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ABSTRACT: The ISCOMATRIX adjuvant has antigen delivery and presentation properties as well as immunomodulatory capabilities, which combine to provide enhanced and accelerated immune responses. The responses are broad, including a range of subclasses of antibodies as well as CD4(+) and CD8(+) T-cells. A range of ISCOMATRIX vaccines (ISCOMATRIX adjuvant combined with antigen) have now been tested in clinical trials and have been shown to be generally safe and well tolerated as well as immunogenic, generating both antibody (Ab) and T-cell responses. The mechanisms by which ISCOMATRIX adjuvant facilitates its immune effects are the scope of significant study and indicate that ISCOMATRIX adjuvant (i) rapidly traffics antigen into the cytosol of multiple dendritic cell subsets, (ii) induces the induction of an array of cytokines and chemokines and (iii) links the innate and adaptive immune responses in vivo in a Toll-like-receptor-independent but MyD88-dependent manner. These data highlight the clinical utility of ISCOMATRIX adjuvant in the development of prophylactic and therapeutic vaccines for infectious disease.
Journal of Medical Microbiology 03/2012; 61(Pt 7):935-43. · 2.50 Impact Factor
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Nicholas S Wilson,
Becky Yang,
Adriana Baz Morelli,
Sandra Koernig,
Annie Yang,
Stefanie Loeser,
Denise Airey,
Larissa Provan,
Phil Hass,
Hal Braley,
Suzana Couto, Debbie Drane,
Jeff Boyle,
Gabrielle T Belz,
Avi Ashkenazi,
Eugene Maraskovsky
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ABSTRACT: Generating a cytotoxic CD8(+) T-cell response that can eradicate malignant cells is the primary objective of cancer vaccine strategies. In this study we have characterized the innate and adaptive immune response to the ISCOMATRIX adjuvant, and the ability of vaccine antigens formulated with this adjuvant to promote antitumor immunity. ISCOMATRIX adjuvant led to a rapid innate immune cell response at the injection site, followed by the activation of natural killer and dendritic cells (DC) in regional draining lymph nodes. Strikingly, major histocompatibility complex (MHC) class I cross-presentation by CD8α(+) and CD8α(-) DCs was enhanced by up to 100-fold when antigen was formulated with ISCOMATRIX adjuvant. These coordinated features enabled efficient CD8(+) T-cell cross-priming, which exhibited prophylactic and therapeutic tumoricidal activity. The therapeutic efficacy of an ISCOMATRIX vaccine was further improved when co-administered with an anti-CD40 agonist antibody, suggesting that ISCOMATRIX-based vaccines may combine favorably with other immune modifiers in clinical development to treat cancer. Finally, we identified a requirement for the myeloid differentiation primary response gene 88 (MyD88) adapter protein for both innate and adaptive immune responses to ISCOMATRIX vaccines in vivo. Taken together, our findings support the utility of the ISCOMATRIX adjuvant for use in the development of novel vaccines, particularly those requiring strong CD8(+) T-cell immune responses, such as therapeutic cancer vaccines.
Immunology and Cell Biology 09/2011; 90(5):540-52. · 3.66 Impact Factor
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ABSTRACT: Adjuvants are components that when added to subunit antigen (Ag) vaccines boost their immunogenicity and thus immune efficacy. However, there are few adjuvants that are approved for clinical use resulting in a critical need for the development of safe and effective adjuvants for use in both prophylactic and therapeutic vaccines. The paucity of appropriate adjuvants is more chronic for the development of therapeutic vaccines for cancer and chronic infectious disease, which need to induce cytotoxic T-cell responses via cross-presentation of the vaccine Ag by dendritic cells. The ISCOMATRIX adjuvant represents a unique adjuvant system that facilitates Ag delivery and presentation as well as immunomodulation to provide enhanced and accelerated immune responses. The immune responses generated are of broad specificity to the vaccine Ag, and include robust antibody responses of multiple subclasses as well as both CD4(+) and CD8(+) T-cell responses. Here we discuss our understanding of the mechanisms of action by which ISCOMATRIX adjuvant may facilitate these integrated immune responses and touch on insights gained through its clinical experience.
Immunology and Cell Biology 05/2009; 87(5):371-6. · 3.66 Impact Factor
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ABSTRACT: The ISCOMATRIX adjuvant has antigen-delivery and -presentation properties, as well as immunomodulatory capabilities that combine to provide enhanced and accelerated immune responses. The responses are broad, including a range of subclasses of antibodies as well as both CD4+ and CD8+ T cells. A range of ISCOMATRIX vaccines (ISCOMATRIX adjuvant combined with antigen) have been evaluated in clinical trials. The results of these completed and ongoing studies indicate that the ISCOMATRIX adjuvant is safe and generally well tolerated and increases the vaccine immune responses.
