The F4/AS01B HIV-1 Vaccine Candidate Is Safe and Immunogenic, But Does Not Show Viral Efficacy in Antiretroviral Therapy-Naive, HIV-1-Infected Adults: A Randomized Controlled Trial

Abstract

The impact of the investigational human immunodeficiency virus type 1 (HIV-1) F4/AS01B vaccine on HIV-1 viral load (VL) was evaluated in antiretroviral therapy (ART)-naive HIV-1 infected adults.This phase IIb, observer-blind study (NCT01218113), included ART-naive HIV-1 infected adults aged 18 to 55 years. Participants were randomized to receive 2 (F4/AS01B_2 group, N = 64) or 3 (F4/AS01B_3 group, N = 62) doses of F4/AS01B or placebo (control group, N = 64) at weeks 0, 4, and 28. Efficacy (HIV-1 VL, CD4 T-cell count, ART initiation, and HIV-related clinical events), safety, and immunogenicity (antibody and T-cell responses) were evaluated during 48 weeks.At week 48, based on a mixed model, no statistically significant difference in HIV-1 VL change from baseline was demonstrated between F4/AS01B_2 and control group (0.073 log10 copies/mL [97.5% confidence interval (CI): -0.088; 0.235]), or F4/AS01B_3 and control group (-0.096 log10 copies/mL [97.5% CI: -0.257; 0.065]). No differences between groups were observed in HIV-1 VL change, CD4 T-cell count, ART initiation, or HIV-related clinical events at intermediate timepoints. Among F4/AS01B recipients, the most frequent solicited symptoms were pain at injection site (252/300 doses), fatigue (137/300 doses), myalgia (105/300 doses), and headache (90/300 doses). Twelve serious adverse events were reported in 6 participants; 1 was considered vaccine-related (F4/AS01B_2 group: angioedema). F4/AS01B induced polyfunctional F4-specific CD4 T-cells, but had no significant impact on F4-specific CD8 T-cell and anti-F4 antibody levels.F4/AS01B had a clinically acceptable safety profile, induced F4-specific CD4 T-cell responses, but did not reduce HIV-1 VL, impact CD4 T-cells count, delay ART initiation, or prevent HIV-1 related clinical events.

FIGURE 1

Flow of participants. F4/AS01_B_3 = participants randomized to receive three doses of F4/AS01_B at weeks 0, 4, and 28; F4/AS01_B_2 = participants randomized to receive 2 doses of F4/AS01_B at weeks 0 and 4, and 1 dose of placebo at week 28; control = participants randomized to receive 3 doses of placebo at weeks 0, 4, and 28; TVC = total vaccinated cohort; ATP = according-to-protocol; N = number of participants.

FIGURE 2

Percentage of participants reporting solicited local and general symptoms during the 7-day postvaccination period after each dose (total vaccinated cohort). F4/AS01_B_3 = participants randomized to receive 3 doses of F4/AS01_B at weeks 0, 4, and 28; F4/AS01_B_2 = participants randomized to receive 2 doses of F4/AS01_B at weeks 0 and 4, and 1 dose of placebo at week 28; control = participants randomized to receive three doses of placebo at weeks 0, 4, and 28; pooled F4/AS01_B = pooled F4/AS01_B_3 and F4/AS01_B_2 groups; errors bars represent exact 95% confidence intervals.

FIGURE 3

(A) Percentage of F4-specific CD40L⁺CD4⁺ T-cells expressing at least IL-2 (alone or together with other cytokines) at each timepoint, (B) cytokine coexpression profile of F4-specific CD4⁺ T-cells in the F4/AS01_B_3 group and the control group at week 30, and (C) pie charts of the cytokine coexpression of F4-specific CD40L⁺CD4⁺ T-cells at each timepoint in the three groups (according-to-protocol cohort for immunogenicity). F4/AS01_B_3 = participants randomized to receive 3 doses of F4/AS01_B at weeks 0, 4, and 28; F4/AS01_B_2 = participants randomized to receive 2 doses of F4/AS01_B at weeks 0 and 4, and 1 dose of placebo at week 28; control = participants randomized to receive 3 doses of placebo at weeks 0, 4, and 28. The box plot: the central box shows the interquartile range (Q1–Q3), with the thick horizontal line representing the median (Q2), and the whiskers (above and below the box), the maximum and the minimum. The percentage of CD40L⁺CD4⁺ T-cells expressing cytokines in response to the fusion protein F4 was determined by adding the individual frequencies of the CD40L⁺CD4⁺ T-cell response to each of the 4 individual antigens. Whiskers were not added to Figure 3B for clarity. The sizes of the pie charts represent the proportions of total CD40L⁺ CD4⁺ T-cells producing at least 1 cytokine. CD40L = CD40-ligand, IFN-γ = interferon-γ, IL-2 = interleukin-2, TNF-α = tumor necrosis factor-α.