Pneumococcal immunization through a novel mechanism
通过新机制进行肺炎球菌免疫
基本信息
- 批准号:7168230
- 负责人:
- 金额:$ 41.02万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-01-15 至 2010-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdjuvantAdoptive Cell TransfersAdoptive TransferAntibodiesAntigensBacteriaCD4 Positive T LymphocytesCarrier ProteinsCell WallCellsCharacteristicsChargeChemicalsChildComplementConfocal MicroscopyConjugate VaccinesCouplingDataDiseaseEncapsulatedGoalsHistopathologyImmune responseImmunityImmunizationInvasiveKnock-outKnockout MiceKnowledgeLeadLifeLigandsLightMediatingMethodologyModificationMucosal ImmunityMusNasopharynxNatureOtitis MediaPneumococcal ColonizationPneumococcal InfectionsPolymersPolysaccharidesPreparationPreventionPropertyProteinsResistanceRoleRouteSerotypingSpecificityStreptococcus pneumoniaeStructureSynthetic VaccinesSystemic diseaseT-LymphocyteTLR4 geneTeichoic AcidsThinkingTimeToll-like receptorsToxoidsVaccinationVaccinesWild Type Mouseacquired immunitybasechemical synthesiscytokineear infectionextracellularmemory CD4 T lymphocytemiddle earneutrophilnovelnovel strategiespathogenpreventresearch studyresponsesuccess
项目摘要
DESCRIPTION (provided by applicant): The capsular polysaccharide-protein conjugate vaccine is effective in prevention of invasive disease by Streptococcus pneumoniae (pneumococci) of the serotypes included but is costly to make and administer, minimally effective against otitis media, and subject to serotype replacement (in which non-included serotypes become more prevalent). Therefore, novel approaches to immunization are needed. We found unexpectedly that mice immunized intranasally with the pneumococcal cell wall polysaccharide (CWPS, an antigen common to all serotypes) develop long-lasting resistance to nasopharyngeal colonization and middle ear infection with pneumococci of different serotypes. Strikingly, protection by the vaccine (i.e. CWPS + mucosal adjuvant) is independent of antibody and dependent on the presence of CD4+ T cells. This polysaccharide-induced, cell-mediated mucosal immunity against colonization by an "extracellular" encapsulated bacterium has not, to our knowledge, been previously demonstrated and therefore represents a novel approach to vaccination. We hypothesize that the zwitterionic property of CWPS is critical in eliciting this T-cell-dependent response. Our first goal is to determine the structural basis of protection by CWPS by further purification, polymer synthesis, chemical modifications to alter the zwitterionic motif, auto-coupling, or coupling to a protein carrier. Thus either the zwitterion hypothesis will be confirmed and/or the minimal protective structure will be defined. Secondly, we will examine in more detail the mechanisms whereby CD4+ T cells confer protection against pneumococcal colonization. Adoptive transfer experiments will characterize the nature of the protective T cell responses. Further approaches will include polarization of T cell responses by use of knockout mice or administration of cytokines, neutrophil depletion experiments, and histopathology with confocal microscopy. In a third aim, we will evaluate the role of innate immune responses in modulating acquired immunity to colonization, by use of Toll-like receptor (TLR) knockout mice and co-administration of TLR ligands as adjuvants at the time of immunization. Our studies will increase basic understanding of immunity to pneumococcal colonization and could lead to a simple, defined, and possibly synthetic vaccine that would complement or replace the multivalent capsular conjugates in vaccination against this highly prevalent pathogen of children.
