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

• 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
• 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

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.

项目主任/主要研究者：Schryvers，Anthony B。 摘要 淋病奈瑟氏菌，导致淋病的细菌病原体，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具有多重耐药性的菌株 在治疗期间。由于这些“超级细菌”菌株的出现，我们正朝着 无法治愈的淋病这种情况增加了开发疫苗的紧迫性， 这些感染，如未经治疗的淋球菌感染可导致盆腔炎，异位 怀孕、不孕和侵入性感染。淋球菌疫苗的开发一直具有挑战性， 细菌改变其表面成分和抑制细菌生长的能力 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。该提案的主要重点是进一步 开发一种基于蛋白质的疫苗，靶向组成型表达的淋球菌转铁蛋白结合 蛋白质B（Tbp B），其从人转铁蛋白捕获铁。它是一个理想的靶点，因为转铁蛋白受体 在N.淋病是粘膜上生存所必需的，我们已经证明它能够减少 在小鼠模型中的定殖。我们已经证明转铁蛋白结合缺陷型TbpB突变体 诱导比野生型蛋白质更具保护性的免疫反应，目前正在最后确定 我们的基于TbpB的疫苗的抗原组成。在这个项目中，我们将扩大和优化生产， 纯化我们的抗原，开发最佳的疫苗配方，并执行所有必要的步骤， 在人体上进行第一阶段试验。将在下生殖道定植中评价交叉保护 使用表达人CEACAM的雌性转基因小鼠的模型和盆腔炎性疾病模型 受体和人转铁蛋白，分别促进淋球菌粘膜附着和生长。 与工业赞助商Vaxiron公司一起，我们将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 生产组织，完成监管要求的所有质量，稳定性和毒理学研究 批准在该项目结束后进行未来的I期临床试验。