OMV vaccine against Gonorrhea

淋病 OMV 疫苗

• 批准号: 10478441
• 负责人: Yingru Liu
• 金额: $ 30万
• 依托单位: THERAPYX, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-22 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10478441
• 关键词: Adjuvant; Antibodies; Antigens; Biodegradable microsphere; CD8-Positive T-Lymphocytes; Centers for Disease Control and Prevention (U.S.); Cervical; Communicable Diseases; Complement; Cytolysis; Development; Drug Kinetics; Drug-resistant Neisseria Gonorrhoeae; Encapsulated; Frequencies; Future; Generations; Genital; Genitalia; Goals; Gonorrhea; Human; Immune response; Immune system; Immunity; Immunization; Immunoglobulin G; In Vitro; Incidence; Infection; Interleukin-10; Knock-out; Measures; Mediating; Membrane; Mucous Membrane; Multi-Drug Resistance; Mus; Neisseria gonorrhoeae; Phagocytes; Phase; Phase I Clinical Trials; Play; Preparation; Production; Public Health; Publishing; Reporting; Resistance; Role; Saliva; Serum; Small Business Innovation Research Grant; T-Lymphocyte; Testing; Time; Toxic effect; Vaccine Antigen; Vaccines; Vagina; Vesicle; Woman; Work; adaptive immune response; base; cross immunity; cross reactivity; cytokine; design; draining lymph node; emerging antibiotic resistance; immunoregulation; memory recall; mouse model; mutant; neutralizing antibody; novel; novel strategies; novel vaccines; particle; phase 2 study; public health relevance; reproductive tract; resistant strain; response; scale up; time interval; vaccination strategy; vaccine development; vaccine strategy

ABSTRACT Gonorrhea is a genital tract infection caused by Neisseria gonorrhoeae, which can be acquired repeatedly and does not naturally induce a state of specific protective immunity against reinfection. Despite public health measures, gonorrhea persists at an unacceptably high frequency, and there is no vaccine against it. The continuing emergence of antibiotic resistance threatens to render gonorrhea untreatable. Our findings have revealed that N. gonorrhoeae subverts the immune system for its own benefit by inducing high levels of the immuno-regulatory cytokine, interleukin-10 (IL-10). Using the established murine model of vaginal gonococcal infection, we propose to investigate a novel strategy of vaccination against N. gonorrhoeae, exploiting neutralizing antibody against IL-10 encapsulated in biodegradable micro-particles (GneXa10®) as adjuvant. As vaccine antigen, outer membrane vesicles (OMV) derived from a double- mutant (dm) strain of N. gonorrhoeae, designed to reduce adverse responses to administration in humans, will be used. We will determine the role of serum and mucosal antibody and T-cell cytokine responses to intra-nasal (i.n.) immunization with dmOMV plus GneXa10®, in resistance to challenge infection with both homologous and heterologous strains. Persistence of immunity and recall of memory responses at increasing time intervals after immunization will be evaluated. Functional antibodies active against N. gonorrhoeae will be assessed in vitro. This work will provide proof-of-principle for a vaccine based on gonococcal dmOMVs and GneXa10®. Future SBIR phase II studies will further elucidate mechanisms of cross-protection against diverse strains of N. gonorrhoeae, and validate the expected applicability of scaled-up vaccine development, evaluating yield, bioactivity, batch-to-batch consistency, and shelf stability. This proposal is part of our company’s response to the CDC’s and WHO’s calls for development of novel vaccine approaches in the face of the public health threat posed by antibiotic-resistant N. gonorrhoeae.

摘要 淋病是一种由淋球菌引起的生殖道感染，可反复获得 并且不会自然地诱导针对再次感染的特定保护性免疫状态。尽管公众 卫生措施，淋病以令人无法接受的高频率持续存在，而且没有预防的疫苗。 它。抗生素耐药性的持续出现有可能使淋病无法治愈。我们的 研究结果表明，淋病奈瑟菌通过诱导 免疫调节细胞因子白介素10(IL-10)水平高。使用已建立的小鼠模型 对于阴道淋球菌感染，我们建议研究一种新的疫苗接种策略。 淋病，利用包裹在可生物降解微粒中的IL-10中和抗体 (GneXa10®)作为佐剂。作为疫苗抗原，外膜囊泡(OMV)来源于双核细胞。 淋病奈瑟氏菌突变株(Dm)，旨在减少人类服用的不良反应， 将会被使用。我们将确定血清和粘膜抗体的作用以及T细胞细胞因子反应 鼻内(I.N.)DmOMV加GneXa10®免疫，抵抗两者的攻击感染 同源和异源菌株。免疫的持久性和记忆反应的回忆 将评估免疫后增加的时间间隔。作用于N。 淋病将在体外进行评估。这项工作将为疫苗提供原理证明，基于 淋球菌dmOMv和GneXa10®。未来的SBIR第二阶段研究将进一步阐明 对不同的淋病奈瑟氏菌株的交叉保护，并验证预期的适用性 扩大疫苗开发，评估产量、生物活性、批次之间的一致性和货架 稳定性。这项建议是我们公司响应疾控中心和世卫组织发展呼吁的一部分 面对耐药奈瑟氏菌构成的公共卫生威胁，新的疫苗方法。 淋病。