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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) 能够利用人转铁蛋白作为唯一来源铁的。人转铁蛋白 (hTf) 的有效铁转运需要表达 TonB 依赖性积分外膜转运蛋白（TbpA）和表面暴露的脂蛋白（TbpB）。 Tbps 的表达式为在男性志愿者研究中，淋球菌是建立人类感染所必需的，这意味着淋球菌的关键作用这些蛋白质存在于人类宿主体内。因为该转运系统由所有淋球菌和蛋白质表达成分得到了很好的保存，本提案将探讨它们作为疫苗靶点的潜力。这在拟议的研究中要测试的总体假设是，合理设计的疫苗包括工程化的 TbpA 和 TbpB 抗原与实验选择的佐剂相结合，将提供针对无症状定植和由以下原因引起的致病性炎症的免疫交叉保护不同的淋病奈瑟菌菌株。该提案的具体目标如下：目标1.合理设计基于 Tbp 的疫苗。为此，将在使用和不使用 hTf 的情况下定义淋球菌 Tbps 的结构。这些结构将指导诱变工作，以产生配体结合缺陷和缺乏的疫苗抗原具有最小结构破坏的高变序列。目标 2. 优化人源化疫苗的递送雌性小鼠下生殖道感染模型。佐剂、给药途径、剂量和时间表将使用表达的人源化小鼠在女性下生殖道感染模型中测试了最佳保护 hTf。免疫学相关性和保护的决定因素将通过广泛测试体液和细胞免疫因素。目标3.测试基于Tbp的疫苗对新的人源化感染的保护效力模型。优化的抗原、佐剂、途径和时间表将在人源化小鼠中进行保护测试盆腔炎、男性尿道炎和鼻咽感染模型。再次，免疫学将描述这些新的感染动物模型中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型中的交叉保护作用。优化、合理—— 设计的疫苗配方将进行针对多种 Ngo 毒株的保护测试，包括具有抗药性的“超级细菌”菌株。保护的免疫相关性将通过这些进行验证所有人源化小鼠感染模型中的菌株。这些研究意义重大，因为它们可能会导致开发针对顽固病原体的有效疫苗，该病原体已产生抗药性现有的治疗方法。这些研究具有创新性，因为它们将采用结构引导的疫苗设计开发配体结合无能力的疫苗抗原，假设这些抗原表现出增强的与野生型蛋白相比具有免疫原性。此外，将测试这些抗原的保护作用将定义新型人源化小鼠感染模型和保护的免疫相关性，结束我们对非政府组织免疫理解的一个关键差距。