Synthetic double stranded RNA reliably induces innate immunity similar to a live viral vaccine in humans
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE32862 | GEO | 2011/10/12
SECONDARY ACCESSION(S): PRJNA146547
REPOSITORIES: GEO
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Project description:Adjuvants are critical for the success of vaccines, and agonists for microbial pattern recognition receptors are promising new candidates. A mechanism for the immune enhancing role of adjuvants is to stimulate innate immunity. We studied the innate immune response in humans to synthetic double stranded RNA (poly ICLC), a ligand for TLR3 and MDA-5 cytosolic RNA helicase. Transcriptional analysis of blood samples from eight volunteers, after subcutaneous administration of poly ICLC showed upregulation of genes involved in multiple innate immune pathways in all subjects, including interferon and inflammasome signaling. Blocking of type I interferon receptor ex vivo significantly dampened the response to poly IC. Comparative transcriptional analysis showed that several innate pathways were similarly induced in volunteers immunized with the highly efficacious Yellow Fever Vaccine. Therefore a chemically defined microbial agonist like poly ICLC can be a reliable and authentic microbial mimic for inducing innate immunity, here for a live attenuated viral vaccine in humans. GSM813292-GSM813386: RNA expression obtained at different time points from Human blood after poly ICLC administration compared to RNA expression obtained from Human blood after placebo administration GSM813387-GSM813410: Blocking of type I interferon receptor ex vivo followed by poly IC stimulation
2011-10-11 | E-GEOD-32862 | biostudies-arrayexpress
Project description:The purpose of this study is to evaluate the immune response to MUC1 - poly-ICLC vaccine, an investigational or study vaccine. The MUC1 - poly-ICLC vaccine is being tested in persons with a history of advanced adenomatous polyps, the precursor to colorectal cancer. The MUC1 - poly-ICLC vaccine is being developed to prevent polyps from advancing into colon cancer and to prevent polyps from recurring.
MUC1 is mucus that is normally present on the lining of the human colon. However, MUC1 is expressed in a larger amount and in a modified form on adenomatous polyps and colorectal cancer. These changes in MUC1 are thought to be part of the process of progression from adenomas toward cancer. The goal of a vaccine is to help the immune system in the body identify the changes in MUC1 that accompany the progression to cancer and eliminate the abnormal cells that make abnormal MUC1.
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Project description:Autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination is a promising immunotherapy for patients with high grade gliomas, but responses have not been demonstrated in all patients. Pre-clinical studies demonstrate that toll-like receptor (TLR) agonists can enhance the anti-tumor immune response from cancer vaccines. To determine the most effective combination of autologous tumor lysate-pulsed DC vaccination, with or without the adjuvant toll-like receptor (TLR) agonists poly-ICLC or resiquimod, we conducted a randomized, open-label multi-arm Phase 2 clinical trial to evaluate immune responses and survival in 23 patients with newly diagnosed or recurrent WHO Grade III-IV malignant gliomas. Patients were randomized to receive ATL-DC vaccination with either a placebo, a TLR-7/8 agonist (resiquimod, topical 0.2%), or a TLR-3 agonist (poly-ICLC, 20 mcg/kg intramuscular). Peripheral blood was obtained at baseline and following the vaccination cycle for immune monitoring. Mass cytometry, bulk and single-cell RNA sequencing analyses were performed. Analysis of the bulk RNAseq data (pre-treatment vs. post-treatment) demonstrated highly significant upregulation of type 1 and type 2 interferon gene expression selectively in patients who received adjuvant TLR agonist (either poly-ICLC or resiquimod) together with ATL-DC. CyTOF analysis of patient peripheral blood mononuclear cells (PBMCs) showed increased levels of memory PD-1+ T-cell and monocyte populations after ATL-DC + TLR agonist administration. In addition, scRNA-seq demonstrated a higher expression fold change of IFN-induced genes with poly-ICLC treatment in both peripheral blood monocytes and T lymphocytes. Median progression-free survival (PFS) was 8.1 months (5.5 placebo vs. 8.1 resiquimod vs. 31.4 poly-ICLC), and median overall survival (OS) was 26.6 months (7.7 placebo vs. 16.7 resiquimod vs. 52.5 poly-ICLC). Patients who had higher expression of interferon response genes lived significantly longer and had longer time to progression compared to those with lower expression. The results suggest that ATL-DC in conjunction with adjuvant poly-ICLCTL induces a polarized interferon response in circulating monocytes and specific activation of a CD8+ T cell population. This combination was associated with extended survival in this patient population. This interferon response signature may represent an important blood biomarker for immunotherapy in patients with malignant glioma.
