Human T cell Lymphotropic Virus Vaccine development

人类T细胞嗜淋巴细胞病毒疫苗的开发

• 批准号: 10481417
• 负责人: GLEN N BARBER
• 金额: $ 29.99万
• 依托单位: STINGINN, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10481417
• 关键词: Adult T-Cell Leukemia/Lymphoma; Affect; Africa; Area; Attenuated; Australia; Barbering; Binding; Blood; Breast Feeding; CD34 gene; CD4 Positive T Lymphocytes; Caribbean region; Cell Culture Techniques; Cell fusion; Cells; Characteristics; Clinic; Clinical; Clinical Trials; Clinical Trials Design; Clonal Expansion; Collaborations; Communities; Data; Development; Disease; Evaluation; Exhibits; Female; Future; Genetic; Giant Cells; Glycoproteins; HIV-1; Harvest; Human; Human T-lymphotropic virus 1; Immune signaling; Immune system; Immunization; Individual; Infection; Inflammatory; Intellectual Property; Japan; Knowledge; Laboratories; Lead; Legal patent; Leukemic Cell; Link; Malignant - descriptor; Manufactured Materials; Mediating; Middle East; Modeling; Mus; Natural Immunity; Nerve Tissue; Nervous system structure; Oncolytic; Organ Transplantation; Patients; Persons; Pharmacology Study; Pharmacology and Toxicology; Phase; Phase I Clinical Trials; Procedures; Process; Production; Proteins; Quality Control; Recombinants; Reporting; Research Project Grants; Resources; Retroviridae; Serum; South America; Spinal Cord Diseases; Suspensions; Symptoms; T-Lymphocyte; Taxes; Technology Transfer; Tertiary Protein Structure; Toxic effect; Translating; Tropical Spastic Paraparesis; United States; Universities; Vaccines; Vertical Disease Transmission; Vesicular stomatitis Indiana virus; Viral; Viral Proteins; Viral Vaccines; Viral Vector; Virus; aged; bZIP Domain; base; design; efficacy evaluation; efficacy testing; experience; genetic regulatory protein; immunogenicity; improved; lymphadenopathy; lytic replication; male; mouse model; mutant; neutralizing antibody; novel; novel vaccines; phase I trial; pre-clinical; preclinical study; prevent; quality assurance; receptor; seropositive; therapeutic vaccine; transcription factor; vaccine candidate; vaccine development; 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 CD4+ T 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 ATLL, 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 vaccines to prevent associated disease or treatment options for ATLL or HAM/TSP afflicted individuals. HTLV-1 has three modes of transmission: mother-to-child, mainly linked to prolonged breast-feeding; sexual, predominantly occurring from male to female; and via transplantation of organs and blood components. Surprisingly, unlike Human Immunodeficiency Virus type-1 (HIV-1), HTLV-1 possesses significant genetic stability. Furthermore, viral amplification via clonal expansion of infected cells and cell-cell fusion (syncytia) formation, rather than viral lytic replication and release is responsible for viral spread. Accordingly, ATLL is a clonal malignant disease. HAM/TSP, in contrast, is thought to be caused by viral-triggered inflammatory damage to the nervous system, by mechanisms that remain unclear. It is also unclear why certain patients may remain infected for years without clinical features, while others develop HAM/TSP and/or ATLL. Given this information, and with improved knowledge of innate immune signaling and vaccine development, we aim to develop and test the efficacy of a novel vaccine to prevent HTLV1-mediated disease. To achieve this, we have generated a vaccine vector based on Vesicular Stomatitis Virus (VSV) and have assembled an experienced team with significant knowledge in innate immunity, HTLV-1, VSV manipulation and manufacture at the GMP level and Phase I clinical trial design. We request resources to manufacture VSV expressing HTLV-1 viral proteins (VSV-gp62-∆HT) at a level sufficient for FDA relevant preclinical studies with facilities at the Mayo Clinic Rochester led by Dr. Mark Federspiel a long-standing collaborator of Dr. Barber. These preclinical studies will produce large-scale VSV-gp62-ΔHT virus stocks with characteristics comparable to the future GMP clinical-grade products, acceptable by the FDA for use in final efficacy, toxicology and pharmacology studies supporting Pre-IND and IND applications. We have patented our intellectual property through the University of Miami’s Office of Technology Transfer (OTT) and this has now been licensed to STINGINN LLC for development, as a collaboration.

项目摘要：对于此提案，我们打算开发一种新型疫苗，以预防和可能的治疗 人类T细胞白血病病毒类型1（HTLV-1）相关疾病。 HTLV-1是人类逆转录病毒 恶性CD4+ T细胞淋巴细胞增生的病因，称为成人T细胞白血病/淋巴瘤 （ATLL），以及几种炎症性疾病，最有问题的是人脊髓病/热带 痉挛性瘫痪（HAM/TSP）。 HTLV-1感染在包括南部在内的世界许多地区是内在的 日本，美国南部，澳大利亚中部，加勒比海，南美，非洲赤道和 中东。全世界可能会感染超过1000万人。据估计，大约5％的HTLV- 1个积极的个体将发展为ATLL和2％HAM/TSP。某些地区的血清阳性率达到20-40％ 在50岁以上的人中。 HTLV-1在全球范围内受到数百万的影响，是内在的主要问题 社区，非常明显的是，没有有效的疫苗来预防相关疾病或治疗 ATLL或HAM/TSP折磨个人的选项。 HTLV-1具有三种传播方式：母亲到孩子， 主要与长时间的母乳喂养有关；性，主要发生从男性到女性；并通过 器官和血液成分的移植。令人惊讶的是，与人类免疫缺陷病毒类型1不同 （HIV-1），HTLV-1具有明显的遗传稳定性。此外，通过克隆扩张的病毒扩增 受感染的细胞和细胞 - 细胞融合（合成曲）的形成，而不是病毒裂解复制和释放是负责的 用于病毒传播。根据，ATLL是一种克隆恶性疾病。相比之下，HAM/TSP被认为是引起的 通过病毒触发的神经系统的炎症损害，通过尚不清楚的机制。也是 尚不清楚某些患者可能会被感染多年而没有临床特征，而其他患者则发展 火腿/TSP和/或ATLL。鉴于此信息，并提高了对先天免疫信号传导的了解和 疫苗开发，我们旨在开发和测试新型疫苗的效率以防止HTLV1介导 疾病。为了实现这一目标，我们已经基于囊泡口腔炎病毒（VSV）生成了疫苗载体和 已经组建了一支经验丰富的团队，具有先天免疫，HTLV-1，VSV操纵 并在GMP级别和I期临床试验设计下制造。我们要求资源制造VSV 表达HTLV-1病毒蛋白（VSV-GP62-∆HT）的水平足以用于FDA相关的临床前研究 由Barber博士的长期合作者Mark Federspiel博士领导的Mayo诊所罗切斯特的设施。 这些临床前研究将产生具有特征的大规模VSV-GP62-ΔHT病毒库存 与未来的GMP临床级产品相媲美，FDA可用于最终效率， 毒理学和药理学研究支持预先应用和IND应用。我们已经申请了我们的专利 通过迈阿密大学技术转移办公室（OTT）的知识产权，现在已经有了 被许可获得Stinginn LLC进行开发，作为合作。