Development of A HTLV-1 Vaccine

HTLV-1 疫苗的开发

• 批准号: 10363730
• 负责人: Glen N. Barber
• 金额: $ 58.87万
• 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/10363730
• 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; Persons; 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.

项目摘要 对于这个建议，我们打算开发一种新的疫苗来预防和治疗人类T细胞白血病 1型病毒（HTLV-1）相关疾病。HTLV-1是一种人逆转录病毒，其是人类免疫缺陷病毒的病原体。 称为成人T细胞白血病/淋巴瘤（ATLL）的恶性T CD 4+细胞淋巴增殖，以及 几种炎性疾病，最有问题的是人类脊髓病/热带痉挛性下肢轻瘫 (HAM/TSP）。HTLV-1感染在世界上许多地区流行，包括日本南部、日本南部和日本南部。 美国、澳大利亚中部、加勒比海、南美洲、赤道非洲和中东。超过10 全世界可能有100万人被感染。据估计，大约5%的HTLV-1阳性个体 将开发ATL和2%HAM/TSP。在某些地区，年龄在15岁以上的人中，血清阳性率达到20-40%。 50年HTLV-1在全球范围内受到数百万人的影响，是地方性社区的一个主要问题， 没有有效的疫苗或治疗选择来预防ATL或HAM/TSP患病的个体。给定 该研究旨在开发和测试预防HTLV 1介导的疾病的新型疫苗的功效。 目的1：在免疫活性鼠模型中评估免疫原性，所述免疫活性鼠模型包括具有人源化抗体的小鼠。 免疫系统（NSG™-SGM 3）基于VSV的疫苗载体，其表达HTLV-1糖蛋白， 调节蛋白TAX和HBZ（VSV-gp 62-HBHT）。我们的候选疫苗产生中和作用的能力 将分析糖蛋白的抗体，以及针对gp 62、TAX的细胞毒性T细胞（CTL）的产生。 和HBZ。 目的2：我们的目的是比较我们的疫苗是否可以用于预防HTLV-1转化相关的 疾病该方法将包括确定VSV-gp 62-HHT是否可以防止HTLV的建立。 1-在NSG™-SGM 3小鼠中的相关白血病/淋巴瘤。我们的目标是收集足够的资料， 因此，需要考虑进行各种I期试验来预防HTLV-1相关疾病。