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

Leroux‐Roels, Geert; Bourguignon, Patricia; Willekens, Julie; Janssens, Michel; Clement, Frédéric; Didierlaurent, Arnaud M.; Fissette, Laurence; Roman, François; Boutriau, Dominique

doi:10.1128/cvi.00617-13

Cited by 14 publications

(10 citation statements)

References 34 publications

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“…HIV-1-specific CD4 + T-cell responses were primarily driven by F4/AS01. This is in accordance with clinical data, showing that the vaccine induces predominantly CD4 + T-cell responses in humans [44][45][46], and with the fact that AS01 is a potent enhancer of T-cell responses, as demonstrated in various clinical studies with a range of antigens (reviewed in [51,52]). In contrast to vaccine antigen-specific CD4 + T-cell responses, specific CD8 + T-cell responses were only detected in recipients of AdC7-GRN, and were comparable between F4/ AS01-primed and naïve macaques.…”

Section: Discussionsupporting

confidence: 88%

“…Developing prophylactic HIV-1 vaccine regimens that are able to elicit balanced T-cell responses consisting of both CD4 + and CD8 + T cells might therefore offer a valuable contribution to the antibody-based vaccine strategies. The candidate vaccine F4/AS01 has been shown to induce robust polyfunctional CD4 + T-cell responses in HIV-seronegative volunteers and HIV-1-infected patients on ART, and lower levels of these responses in ART-naïve HIV-1-infected subjects [44][45][46]. The present study in NHP and mice HIV-1 Candidate Vaccines F4/AS01 and AdC7-GRN in Macaques aimed to assess the immunogenicity and functionality of CMI responses induced by heterologous prime-boost regimens using the adjuvanted protein vaccine F4/AS01 and the chimpanzee recombinant adenoviral vector AdC7-GRN.…”

Section: Discussionmentioning

confidence: 99%

“…could ultimately induce enhanced protective responses against HIV replication in humans, relative to vectors based on human serotypes. We have previously reported that the F4/AS01 candidate vaccine, consisting of the F4 recombinant fusion protein containing four HIV-1 clade B antigens (Gag p24, Pol reverse transcriptase [RT], Nef and Gag p17) and the AS01 Adjuvant System, induced potent polyfunctional CD4 + T-cell responses in HIV-seronegative volunteers, as well as in HIV-1infected patients on antiretroviral therapy (ART) [44][45][46]. Here, we have investigated the immunogenicity of heterologous prime-boost regimens with F4/AS01 and a recombinant AdC7 vector expressing HIV-1 clade B Gag, RT and Nef (AdC7-GRN), when delivered intramuscularly in rhesus macaques and mice.…”

Section: Introductionmentioning

confidence: 99%

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Heterologous Prime-Boost Regimens with a Recombinant Chimpanzee Adenoviral Vector and Adjuvanted F4 Protein Elicit Polyfunctional HIV-1-Specific T-Cell Responses in Macaques

et al. 2015

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HIV-1-specific CD4+ and CD8+ T lymphocytes are important for HIV-1 replication control. F4/AS01 consists of F4 recombinant fusion protein (containing clade B Gag/p24, Pol/RT, Nef and Gag/p17) formulated in AS01 Adjuvant System, and was shown to induce F4-specific polyfunctional CD4+ T-cell responses in humans. While replication-incompetent recombinant HIV-1/SIV antigen-expressing human adenoviral vectors can elicit high-frequency antigen-specific CD8+ T-cell responses, their use is hampered by widespread pre-existing immunity to human serotypes. Non-human adenovirus serotypes associated with lower prevalence may offer an alternative strategy. We evaluated the immunogenicity of AdC7-GRN (‘A’), a recombinant chimpanzee adenovirus type 7 vector expressing clade B Gag, RT and Nef, and F4/AS01 (‘P’), when delivered intramuscularly in homologous (PP or AA) and heterologous (AAPP or PPAA) prime-boost regimens, in macaques and mice. Vaccine-induced HIV-1-antigen-specific T cells in peripheral blood (macaques), liver, spleen, and intestinal and genital mucosa (mice) were characterized by intracellular cytokine staining. Vaccine-specific IgG antibodies (macaques) were detected using ELISA. In macaques, only the heterologous prime-boost regimens induced polyfunctional, persistent and balanced CD4+ and CD8+ T-cell responses specific to each HIV-1 vaccine antigen. AdC7-GRN priming increased the polyfunctionality of F4/AS01-induced CD4+ T cells. Approximately 50% of AdC7-GRN-induced memory CD8+ T cells exhibited an effector-memory phenotype. HIV-1-specific antibodies were detected with each regimen. In mice, antigen-specific CD4+ and CD8+ T-cell responses were detected in the mucosal and systemic anatomical compartments assessed. When administered in heterologous prime-boost regimens, AdC7-GRN and F4/AS01 candidate vaccines acted complementarily in inducing potent and persistent peripheral blood HIV-1-specific CD4+ and CD8+ T-cell responses and antibodies in macaques. Besides, adenoviral vector priming modulated the cytokine-expression profile of the protein-induced CD4+ T cells. Each regimen induced HIV-1-specific T-cell responses in systemic/local tissues in mice. This suggests that prime-boost regimens combining adjuvanted protein and low-seroprevalent chimpanzee adenoviral vectors represent an attractive vaccination strategy for clinical evaluation.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Heterologous Prime-Boost Regimens with a Recombinant Chimpanzee Adenoviral Vector and Adjuvanted F4 Protein Elicit Polyfunctional HIV-1-Specific T-Cell Responses in Macaques

