Safety and immunogenicity of therapeutic DNA vaccination in individuals treated with antiretroviral therapy during acute/early HIV-1 infection

Abstract

Background: An effective therapeutic vaccine that could augment immune control of HIV-1 replication may abrogate or delay the need for antiretroviral therapy. AIDS Clinical Trials Group (ACTG) A5187 was a phase I/II, randomized, placebo-controlled, double-blinded trial to evaluate the safety and immunogenicity of an HIV-1 DNA vaccine (VRC-HVDNA 009-00-VP) in subjects treated with antiretroviral therapy during acute/early HIV-1 infection. (clinicaltrials.gov NCT00125099)

Methods: Twenty healthy HIV-1 infected subjects who were treated with antiretroviral therapy during acute/early HIV-1 infection and had HIV-1 RNA<50 copies/mL were randomized to receive either vaccine or placebo. The objectives of this study were to evaluate the safety and immunogenicity of the vaccine. Following vaccination, subjects interrupted antiretroviral treatment, and set-point HIV-1 viral loads and CD4 T cell counts were determined 17-23 weeks after treatment discontinuation.

Results: Twenty subjects received all scheduled vaccinations and discontinued antiretroviral therapy at week 30. No subject met a primary safety endpoint. No evidence of differences in immunogenicity were detected in subjects receiving vaccine versus placebo. There were also no significant differences in set-point HIV-1 viral loads or CD4 T cell counts following treatment discontinuation. Median set-point HIV-1 viral loads after treatment discontinuation in vaccine and placebo recipients were 3.5 and 3.7 log(10) HIV-1 RNA copies/mL, respectively.

Conclusions: The HIV-1 DNA vaccine (VRC-HIVDNA 009-00-VP) was safe but poorly immunogenic in subjects treated with antiretroviral therapy during acute/early HIV-1 infection. Viral set-points were similar between vaccine and placebo recipients following treatment interruption. However, median viral load set-points in both groups were lower than in historical controls, suggesting a possible role for antiretroviral therapy in persons with acute or early HIV-1 infection and supporting the safety of discontinuing treatment in this group.

Trial registration: Clinicaltrials.gov NCT00125099.

Figure 1. HIV-1 RNA levels following treatment interruption in Arm A (vaccine) and Arm B (placebo).

The set-point viral load was determined by measuring HIV-1 RNA between weeks 17–23 of the treatment interruption. The median viral loads at setpoint were 3.5 and 3.7 log₁₀ copies/ml in Arms A and B, respectively.

Figure 2. CD4+ T cell counts in Vaccine (Arm A) and Placebo (Arm B).

Antiretroviral therapy was discontinued at study week 30. The set-point CD4+ T cell count was determined by measuring T cell subsets between weeks 17–23 of the treatment interruption. The median CD4+ T cell counts at setpoint were 629 and 728 cells/mm³ in Arms A and B. The symbol V indicates when vaccine or placebo was administered. The shaded area indicates the time period when subjects were off antiretroviral therapy.

Figure 3. CD4 IFN-γ ELISPOT profile by antigen and treatment arm.

Antiretroviral therapy was discontinued at study week 30. Positive responses were defined as a 2-fold increase from baseline that were also ≥100 spot forming cells (SFC) per million PBMC. The symbol V indicates when vaccine or placebo was administered. The shaded area indicates the time period when subjects were off antiretroviral therapy.

Figure 4. CD8 IFN-γ ELISPOT profile by antigen and treatment arm.

Antiretroviral therapy was discontinued at study week 30. Positive responses were defined as a 2-fold increase from baseline that were also ≥100 spot forming cells (SFC) per million PBMC. The symbol V indicates when vaccine or placebo was administered. The shaded area indicates the time period when subjects were off antiretroviral therapy.

Figure 5. Lymphocyte proliferation responses (Stimulation Index) by antigen and treatment arm.

Antiretroviral therapy was discontinued at study week 30. The symbol V indicates when vaccine or placebo was administered. The shaded area indicates the time period when subjects were off antiretroviral therapy.