于人类试验。 AIM 2研究将包括符合FDA的药物质量和开发活动 疫苗成分。成功完成目标1和2后，Therapyx将要求B型会议 使用FDA确认完成的非临床辅助计划，包括NHP毒理学研究 计划和初步临床研究设计足以支持IND（AIM 3）。在AIM 4，遵循FDA 指导和B型会议的结果，我们将使用AIM 2中生成的验证产品来评估 Ngoxim在cynomolgus猴子中的初始血清药代动力学（PK）和毒性谱。总体目标 该项目的目的是生产世界上第一种针对生殖道感染奈瑟氏菌的预防性疫苗 淋病。