A Novel Sublingual Vaccine to Prevent Neisseria Gonorrhoeae Infection

项目摘要 我们的目标是开发一种新型、安全、有效的淋病奈瑟菌舌下疫苗 感染 抗生素耐药性Ng是对人类、动物和环境的相互关联的全球威胁。此外，委员会认为， 在美国，每年约有50%的Ng感染是耐药性的1。抗药性的出现 Ng正在加速，之前的抗生素治疗，如青霉素，四环素，环丙沙星， 头孢克肟不再推荐1，2。一个单一的推荐治疗仍然是-头孢曲松。电流 研究表明，这是由Ng抑制Th 1和Th 2反应，通过增加Th 17调节， 反应，这驱动了Ng感染和再感染3 -5。Ng的保护被认为受益于强大的 Th 1反应或平衡的Th 1/Th 2反应3，6，7.然而，目前的Ng疫苗接种方法主要使用 铝盐不能诱导适当的Th 1/2应答，限制了疫苗效力4，8，9。的疫苗 产生强的Th 1或更平衡的Th 1/Th 2应答，具有强的粘膜免疫， 显著增强Ng疫苗效力。 目前的Ng疫苗方法主要集中在开发新型肠胃外疫苗4，8。肠胃外 疫苗通常在刺激全身性抗体介导的免疫应答方面是有效的， 有效诱导粘膜免疫10 -12。胃肠外疫苗需要大量的冷链资源 管理和行政，这转化为缓慢的全球疫苗接种。由于中低收入 由于这些国家的Ng负担最高，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，将使一个新颖的SL Ng 疫苗成为现实首先，我们已经鉴定了在自然粘膜感染期间表达的新的Ng抗原， 产生交叉反应性抗体反应。其次，我们的新型TLR 4激动剂INI-2005诱导了强有力的 SL给药后全身和粘膜免疫应答。第三，INI-2005展示了良好的 合成和热稳定性，并且看起来安全。 在这项工作的基础上，该应用程序被设计用于验证由新型SL Ng疫苗组成的SL Ng疫苗。 佐剂，INI-2005，和三个独特的Ng抗原从一个反向疫苗样方法鉴定。的 该I期SBIR应用的具体目标是：1）生产TLR激动剂和Ng并对其进行基准测试， 2）确定最佳SL制剂以使小鼠中的免疫应答最大化;以及3） 证明SL制剂有效地保护小鼠免受Ng感染。本申请的资金来源 将验证SL疫苗，以防止Ng感染，设计用于强大的Th 1免疫应答和粘膜 免疫力强，易于管理，热稳定，可快速全球分布。

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.