Exploratory clinical studies of a synthetic HIV-1 Tat epitope vaccine in asymptomatic treatment-naïve and antiretroviral-controlled HIV-1 infected subjects plus healthy uninfected subjects

Abstract

TUTI-16 is a synthetic universal HIV-1 Tat epitope vaccine, designed to induce anti-Tat antibodies that block the function of circulating Tat, an HIV encoded protein secreted by HIV-1 infected cells. Circulating Tat activates CD4 T cells, permitting HIV replication and sustained viremia. Safety, immunogenicity and antiretroviral potential of TUTI-16 were explored in a randomized double-blind dose-escalating study in asymptomatic treatment-naïve HIV-1 infected subjects. TUTI-16 was safe, with mild local and systemic injection-related adverse reactions, but the antibody response was barely detectable. Surprisingly, a highly statistically significant reduction of HIV-1 viral load was found in the lowest 30 μg vaccine dose group (p < 0.01) but not at the higher doses. We posited that an anti-Tat antibody response below the limit of detection inhibited HIV viral load at this dose, an effect nullified at higher vaccine doses by activating cytokines induced by adjuvant components in TUTI-16. To clarify this immunogenicity/activation conundrum open label immunogenicity studies were performed in healthy HIV uninfected and aviremic ART-controlled HIV-infected subjects. These established that (1) healthy HIV negative subjects had robust antibody responses, maximal with 1 mg TUTI-16, (2) ART-controlled aviremic HIV infected subjects had similarly robust antibody responses, and (3) adjuvant-induced increases of HIV viral load did not occur in the presence of ART. These studies provided us a basis for the design of a protocol to explore the therapeutic potential of TUTI-16 vaccination to provide drug free control of HIV-1 viremia.

Keywords: :

• HIV-1
• TUTI-16
• Tat
• antiretroviral
• clinical trial
• human vaccine
• prophylactic
• therapeutic

Disclosure of Potential Conflicts of Interest

An IRS Qualified Therapeutic Discovery Grant was the only external funding provided for this study. GG is the founder of Thymon LLC, a virtual company formed to develop an HIV vaccine, and the inventor on 8 issued US patents related to HIV-1 Tat that are assigned to Thymon LLC.

Acknowledgments

We thank the participants for their participation in this study, Eve Damiano for her invaluable regulatory guidance, the staff of the Conant Medical Group, that conducted the double blind study, Marcus Conant and Chris Eden; the staff at Clinilabs, Inc., that performed the open label studies, Malika Pasha, Mardik Donikyan, Emily Muller, Brian Pondracz, Ray Ramondi; and Michael Willet and Melissa Carbon of Ready Clinical, for their meticulous care and expertise. Harvey Motulsky of GraphPad Sofware Inc. and Alan Fisher provided valued statistical support. We also thank Katherine Berkousen, Brenda Baldwin and the staff at FDA/CBER/OVRR for their valued guidance throughout this development.

GG developed the concepts and the protocol, with assistance from Eve Damiano, supervised the trial, performed the statistics, with support from Alan Fisher, and wrote the paper. JJC developed and performed the sandwich ELISA for measuring antibodies to Tat and wrote the assay section in Methods.

This study was performed under IND 1374 from CBER, USFDA, and ethical review from the Western Institutional Review Board, Olympia, WA (randomized study) and the New England Institutional Review Board, Newton, MA (open label study). All subjects signed approved informed consent forms before admission into the study. The randomized study was conducted at the Conant Medical Group, San Francisco, CA and the open label study at Clinilabs, Inc., New York, NY. Clinicaltrials.gov identifiers # NCT00848211, # NCT01144026.