Production of a Gonococcal Vaccine for Countering Antimicrobial Resistance

用于对抗抗生素耐药性的淋球菌疫苗的生产

基本信息

批准号：
10335178
负责人：
SCOTT D GRAY-OWEN
金额：
$ 60.25万
依托单位：
UNIVERSITY OF CALGARY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10335178
关键词：
Adolescent and Young Adult Animal Model Antibiotic Resistance Antibiotic Therapy Antibiotics Antigens Antimicrobial Resistance Bacteria Binding Binding Proteins Biochemical Clinical Trials Contracts Development Dose Ectopic Pregnancy Engineering Ensure Etiology Evaluation Female Formulation Future Gonorrhea Grant Growth Human Human Volunteers Immune response Immunity Incidence Industrialization Infection Infection prevention Infertility Investigational Drugs Iron Legal Life Male urethral structure Membrane Methods Modeling Mucous Membrane Multi-Drug Resistance Neisseria gonorrhoeae Oryctolagus cuniculus Patients Pelvic Inflammatory Disease Phase Phase I Clinical Trials Positioning Attribute Principal Investigator Procedures Process Production Proteins Public Health Quality Control Recommendation Research Sexually Transmitted Agents Sexually Transmitted Diseases Specific qualifier value Superbug Surface System TFRC gene Testing Toxic effect Toxicology Transferrin Transferrin-Binding Protein B Transgenic Mice Vaccine Antigen Vaccines Variant assay development clinical development clinically relevant combat cross immunity experience experimental study human male in vitro Assay large scale production manufacturing organization monoclonal antibody production mouse model mutant novel pathogen pathogenic bacteria phase I trial preclinical development programs receptor reproductive reproductive tract resistant strain scale up tool vaccine candidate vaccine development vaccine efficacy vaccine evaluation vaccine formulation

项目摘要

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.

项目总监/首席研究员：Schryvers, Anthony B. 抽象的淋病奈瑟菌是引起淋病的细菌病原体，现在被认为是“紧急威胁” 由于最近出现了对常用抗生素具有多重耐药性的菌株由于这些“超级细菌”菌株的出现，我们正在朝着传播的方向前进。这种情况增加了开发疫苗来预防的紧迫性。这些感染，如未经治疗的淋球菌感染，可导致盆腔炎、异位由于怀孕、不孕和侵袭性感染，淋球菌疫苗的开发一直具有挑战性。细菌具有改变其表面成分并抑制细菌发展的卓越能力由于缺乏适当的动物模型，保护性免疫反应对人类的再感染产生了影响该提案的主要重点是进一步研究这种病原体的感染和免疫。开发一种基于蛋白质的疫苗，针对组成型表达的淋球菌转铁蛋白结合蛋白 B (TbpB) 可从人转铁蛋白中捕获铁，是转铁蛋白受体以来的理想靶标。淋病奈瑟菌是在粘膜上生存所必需的，我们已经证明它能够减少我们已经证明 TbpB 的转铁蛋白结合缺陷突变体在小鼠模型中定植。诱导比野生型蛋白更具保护性的免疫反应，目前正在最终确定我们基于 TbpB 的疫苗的抗原成分在这个项目中，我们将扩大和优化生产和纯化我们的抗原，开发最佳疫苗配方并执行所需的所有步骤在人类中实施第一阶段试验将在下生殖道定植中进行评估。使用表达人 CEACAM 的雌性转基因小鼠模型和盆腔炎模型受体和人转铁蛋白，分别促进淋球菌粘膜附着和生长。我们将与工业赞助商 Vaxiron, Inc. 一起开发质量控制工具和指标评估疫苗抗原配方，将我们的疫苗配方生产转移到合同中制造组织，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完成后进行未来的一期临床试验。