Specific T and B cell responses to candidate Treponema pallidum outer membrane protein vaccine antigens
Specific T and B cell responses to candidate Treponema pallidum outer membrane protein vaccine antigens
批准号:
10219125
负责人:
David M Koelle
金额:
$75.64万
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
项目状态:
已结题
起止时间:
2019-08-01 至 2024-07-31
关键词:
AdjuvantAffinityAftercareAnimal ModelAnti-Bacterial AgentsAntibodiesAntibody ResponseAntigensB-LymphocytesBindingBiological AssayBloodCD4 Positive T LymphocytesCD69 antigenCell AdhesionCellsCellular ImmunityClinical TrialsComplexCrystallizationEndothelial CellsEpitopesEvaluationExhibitsFamilyGlobus PallidusGoalsHelper-Inducer T-LymphocyteHumanImmuneImmune responseImmunityImmunizationIndividualInfectionIngestionInterferon Type IIKnowledgeLeadLengthLesionMediatingMembrane ProteinsMemoryMemory B-LymphocyteModelingMonoclonal AntibodiesMusN-terminalOrganismOryctolagus cuniculusPatientsPeripheral Blood Mononuclear CellPersonsPositioning AttributePrevalencePreventive vaccineProcessProductionResearchResolutionSeriesSerumSexually Transmitted DiseasesSiteSkinStructureSyphilisSyphilitic chancreSystemT cell responseT memory cellT-LymphocyteTechnologyTestingTh1 CellsTissuesTreponema pallidumUniversitiesUrsidae FamilyVaccinatedVaccinationVaccine AntigenWashingtonWorkcytokinedesignfirst-in-humanimmunogenicimmunogenicityimprovedmacrophagemembermemory CD4 T lymphocyteresponseseropositiveskin lesionsyphilis vaccinevaccine candidatevaccinology
中文摘要
摘要
梅毒是由梅毒螺旋体(TP)引起的一种毁灭性的人类感染。在整个STI CRC范围内
题为“梅毒疫苗预防本地及播散性梅毒螺旋体感染”的申请,此
该项目涉及对已确定的TP疫苗候选抗原(TpVCA)的CD4T细胞和抗体反应
由项目1和项目2领导。其中包括Tp0751,一种与内皮细胞有关的外膜蛋白
细胞黏附,以及Tpr家族的成员。总而言之,我们的研究团队已经证明了使用兔子
TP疫苗接种模型和用这些TpVCA接种导致显著、部分保护的感染
对抗挑战。保护作用被认为是由抗体介导的。反过来,抗体反应依赖于
在CD4T细胞上,辅助性T滤泡(TFH)细胞的作用。TH1CD4T细胞反应也有助于TP特异性
抗体通过分泌干扰素-γ激活巨噬细胞吞噬包被的TP生物体
特异性抗体。项目3的前提是详细了解获得性免疫反应
TpVCA将有助于项目1和2能够改进TpVCA设计的反复过程,
项目3包含三个目标。在目标1中,将使用最先进的单个B细胞技术来分离幼稚
以及产生TpVCA特异性单抗(MAb)的记忆兔和人B细胞。这些
项目1和项目2将在功能分析中研究单抗的抗TP功能活性,如
感染挑战模型中的吞噬细胞和TP中和作用。最受认可的表位
将确定有效的单抗,如果可能的话,还将确定单抗-TpVCA络合物的晶体结构,
揭示具有抗菌功能表位的TpVCA结构域。目标2将对TpVCA进行排名
有症状和无症状者外周血中CD_4、TFH和TH_1细胞的患病率和水平
TP感染,并探索TP特异性的CD4T细胞是迁移到感染部位还是保留在组织中
常驻记忆T细胞。Aim 3将测试项目1和2中的最佳候选TpVCA,其中包括一系列
适用于人类、小鼠体液和CD4免疫原性检测的专利佐剂。
在STI CRC期间,项目3将与其他项目和核心进行关键的协同,以进行下选择
并优化抗原和佐剂,目标是提供一种适合于
在人类临床试验中取得第一名。
英文摘要
ABSTRACT
Syphilis is a devastating human infection caused by Treponoma pallidum (Tp). Within this overall STI CRC
application entitled “Syphilis vaccine to protect against local and disseminated T. pallidum infection”, this
Project concerns the CD4 T cell and antibody response to Tp Vaccine Candidate Antigens (TpVCA) identified
by Project 1 and Project 2 Leaders. These include Tp0751, an outer membrane protein involved in endothelial
cell adhesion, and members of the Tpr family. Collectively, our research team has shown using the rabbit
model of Tp vaccination and infection that vaccination with these TpVCA leads to significant, partial protection
against challenge. Protection is thought to be antibody mediated. In turn, antibody responses are dependent
on CD4 T cell help from T follicular helper (TFH) cells. The TH1 CD4 T cell response also assists Tp-specific
antibody by secreting interferon-gamma to activate macrophages to phagocytose Tp organisms coated by
specific antibody. The premise of Project 3 is that a detailed understanding of the acquired immune response
to TpVCA will assist a reiterative process by which Projects 1 and 2 will be able to improve TpVCA design,
Project 3 contains three Aims. In Aim 1, state-of-the-art single B cell technology will be used to isolate naïve
and memory rabbit and human B cells that produce TpVCA-specific monoclonal antibodies (mAb). These
mAbs will be studied in functional assays by Projects 1 and 2 for anti-Tp functional activities such as
opsonophagocytosis and Tp neutralization in infection challenge models. The epitopes recognized by the most
potent mAbs will be determined, and the crystal structures of mAb-TpVCA complexes determined if possible,
to uncover the TpVCA domains that bear functional anti-bacterial epitopes. Aim 2 will rank the TpVCA for
prevalence and levels of CD4 TFH and TH1 cells in the blood of persons with symptomatic and asymptomatic
Tp infection, and explore whether Tp-specific CD4 T-cells migrate to sites of infection or are retained as tissue
resident memory T cells. Aim 3 will test the best candidate TpVCA from Projects 1 and 2, with a series of
proprietary adjuvants that are suitable for use in humans, in mouse humoral and CD4 immunogenicity assays.
During the STI CRC period, Project 3 will critically synergize with the other Projects and Cores to downselect
and optimize antigen and adjuvants with the goal of delivering a lead Tp vaccine candidate suitable for
advancement to first in human clinical trials.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
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