Specific T and B cell responses to candidate Treponema pallidum outer membrane protein vaccine antigens

对候选梅毒螺旋体外膜蛋白疫苗抗原的特异性 T 和 B 细胞反应

• 批准号: 10219125
• 负责人: David M Koelle
• 金额: $ 75.64万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219125
• 关键词: Adjuvant; Affinity; Aftercare; Animal Model; Anti-Bacterial Agents; Antibodies; Antibody Response; Antigens; B-Lymphocytes; Binding; Biological Assay; Blood; CD4 Positive T Lymphocytes; CD69 antigen; Cell Adhesion; Cells; Cellular Immunity; Clinical Trials; Complex; Crystallization; Endothelial Cells; Epitopes; Evaluation; Exhibits; Family; Globus Pallidus; Goals; Helper-Inducer T-Lymphocyte; Human; Immune; Immune response; Immunity; Immunization; Individual; Infection; Ingestion; Interferon Type II; Knowledge; Lead; Length; Lesion; Mediating; Membrane Proteins; Memory; Memory B-Lymphocyte; Modeling; Monoclonal Antibodies; Mus; N-terminal; Organism; Oryctolagus cuniculus; Patients; Peripheral Blood Mononuclear Cell; Persons; Positioning Attribute; Prevalence; Preventive vaccine; Process; Production; Research; Resolution; Series; Serum; Sexually Transmitted Diseases; Site; Skin; Structure; Syphilis; Syphilitic chancre; System; T cell response; T memory cell; T-Lymphocyte; Technology; Testing; Th1 Cells; Tissues; Treponema pallidum; Universities; Ursidae Family; Vaccinated; Vaccination; Vaccine Antigen; Washington; Work; cytokine; design; first-in-human; immunogenic; immunogenicity; improved; macrophage; member; memory CD4 T lymphocyte; response; seropositive; skin lesion; syphilis vaccine; vaccine candidate; vaccinology

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.

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。