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Rational design of transferrin binding protein-based vaccines to combat gonorrhea

合理设计基于转铁蛋白结合蛋白的淋病疫苗

基本信息

批准号：
10088372
负责人：
CYNTHIA N CORNELISSEN
金额：
$ 62.8万
依托单位：
GEORGIA STATE UNIVERSITY
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：
2019-03-06 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10088372
关键词：
Adjuvant Animal Model Antibiotic Resistance Antigenic Variation Antigens Antimicrobial Resistance Binding Cellular Immunity Chimera organism Crystallization Crystallography Data Development Disease Disease model Dose Engineering Epitopes Exhibits Female Female genitalia Frequencies Gender Goals Gonorrhea Hemoglobin Human Humoral Immunities Immune response Immunity Immunization Immunologic Memory Immunologics Infection Inflammation Iron Iron-Binding Proteins Lactoferrin Lead Ligand Binding Ligands Lipoproteins Maps Mediator of activation protein Membrane Transport Proteins Methods Modeling Mucosal Immunity Multi-Drug Resistance Mutagenesis Neisseria gonorrhoeae Neisseria meningitidis Nutrient Nutritional Immunity Pathogenicity Pelvic Inflammatory Disease Preventive vaccine Process Protein Conformation Proteins Publishing Resistance development Role Route Schedule Self Tolerance Sexually Transmitted Diseases Siderophores Source Structure Superbug Surface Syndrome System TFRC gene Testing Therapeutic Tissues Transferrin Transferrin-Binding Proteins Urethritis Uterus Vaccination Vaccine Antigen Vaccine Design Vaccine Production Vaccines Variant base combat cross reactivity design experimental study human pathogen humanized mouse immunogenicity in silico in vivo innovation male mouse model mucosal site mutant novel pathogen protective efficacy reproductive tract vaccine candidate vaccine delivery vaccine development volunteer

项目摘要

The human pathogen, Neisseria gonorrhoeae (Ngo) is capable of utilizing human transferrin as the sole source of iron. Efficient iron transport from human transferrin (hTf) requires expression of a TonB-dependent, integral outer membrane transporter (TbpA), and a surface-exposed lipoprotein (TbpB). Expression of the Tbps is necessary for the gonococcus to establish human infection in male volunteer studies, implying a critical role for these proteins in the human host. Because this transport system is expressed by all gonococci and the protein components are well conserved, their potential as vaccine targets will be explored in this proposal. The overarching hypothesis to be tested in the proposed study is that a rationally-designed vaccine consisting of engineered TbpA and TbpB antigens, combined with an experimentally selected adjuvant, will provide immunologic cross-protection against both asymptomatic colonization and pathogenic inflammation caused by diverse N. gonorrhoeae strains. The specific aims of the proposal are as follows: Aim 1. Rational design of Tbp-based vaccines. In this aim, structures of the gonococcal Tbps will be defined with and without hTf. These structures will guide mutagenesis efforts to produce vaccine antigens defective in ligand binding and lacking hypervariable sequences with minimal structure disruption. Aim 2. Optimizing vaccine delivery in humanized female mouse model of lower genital tract infection. Adjuvants, delivery routes, doses and schedules will be tested for optimal protection in the female lower genital tract infection model using humanized mice expressing hTf. Immunological correlates and determinants of protection will be defined by broadly testing humoral and cellular immunity factors. Aim 3. Test for protective efficacy of Tbp-based vaccines in new humanized infection models. Optimized antigens, adjuvants, routes and schedules will be tested for protection in humanized mouse models of pelvic inflammatory disease, male urethritis and nasopharyngeal infection. Again, immunological correlates and determinants of protection in these new animal models of infection will be characterized. Aim 4. Evaluate rationally designed vaccines for cross protection in all models of infection. Optimized, rationally- designed vaccine formulations will be tested for protection against a broad group of Ngo strains, including antimicrobial resistant “superbug” strains. Immunological correlates of protection will be validated with these strains in all of the humanized mouse models of infection. These studies are significant since they may lead to the development of an efficacious vaccine against a recalcitrant pathogen that has developed resistance to existing therapeutic methods. These studies are innovative because they will employ structure-guided vaccine design to develop ligand-binding incompetent vaccine antigens, which are hypothesized exhibit enhanced immunogenicity compared to the wild-type proteins. Moreover, these antigens will be tested for protection in novel humanized mouse models of infection and immunological correlates of protection will be defined, closing a key gap in our understanding of immunity against Ngo.

人类病原体淋病奈瑟菌(Ngo)能够利用人类转铁蛋白作为唯一来源。铁制的。人转铁蛋白(HTF)的高效铁转运需要TonB依赖的整合型表达外膜转运蛋白(TbpA)和表面暴露的脂蛋白(TbpB)。Tbps的表达式为淋球菌在男性志愿者研究中确定人类感染所必需的，这意味着人类宿主中的这些蛋白质。因为这个运输系统是由所有淋球菌和蛋白质表达的组分被很好地保存，它们作为疫苗靶标的潜力将在这项提案中得到探索。这个在拟议的研究中要检验的最重要的假设是，合理设计的疫苗包括改造的TbpA和TbpB抗原，与实验选择的佐剂相结合，将提供对无症状定植和致病性炎症的免疫交叉保护不同的淋病奈瑟菌菌株。该方案的具体目标如下：目标1.合理设计基于TBP的疫苗。在这一目标中，将定义有无HTF的淋球菌TBP的结构。这些结构将指导突变努力，以产生在配基结合上有缺陷和缺乏的疫苗抗原结构破坏最小的超变量序列。目标2.优化人性化疫苗投放雌性小鼠下生殖道感染模型。佐剂、给药路线、剂量和时间表在女性下生殖道感染模型中使用人源化小鼠表达的最佳保护测试 HTF。免疫学相关因素和保护决定因素将通过广泛检测体液和细胞免疫因子。目的3.TBP疫苗对新型人源化感染的保护效果测试模特们。优化的抗原、佐剂、路线和时间表将在人源化小鼠身上进行保护测试盆腔炎、男性尿道炎、鼻咽部感染模型。再一次，免疫学在这些新的感染动物模型中，将描述保护的相关性和决定因素。目标4. 评估合理设计的疫苗在所有感染模式中的交叉保护作用。优化的，合理的- 将对设计的疫苗配方进行测试，以防止广泛的NGO毒株，包括抗菌素耐药的“超级细菌”菌株。免疫学上的保护性关联将用这些来验证所有人源化小鼠感染模型中的菌株。这些研究具有重要意义，因为它们可能会导致对一种顽固的病原体产生抗药性的有效疫苗的开发现有的治疗方法。这些研究是创新的，因为他们将使用结构导向疫苗设计开发与配体结合的无能疫苗抗原，假想显示增强与野生型蛋白的免疫原性比较。此外，这些抗原将在将定义新的人源化小鼠感染模型和免疫学保护相关因素，结束我们在理解对NGO的免疫力方面存在一个关键差距。