Expert Review of Vaccines 11/2007; 6(5):761-72. · 4.25 Impact Factor
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ABSTRACT: The capacity of an adjuvant to reduce the amount of antigen required in vaccines would be beneficial in a variety of settings, including situations where antigen is difficult or expensive to manufacture, or in situations where demand exceeds production capacity, such as pandemic influenza. The ability to reduce antigen dose would also be a significant advantage in combination vaccines, and vaccines that by necessity must contain multiple antigens to accommodate variability between strains or genotypes. ISCOMATRIX adjuvant was compared to aluminium hydroxide adjuvant (Al(OH3)) for induction of antibody responses and dose sparing of a recombinant HIV gp120 vaccine. Neutralising antibody responses were significantly greater, at the same protein dose, when the gp120 protein was formulated with ISCOMATRIX adjuvant compared to Al(OH3). Moreover, strong responses were achieved with up to 100-fold lower doses of gp120 using ISCOMATRIX adjuvant. Therefore, ISCOMATRIX adjuvant has the potential to substantially reduce the dose of antigen required in human vaccines, without compromising the immune response.
Vaccine 04/2007; 25(14):2541-4. · 3.77 Impact Factor
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Max Schnurr,
Qiyuan Chen,
Amanda Shin,
Weisan Chen,
Tracey Toy,
Corinna Jenderek,
Simon Green,
Lena Miloradovic, Debbie Drane,
Ian D Davis,
Jose Villadangos,
Ken Shortman,
Eugene Maraskovsky,
Jonathan Cebon
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ABSTRACT: Dendritic cells (DCs) are being evaluated for cancer immunotherapy due to their unique ability to induce tumor-directed T-cell responses. Here we report that the type of human DC, the mode of activation, and the strategy for delivery of antigen are 3 critical factors for efficient stimulation of tumor-specific CD8+ and CD4+ T cells. Only CD1c+ blood DCs and monocyte-derived DCs (MoDCs) were capable of presenting epitopes of the full-length tumor antigen NY-ESO-1 on both major histocompatibility complex (MHC) class I (cross-presentation) and MHC II, whereas plasmacytoid DCs were limited to MHC II presentation. Cross-presentation was inefficient for soluble protein, but highly efficient for antigen-antibody immune complexes (NY-ESO-1/IC) and for protein formulated with ISCOMATRIX adjuvant (NY-ESO-1/IMX). DC activation with CD40L further enhanced cross-presentation efficiency. The mode of antigen delivery was found to be a determining factor for cytosolic proteolysis by DCs. Immune complexes (ICs) targeted a slow, proteasome-dependent cross-presentation pathway, whereas ISCOMATRIX (IMX) targeted a fast, proteasome-independent pathway. Both cross-presentation pathways resulted in a long-lived, T-cell stimulatory capacity, which was maintained for several days longer than for DCs pulsed with peptide. This may provide DCs with ample opportunities for sensitizing tumor-specific T cells against a broad array of tumor antigen epitopes in lymph nodes.
Blood 04/2005; 105(6):2465-72. · 9.90 Impact Factor
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ABSTRACT: The immunostimulating complex, referred to as 'iscom', was first described by Morein et al. in 1984 as a novel structure for antigenic presentation of membrane proteins from enveloped viruses with potent immunomodulatory capability . Since this discovery, many vaccines have been tested in animal models showing the induction of both humoral and cellular immune responses . The ISCOMATRIX adjuvant is essentially the same structure as the iscom but without the incorporated antigen . Antigens can be formulated with the ISCOMATRIX adjuvant to produce ISCOMATRIX vaccines that can provide the same antigen presentation and immunomodulatory properties as the iscom but with much broader application as they are not limited to hydrophobic membrane proteins. Various ISCOMATRIX vaccines have been tested in animal models and more recently in human clinical trials . These studies have shown that the ISCOMATRIX adjuvant is safe and induces both humoral and cellular immune responses. The ability of the ISCOMATRIX adjuvant to induce these broad immune responses is due to the combination of antigen presentation by both MHC class I and class II pathways, and the powerful immunomodulatory capability of the saponin. Additionally, the ISCOMATRIX adjuvant is simple to manufacture and can be combined with a wide range of antigens making it suitable for the development of novel human vaccines.
Advanced Drug Delivery Reviews 02/2005; 57(3):465-74. · 11.50 Impact Factor
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ABSTRACT: Human Papillomavirus type 16 (HPV16) E6 and E7 oncoproteins are associated with cervical cancer development and progression and can therefore be used as target antigens for cancer immunotherapy. In this study we evaluated the immunogenicity in mice, of different vaccine formulations using recombinant HPV16 derived E6E7 or E7GST fusion proteins. When co-administered with ISCOMATRIX adjuvant, these E6E7 proteins consistently induced E7 specific CTL, in vivo tumor protection, antibody and DTH responses. ISCOMATRIX adjuvant has been developed for use in the formulation of novel human vaccines and has been evaluated for safety and toxicity in human trials. A formulation containing aluminum hydroxide (Al(OH)3) gave a lesser degree of E7 specific antibody, and no local E7 specific CTL response but similar DTH and tumor protection. These findings demonstrate the potential of ISCOMATRIX adjuvant to stimulate both cellular and humoral immune responses to endogenously processed target antigens, and hence is the preferred adjuvant when CTL responses are desirable.
