Human T Cell Lymphotropic Virus Vaccine Development

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.

Grant Number: 9R42CA290612-03
NIH Institute/Center: NIH
Principal Investigator: GLEN BARBER