Human T cell Lymphotropic Virus Vaccine development

项目总结：对于这个建议，我们打算开发一种新的疫苗来预防和可能的治疗

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.