Expansion and Diversification of Virus-Specific T Cells following Immunization of Human Immunodeficiency Virus Type 1 (HIV-1)-Infected Individuals with a Recombinant Modified Vaccinia Virus Ankara/HIV-1 Gag Vaccine

Abstract

Affordable therapeutic strategies that induce sustained control of human immunodeficiency virus type 1 (HIV-1) replication and are tailored to the developing world are urgently needed. Since CD8 ؉ and CD4 ؉ T cells are crucial to HIV-1 control, stimulation of potent cellular responses by therapeutic vaccination might be exploited to reduce antiretroviral drug exposure. However, therapeutic vaccines tested to date have shown modest immunogenicity. In this study, we performed a comprehensive analysis of the changes in virus-specific CD8 ؉ and CD4 ؉ T-cell responses occurring after vaccination of 16 HIV-1-infected individuals with a recombinant modified vaccinia virus Ankara-vectored vaccine expressing the consensus HIV-1 clade A Gag p24/p17 sequences and multiple CD8 ؉ T-cell epitopes during highly active antiretroviral therapy. We observed significant amplification and broadening of CD8 ؉ and CD4 ؉ gamma interferon responses to vaccine-derived epitopes in the vaccinees, without rebound viremia, but not in two unvaccinated controls followed simultaneously. Vaccine-driven CD8 ؉ T-cell expansions were also detected by tetramer reactivity, predominantly in the CD45RA ؊ CCR7 ؉ or CD45RA ؊ CCR7 ؊ compartments, and persisted for at least 1 year. Expansion was associated with a marked but transient up-regulation of CD38 and perforin within days of vaccination. Gag-specific CD8؉ and CD4 ؉ T-cell proliferation also increased postvaccination. These data suggest that immunization with MVA

Induction of long‐lasting multi‐specific CD8+ T cells by a four‐component DNA‐MVA/HIVA‐RENTA candidate HIV‐1 vaccine in rhesus macaques

“…Thus, in our initial rhesus macaque study using polyepitope immunogen HW and the same pTH and MVA vectors as used here, we showed that the DNA prime-rMVA boost regimen was more potent for induction of T cells than MVA alone [35,36], and that the tetramer frequencies of vaccine-induced T cells peaked 1 wk after the rMVA dosing and decreased thereafter [36]. These results are similar to our recent data in humans [26,27], with the difference in healthy HIV-1-uninfected individuals that in NHP an efficient boost was delivered even with the second and third rMVA dosing [36]. Here, we showed that vaccineinduced responses were detectable over 1 year after vaccination.…”

“…Through gradual pre-clinical and clinical protocol improvements, we were able to demonstrate priming of HIV-1-specific T cell responses in 8/8 healthy and boost pre-existing HIV-1-specific responses in 16/16 HIV-1-infected vaccine recipients [26,27].…”

Immunisation with recombinant modified vaccinia virus Ankara expressing HIV‐1 gag in HIV‐1‐infected subjects stimulates broad functional CD4+ T cell responses

“…Study participants were HAART-treated HIV-1-seropositive subjects with CD4 + T cell counts >300 cells/lL and plasma viral RNA <50 copies/mL (Roche Amplicor assay) for at least 12 months. Participants' clinical details and the study bleed schedule have been described [23]. All subjects gave written informed consent and remained on HAART throughout the study.…”

Vaccine properties of a novel marker gene-free recombinant modified vaccinia Ankara expressing immunodominant CMV antigens pp65 and IE1

“…Using dendritic cells infected with poxvirus encoding CEA and co-stimulatory molecules B7-1, ICAM-1 and LFA-3 activates potent CEA-specific immune responses [51]. Recent clinical studies indicated that MVA expressing HIV-1 Gag coupled to other CD8+ T-cell epitopes could induce multifunctional HIV-1-specific T cells in healthy subjects or in individuals with chronic HIV-1 infection [13,52].…”

“…An increasing number of MVA vector-based vaccines have entered into clinical trials [5][6][7][8][9][10][11][12]. Recent studies demonstrated that administration of MVA carrying HIV-1 Gag p24/p17 to HIV-1 infected individuals was safe and feasible [13]. However, no such MVA-based cytomegalovirus (CMV) vaccine has yet to reach the clinic.…”