Development of A HTLV-1 Vaccine

HTLV-1 疫苗的开发

• 批准号: 10209750
• 负责人: Glen N. Barber
• 金额: $ 62.37万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-03 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10209750
• 关键词: Adult T-Cell Leukemia/Lymphoma; Affect; Africa; Area; Attenuated; Australia; Binding; CD4 Positive T Lymphocytes; Caribbean region; Cell fusion; Cells; Clinical; Communities; Complement; Cytotoxic T-Lymphocytes; Development; Disease; Evaluation; Exhibits; Future; Giant Cells; Glycoproteins; Human; Human T-lymphotropic virus 1; Immune response; Immune system; Immunization; Immunocompetent; In Vitro; Individual; Infection; Inflammatory; Japan; Knowledge; Lead; Lymphoproliferative Disorders; Malignant - descriptor; Malignant Neoplasms; Measures; Mediating; Middle East; Mus; Nerve Tissue; Nervous system structure; Oncolytic; Prevention; Production; Proteins; Reporting; Retroviridae; South America; Spinal Cord Diseases; Symptoms; Taxes; Tertiary Protein Structure; Tropical Spastic Paraparesis; Tropism; United States; Vaccines; Vesicular stomatitis Indiana virus; Viral; Viral Proteins; Viral Vaccines; aged; bZIP Domain; base; design; efficacy testing; experience; genetic regulatory protein; immunogenicity; in vivo; insight; leukemia/lymphoma; mouse model; mutant; neutralizing antibody; novel; novel vaccines; phase I trial; prevent; receptor; seropositive; tax Gene Products; therapeutic vaccine; transcription factor; vaccine candidate; vector; vector-based vaccine

PROJECT SUMMARY For this proposal we intend to develop a novel vaccine to prevent and possibly treat Human T cell leukemia virus type-1 (HTLV-1) associated diseases. HTLV-1 is a human retrovirus that is the causative agent of a malignant T CD4+ cell lymphoproliferation referred to as Adult T cell leukemia/lymphoma (ATLL), as well as several inflammatory disorders with the most problematic being human myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 infection is endemic in many areas around the world including southern Japan, the southern United States, central Australia, the Caribbean, South America, equatorial Africa, and the middle East. Over 10 million people may be infected worldwide. It is estimated that approximately 5% of HTLV-1 positive individuals will develop ATL, and 2% HAM/TSP. Seropositive rates in certain areas reach 20–40% among people aged over 50 years. With millions affected worldwide, HTLV-1 is a major problem in endemic communities and remarkably, there are no effective vaccine or treatment options to prevent ATL or HAM/TSP afflicted individuals. Given this, aim to develop and test the efficacy of a novel vaccine to prevent HTLV1-mediated disease. Aim 1: To evaluate the immunogenicity, in immunocompetent murine models, including mice with a humanized immune system (NSG™-SGM3) VSV-based vaccine vectors that express the HTLV-1 glycoprotein and regulatory proteins TAX and HBZ (VSV-gp62-∆HT). The ability of our candidate vaccine to generate neutralizing antibodies to the glycoprotein will be analyzed, as well as the production of cytotoxic T cells (CTLs) to gp62, TAX and HBZ. Aim 2: We aim to compare whether our vaccine can be used to prevent HTLV-1 transformation associated disease. This approach will include establishing whether VSV-gp62-∆HT can prevent the establishment of HTLV- 1-assocated leukemia/lymphoma in NSG™-SGM3 mice. Our objectives are to collate sufficient information to warrant the consideration of a variety of Phase I trials to prevent HTLV-1 -associated disease.

项目概要 对于这项提案，我们打算开发一种新型疫苗来预防并可能治疗人类 T 细胞白血病 1 型病毒 (HTLV-1) 相关疾病 HTLV-1 是一种人类逆转录病毒，是一种病原体。 恶性 T CD4+ 细胞淋巴增殖，称为成人 T 细胞白血病/淋巴瘤 (ATLL)，以及 几种炎症性疾病，其中最严重的是人类脊髓病/热带痉挛性截瘫 (HAM/TSP) HTLV-1 感染在世界许多地区流行，包括日本南部、南部地区。 美国、澳大利亚中部、加勒比地区、南美洲、赤道非洲和中东 10 多个。 据估计，全球约有 5% 的 HTLV-1 阳性个体受到感染。 会出现 ATL，某些地区 2% 的 HAM/TSP 血清阳性率在 20 岁以上人群中达到 20-40%。 50 年来，HTLV-1 是流行社区的一个主要问题，在全世界范围内有数百万人受到影响。 没有有效的疫苗或治疗方案来预防 ATL 或 HAM/TSP 受影响的个体。 该项目旨在开发并测试一种新型疫苗预防 HTLV1 介导的疾病的功效。 目标 1：评估免疫活性小鼠模型（包括带有人源化抗体的小鼠）的免疫原性 免疫系统 (NSG™-SGM3) 基于 VSV 的疫苗载体，表达 HTLV-1 糖蛋白和 调节蛋白 TAX 和 HBZ (VSV-gp62-ΔHT) 我们的候选疫苗产生中和的能力。 将分析针对糖蛋白的抗体，以及针对 gp62、TAX 的细胞毒性 T 细胞 (CTL) 的产生 和 H.B.Z。 目标 2：我们的目标是比较我们的疫苗是否可以用于预防与 HTLV-1 相关的转化 该方法将包括确定 VSV-gp62-ΔHT 是否可以预防 HTLV- 的形成。 NSG™-SGM3 小鼠中的 1 相关白血病/淋巴瘤我们的目标是整理足够的信息以进行研究。 值得考虑进行各种 I 期试验来预防 HTLV-1 相关疾病。