Parallel Conduction of the Phase I Preventive and Therapeutic Trials Based on the Tat Vaccine Candidate

Abstract

The native HIV-1 Tat protein was chosen as vaccine candidate for phase I clinical trials in both uninfected (ClinicalTrials.gov identifier: NCT00529698) and infected volunteers (ClinicalTrials.gov identifier: NCT00505401). The rationale was based on the role of Tat in the natural infection and AIDS pathogenesis, on the association of Tat-specific immune responses with the asymptomatic stage and slow-progression rate as well as on its sequence conservation among HIV clades (http://www.hiv1tat-vaccines.info/). The parallel conduction in the same clinical centers of randomized, double blind, placebo-controlled phase I studies both in healthy, immunologically competent adults and in HIV-infected, clinically asymptomatic, individuals represents a unique occasion to compare the vaccine-induced immune response in both the preventive and therapeutic setting. In both studies, the same lot of the native Tat protein was administered 5 times, every four weeks, subcute (SC) with alum adjuvant or intradermic (ID), in the absence of adjuvant, at 7.5 microg, 15 microg or 30 microg doses, respectively. The primary and secondary endpoints of these studies were the safety and immunogenicity of the vaccine candidate, respectively. The study lasted 52 weeks and monitoring was conducted for on additional 3 years. The results of both studies indicated that the Tat vaccine is safe and well tolerated both locally and systemically and it is highly immunogenic at all the dosages and by both routes of administration. Vaccination with Tat induced a balanced immune response in uninfected and infected individuals. In particular, therapeutic immunization induced functional antibodies and partially reverted the marked Th1 polarization of anti-Tat immunity seen in natural infection, and elicited a more balanced Th1/Th2 immune response. Further, the number of CD4 T cells correlated positively with anti-Tat antibody titers. Based on these results, a phase II study is ongoing in infected drug-treated individuals (http://www.hiv1tat-vaccines.info/).

An Attenuated Herpes Simplex Virus Type 1 (HSV1) Encoding the HIV-1 Tat Protein Protects Mice from a Deadly Mucosal HSV1 Challenge

“…The HIV-1 Tat protein (HTLV-IIIB isolate, BH10 clone), provided by Diatheva, was produced in E. coli , as previously described [70]. For in vivo experiments the Tat protein was diluted in saline buffer containing 1% sucrose and 1% human serum albumin as previously described [44].…”

Impact of Viral Dose and Major Histocompatibility Complex Class IB Haplotype on Viral Outcome in Mauritian Cynomolgus Monkeys Vaccinated with Tat upon Challenge with Simian/Human Immunodeficiency Virus SHIV89.6P

“…Notably, on the basis of these preclinical data, Tat has been tested in phase I preventative and therapeutic trials (2,(9)(10)(11)16) and is being evaluated in a phase II therapeutic trial (http://www.hiv1tat-vaccines.info/).…”

Approaches to preventative and therapeutic HIV vaccines

“…Phase 1 preventative and therapeutic studies demonstrated that Tat vaccination is safe and immunogenic [36-38]. A phase 2 study that was not blinded and did not have placebo controls suggest that in virologically-suppressed HAART-treated participants, Tat vaccination induced restoration of CD4 + and CD8 + T-cell numbers and functional central memory T-cell subsets, of B and natural killer (NK) cell number and a reduction of immune activation [39,40*].…”