University of Washington (UW) Sexually Transmitted Infections (STI) Cooperative Research Center (CRC) - Syphilis Vaccine to Protect against Local and Disseminated T. pallidum Infection

华盛顿大学 (UW) 性传播感染 (STI) 合作研究中心 (CRC) - 梅毒疫苗可预防局部和播散性梅毒螺旋体感染

• 批准号: 10544247
• 负责人: Anna Wald
• 金额: $ 12.37万
• 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/10544247
• 关键词: Adult; Antibodies; Antigens; B-Lymphocytes; Biological; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Child; Color; Congenital Syphilis; Disease; Epidemic; Epitopes; Future; Health Campaign; Human; Humanities; Immune response; Immunohistochemistry; Incidence; Infection; Knowledge; Lesion; Lymphocyte; Measures; Mediating; Membrane Proteins; Modeling; Oryctolagus cuniculus; Peptides; Phenotype; Proteins; Public Health; Recombinant Proteins; Reporting; Research; Scourge; Sexually Transmitted Diseases; Sorting; Subunit Vaccines; Syphilis; T cell response; T-Cell Immunologic Specificity; T-Lymphocyte; Time; Treponema pallidum; Universities; Vaccine Antigen; Vaccines; Washington; Woman; curative treatments; design; extracellular; follow-up; improved; insight; men who have sex with men; next generation; novel strategies; response; skin lesion; syphilis vaccine; tool; vaccine candidate; γδ T cells

PROJECT SUMMARY Syphilis has been a scourge on humanity for hundreds of years. It has been impossible to eradicate due to biological and societal barriers. Despite curative therapy and multiple public health campaigns to eliminate syphilis in the US, the incidence is rising in diverse groups: men who have sex with men, women, and children. An effective syphilis vaccine will be a key tool in the eradication of this disease. Prior efforts to create a protective syphilis vaccine focused on raising antibodies against rare outer membrane proteins to facilitate antibody mediated opsonophagocytosis of Treponema pallidum (Tp) in infectious lesions. These vaccines only generate partial protection in the rabbit model and have not advanced to human trials. Notably, these candidate antigens did not specifically target T cell responses. We believe that better understanding of T cell specificity and phenotype will provide insights into novel strategies to design an effective syphilis vaccine. For example, the inclusion of immunodominant T cell antigens in a subunit vaccine can provide CD4 T cell help to B cells to produce opsonic antibodies. At this time, there are no reported human Tp T cell antigens validated to the epitope level. Aim 1 focuses on identifying immunodominant CD4 T cell antigens. We will use rare cell enrichment to measure, sort and then expand Tp-specific CD4 T cells. We will expand our extant panel of recombinant proteins to probe CD4 T cells, determine which Tp protein antigens are recognized, and follow up antigen-level hits to the peptide epitope level. Less is known about the CD8 response during syphilis. While T. pallidum is canonically extracellular and as such not expected to elicit a classic peptide-specific CD8 T cell response, we know that there are abundant CD8-expressing cells within active syphilis lesions. We don't know if they are responding to Tp peptide epitopes, or if they are classic or innate-spectrum lymphocytes. Aim 2 focuses on better understanding the CD8 response. Multicolor immunohistochemistry will determine if these CD8-expressing cells are classic T cells with hypervariable TCRs, or cells such as NK, NKT, MAIT, or gamma-delta T cells. Their phenotype will guide future studies towards determination of the Tp-associated molecules recognized by these cells. Overall, knowledge of Tp T cell antigens will significantly improve our ability to design the next- generation candidate vaccines against syphilis.

项目摘要 数百年来，Syphilis一直是人类的祸害。一直无法 消除由于生物和社会障碍。尽管有治愈性治疗和多种公众 在美国消除梅毒的健康运动中，不同群体的发病率正在上升：男性 与男人女人和孩子发生性关系的人一种有效的梅毒疫苗将是一个关键的工具， 根除这种疾病。先前创造保护性梅毒疫苗的努力主要集中在 产生针对稀有外膜蛋白的抗体以促进抗体介导的 感染性病变中梅毒螺旋体（Tp）的调理吞噬作用。这些疫苗仅 在兔子模型中产生部分保护作用，尚未进入人体试验。值得注意的是， 这些候选抗原不特异性靶向T细胞应答。我们相信， 对T细胞特异性和表型的理解将为研究新的策略提供新的见解， 设计有效的梅毒疫苗例如，包括免疫显性T细胞 亚单位疫苗中的抗原可提供CD 4 T细胞帮助B细胞产生调理素 抗体的目前，还没有报道针对表位验证的人Tp T细胞抗原 水平目的1：鉴定免疫显性CD 4 T细胞抗原。我们将使用稀有细胞 富集以测量、分选然后扩增Tp特异性CD 4 T细胞。我们将扩大我们 现有的重组蛋白组来探测CD 4 T细胞，确定哪些Tp蛋白抗原 被识别，并跟踪抗原水平命中到肽表位水平。知之甚少 梅毒时的CD 8反应而T.苍白球通常位于细胞外， 这种预期不会引发经典的肽特异性CD 8 T细胞应答，我们知道， 在活动性梅毒病灶中有大量表达CD 8的细胞。我们不知道他们是不是 应答Tp肽表位，或者如果它们是经典的或先天谱的淋巴细胞。目的2 重点是更好地了解CD 8反应。多色免疫组化将 确定这些表达CD 8的细胞是具有高变TCR的经典T细胞，还是 如NK、NKT、MAIT或γ-δ T细胞。它们的表型将指导未来的研究 确定这些细胞识别的TP相关分子。总的来说， Tp T细胞抗原的知识将大大提高我们设计下一个- 梅毒疫苗的研制