A Novel Sublingual Vaccine to Prevent Neisseria Gonorrhoeae Infection

预防淋病奈瑟菌感染的新型舌下疫苗

• 批准号: 10699065
• 负责人: Neil A Fanger
• 金额: $ 30.65万
• 依托单位: VIRTICI, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-20 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10699065
• 关键词: Acceleration; Adjuvant; Advanced Development; Adverse event; Affect; Agonist; Aluminum; Animals; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antibodies; Antibody Response; Antigens; Area; Benchmarking; Biological Assay; Cefixime; Ceftriaxone; Cells; Cephalosporins; Cessation of life; Ciprofloxacin; Cold Chains; Communicable Diseases; Communities; Coupled; Data; Dose; Drug resistance; Drug-resistant Neisseria Gonorrhoeae; Environment; Epithelium; Female; Female genitalia; Film; Formulation; Funding; Future; Goals; Human; Immune; Immune response; Immunization; Immunize; Individual; Industry; Infection; Infection Control; Intramuscular; Investments; Measures; Mediating; Modality; Modeling; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Mus; Neisseria gonorrhoeae; Neisseria meningitidis; Newborn Infant; Oral; Pelvic Inflammatory Disease; Penicillins; Persons; Pharmacotherapy; Phase; Positioning Attribute; Production; Property; Public Health; Recommendation; Research; Resources; Route; Safety; Self Administration; Shipping; Small Business Innovation Research Grant; Sodium Chloride; Sublingual drug administration; Surface; Symptoms; T cell response; TLR4 gene; Testing; Tetracyclines; Translating; Vaccination; Vaccine Adjuvant; Vaccines; Work; aluminum sulfate; assault; cross reactivity; design; drug development; efficacy testing; epidemiologic data; gonorrhea vaccine; improved; industry partner; infection rate; innovation; interest; lot production; low and middle-income countries; mouse model; mucosal vaccination; nonhuman primate; novel; novel vaccines; pathogen; prevent; programs; reproductive tract; resistant strain; response; side effect; thermostability; urogenital tract; vaccine delivery; vaccine development; vaccine efficacy; vaccine formulation; vaccinology

Project Summary Our goal is to advance a novel, safe and effective sublingual (SL) vaccine against Neisseria gonorrhoeae (Ng) infection. Antibiotic resistant Ng is an interconnected global threat to people, animals, and the environment. Furthermore, approximately 50% of all annual Ng infections in the US are drug-resistant1. The emergence of drug-resistant Ng is accelerating, and previous antibiotic treatments such as penicillin, tetracycline, ciprofloxacin, and cefixime are no longer recommended1, 2. A single recommended treatment remains – ceftriaxone. Current research suggests that it is the suppression of Th1 and Th2 responses by Ng, modulated by increased Th17 responses, which drives Ng infection and re-infection3-5. Protection from Ng is thought to benefit from a robust Th1 response or balanced Th1/Th2 response3, 6, 7. However, current Ng vaccination approaches mainly using aluminum salt do not induce appropriate Th1/2 responses, limiting vaccine efficacy4, 8, 9. A vaccine that generates a strong Th1, or a more balanced Th1/Th2 response, with robust mucosal immunity, would significantly enhance Ng vaccine efficacy. Current Ng vaccine approaches are mainly focused on developing novel parenteral vaccines4, 8. Parenteral vaccines are generally effective at stimulating systemic antibody-mediated immune responses but are less effective at inducing mucosal immunity10-12. Parenteral vaccines require significant resources for cold-chain management and administration, which translate into slow global vaccination. Since low- and middle-income countries have the highest Ng burden, new vaccines must support global delivery. Our project team brings together three innovative aspects and areas of expertise that will make a novel SL Ng vaccine a reality. First, we have identified novel Ng antigens expressed during natural mucosal infection that generate cross-reactive antibody responses. Second, our novel TLR4 agonist, INI-2005, induces robust systemic and mucosal immune response following SL administration. Third, INI-2005 demonstrates good synthesis and thermostability properties and appears safe. Building from this work, this application is designed to validate a SL Ng vaccine consisting of a novel SL adjuvant, INI-2005, and three unique Ng antigens identified from a reverse vaccinology-like approach. The specific aims of this Phase I SBIR application are to: 1) Produce and benchmark the TLR agonist and Ng antigens; 2) Determine the optimal SL formulation to maximize immune responses in mice; and 3) Demonstrate that the SL formulation effectively protects mice against Ng infection. Funding of this application will validate a SL vaccine to prevent Ng infection, designed for robust Th1 immune responses and mucosal immunity, administered easily, and thermostable for rapid, global distribution.

项目摘要 我们的目标是推进针对淋病奈瑟氏菌（NG）的新颖，安全有效的舌下疫苗（SL）疫苗 感染。 抗生素耐药性NG是对人，动物和环境的全球威胁。此外， 在美国所有年度NG感染中，约有50％是耐药1。耐药的出现 NG正在加速，以前的抗生素治疗，例如青霉素，四环素，环丙沙星和 头衔不再推荐1，2。保留单个建议的治疗 - 头孢曲松。当前的 研究表明，这是Ng对Th1和Th2响应的抑制，由TH17的增加调节 反应，驱动NG感染和重新感染3-5。人们认为免受NG的保护可以从强大的 Th1响应或平衡TH1/TH2响应3，6，7。但是，当前NG疫苗接种主要使用 铝盐不会引起适当的TH1/2反应，限制疫苗效率4，8，9。一种疫苗 产生强大的TH1或具有强大粘膜免疫的更平衡的Th1/Th2响应将 显着提高了NG疫苗效率。 当前的NG疫苗方法主要集中于开发新型肠胃外疫苗4，8。肠胃外 疫苗通常可有效刺激全身性抗体介导的免疫血液，但较少 有效诱导粘膜免疫10-12。肠胃外疫苗需要大量的冷链资源 管理和管理，转化为全球疫苗接种缓慢。由于低收入和中等收入 国家拥有最高的NG Burnen，新疫苗必须支持全球交付。 我们的项目团队汇集了三个创新方面和专业领域 疫苗是现实。首先，我们已经确定了在自然粘膜感染期间表达的新型NG抗原 产生交叉反应性抗体反应。第二，我们的小说TLR4激动剂，INI-2005，诱导了强大的 SL给药后系统性和粘膜免疫反应。第三，INI-2005表现不错 合成和热稳定性特性，并且看起来很安全。 根据这项工作的构建，该应用程序旨在验证由新型SL组成的SL NG疫苗 辅助，INI-2005和三种独特的NG抗原，从类似疫苗的方法中鉴定出来。 该阶段I SBIR应用的具体目的是：1）生产和基准测试TLR激动剂和NG 抗原； 2）确定最大化小鼠免疫复杂的最佳SL公式； 3） 证明SL配方有效保护小鼠免受NG感染的影响。此申请的资金 将验证SL疫苗以防止NG感染，该疫苗是为强大的Th1免疫反应和粘膜设计的 免疫力，容易施用，可用于快速全球分布。