Human T cell Lymphotropic Virus Vaccine development

人类T细胞嗜淋巴细胞病毒疫苗的开发

基本信息

  • 批准号:
    10554389
  • 负责人:
  • 金额:
    $ 28.83万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-02-01 至 2024-06-30
  • 项目状态:
    已结题

项目摘要

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.
项目概述:对于这项提案,我们打算开发一种新的疫苗,以预防和可能治疗 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, 称为成人T细胞白血病/淋巴瘤的恶性CD 4 + T细胞淋巴增殖的病原体 (ATLL),以及几种炎症性疾病,其中最有问题的是人类脊髓病/热带 痉挛性轻瘫(HAM/TSP)。HTLV-1感染在世界上许多地区流行,包括南部非洲, 日本、美国南部、澳大利亚中部、加勒比海、南美洲、赤道非洲和 中东全世界可能有1 000多万人受到感染。据估计,大约5%的HTLV- 1例阳性个体将发展为ATLL,2% 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。HTLV-1是世界各地数百万人感染的主要问题, 值得注意的是,没有有效的疫苗来预防相关疾病或治疗 ATLL或HAM/TSP患者的选择。HTLV-1有三种传播方式:母婴传播, 主要与长期母乳喂养有关;性,主要发生在男性到女性之间;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。相反,HAM/TSP被认为是由 由病毒引发的神经系统炎症损伤引起,其机制尚不清楚。也是 目前尚不清楚为什么某些患者可能会持续感染多年而没有临床特征,而另一些患者则会发展为 HAM/TSP和/或ATLL。鉴于这些信息,并与先天免疫信号的知识, 疫苗开发,我们的目标是开发和测试一种新的疫苗,以防止HTLV 1介导的 疾病为了实现这一点,我们已经产生了基于水泡性口炎病毒(VSV)的疫苗载体, 我组建了一个经验丰富的团队,在先天免疫,HTLV-1,VSV操作方面具有丰富的知识 并按GMP水平生产和I期临床试验设计。我们请求资源来制造VSV 以足以用于FDA相关临床前研究的水平表达HTLV-1病毒蛋白(VSV-gp 62-HTV-gp 62), 在马约诊所罗切斯特由马克Federspiel博士,巴伯博士的长期合作者领导的设施。 这些临床前研究将产生大规模VSV-gp 62-ΔHT病毒原液, 与未来的GMP临床级产品相当,FDA可接受用于最终疗效, 支持Pre-IND和IND申请的毒理学和药理学研究。我们已经申请了专利, 知识产权通过迈阿密大学的技术转让办公室(OTT),这现在已经 授权给STINGINN LLC进行开发,作为合作。

项目成果

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GLEN N BARBER其他文献

GLEN N BARBER的其他文献

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{{ truncateString('GLEN N BARBER', 18)}}的其他基金

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
  • 财政年份:
    2022
  • 资助金额:
    $ 28.83万
  • 项目类别:
Anti-inflammatory Activity of a Systemic STING Inhibitory Non-Nucleotide
系统性 STING 抑制性非核苷酸的抗炎活性
  • 批准号:
    10382621
  • 财政年份:
    2021
  • 资助金额:
    $ 28.83万
  • 项目类别:

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