ISCOMATRIX™ vaccines: Safety in human clinical studies

McKenzie, Andrew; Watt, Marli; Gittleson, Charmaine

doi:10.4161/hv.6.3.10754

Cited by 35 publications

(26 citation statements)

References 23 publications

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“…The ISCOMATRIX™ adjuvant can then be formulated with virtually any antigen to make a vaccine. Formulating saponin with cholesterol and phospholipid appears to ameliorate the reactogenicity associated with using free saponin, as ISCOMATRIX™ adjuvant retains the immunogenic potency and antigen dose reduction potential of saponin but demonstrates improved tolerability [10,11]. ISCOMATRIX™ adjuvant promotes a balanced Th1/Th2 response, as well as a uniquely strong cytotoxic T cell response and long-lasting antibody responses in both animal and human models [12–15].…”

Section: Introductionmentioning

confidence: 99%

Serum Cytokine Profiles Associated with Specific Adjuvants Used in a DNA Prime-Protein Boost Vaccination Strategy

et al. 2013

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In recent years, heterologous prime-boost vaccines have been demonstrated to be an effective strategy for generating protective immunity, consisting of both humoral and cell-mediated immune responses against a variety of pathogens including HIV-1. Previous reports of preclinical and clinical studies have shown the enhanced immunogenicity of viral vector or DNA vaccination followed by heterologous protein boost, compared to using either prime or boost components alone. With such approaches, the selection of an adjuvant for inclusion in the protein boost component is expected to impact the immunogenicity and safety of a vaccine. In this study, we examined in a mouse model the serum cytokine and chemokine profiles for several candidate adjuvants: QS-21, Al(OH)3, monophosphoryl lipid A (MPLA) and ISCOMATRIX™ adjuvant, in the context of a previously tested pentavalent HIV-1 Env DNA prime-protein boost formulation, DP6-001. Our data revealed that the candidate adjuvants in the context of the DP6-001 formulation are characterized by unique serum cytokine and chemokine profiles. Such information will provide valuable guidance in the selection of an adjuvant for future AIDS vaccine development, with the ultimate goal of enhancing immunogenicity while minimizing reactogenicity associated with the use of an adjuvant. More significantly, results reported here will add to the knowledge on how to include an adjuvant in the context of a heterologous prime-protein boost vaccination strategy in general.

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Section: Introductionmentioning

confidence: 99%

Serum Cytokine Profiles Associated with Specific Adjuvants Used in a DNA Prime-Protein Boost Vaccination Strategy

et al. 2013

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“…This type of complex belongs to a group of nanoparticle adjuvants such as ISCOMATRIX TM and NovaMatrix TM all composed of saponins, cholesterol and phospholipids (22). They are proposed to be less toxic than pure QS-21 while maintaining the ability to induce antigen-specific antibody titers and directed T cell responses (58,59). Further, similar saponin particles are known to induce IL-1␤ production both in vivo and in vitro (44,45).…”

Section: Qs-21 Induces Caspase-1-dependent Il-1␤ Secretion-tomentioning

confidence: 99%

Identification of QS-21 as an Inflammasome-activating Molecular Component of Saponin Adjuvants

