PROJECT SUMMARY For this proposal we intend to evaluate the safety and efficacy of a novel immunotherapeutic 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 T CD4+ cell lymphoproliferative disorder referred to as adult T cell leukemia/lymphoma (ATLL), as well as several inflammatory disorders with the most problematic being HTLV-1 associated 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. HTLV-1 is also a major problem in southern Florida communities and remarkably, there are no effective vaccine or treatment options to prevent HAM/TSP or ATLL afflicted individuals. Given this, aim to develop and test the efficacy of a novel vaccine/immunotherapeutic to prevent HTLV1-mediated disease. For this proposal, and through our previous STTR award (Human T-Cell Lymphotropic Virus GMP Vaccine Development; R41AI 165061), we are happy to report that we have now successfully GMP manufactured vesicular stomatitis virus (VSV) with the VSV glycoprotein (G) substituted for the HTLV1 glycoprotein gp62. We have also designed our vaccine to express two defective, regulatory HTLV-1 proteins (HBZ and TAX). We aim to confirm that our candidate vaccine, referred to as (VSV-gp62-∆HT) generates neutralizing antibodies to the glycoprotein, as well as cytotoxic T cells (CTLs) to gp62, TAX and HBZ (as we effectively demonstrate in murine models, data enclosed herein). Aim 1: To evaluate the safety, immunogenicity and clinical activity of VSV-gp62-∆HT in healthy, HTLV-1 infected individuals at low dose inoculation (1 x 106 PFU x 3). Interim safety analysis will be performed, and detection of recombinant viral vectors determined, post inoculation (by plaque assay and RT-PCR). The ability of VSV-gp62- ∆HT to generate neutralizing antibodies to the glycoprotein will also be analyzed, as well as the production of cytotoxic T cells (CTLs) to gp62, TAX and HBZ and the vaccine’s impact on HTLV-1 proviral loads. Aim 2: Should we achieve the first aim, we will perform a second stage analysis at a higher dose (1 x 107 and plausibly 1 x 108 PFU x 3) and compare whether we observe an increases in neutralizing antibody to gp62 and/or CTL activity to gp62, HBZ and/or TAX. We will also monitor safety and viremia, as above. Our objectives are to collate sufficient information to warrant the consideration of utilizing VSV-gp62-∆HT in putative Phase II trials to prevent HTLV1-associated malaise, such as HAM/TSP and ATLL.

PROJECT NARRATIVE Human T cell leukemia virus type-1 (HTLV-1) is a human retrovirus that is the causative agent of a malignant T CD4+ cell lymphoproliferative disorder referred to as adult T cell leukemia/lymphoma (ATLL), as well as several inflammatory disorders with the most problematic being HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). Remarkable, while millions are affected worldwide, there is no effective vaccine or treatment options to prevent ATLL or HAM/TSP afflicted individuals. We thus aim here, to develop a candidate immunotherapeutic vaccine to prevent and plausibly treat HTLV1-associated disease.