Safety and immunogenicity of an adjuvanted protein therapeutic HIV-1 vaccine in subjects with HIV-1 infection: A randomised placebo-controlled study

Abstract

The human immunodeficiency virus type-1 (HIV-1) vaccine candidate F4/AS01 has previously been shown to induce potent and persistent polyfunctional CD4(+) T-cell responses in HIV-1-seronegative volunteers. This placebo-controlled study evaluated two doses of F4/AS01 1-month apart in antiretroviral treatment (ART)-experienced and ART-naïve HIV-1-infected subjects (1:1 randomisation in each cohort). Safety, HIV-1-specific CD4(+) and CD8(+) T-cell responses, absolute CD4(+) T-cell counts and HIV-1 viral load were monitored for 12 months post-vaccination. Reactogenicity was clinically acceptable and no vaccine-related serious adverse events were reported. The frequency of HIV-1-specific CD4(+) T-cells 2 weeks post-dose 2 was significantly higher in the vaccine group than in the placebo group in both cohorts (p<0.05). Vaccine-induced HIV-1-specific CD4(+) T-cells exhibited a polyfunctional phenotype, expressing at least CD40L and IL-2. No increase in HIV-1-specific CD8(+) T-cells or change in CD8(+) T-cell activation marker expression profile was detected. Absolute CD4(+) T-cell counts were variable over time in both cohorts. Viral load remained suppressed in ART-experienced subjects. In ART-naïve subjects, a transient reduction in viral load from baseline was observed 2 weeks after the second F4/AS01 dose, which was concurrent with a higher frequency of HIV-1-specific CD4(+) T-cells expressing at least IL-2 in this cohort. In conclusion, F4/AS01 showed a clinically acceptable reactogenicity and safety profile, and induced polyfunctional HIV-1-specific CD4(+) T-cell responses in ART-experienced and ART-naïve subjects. These findings support further clinical investigation of F4/AS01 as a potential HIV-1 vaccine for therapeutic use in individuals with HIV-1 infection.

Immunogenicity and Safety of a Booster Dose of an Investigational Adjuvanted Polyprotein HIV-1 Vaccine in Healthy Adults and Effect of Administration of Chloroquine

“…The lack of F4-specific CD8 ϩ T-cell responses observed in both groups was in line with the results of the initial study, in which no F4-specific CD8 ϩ T cells were detected in healthy HIV-uninfected adults following primary vaccination with the F4/AS01 B vaccine (16). High levels of F4-specific CD8 ϩ T cells were detected in HIV-1-infected patients using this assay (17), suggesting that the absence of detectable CD8 ϩ T cells was more linked to the lack of vaccine response than to the ICS assay.…”

“…The booster dose of the F4/AS01 B vaccine induced a strong F4-specific CD4 ϩ T-cell recall response, which persisted for at least 6 months, had approximately the same frequency and exhibited a similar polyfunctional phenotype as that observed following primary vaccination. Strong and persistent CD4 ϩ T-cell responses were also induced by the F4/AS01 B vaccine (16) or by a previous HIV-1 vaccine candidate comprising gp120 and a Nef-Tat fusion protein in healthy adults and in subjects with HIV-1 infection (2,(17)(18)(19). These findings are important since the presence of polyfunctional and persistent HIV-specific CD4 ϩ T cells in HIV-infected individuals is associated with long-term nonprogression (11,(34)(35)(36).…”

“…The F4/AS01 B investigational vaccine has been shown to have an acceptable safety and reactogenicity profile and to induce high frequencies of long-lasting, F4-specific, polyfunctional CD4 ϩ T-cell responses, but no F4-specific CD8 ϩ T-cell responses, in healthy seronegative adults and in HIV-1-infected subjects (16,17). The efficacy of this vaccine in reducing viral load was specifically assessed in a phase IIb, proof-of-concept trial (ClinicalTrials.gov registration number NCT01218113), but results are not available yet.…”

The Use of Leaves from Young Trees of Quillaja saponaria (Molina) Plantations as a New Source of Saponins

“…The tree has been used extensively for extraction of saponins, which are high molecular weight glycosides containing a hydrophobic triterpenic nucleus and two hydrophilic sugar chains (Nord and Kenne 1999;San Martín 2000). Q. saponaria saponins have been traditionally used in various industries, such as biopesticides and plant growth stimulant in agriculture (Chapagain et al 2007;Fischer et al 2011;Zúñiga et al 2012), emulsifier and foaming agent for animal and human food and beverage (Yang et al 2013), wetting agent in film production and mining (San Martín et al 2005a, b), and as vaccine adjuvants for human and non-human animals vaccines (Barhate et al 2013;Harrer et al 2014;Kensil et al 1991;Kensil and Kammer 1998;Sun et al 2009). …”

Processing of blood samples influences PBMC viability and outcome of cell-mediated immune responses in antiretroviral therapy-naïve HIV-1-infected patients

“…In recent HIV-1 vaccine trials, HIV-1-specific CD4 + and CD8 + T-cell responses were evaluated by ICS following in vitro stimulation with p17, p24, reverse transcriptase (RT) and Nef peptide pools to assess the expression of interleukin-2 (IL-2), interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and CD40-ligand (CD40L), using PBMCs isolated from venous blood (Van Braeckel et al, 2011;Harrer et al, 2014). By compiling previous evaluations, we observed a lower PBMC viability after ICS in antiretroviral therapy (ART)-naïve HIV-1-infected patients (ART − HIV + ) compared to ART-experienced HIV-1-infected patients (ART + HIV + ) (samples from trial published in Harrer et al, 2014) or uninfected volunteers (HIV − ) (samples from trial published in Denny et al, 2013) (Fig.…”