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。
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。
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
CYNTHIA N CORNELISSEN的其他文献
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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:
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:
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:
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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