An Ad5-Vectored HIV-1 Vaccine Elicits Cell-mediated Immunity but does not Affect Disease Progression in HIV-1-infected Male Subjects: Results From a Randomized Placebo-Controlled Trial (The Step Study)

Center for Global Health, Weill Cornell Medical College, New York, New York 10021, USA.
The Journal of Infectious Diseases (Impact Factor: 6). 03/2011; 203(6):765-72. DOI: 10.1093/infdis/jiq114
Source: PubMed


The Step study was a randomized trial to determine whether an adenovirus type 5 (Ad5) vector vaccine, which elicits T cell immunity, can lead to control of human immunodeficiency virus (HIV) replication in participants who became HIV-infected after vaccination.
We evaluated the effect of the vaccine on trends in HIV viral load, CD4+ T cell counts, time to initiation of antiretroviral therapy (ART), and AIDS-free survival in 87 male participants who became infected with HIV during the Step study and who had a median of 24 months of post-infection follow-up.
There was no overall effect of vaccine on mean log(10) viral load (estimated difference between groups, -0.11; P = .47). In a subset of subjects with protective HLA types (B27, B57, B58), mean HIV-1 RNA level over time was lower among vaccine recipients. There was no significant difference in CD4+ T cell counts, time to ART initiation, or in AIDS-free survival between HIV-1-infected subjects who received vaccine versus those who received placebo.
HIV RNA levels, CD4+ T cell counts, time to initiation of ART, and AIDS-free survival were similar in vaccine and placebo recipients. There may have been a favorable effect of vaccine on HIV-1 RNA levels in participants with HLA types associated with better control of HIV-1.