描述(由申请人提供):荚膜多糖-蛋白质缀合物疫苗可有效预防所包括血清型的肺炎链球菌(肺炎球菌)的侵袭性疾病,但制备和施用成本高,对中耳炎的有效性最低,并且需要进行血清型替换(其中未包括的血清型变得更普遍)。因此,需要新的免疫方法。我们出乎意料地发现,小鼠鼻内免疫的肺炎球菌细胞壁多糖(CWPS,一种抗原常见的所有血清型)开发持久的抵抗鼻咽定植和中耳感染的不同血清型的肺炎球菌。引人注目的是,疫苗(即CWPS +粘膜佐剂)的保护作用不依赖于抗体,而依赖于CD 4 + T细胞的存在。据我们所知,这种多糖诱导的、细胞介导的针对“细胞外”包囊细菌定植的粘膜免疫性先前尚未得到证实,因此代表了一种新的疫苗接种方法。我们假设CWPS的两性离子性质在引发这种T细胞依赖性反应中是至关重要的。我们的第一个目标是通过进一步纯化、聚合物合成、化学修饰以改变两性离子基序、自偶联或偶联至蛋白质载体来确定CWPS保护的结构基础。因此,要么zwitzerland假说将被证实和/或最低限度的保护结构将被定义。其次,我们将更详细地研究CD 4 + T细胞保护肺炎球菌定植的机制。连续转移实验将表征保护性T细胞应答的性质。进一步的方法将包括通过使用基因敲除小鼠或给予细胞因子、中性粒细胞耗竭实验和用共聚焦显微镜进行组织病理学来极化T细胞应答。在第三个目标中,我们将通过使用Toll样受体(TLR)敲除小鼠和在免疫时共施用TLR配体作为佐剂来评估先天免疫应答在调节针对定植的获得性免疫中的作用。我们的研究将增加对肺炎球菌定植免疫的基本理解,并可能导致一种简单、明确和可能的合成疫苗,该疫苗将补充或取代针对这种高度流行的儿童病原体的疫苗接种中的多价荚膜缀合物。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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RICHARD MALLEY其他文献
RICHARD MALLEY的其他文献
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{{ truncateString('RICHARD MALLEY', 18)}}的其他基金
Optimization and preclinical development of a TB Multiple Antigen Presenting System (MAPS) vaccine
结核病多抗原呈递系统 (MAPS) 疫苗的优化和临床前开发
- 批准号:
10316230 - 财政年份:2017
- 资助金额:
$ 41.02万 - 项目类别:
S. pneumoniae pilus regulation and host response
肺炎链球菌菌毛调节和宿主反应
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8893197 - 财政年份:2014
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$ 41.02万 - 项目类别:
Enhancing neonatal immunity to Streptococcus pneumoniae
增强新生儿对肺炎链球菌的免疫力
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8299197 - 财政年份:2012
- 资助金额:
$ 41.02万 - 项目类别:
Enhancing neonatal immunity to Streptococcus pneumoniae
增强新生儿对肺炎链球菌的免疫力
- 批准号:
8639459 - 财政年份:2012
- 资助金额:
$ 41.02万 - 项目类别:
Enhancing neonatal immunity to Streptococcus pneumoniae
增强新生儿对肺炎链球菌的免疫力
- 批准号:
8815256 - 财政年份:2012
- 资助金额:
$ 41.02万 - 项目类别:
Enhancing neonatal immunity to Streptococcus pneumoniae
增强新生儿对肺炎链球菌的免疫力
- 批准号:
8446269 - 财政年份:2012
- 资助金额:
$ 41.02万 - 项目类别:
Enhancing neonatal immunity to Streptococcus pneumoniae
增强新生儿对肺炎链球菌的免疫力
- 批准号:
9036324 - 财政年份:2012
- 资助金额:
$ 41.02万 - 项目类别:
Mechanisms of Immunity to Pneumococcal Colonization
肺炎球菌定植的免疫机制
- 批准号:
7364622 - 财政年份:2007
- 资助金额:
$ 41.02万 - 项目类别:
Mechanisms of Immunity to Pneumococcal Colonization
肺炎球菌定植的免疫机制
- 批准号:
8018651 - 财政年份:2007
- 资助金额:
$ 41.02万 - 项目类别:
Mechanisms of Immunity to Pneumococcal Colonization
肺炎球菌定植的免疫机制
- 批准号:
7266115 - 财政年份:2007
- 资助金额:
$ 41.02万 - 项目类别:
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