Human T cell Lymphotropic Virus Vaccine development

项目摘要：对于这项提议，我们打算开发一种新的疫苗来预防和可能治疗 人类T细胞白血病病毒1型(HTLV-1)相关疾病。HTLV-1是一种人类逆转录病毒， 一种称为成人T细胞白血病/淋巴瘤的恶性CD4+T细胞淋巴组织增殖的病原体 (ATLL)，以及几种炎症性疾病，最有问题的是人类脊髓病/热带 痉挛性截瘫(Ham/TSP)。HTLV-1感染在世界许多地区流行，包括南方 日本、美国南部、澳大利亚中部、加勒比海、南美洲、赤道非洲和 中东。全球可能有超过1000万人受到感染。据估计，大约5%的HTLV- 1个阳性个体将发展成AT11，2%的HAM/TSP。某些地区的血清阳性率达到20%-40% 在50岁以上的人群中。随着全球数百万人受到影响，HTLV-1是地方性疾病中的一个主要问题 而且值得注意的是，没有有效的疫苗来预防相关疾病或治疗。 可供ATLL或HAM/TSP受影响的个人选择。HTLV-1有三种传播方式：母婴传播， 主要与长时间母乳喂养有关；性行为，主要发生在男性和女性之间；以及通过 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1型不同 (HIV-1)，HTLV-1具有显著的遗传稳定性。此外，通过克隆扩增的病毒扩增 感染细胞和细胞-细胞融合(合胞体)的形成，而不是病毒的裂解复制和释放负责 用于病毒传播。因此，ATLL是一种克隆性恶性疾病。相比之下，Ham/TSP被认为是由 通过病毒引发的神经系统炎症损害，通过尚不清楚的机制。它也是 不清楚为什么某些患者可能会在没有临床特征的情况下持续感染多年，而其他患者则会发展为 火腿/TSP和/或ATLL。有了这些信息，并有了更好的关于先天性免疫信号和 疫苗的开发，我们的目标是开发和测试一种新型疫苗的效力，以防止HTLV1介导的 疾病。为了实现这一点，我们已经产生了一种基于水疱性口炎病毒(VSV)的疫苗载体 我组建了一支经验丰富的团队，在先天免疫、HTLV-1、VSV操作方面具有丰富的知识 并在GMP水平和I期临床试验设计中进行生产。我们需要资源来制造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 罗切斯特梅奥诊所的设施由马克·费德斯佩尔博士领导，他是巴伯博士的长期合作者。 这些临床前研究将产生具有特征的大规模VSV-gp62-ΔHT毒株 可与未来的GMP临床级产品相媲美，可被FDA接受用于最终疗效， 毒理学和药理学研究支持IND前和IND应用。我们已经为我们的 通过迈阿密大学的技术转让办公室(OTT)获得知识产权 作为一项合作，已授权给STINGINN LLC进行开发。

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.