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    • "The vaccine did not significantly reduce acute log viral load, although the point estimate of a 0.4 log10 reduction suggests the possibility of weak suppression that would need confirmation in a study with more acute viral load data. Separate analyses of viral load data in Step from HIV diagnosis to 4 years post-infection (median follow-up two years post-infection) demonstrated that the vaccine did not reduce post-acute viral load [19]. Therefore any impact of the vaccine on viral load was early and transient. "
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    ABSTRACT: The sieve analysis for the Step trial found evidence that breakthrough HIV-1 sequences for MRKAd5/HIV-1 Gag/Pol/Nef vaccine recipients were more divergent from the vaccine insert than placebo sequences in regions with predicted epitopes. We linked the viral sequence data with immune response and acute viral load data to explore mechanisms for and consequences of the observed sieve effect. Ninety-one male participants (37 placebo and 54 vaccine recipients) were included; viral sequences were obtained at the time of HIV-1 diagnosis. T-cell responses were measured 4 weeks post-second vaccination and at the first or second week post-diagnosis. Acute viral load was obtained at RNA-positive and antibody-negative visits. Vaccine recipients had a greater magnitude of post-infection CD8+ T cell response than placebo recipients (median 1.68% vs 1.18%; p = 0·04) and greater breadth of post-infection response (median 4.5 vs 2; p = 0·06). Viral sequences for vaccine recipients were marginally more divergent from the insert than placebo sequences in regions of Nef targeted by pre-infection immune responses (p = 0·04; Pol p = 0·13; Gag p = 0·89). Magnitude and breadth of pre-infection responses did not correlate with distance of the viral sequence to the insert (p>0·50). Acute log viral load trended lower in vaccine versus placebo recipients (estimated mean 4·7 vs 5·1) but the difference was not significant (p = 0·27). Neither was acute viral load associated with distance of the viral sequence to the insert (p>0·30). Despite evidence of anamnestic responses, the sieve effect was not well explained by available measures of T-cell immunogenicity. Sequence divergence from the vaccine was not significantly associated with acute viral load. While point estimates suggested weak vaccine suppression of viral load, the result was not significant and more viral load data would be needed to detect suppression.
    PLoS ONE 08/2012; 7(8):e43396. DOI:10.1371/journal.pone.0043396 · 3.23 Impact Factor
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    • "A follow up study from the same group showed that peptide presentation properties of particular B*35 subtypes explain much of this association [38]. The dominance of HLA-B in the control of HIV-1 infection is supported by several studies which associated HLA-B*57, B*5801 and B*27 with slower disease progression rates (time to AIDS) and strong virologic (viral load) and immunologic control (CD4 count) [39-48], while B*35, B*5802 and B*18 were associated with ineffective control of viral replication and rapid progression to AIDS [37,43,44,47,49,50]. In addition, a significantly greater number of CD8+ T cell responses are HLA-B restricted, compared to HLA-A and -C. "
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    ABSTRACT: The major histocompatibility complex class I protein HLA-C plays a crucial role as a molecule capable of sending inhibitory signals to both natural killer (NK) cells and cytotoxic T lymphocytes (CTL) via binding to killer cell Ig-like receptors (KIR). Recently HLA-C has been recognized as a key molecule in the immune control of HIV-1. Expression of HLA-C is modulated by a microRNA binding site. HLA-C alleles that bear substitutions in the microRNA binding site are more expressed at the cell surface and associated with the control of HIV-1 viral load, suggesting a role of HLA-C in the presentation of antigenic peptides to CTLs. This review highlights the role of HLA-C in association with HIV-1 viral load, but also addresses the contradiction of the association between high cell surface expression of an inhibitory molecule and strong cell-mediated immunity. To explore additional mechanisms of control of HIV-1 replication by HLA-C, we address specific features of the molecule, like its tendency to be expressed as open conformer upon cell activation, which endows it with a unique capacity to associate with other cell surface molecules as well as with HIV-1 proteins.
    Retrovirology 05/2012; 9(1):39. DOI:10.1186/1742-4690-9-39 · 4.19 Impact Factor
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    • "Replication-defective Ad35 and Ad26 carrying HIV-1 genes are being tested in Phase I clinical trials, whereas Ad5 is being tested in a Phase II trial that has enrolled Ad5 nAbnegative and circumcised male volunteers ( The Ad5-based HIV-1 vaccine constructs are under extensive investigation for human use [27] [28] [29] [30]. The Lmdd-BdopSIVgag prime and Ad5hr-SIVgag boost was designed to induce strong cellular responses against SIV Gag in RM. "
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    ABSTRACT: We sought to induce primate immunodeficiency virus-specific cellular and neutralizing antibody (nAb) responses in rhesus macaques (RM) through a bimodal vaccine approach. RM were immunized intragastrically (i.g.) with the live-attenuated Listeria monocytogenes (Lm) vector Lmdd-BdopSIVgag encoding SIVmac239 gag. SIV Gag-specific cellular responses were boosted by intranasal and intratracheal administration of replication-competent adenovirus (Ad5hr-SIVgag) encoding the same gag. To broaden antiviral immunity, the RM were immunized with multimeric HIV clade C (HIV-C) gp160 and HIV Tat. SIV Gag-specific cellular immune responses and HIV-1 nAb developed in some RM. The animals were challenged intrarectally with five low doses of R5 SHIV-1157ipEL-p, encoding a heterologous HIV-C Env (22.1% divergent to the Env immunogen). All five controls became viremic. One out of ten vaccinees was completely protected and another had low peak viremia. Sera from the completely and partially protected RM neutralized the challenge virus > 90%; these RM also had strong SIV Gag-specific proliferation of CD8⁺ T cells. Peak and area under the curve of plasma viremia (during acute phase) among vaccinees was lower than for controls, but did not attain significance. The completely protected RM showed persistently low numbers of the α4β7-expressing CD4⁺ T cells; the latter have been implicated as preferential virus targets in vivo. Thus, vaccine-induced immune responses and relatively lower numbers of potential target cells were associated with protection.
    Vaccine 06/2011; 29(34):5611-22. DOI:10.1016/j.vaccine.2011.06.017 · 3.62 Impact Factor
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