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

基本信息

批准号：
10671517
负责人：
David M Koelle
金额：
$ 63.87万
依托单位：
UNIVERSITY OF WASHINGTON
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：
2019-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10671517
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 Cell Adhesion Cells Cellular Immunity Clinical Trials Complex 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 Macrophage 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-Lymphocyte Technology Testing Th1 Cells Tissues Treponema pallidum Universities Vaccinated Vaccination Vaccine Antigen Washington Work candidate identification cell motility cytokine design first-in-human immunogenic immunogenicity improved member memory CD4 T lymphocyte response seropositive skin lesion synergism syphilis vaccine tissue resident memory T cell vaccine candidate vaccinology

项目摘要

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.

抽象的梅毒是一种由梅毒螺旋体 (Tp) 引起的毁灭性人类感染。题为“预防局部和播散性梅毒螺旋体感染的梅毒疫苗”的申请，该申请项目涉及 CD4 T 细胞和抗体对已确定的 Tp 疫苗候选抗原 (TpVCA) 的反应由项目 1 和项目 2 负责人提供，其中包括 Tp0751，一种参与内皮细胞的外膜蛋白。我们的研究小组利用兔子证明了细胞粘附和 Tpr 家族成员的共同作用。 Tp 疫苗接种和感染模型表明，接种这些 TpVCA 会产生显着的部分保护作用抵抗攻击被认为是抗体介导的。反过来，抗体反应是依赖的。滤泡辅助 T (TFH) 细胞对 CD4 T 细胞的帮助 TH1 CD4 T 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 Tp 生物体项目3的前提是详细了解获得性免疫反应。 TpVCA 将协助重复过程，项目 1 和 2 将能够改进 TpVCA 设计，项目 3 包含三个目标在目标 1 中，将使用最先进的单 B 细胞技术来分离幼稚细胞。以及产生 TpVCA 特异性单克隆抗体 (mAb) 的记忆兔和人 B 细胞。项目 1 和 2 将在功能测定中研究 mAb，用于抗 Tp 功能测定活动，例如感染挑战模型中的调理吞噬作用和 Tp 中和作用是最受认可的表位。将确定有效的 mAb，并在可能的情况下确定 mAb-TpVCA 复合物的晶体结构，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。有症状和无症状者血液中 CD4 TFH 和 TH1 细胞的患病率和水平 Tp 感染，并探讨 Tp 特异性 CD4 T 细胞是否迁移到感染部位或保留为组织目标 3 将通过一系列测试测试项目 1 和 2 中的最佳候选 TpVCA。适用于人类、小鼠体液和 CD4 免疫原性测定的专有佐剂。在 STI CRC 期间，项目 3 将与其他项目和核心发挥重要协同作用，以减少选择并优化抗原和佐剂，目标是提供适合的先导 Tp 候选疫苗在人体临床试验中取得第一名。