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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