Step Study Protocol Team. 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: 5.78). 03/2011; 203(6):765-72. DOI: 10.1093/infdis/jiq114
Source: PubMed

ABSTRACT 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.

  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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 · 3.49 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Acquired immune deficiency syndrome (AIDS), malaria and tuberculosis collectively cause more than five million deaths per year, but have nonetheless eluded conventional vaccine development; for this reason they represent one of the major global public health challenges as we enter the second decade of the twenty-first century. Recent trials have provided evidence that it is possible to develop vaccines that can prevent infection by human immunodeficiency virus (HIV) and malaria. Furthermore, advances in vaccinology, including novel adjuvants, prime-boost regimes and strategies for intracellular antigen presentation, have led to progress in developing a vaccine against tuberculosis. Here we discuss these advances and suggest that new tools such as systems biology and structure-based antigen design will lead to a deeper understanding of mechanisms of protection which, in turn, will lead to rational vaccine development. We also argue that new and innovative approaches to clinical trials will accelerate the availability of these vaccines.
    Nature 05/2011; 473(7348):463-9. DOI:10.1038/nature10124 · 42.35 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Immune escape mutations selected by human leukocyte antigen class I-restricted CD8(+) cytotoxic T lymphocytes (CTLs) can result in biologically and clinically relevant costs to HIV-1 replicative fitness. This phenomenon may be exploited to design an HIV-1 vaccine capable of stimulating effective CTL responses against highly conserved, mutationally constrained viral regions, where immune escape could occur only at substantial functional costs. Such a vaccine might 'channel' HIV-1 evolution towards a less-fit state, thus lowering viral load set points, attenuating the infection course and potentially reducing the risk of transmission. A major barrier to this approach, however, is the accumulation of immune escape variants at the population level, possibly leading to the loss of immunogenic CTL epitopes and diminished vaccine-induced cellular immune responses as the epidemic progresses. Here, we review the evidence supporting CTL-driven replicative defects in HIV-1 and consider the implications of this work for CTL-based vaccines designed to attenuate the infection course.
    Future Virology 08/2011; 6(8):917-928. DOI:10.2217/fvl.11.68 · 1.00 Impact Factor
Show more


Available from