et al. 2015

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“…Interestingly, inhibition of lysosome acidification also inhibits the response to QS-21 in human PBMCs. Indeed, treatment with chloroquine inhibited QS-21-induced production of IL-6 by PBMCs, although no effect of chloroquine administration was observed on T cell or antibody responses in healthy adults immunized with AS01-adjuvanted antigens (48). …”

Section: Discussionmentioning

confidence: 99%

Lysosome-Dependent Activation of Human Dendritic Cells by the Vaccine Adjuvant QS-21

et al. 2017

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The adjuvant properties of the saponin QS-21 have been known for decades. It is a component of the Adjuvant System AS01 that is used in several vaccine candidates. QS-21 strongly potentiates both cellular and humoral immune responses to purified antigens, yet how it activates immune cells is largely unknown. Here, we report that QS-21 directly activated human monocyte-derived dendritic cells (moDCs) and promoted a pro-inflammatory transcriptional program. Cholesterol-dependent QS-21 endocytosis followed by lysosomal destabilization and Syk kinase activation were prerequisites for this response. Cathepsin B, a lysosomal cysteine protease, was essential for moDC activation in vitro and contributed to the adjuvant effects of QS-21 in vivo. Collectively, these findings provide new insights into the pathways involved in the direct activation of antigen-presenting cells by a clinically relevant QS-21 formulation.

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“…QS-21 ( Figure 6 ), is a soluble fraction of triterpenoid saponins from Q. saponaria with immunological adjuvant activity. QS-21 is currently being clinically evaluated in phase I and II studies for use in human vaccines against HIV (Leroux-Roels et al ., 2014 ), Mycobacterium tuberculosis (Montoya et al ., 2013 ), varicella-zoster virus (Lal et al ., 2013 ), cancer (Garçon & Van Mechelen, 2011 ) and malaria (Ndungu et al ., 2012 ).…”

Section: Industrial Potential As Bioactive Principlesmentioning

confidence: 99%

Metabolic and functional diversity of saponins, biosynthetic intermediates and semi-synthetic derivatives

Moses

Papadopoulou

Osbourn

2014

Critical Reviews in Biochemistry and Molecular Biology

389

282

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Saponins are widely distributed plant natural products with vast structural and functional diversity. They are typically composed of a hydrophobic aglycone, which is extensively decorated with functional groups prior to the addition of hydrophilic sugar moieties, to result in surface-active amphipathic compounds. The saponins are broadly classified as triterpenoids, steroids or steroidal glycoalkaloids, based on the aglycone structure from which they are derived. The saponins and their biosynthetic intermediates display a variety of biological activities of interest to the pharmaceutical, cosmetic and food sectors. Although their relevance in industrial applications has long been recognized, their role in plants is underexplored. Recent research on modulating native pathway flux in saponin biosynthesis has demonstrated the roles of saponins and their biosynthetic intermediates in plant growth and development. Here, we review the literature on the effects of these molecules on plant physiology, which collectively implicate them in plant primary processes. The industrial uses and potential of saponins are discussed with respect to structure and activity, highlighting the undoubted value of these molecules as therapeutics.

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

Cited by 14 publications

References 34 publications

Heterologous Prime-Boost Regimens with a Recombinant Chimpanzee Adenoviral Vector and Adjuvanted F4 Protein Elicit Polyfunctional HIV-1-Specific T-Cell Responses in Macaques

Heterologous Prime-Boost Regimens with a Recombinant Chimpanzee Adenoviral Vector and Adjuvanted F4 Protein Elicit Polyfunctional HIV-1-Specific T-Cell Responses in Macaques

Lysosome-Dependent Activation of Human Dendritic Cells by the Vaccine Adjuvant QS-21

Metabolic and functional diversity of saponins, biosynthetic intermediates and semi-synthetic derivatives

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