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:
- 金额:$ 62.8万
- 依托单位:
- 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:
- 关键词:AdjuvantAnimal ModelAntibiotic ResistanceAntigenic VariationAntigensAntimicrobial ResistanceBindingCellular ImmunityChimera organismCrystallizationCrystallographyDataDevelopmentDiseaseDisease modelDoseEngineeringEpitopesExhibitsFemaleFemale genitaliaFrequenciesGenderGoalsGonorrheaHemoglobinHumanHumoral ImmunitiesImmune responseImmunityImmunizationImmunologic MemoryImmunologicsInfectionInflammationIronIron-Binding ProteinsLactoferrinLeadLigand BindingLigandsLipoproteinsMapsMediator of activation proteinMembrane Transport ProteinsMethodsModelingMucosal ImmunityMulti-Drug ResistanceMutagenesisNeisseria gonorrhoeaeNeisseria meningitidisNutrientNutritional ImmunityPathogenicityPelvic Inflammatory DiseasePreventive vaccineProcessProtein ConformationProteinsPublishingResistance developmentRoleRouteScheduleSelf ToleranceSexually Transmitted DiseasesSiderophoresSourceStructureSuperbugSurfaceSyndromeSystemTFRC geneTestingTherapeuticTissuesTransferrinTransferrin-Binding ProteinsUrethritisUterusVaccinationVaccine AntigenVaccine DesignVaccine ProductionVaccinesVariantbasecombatcross reactivitydesignexperimental studyhuman pathogenhumanized mouseimmunogenicityin silicoin vivoinnovationmalemouse modelmucosal sitemutantnovelpathogenprotective efficacyreproductive tractvaccine candidatevaccine deliveryvaccine developmentvolunteer
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
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Neisseria gonorrhoeae co-infection exacerbates vaginal HIV shedding without affecting systemic viral loads in human CD34+ engrafted mice.
淋病奈瑟菌合并感染会加剧阴道 HIV 脱落,但不会影响人类 CD34 移植小鼠的全身病毒载量。
- DOI:10.1371/journal.pone.0191672
- 发表时间:2018
- 期刊:
- 影响因子:3.7
- 作者:Xu,StaceyX;Leontyev,Danila;Kaul,Rupert;Gray-Owen,ScottD
- 通讯作者:Gray-Owen,ScottD
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CYNTHIA N CORNELISSEN其他文献
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{{ truncateString('CYNTHIA N CORNELISSEN', 18)}}的其他基金
Starve and Kill: Engineered Antigens Targeting Nutrient Acquisition Pathways Essential for Gonococcal Infection and Disease
挨饿和杀死:针对淋球菌感染和疾病所必需的营养获取途径的工程抗原
- 批准号:
10595567 - 财政年份:2019
- 资助金额:
$ 62.8万 - 项目类别:
Starve and Kill: Engineered Antigens Targeting Nutrient Acquisition Pathways Essential for Gonococcal Infection and Disease
挨饿和杀死:针对淋球菌感染和疾病所必需的营养获取途径的工程抗原
- 批准号:
10355467 - 财政年份:2019
- 资助金额:
$ 62.8万 - 项目类别:
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
- 批准号:
9888316 - 财政年份:2019
- 资助金额:
$ 62.8万 - 项目类别:
Using gonococcal TonB-dependent transporters as vaccine antigens
使用淋球菌 TonB 依赖性转运蛋白作为疫苗抗原
- 批准号:
10560825 - 财政年份:2019
- 资助金额:
$ 62.8万 - 项目类别:
Starve and Kill: Engineered Antigens Targeting Nutrient Acquisition Pathways Essential for Gonococcal Infection and Disease
挨饿和杀死:针对淋球菌感染和疾病所必需的营养获取途径的工程抗原
- 批准号:
10116966 - 财政年份:2019
- 资助金额:
$ 62.8万 - 项目类别:
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