Production of a Gonococcal Vaccine for Countering Antimicrobial Resistance

项目主任/首席调查员：安东尼·B·施里弗斯 摘要 淋病奈瑟氏菌是引起淋病的细菌病原体，现在被认为是一个“紧迫的威胁”。 由于最近出现了对常用抗生素产生多重抗药性的菌株 在治疗过程中。由于这些超级细菌菌株的出现，我们正在朝着传播的方向前进 无法治愈的淋球菌感染。这种情况增加了开发疫苗以预防的紧迫性 这些感染，如淋球菌感染未经治疗可导致盆腔炎、异位 怀孕、不孕和侵袭性感染。淋球菌疫苗的开发一直是具有挑战性的 由于细菌具有改变其表面成分并抑制细菌发展的非凡能力 人类对再感染的保护性免疫反应，以及由于缺乏适当的动物模型 可用于研究该病原体的感染和免疫。这项提议的主要重点是进一步 研制针对成分表达的淋球菌转铁蛋白结合的蛋白质疫苗 蛋白B(TbpB)，从人类转铁蛋白中捕获铁。它是一个理想的靶点，因为转铁蛋白受体 淋球菌是在粘膜上生存所必需的，我们已经证明它能够减少 在小鼠模型中的定植。我们已经证明TbpB的转铁蛋白结合缺陷突变体 诱导比野生型蛋白更具保护性的免疫反应，目前正在敲定 我们的结核分枝杆菌疫苗的抗原成分。在这个项目中，我们将扩大和优化生产和 提纯我们的抗原，开发最佳疫苗配方，并执行所需的所有步骤 在人体上进行第一阶段试验。交叉保护将在下生殖道定植中进行评估 表达人CEACAM的雌性转基因小鼠盆腔炎模型及模型的建立 受体和人转铁蛋白，分别促进淋球菌粘膜附着和生长。 我们将与行业赞助商VaxIron，Inc.一起开发质量控制工具和指标，以 评估疫苗抗原配方，将我们疫苗配方的生产转移到合同 制造组织，完成监管所需的所有质量、稳定性和毒理学研究 批准在该项目达到顶峰后进行未来的第一阶段临床试验。

Program Director/Principal Investigator: Schryvers, Anthony B. ABSTRACT Neisseria gonorrhoeae, the bacterial pathogen that causes gonorrhea, is now considered an “Urgent Threat” due to the recent emergence of strains with multi-drug resistance to the antibiotics that are frequently used during treatment. Due to the emergence of these `superbug' strains, we are progressing towards the spread of untreatable gonococcal infections. This situation has added to the urgency for developing a vaccine to prevent these infections, as untreated gonococcal infections can lead to pelvic inflammatory disease, ectopic pregnancy, infertility and invasive infections. Development of a gonococcal vaccine has been challenging due to the remarkable ability of the bacterium to vary its surface components and suppress the development of a protective immune response against reinfection in humans, and due to the lack of appropriate animal models available to study infection and immunity of this pathogen. The primary focus of this proposal is to further develop a protein-based vaccine that targets the constitutively-expressed gonococcal transferrin binding protein B (TbpB), which captures iron from human transferrin. It is an ideal target since the transferrin receptor in N. gonorrhoeae is required for survival on the mucosa and we have shown that it is capable of reducing colonization in a mouse model. We have demonstrated that transferrin-binding defective mutants of TbpB induce a more protective immune response than the wild type proteins, and are currently finalizing the antigenic composition of our TbpB-based vaccine. In this project, we will scale-up and optimize production and purification of our antigens, develop an optimal vaccine formulation and perform all the steps required for implementing Phase I trials in humans. Cross-protection will be evaluated in a lower genital tract colonization model and a model of pelvic inflammatory disease using female transgenic mice expressing human CEACAM receptors and human transferrin, which facilitate gonococcal mucosal attachment and growth, respectively. Together with an industrial sponsor, Vaxiron, Inc., we will develop quality control tools and metrics for assessing vaccine antigen formulations, transfer production of our vaccine formulation to a contract manufacturing organization, complete all the quality, stability and toxicology studies required for regulatory approval to proceed to a future Phase I clinical trial after the culmination of this project.