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、有效的淋球菌舌下疫苗(SL)。 感染。 耐药Ng是一个相互关联的全球对人、动物和环境的威胁。此外， 在美国，每年大约50%的Ng感染是耐药的1。抗药性的出现 NG正在加速，以前的抗生素治疗，如青霉素、四环素、环丙沙星和 头孢克新不再被推荐使用1，2。推荐的单一治疗方法仍然是头孢曲松。当前 研究表明，这是Ng抑制Th1和Th2反应，受Th17增加的调节 应答，这推动了Ng感染和再感染3-5。对Ng的保护被认为受益于强健的 Th1应答或Th1/Th2平衡应答3、6、7。然而，目前的疫苗接种方法主要是使用 铝盐不能诱导适当的Th1/2反应，从而限制了疫苗的效力4、8、9。 产生强大的Th1，或更平衡的Th1/Th2反应，具有强大的粘膜免疫力，将 显著提高新城疫疫苗效力。 目前的疫苗接种方法主要集中在开发新型非肠道疫苗4、8。 疫苗在刺激全身性抗体介导的免疫反应方面通常有效，但效果较差。 有效诱导粘膜免疫10-12。非肠道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。由于中低收入者 各国的Ng负担最高，新疫苗必须支持全球交付。 我们的项目团队将三个创新方面和专业知识领域结合在一起，将形成一个新颖的SL Ng 让疫苗成为现实。首先，我们鉴定了在自然粘膜感染过程中表达的新的Ng抗原 产生交叉反应的抗体反应。其次，我们的新型TLR4激动剂INI-2005可以诱导强大的 SL给药后的全身和粘膜免疫反应。第三，INI-2005展示了良好的 具有良好的合成性能和热稳定性，且看起来安全。 在这项工作的基础上，这个应用程序被设计来验证由新的SL组成的SL Ng疫苗 佐剂，INI-2005，以及从反向疫苗学类方法中鉴定的三种独特的Ng抗原。这个 第一阶段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 抗原；2)确定最佳SL配方以最大限度地提高小鼠的免疫反应；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，该疫苗旨在实现强大的Th1免疫反应和粘膜 免疫，易于管理，耐热，可快速在全球范围内分发。

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.