AIDS clinical trials group 5197: a placebo-controlled trial of immunization of HIV-1-infected persons with a replication-deficient adenovirus type 5 vaccine expressing the HIV-1 core protein

Abstract

Background: Human immunodeficiency virus type 1 (HIV-1)-specific cellular immunity contributes to the control of HIV-1 replication. HIV-1-infected volunteers who were receiving antiretroviral therapy were given a replication-defective adenovirus type 5 HIV-1 gag vaccine in a randomized, blinded therapeutic vaccination study.

Methods: HIV-1-infected vaccine or placebo recipients underwent analytical treatment interruption (ATI) for 16 weeks. The log(10) HIV-1 RNA load at the ATI set point and the time-averaged area under the curve served as co-primary end points. Immune responses were measured by intracellular cytokine staining and carboxyfluorescein succinimidyl ester dye dilution.

Results: Vaccine benefit trends were seen for both primary end points, but they did not reach a prespecified significance level of P < or = 25. The estimated shifts in the time-averaged area under the curve and the ATI set point were 0.24 (P=.04, unadjusted) and 0.26 (P=.07, unadjusted) log(10) copies lower, respectively, in the vaccine arm than in the placebo arm. HIV-1 gag-specific CD4(+) cells producing interferon-gamma were an immunologic correlate of viral control.

Conclusion: The vaccine was generally safe and well tolerated. Despite a trend favoring viral suppression among vaccine recipients, differences in HIV-1 RNA levels did not meet the prespecified level of significance. Induction of HIV-1 gag-specific CD4 cells correlated with control of viral replication in vivo. Future immunogenicity studies should require a substantially higher immunogenicity threshold before an ATI is contemplated.

Figure 1. Study Design. a) Vaccination and treatment interruption schedule. b) Protocol Defined Study Steps

Study participants were randomized 2: 1 to receive vaccine or placebo at weeks 0, 4 and 26. Twelve weeks after the last vaccination, those with a CD4 cell count ≥ 500/mm³ and without a confirmed HIV-1 RNA level >500 copies/mL during the vaccination period could undergo a 16 week ATI (Step II) (Figure 1b). Participants ineligible for ATI or who wished to continue therapy entered a 240-week observation phase (Step V). Participants could resume antiretroviral therapy at their discretion or on the recommendation of their care provider. Participants were strongly encouraged to resume therapy for signs of an acute retroviral illness or of immunodeficiency, for CD4 cells <300 cells/mm³ or < 50% of the value prior to vaccination on two consecutive occasions, or for HIV-1 plasma HIV-1 RNA levels ≥300,000 copies/mL on three consecutive measurements. Participants who did not resume therapy after the 16-week ATI entered Step III; those restarting antiretroviral therapy any time before week 87 entered Step IV. After week 87 study participants entered the long-term observation period (Step V).

Figure 2. Viral Rebound Kinetics Following Interruption of Antiretroviral Therapy

Consenting study participants interrupted antiviral treatment interruption 38 weeks from the beginning of the study and plasma HIV-1 RNA levels were monitored serially. For clarity, the top time axis shows the number of weeks from the initiation of the study; the number of weeks following the initiation of the analytical treatment interruption is depicted in the lower time axis. Plasma HIV-1 RNA values at each time point depict the mean and the 95% confidence intervals.

Figure 3. a) - Interferon- γ categorical responses to gag, nef pol1 or pol2 peptide pools in the CD4+ T-cell (a) or the CD8+ T-cell (b) subpopulation vs. time following initiation of vaccination sequence

The figure shows the percentage of study participants in the vaccine or the placebo arm at each time point demonstrating response to each peptide pool is shown. Responders were those with ≥ 400 interferon-γ producing cells/10⁶ CD4+ or a CD8+ cells and > 3 times greater than that to the mock peptide pool (except for the CD8+ response to the POL2 peptide pool which required ≥ 500 interferon-γ producing cells/10⁶ CD8+ cells and a response > 3 times greater than that to the mock peptide pool). The week 38 response was the response at treatment interruption and occurred 12 weeks after the third vaccination.

Figure 3. a) - Interferon- γ categorical responses to gag, nef pol1 or pol2 peptide pools in the CD4+ T-cell (a) or the CD8+ T-cell (b) subpopulation vs. time following initiation of vaccination sequence

The figure shows the percentage of study participants in the vaccine or the placebo arm at each time point demonstrating response to each peptide pool is shown. Responders were those with ≥ 400 interferon-γ producing cells/10⁶ CD4+ or a CD8+ cells and > 3 times greater than that to the mock peptide pool (except for the CD8+ response to the POL2 peptide pool which required ≥ 500 interferon-γ producing cells/10⁶ CD8+ cells and a response > 3 times greater than that to the mock peptide pool). The week 38 response was the response at treatment interruption and occurred 12 weeks after the third vaccination.

Figure 4. Interferon-γ categorical increase to gag, nef, pol1 or pol2 peptide pools in the CD4+ T-cell (a) or the CD8+ T-cell subpopulation (b) vs. time following initiation of vaccination sequence

The figure shows the percentage of study participants who exhibited a ≥ 2-fold increase CD4+ or CD8+ lymphocytes producing interferon-γ in response to each peptide pool when compared to the pre-vaccination value at week 1.

Figure 4. Interferon-γ categorical increase to gag, nef, pol1 or pol2 peptide pools in the CD4+ T-cell (a) or the CD8+ T-cell subpopulation (b) vs. time following initiation of vaccination sequence

The figure shows the percentage of study participants who exhibited a ≥ 2-fold increase CD4+ or CD8+ lymphocytes producing interferon-γ in response to each peptide pool when compared to the pre-vaccination value at week 1.

Figure 5. a) Gag-specific interferon- γ producing CD4+ cell (a) or CD8+ cell (B) count kinetics following initiation of vaccination sequence

The figure demonstrates the mean number and the 95% confidence intervals of CD4+ or CD8+ cells producing interferon-γ in response to the HIV-1 gag peptide pool at each time point during the study.

Figure 5. a) Gag-specific interferon- γ producing CD4+ cell (a) or CD8+ cell (B) count kinetics following initiation of vaccination sequence

The figure demonstrates the mean number and the 95% confidence intervals of CD4+ or CD8+ cells producing interferon-γ in response to the HIV-1 gag peptide pool at each time point during the study.

Figure 6. Associations between ATI viral set point and gag-specific interferon-γ producing CD4+ cell count at study weeks 8, 38 and 42

The figure demonstrates the inverse relationship between the HIV-1 RNA value at set point for each study participant and the log₁₀ of the number of CD4+ cells producing interferon-γ in response to the HIV-1 gag peptide pool at each time point.