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：
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
项目类别：
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

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.

项目摘要：对于这项提案，我们打算开发一种新型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。恶性 CD4+ T 细胞淋巴增殖的病原体，称为成人 T 细胞白血病/淋巴瘤（ATLL），以及几种炎症性疾病，其中最成问题的是人类脊髓病/热带病痉挛性截瘫 (HAM/TSP) 感染在世界许多地区（包括南部地区）流行。日本、美国南部、澳大利亚中部、加勒比地区、南美洲、赤道非洲和中东。估计全世界有超过 1000 万人感染 HTLV。 1个阳性者将出现ATLL，某些地区2%的HAM/TSP血清阳性率达到20-40%。在 50 岁以上的人群中，HTLV-1 是流行病的一个主要问题。特别是，没有有效的疫苗来预防相关疾病或治疗 ATLL 或 HAM/TSP 感染者的选择 HTLV-1 具有三种传播方式：母婴传播。主要与长期母乳喂养有关；主要发生在男性和女性之间；令人惊讶的是，与人类免疫缺陷病毒 1 型不同的是，器官和血液成分的移植。 (HIV-1)、HTLV-1 具有显着的遗传稳定性，此外，病毒可通过克隆扩增进行扩增。受感染的细胞和细胞间融合（合胞体）的形成，而不是病毒的裂解复制和释放负责因此，ATLL 被认为是由 HAM/TSP 引起的。病毒引发的神经系统炎症损伤，其机制尚不清楚。尚不清楚为什么某些患者可能在没有临床特征的情况下持续感染数年，而其他患者则发展考虑到这些信息，以及对先天免疫信号和/或 ATLL 的了解，HAM/TSP 和/或 ATLL。疫苗开发，我们的目标是开发并测试一种新型疫苗的功效，以预防 HTLV1 介导的为了实现这一目标，我们开发了一种基于水泡性口炎病毒（VSV）的疫苗载体和组建了一支经验丰富的团队，在先天免疫、HTLV-1、VSV 操作方面拥有丰富的知识并按照 GMP 水平和 I 期临床试验设计进行生产。表达 HTLV-1 病毒蛋白 (VSV-gp62-ΔHT)，其水平足以进行 FDA 相关的临床前研究罗切斯特梅奥诊所的设施由 Barber 博士的长期合作者 Mark Federspiel 博士领导。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 临床级产品相当，被 FDA 接受用于最终功效，我们已为 IND 前和 IND 申请提供支持的毒理学和药理学研究。通过迈阿密大学技术转让办公室 (OTT) 获得知识产权，现已已授权给 STINGINN LLC 进行开发合作。