Marty-Roix

Vladimer

Pouliot

et al. 2016

Journal of Biological Chemistry

159

154

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Many immunostimulants act as vaccine adjuvants via activation of the innate immune system, although in many cases it is unclear which specific molecules contribute to the stimulatory activity. QS-21 is a defined, highly purified, and soluble saponin adjuvant currently used in licensed and exploratory vaccines, including vaccines against malaria, cancer, and HIV-1. However, little is known about the mechanisms of cellular activation induced by QS-21. We observed QS-21 to elicit caspase-1-dependent IL-1␤ and IL-18 release in antigen-presenting cells such as macrophages and dendritic cells when co-stimulated with the TLR4-agonist adjuvant monophosphoryl lipid A. Furthermore, our data suggest that the ASC-NLRP3 inflammasome is responsible for QS-21-induced IL-1␤/IL-18 release. At higher concentrations, QS-21 induced macrophage and dendritic cell death in a caspase-1-, ASC-, and NLRP3-independent manner, whereas the presence of cholesterol rescued cell viability. A nanoparticulate adjuvant that contains QS-21 as part of a heterogeneous mixture of saponins also induced IL-1␤ in an NLRP3-dependent manner. Interestingly, despite the role NLRP3 plays for cellular activation in vitro, NLRP3-deficient mice immunized with HIV-1 gp120 and QS-21 showed significantly higher levels of Th1 and Th2 antigen-specific T cell responses and increased IgG1 and IgG2c compared with wild type controls. Thus, we have identified QS-21 as a nonparticulate single molecular saponin that activates the NLRP3 inflammasome, but this signaling pathway may contribute to decreased antigenspecific responses in vivo.Because many protein antigens do not elicit strong immune responses on their own, vaccines often contain stimulatory adjuvants that enhance cell-mediated and humoral immune responses to help confer stronger protection. However, despite widespread use, there is little known regarding the pathways affected by many adjuvants. A better understanding of the mechanisms involved in adjuvant-generated protection can assist in the design of better vaccines against infections that currently lack effective immunization.Adjuvants activate an innate immune response, which in turn determines the strength and quality of the adaptive immune response. This response is first mediated by activation of antigen-presenting cells (APCs) such as dendritic cells and macrophages. Engagement of pattern recognition receptors, such as extracellular, membrane-bound Toll-like receptors (TLRs) 2 and cytosolic inflammasome-stimulating Nod-like receptors (NLRs) by their ligands elicits an inflammatory milieu and can eventually lead to a honed adaptive immune response.The NLR inflammasomes are multiprotein complexes that upon activation license the proteolytic processing of the zymogen pro-caspase-1 into mature caspase-1 (1). caspase-1 can then activate pro-forms of the inflammatory cytokines IL-1␤ and IL-18 into mature proteins, which are then secreted through unknown pathways. IL-1␤ and IL-18 are potent proinflammatory cytokines that can, for instance, promote T helper 17 ...

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“…SBAs are now being applied in human vaccines, and several clinical trials have proven safety and efficacy4589. Next to viral antigens (for example, H5N1), SBAs have been shown to facilitate responses to cancer antigens10.…”

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confidence: 99%

Saponin-based adjuvants induce cross-presentation in dendritic cells by intracellular lipid body formation

et al. 2016

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Saponin-based adjuvants (SBAs) are being used in animal and human (cancer) vaccines, as they induce protective cellular immunity. Their adjuvant potency is a factor of inflammasome activation and enhanced antigen cross-presentation by dendritic cells (DCs), but how antigen cross-presentation is induced is not clear. Here we show that SBAs uniquely induce intracellular lipid bodies (LBs) in the CD11b+ DC subset in vitro and in vivo. Using genetic and pharmacological interference in models for vaccination and in situ tumour ablation, we demonstrate that LB induction is causally related to the saponin-dependent increase in cross-presentation and T-cell activation. These findings link adjuvant activity to LB formation, aid the application of SBAs as a cancer vaccine component, and will stimulate development of new adjuvants enhancing T-cell-mediated immunity.

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ISCOMATRIX™ vaccines: Safety in human clinical studies

Cited by 35 publications

References 23 publications

Serum Cytokine Profiles Associated with Specific Adjuvants Used in a DNA Prime-Protein Boost Vaccination Strategy

Serum Cytokine Profiles Associated with Specific Adjuvants Used in a DNA Prime-Protein Boost Vaccination Strategy

Identification of QS-21 as an Inflammasome-activating Molecular Component of Saponin Adjuvants

Saponin-based adjuvants induce cross-presentation in dendritic cells by intracellular lipid body formation

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