Induction of strong HIV-1-specific CD4+ T-cell responses using an HIV-1 gp120/NefTat vaccine adjuvanted with AS02A in antiretroviral-treated HIV-1-infected individuals

Abstract

Background: Induction of HIV-1-specific CD4(+) T-cell responses by therapeutic vaccination represents an attractive intervention to potentially increase immune control of HIV-1.

Methods: We performed a double-blinded, randomized, placebo-controlled clinical trial to determine the safety and immunogenicity of GlaxoSmithKline Biologicals' HIV-1 gp120/NefTat subunit protein vaccine formulated with the AS02(A) Adjuvant System in subjects with well-controlled chronic HIV-1 infection on highly active antiretroviral therapy. Ten individuals received the vaccine; whereas adjuvant alone or placebo was given to 5 subjects each. Immunogenicity was monitored by intracellular cytokine flow cytometry and carboxyfluorescein succinimidyl ester-based proliferation assays.

Results: The vaccine was well tolerated with no related serious adverse events. Vaccine recipients had significantly stronger gp120-specific CD4(+) T-cell responses which persisted until week 48 and greater gp120-specific CD4(+) T-cell proliferation activity as compared with controls. In the vaccine group, the number of participants who demonstrated positive responses for both gp120-specific CD4(+) T-cell interleukin-2 production and gp120-specific CD8(+) T-cell proliferation were significantly higher at week 6.

Conclusions: The gp120/NefTat/AS02(A) vaccine induced strong gp120-specific CD4(+) T-cell responses and a higher number of vaccinees developed both HIV-1-specific CD4(+) T-cell responses and CD8(+) T-cell proliferation. The induction of these responses may be important in enhancing immune-mediated viral control.

Figure 1

A) Longitudinal assessment of CD4+ T cell production of IL-2. Proportion of CD4+ T cells that produce IL-2 quantified by intracellular cytokine staining in response to vaccine-derived HIV-1 peptides (gp120, nef, tat) and a non-vaccine derived HIV-1 peptide (gag) before and after vaccination. B) Longitudinal evaluation of CD4+ T cell proliferation. Proportion of CD4+ T cells proliferating following stimulation with vaccine-derived HIV-1 peptides (gp120, nef, tat) and a non-vaccine derived HIV-1 peptide (gag) before and at four time points following vaccination as measured by an ex-vivo proliferation assay. The top rows represent the vaccine group, and the bottom rows represent the control group. The horizontal lines are the medians. The stated p values were calculated using Kruskal-Wallis test for non-parametric data. Data are reported following background subtraction. & - P < 0.05 compared to week 0, and P < 0.05 compared to respective timepoint in control group. # - P < 0.05 compared to week 0. ‡ - P < 0.05 compared to control group.

Figure 2

A) Longitudinal assessment of CD8+ T cell production of IFN-γ. Proportion of CD8+ T cells that produce IFN-γ quantified by intracellular cytokine staining in response to vaccine-derived HIV-1 peptides (gp120, nef, tat) and a non-vaccine derived HIV-1 peptide (gag) before and after vaccination. B) Longitudinal evaluation of CD8+ T cell proliferation. Proportion of CD8+ T cells proliferating following stimulation with HIV-1 peptides as measured by ex-vivo proliferation assay. The top rows represent the vaccine group, and the bottom rows represent the control group. The horizontal lines are the medians. The stated p values are calculated using Kruskal-Wallis test for non-parametric data. Data are reported following background subtraction. & - P < 0.05 compared to week 0, and P < 0.05 compared to respective timepoint in control group. # - P < 0.05 compared to week 0. ‡ - P < 0.05 compared to control group.

Figure 3. Relationship between CD8+ T cell proliferation and CD4+ T cell IL-2 production in response to vaccine-derived gp120 over time

The dashed lines indicate the threshold for a positive test. A responder for cytokine production or CD8+ T cell proliferation following peptide stimulation was defined as an individual with ≥ 0.03% antigen-specific cells and at least an increase of 0.05% (after week 0) or ≥ 0.5% antigen-specific proliferating cells and at least an increase of 0.1% (after week 0), respectively. The p value was calculated by comparing the proportion of dual responders (met criteria for both CD8+ T cell proliferation and for CD4+ T cell IL-2 production) to gp120 in the control group to the proportion of dual responders in the vaccine group using the Fischer Exact test.