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: 9982776
• 负责人: David M Koelle
• 金额: $ 69.39万
• 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/9982776
• 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 梅毒是一种由梅毒螺旋体（TP）引起的毁灭性人类感染。在这一总体科技创新审查委员会内， 申请题为“预防局部和传播的T.梅毒感染”，这 项目涉及确定的对Tp疫苗候选抗原（TpVCA）的CD 4 T细胞和抗体应答 项目1和项目2负责人。这些包括Tp 0751，一种参与内皮细胞增殖的外膜蛋白。 细胞粘附和Tpr家族成员。总的来说，我们的研究团队已经证明， 接种这些TpVCA导致显著的、部分的保护， 对抗挑战保护作用被认为是抗体介导的。反过来，抗体反应依赖于 在CD 4 T细胞的帮助下，T滤泡辅助细胞（TFH）。TH 1 CD 4 T细胞应答也有助于TP特异性免疫应答。 抗体通过分泌干扰素-γ来激活巨噬细胞以吞噬被 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设计的迭代过程， 项目3包含三个目标。在目标1中，将使用最先进的单B细胞技术分离未处理的 以及产生TpVCA特异性单克隆抗体（mAb）的记忆兔和人B细胞。这些 项目1和2将在功能测定中研究mAb的抗Tp功能活性，例如 感染激发模型中的调理吞噬和Tp中和。大多数人识别的表位 将确定有效的单克隆抗体，如果可能的话，确定mAb-TpVCA复合物的晶体结构， 以揭示具有功能性抗菌表位的TpVCA结构域。目标2将对TpVCA进行排名， 有症状和无症状的人血液中CD 4 TFH和TH 1细胞的患病率和水平 TP感染，并探讨TP特异性CD 4 T细胞是否迁移到感染部位或作为组织保留 常驻记忆T细胞目标3将测试项目1和项目2中的最佳候选TpVCA， 适用于人类、小鼠体液和CD 4免疫原性试验的专有佐剂。 在STI CRC期间，项目3将与其他项目和核心进行关键协同， 并优化抗原和佐剂，目的是递送适合于以下的先导Tp疫苗候选物： 首次进入人体临床试验。