2023-10-11 | GSE237562 | GEO
Project description:Autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination is a promising immunotherapy for patients with high grade gliomas, but responses have not been demonstrated in all patients. Pre-clinical studies demonstrate that toll-like receptor (TLR) agonists can enhance the anti-tumor immune response from cancer vaccines. To determine the most effective combination of autologous tumor lysate-pulsed DC vaccination, with or without the adjuvant toll-like receptor (TLR) agonists poly-ICLC or resiquimod, we conducted a randomized, open-label multi-arm Phase 2 clinical trial to evaluate immune responses and survival in 23 patients with newly diagnosed or recurrent WHO Grade III-IV malignant gliomas. Patients were randomized to receive ATL-DC vaccination with either a placebo, a TLR-7/8 agonist (resiquimod, topical 0.2%), or a TLR-3 agonist (poly-ICLC, 20 mcg/kg intramuscular). Peripheral blood was obtained at baseline and following the vaccination cycle for immune monitoring. Mass cytometry, bulk and single-cell RNA sequencing analyses were performed. Analysis of the bulk RNAseq data (pre-treatment vs. post-treatment) demonstrated highly significant upregulation of type 1 and type 2 interferon gene expression selectively in patients who received adjuvant TLR agonist (either poly-ICLC or resiquimod) together with ATL-DC. CyTOF analysis of patient peripheral blood mononuclear cells (PBMCs) showed increased levels of memory PD-1+ T-cell and monocyte populations after ATL-DC + TLR agonist administration. In addition, scRNA-seq demonstrated a higher expression fold change of IFN-induced genes with poly-ICLC treatment in both peripheral blood monocytes and T lymphocytes. Median progression-free survival (PFS) was 8.1 months (5.5 placebo vs. 8.1 resiquimod vs. 31.4 poly-ICLC), and median overall survival (OS) was 26.6 months (7.7 placebo vs. 16.7 resiquimod vs. 52.5 poly-ICLC). Patients who had higher expression of interferon response genes lived significantly longer and had longer time to progression compared to those with lower expression. The results suggest that ATL-DC in conjunction with adjuvant poly-ICLCTL induces a polarized interferon response in circulating monocytes and specific activation of a CD8+ T cell population. This combination was associated with extended survival in this patient population. This interferon response signature may represent an important blood biomarker for immunotherapy in patients with malignant glioma.
2023-10-11 | GSE237579 | GEO
Project description:Saponin-based vaccine adjuvants are potent in preclinical animal models and humans, but their mechanisms of action remain poorly understood. Using a stabilized HIV envelope trimer as a model immunogen, we carried out studies in non-human primates (NHPs), comparing the most common clinical adjuvant alum and Saponin/MPLA Nanoparticles (SMNP), a novel ISCOMs-like adjuvant. SMNP elicited substantially stronger humoral immune responses than alum and induced strong type I interferon transcriptional signatures, expansion of innate immune cells, and increased antigen presenting cell activation in LNs. These findings indicate that SMNP promotes multiple facets of the early immune response relevant for enhanced immunity to vaccination.
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Project description:This randomized phase II clinical trial studies how well MUC1 peptide-poly-ICLC adjuvant vaccine works in treating patients with newly diagnosed advanced colon polyps (adenomatous polyps). Adenomatous polyps are growths in the colon that may develop into colorectal cancer over time. Vaccines made from peptides may help the body build an effective immune response to kill polyp cells. MUC1 peptide-poly-ICLC adjuvant vaccine may also prevent the recurrence of adenomatous polyps and may prevent the development of colorectal cancer.
