Induction and maintenance of bi-functional (IFN-γ + IL-2+ and IL-2+ TNF-α+) T cell responses by DNA prime MVA boosted subtype C prophylactic vaccine tested in a Phase I trial in India.

Effective vaccine design relies on accurate knowledge of protection against a pathogen, so as to be able to induce relevant and effective protective responses against it. An ideal Human Immunodeficiency virus (HIV) vaccine should induce humoral as well as cellular immune responses to prevent initial infection of host cells or limit early events of viral dissemination. A Phase I HIV-1 prophylactic vaccine trial sponsored by the International AIDS Vaccine Initiative (IAVI) was conducted in India in 2009.The trial tested a HIV-1 subtype C vaccine in a prime-boost regimen, comprising of a DNA prime (ADVAX) and Modified Vaccine Ankara (MVA) (TBC-M4) boost. The trial reported that the vaccine regimen was safe, well tolerated, and resulted in enhancement of HIV-specific immune responses. However, preliminary immunological studies were limited to vaccine-induced IFN-γ responses against the Env and Gag peptides. The present study is a retrospective study to characterize in detail the nature of the vaccine-induced cell mediated immune responses among volunteers, using Peripheral Blood Mononuclear Cells (PBMC) that were archived during the trial. ELISpot was used to measure IFN-γ responses and polyfunctional T cells were analyzed by intracellular multicolor flow cytometry. It was observed that DNA priming and MVA boosting induced Env and Gag specific bi-functional and multi-functional CD4+ and CD8+ T cells expressing IFN-γ, TNF-α and IL-2. The heterologous prime-boost regimen appeared to be slightly superior to the homologous prime-boost regimen in inducing favorable cell mediated immune responses. These results suggest that an in-depth analysis of vaccine-induced cellular immune response can aid in the identification of correlates of an effective immunogenic response, and inform future design of HIV vaccines

Evaluation of antiviral T cell responses and TSCM cells in volunteers enrolled in a phase I HIV-1 subtype C prophylactic vaccine trial in India.

T cells play an important role in controlling viral replication during HIV infection. An effective vaccine should, therefore, lead to the induction of a strong and early viral-specific CD8+ T cell response. While polyfunctional T cell responses are thought to be important contributors to the antiviral response, there is evidence to show that polyfunctional HIV- specific CD8+ T cells are just a small fraction of the total HIV-specific CD8+ T cells and may be absent in many individuals who control HIV replication, suggesting that other HIV-1 specific CD8+ effector T cell subsets may be key players in HIV control. Stem cell-like memory T cells (TSCM) are a subset of T cells with a long half-life and self-renewal capacity. They serve as key reservoirs for HIV and contribute a significant barrier to HIV eradication. The present study evaluated vaccine-induced antiviral responses and TSCM cells in volunteers vaccinated with a subtype C prophylactic HIV-1 vaccine candidate administered in a prime-boost regimen. We found that ADVAX DNA prime followed by MVA boost induced significantly more peripheral CD8+ TSCM cells and higher levels of CD8+ T cell-mediated inhibition of replication of different HIV-1 clades as compared to MVA alone and placebo. These findings are novel and provide encouraging evidence to demonstrate the induction of TSCM and cytotoxic immune responses by a subtype C HIV-1 prophylactic vaccine administered using a prime-boost strategy