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.

项目总结 数百年来，梅毒一直是人类的祸害。这是不可能的 由于生物和社会障碍而导致的根除。尽管接受了根治疗法和多个公众 在美国开展消除梅毒的健康运动，梅毒在不同群体中的发病率正在上升：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预防梅毒的关键工具 根除这种疾病。之前创造保护性梅毒疫苗的努力主要集中在 提高稀有外膜蛋白抗体以促进抗体介导 梅毒螺旋体在感染性病变中的吞噬作用。仅限这些疫苗 在兔模型中产生部分保护，尚未进入人体试验。值得注意的是， 这些候选抗原并不是针对T细胞反应的。我们认为这是更好的 对T细胞特异性和表型的了解将为新的治疗策略提供见解 设计一种有效的梅毒疫苗。例如，包括免疫优势T细胞 亚单位疫苗中的抗原可以为B细胞提供CD4T细胞帮助产生调理 抗体。目前，还没有针对该表位验证的人类TP T细胞抗原的报道 水平。目的1鉴定免疫优势的CD4T细胞抗原。我们将使用稀有细胞 浓缩以测量、分类和扩增TP特异性的CD4T细胞。我们将扩大我们的 现有的重组蛋白小组探测CD4T细胞，确定哪些TP蛋白抗原 都是被识别的，并后续抗原水平的打击到多肽表位水平。鲜为人知 关于梅毒期间的CD8反应。而梅毒螺旋体是典型的胞外和AS 这样预计不会引发典型的多肽特异性CD8 T细胞反应，我们知道 在活动性梅毒皮损中有丰富的CD8表达细胞。我们不知道他们是不是 对TP多肽表位的反应，或者如果他们是经典的或固有的谱系淋巴细胞。目标2 重点是更好地了解CD8响应。多色免疫组织化学将 确定这些表达CD8的细胞是具有高变量TCRs的经典T细胞，还是细胞 如NK、NKT、MAIT或γ-增量T细胞。它们的表型将指导未来的研究 这些细胞识别的TP相关分子的测定。总的来说， 对TP T细胞抗原的了解将显著提高我们设计下一代- 新一代梅毒候选疫苗。