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Project description:Many modern vaccines use defined adjuvants to stimulate the innate immune system and shape the adaptive immune response. The exact nature of these innate signals and whether immune differentiation can originate within the periphery is not known. In the present study we used an ovine lymphatic cannulation model to characterise the cellular and transcriptomic profile of the afferent lymph following injection of a liposomal vaccine formulation incorporating diphtheria toxoid and the innate stimulator poly (I:C) over a 78 h period. The response to this vaccine featured an early activation of broad proinflammatory pathways (e.g. TLR signalling and inflammasome pathways) and the transient recruitment of granulocytes into the lymph. At 24hrs a more monocytic cellular profile arose coinciding with a transition to a specific antiviral response characterised by the up-regulation of genes associated with the receptors typical for the viral mimic, poly (I:C) (e.g. TLR3, RIG-I and MDA5). At the latest time points the up-regulation of IL-17A and IL-17F suggested that Th17 cells may participate in the earliest adaptive response to this vaccine. Together these data provide the most comprehensive picture of the cellular and molecular mechanisms that link the periphery to the draining lymph node following vaccination and indicate that the immune response is capable of specialising within the periphery. This study employed an ovine model of pseudoafferent lymphatic cannulation (see de Veer et al. 2010, Vaccine) to characterise the innate immune response within the afferent lymph to vaccination with liposomes+poly (I:C)+ diptheria toxoid. The sheep used in this study had both their pre-femoral lymph nodes removed at 1 year of age. Approximately 1 year after the lymph node removal, a second surgery was performed to insert a 0.96_0.58mm heparin-coated polyvinyl chloride cannula into the pseudoafferent (previous efferent) lymphatic duct of both sides. At least seven days were allowed for healing to occur after surgery before vaccinations were administered and experimental lymph samples were collected. Handling of animals and experimental procedures were all approved by the Monash University Animal Ethics Committee in accordance with the relevant licensing agreement. Vaccinations were injected subcutaneously in the area drained by the prefemoral lymph node. Afferent lymphatic samples were collected prior to vaccination as a control (PRE) and at 4-6, 26-28, 51-53 and 76-78 hours post vaccination with liposomes+poly (I:C)+ diptheria toxoid. Lymphocytes were removed from the afferent lymph using immunomagnetic separation. Next-generation sequencing was performed on RNA derived from the remaining innate immune cells. Samples from three sheep were used at all time points except 4-6 and 26-28 hours, where only two samples yielded sufficient RNA for sequencing.
2013-08-01 | E-GEOD-38533 | biostudies-arrayexpress
Project description:Many modern vaccines use defined adjuvants to stimulate the innate immune system and shape the adaptive immune response. The exact nature of these innate signals and whether immune differentiation can originate within the periphery is not known. In the present study we used an ovine lymphatic cannulation model to characterise the cellular and transcriptomic profile of the afferent lymph following injection of a liposomal vaccine formulation incorporating diphtheria toxoid and the innate stimulator poly (I:C) over a 78 h period. The response to this vaccine featured an early activation of broad proinflammatory pathways (e.g. TLR signalling and inflammasome pathways) and the transient recruitment of granulocytes into the lymph. At 24hrs a more monocytic cellular profile arose coinciding with a transition to a specific antiviral response characterised by the up-regulation of genes associated with the receptors typical for the viral mimic, poly (I:C) (e.g. TLR3, RIG-I and MDA5). At the latest time points the up-regulation of IL-17A and IL-17F suggested that Th17 cells may participate in the earliest adaptive response to this vaccine. Together these data provide the most comprehensive picture of the cellular and molecular mechanisms that link the periphery to the draining lymph node following vaccination and indicate that the immune response is capable of specialising within the periphery.
2013-08-01 | GSE38533 | GEO
Project description:Phase 1 study for patients with resected PDAC after neoadjuvant and/ or adjuvant chemotherapy and/or radiation, as well as patients with metastatic MSS CRC who have exposure to 2 or more lines of chemotherapy, to evaluate safety and the immune response to pooled mutant-KRAS peptide vaccine (KRAS peptide vaccine) with poly-ICLC adjuvant in combination with nivolumab and ipilimumab.
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Project description:Vaccine adjuvants enhance adaptive immunity to co-administered antigens. Whereas the modes of action are multiple, the activation of antigen-presenting cells (APC) like dendritic cells by adjuvants is a prerequisite. Detection of microbial signals by innate sensors like Toll-like receptors (TLR) is a major mechanism of APC activation. Most candidate or licensed vaccines assume that adjuvant activity of TLR agonists depends on direct effect on APCs. This study addressed whether TLR stimulation of non-hematopoietic cells could contribute to the adjuvant effect. Nasal administration of flagellin enhanced T cell- and antibody-mediated immunity to co-administered antigens in a TLR5-dependent but inflammasome-independent manner. We found that lung radioresistant cells were sufficient to promote immunity, thereby suggesting that direct TLR5-mediated APC stimulation is dispensable to adjuvant activity. Consistent with this, radioresistant compartment is essential to stimulate the swift TLR5-dependent transcription. The transcriptional response was restricted to the epithelial compartment and was associated to the production of a narrow set of mediators including the chemokine CCL20, known to promote APC recruitment in mucosal tissues. Besides, flagellin was rapidly degraded in lower airways and was not transported into lung parenchyma or peripheral tissues. This study therefore suggests an unexpected mechanism for how TLR agonists act as adjuvant and how epithelium is instrumental to sense and integrate microbial signals to promote adaptive immunity. In conclusion, the immune-enhancing effect of adjuvants on epithelial cells can be harnessed for improving vaccines. 1 µg of flagellin was instillated intranasally to LPS-unresponsive C3H/HeJ mice. Total lung RNA was extracted 1h later and prepare for hybridization on Affymetrix microarrays.
2013-03-22 | E-GEOD-45369 | biostudies-arrayexpress