Vaccine 10/2004; 22(27-28):3738-43. · 3.77 Impact Factor
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ABSTRACT: Immunostimulating complex (ISCOM) vaccines are particulate antigen delivery vehicles composed of saponin, cholesterol, phospholipid and immunogen. Here we illustrate that ISCOM-based vaccines represent an attractive modality for the development of anti-cancer vaccines. Using murine models and a model cancer antigen, ISCOM vaccines were shown to induce potent CD8 T cell responses, to mediate protection in three different tumor models, to promote Th1-biased immunity, and to induce CD8 T cell responses in the absence of CD4+ T cell help. The former three activities were also found to be substantially improved when the vaccine antigen was associated with the ISCOM structure. Furthermore, the presence in vivo of pre-existing antibodies against the vaccine antigen did not inhibit CD8 T cell induction by the ISCOM vaccine. Although vaccination was effective against challenge with vaccine-antigen expressing tumors, no activity against neighboring vaccine-antigen negative tumor cells was observed, indicating that determinant spreading or bystander activity does not lead to significant anti-cancer activity.
Vaccine 03/2004; 22(8):963-74. · 3.77 Impact Factor
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ABSTRACT: Mucosal delivery of inactivated vaccines that are able to elicit protective immune responses against respiratory diseases has been a long time goal of vaccinologists. Such vaccines would enable a more appropriate means of vaccination against respiratory diseases than those currently delivered by a parenteral route. The intranasal delivery of inactivated influenza vaccine plus the ISCOMATRIX (IMX) adjuvant, simply mixed together, was able to induce serum haemagglutination inhibition (HAI) titres in mice far superior to those obtained with unadjuvanted vaccine delivered subcutaneously. Furthermore, the IMX adjuvanted vaccine delivered intranasally induced mucosal IgA responses in the lung, nasal passages and large intestine, together with high levels of serum IgA. Intranasal delivery of IMX adjuvanted influenza vaccine in sheep gave antibody responses in both serum and nasal secretions that surpassed the levels obtained with unadjuvanted vaccine administered subcutaneously. These observations suggest that it may be possible to induce effective immunity to influenza in humans by intranasal vaccination with an IMX adjuvanted inactivated vaccine.
Vaccine 03/2003; 21(9-10):946-9. · 3.77 Impact Factor
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ABSTRACT: CD8 αβ cytotoxic T lymphocyte (CTL) polyepitope or polytope vaccines have traditionally been delivered using recombinant vector or DNA based delivery modalities. Here we show the delivery of polytope vaccines in the form of either synthetic polypeptides or recombinant polytope proteins by ImmunoStimulatory COMplexes (ISCOMs®). Induction of multiple protective CTL responses by these polytope-ISCOM formulations were comparable to viral vector or DNA based delivery modalities as assessed by IFNγ ELISpot, chromium release and viral challenge assays. Measurement of CTL responses specific for the different epitopes revealed immunodominance patterns, which were largely independent of the vaccine vector or the order of the epitopes in the polytope. ISCOMs thus emerge as a viable human delivery modality for protein-based polytope vaccines.
Vaccine 10/2001; · 3.77 Impact Factor
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ABSTRACT: ISCOMs® are typically 40 nm cage-like structures comprising antigen, saponin, cholesterol and phospholipid. ISCOMs® have been shown to induce antibody responses and activate T helper cells and cytolytic T lymphocytes in a number of animal species, including non-human primates. Recent clinical studies have demonstrated that ISCOMs® are also able to induce antibody and cellular immune responses in humans. This review describes the current understanding of the ability of ISCOMs® to induce immune responses and the mechanisms underlying this property. Recent progress in the characterisation and manufacture of ISCOMs® will also be discussed.
Vaccine.
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ABSTRACT: Human Papillomavirus type 16 (HPV16) E6 and E7 oncoproteins are associated with cervical cancer development and progression and can therefore be used as target antigens for cancer immunotherapy. In this study we evaluated the immunogenicity in mice, of different vaccine formulations using recombinant HPV16 derived E6E7 or E7GST fusion proteins. When co-administered with ISCOMATRIX™ adjuvant, these E6E7 proteins consistently induced E7 specific CTL, in vivo tumor protection, antibody and DTH responses. ISCOMATRIX™ adjuvant has been developed for use in the formulation of novel human vaccines and has been evaluated for safety and toxicity in human trials. A formulation containing aluminum hydroxide (Al(OH)3) gave a lesser degree of E7 specific antibody, and no local E7 specific CTL response but similar DTH and tumor protection. These findings demonstrate the potential of ISCOMATRIX™ adjuvant to stimulate both cellular and humoral immune responses to endogenously processed target antigens, and hence is the preferred adjuvant when CTL responses are desirable.
Vaccine.
