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Project description:There have been few in vivo studies on the effect of aluminum hydroxide adjuvant and its influence on the immune response to vaccination. In this study, lambs received a parallel subcutaneous treatment with either commercial vaccines containing aluminum hydroxide or an equivalent dose of this compound only with the aim of identifying the activated molecular signature. Blood samples were taken from each animal at the beginning and at the end of the experiment and PBMCs isolated. Total RNA and miRNA libraries were prepared and sequenced. After alignment to the Oar3.1 reference genome and differential expression with 3 programs, gene enrichment modeling was performed. For miRNAs, miRBase and RNAcentral databases were used for detection and characterization. Three expression comparisons were made: vaccinated animals at the beginning and at the end of the treatment, adjuvanted animals at the same times, and animals of both treatments at the end of the experiment. After exposure to both treatments, a total of 2,473; 2,980 and 429 differentially expressed genes were identified in vaccinated animals, adjuvanted animals and animals at the end of both treatments, respectively. In both adjuvant and vaccine treated animals the NF-κB signaling pathway was enriched. On the other hand, it can be observed a downregulation of cytokines and cytokine receptors in the adjuvanted group compared to the vaccinated group at the final time, suggesting a milder induction of the immune response when the adjuvant is alone. As for the miRNA analysis, 95 miRNAs were detected: 64 previously annotated in Ovis aries, 11 annotated in Bos taurus and 20 newly described. Interestingly, 6 miRNAs were differentially expressed in adjuvant treated animals, and 3 and 1 in the other two comparisons. Lastly, an integrated miRNA-mRNA expression profile was developed, in which a miRNA-mediated regulation of genes related to DNA damage stimulus was observed. In brief, it seems that aluminum-containing adjuvants are not simple delivery vehicles for antigens, but also induce endogenous danger signals that can stimulate the immune system. Whether this contributes to long-lasting immune activation or to the overstimulation of the immune system remains to be elucidated.
| S-EPMC6206264 | biostudies-literature
Project description:Molecular signature of Aluminum hydroxide adjuvant in ovine PBMCs by integrated mRNA and microRNA transcriptome sequencing
| PRJNA454385 | ENA
Project description:Aluminum hydroxide is used as a vaccine adjuvant in various human vaccines. Unfortunately, despite its favorable safety profile, aluminum hydroxide can only weakly or moderately potentiate antigen-specific antibody responses. When dispersed in an aqueous solution, aluminum hydroxide forms particulates of 1-20μm. There is increasing evidence that nanoparticles around or less than 200nm as vaccine or antigen carriers have a more potent adjuvant activity than large microparticles. In the present study, we synthesized aluminum hydroxide nanoparticles of 112nm. Using ovalbumin and Bacillus anthracis protective antigen protein as model antigens, we showed that protein antigens adsorbed on the aluminum hydroxide nanoparticles induced a stronger antigen-specific antibody response than the same protein antigens adsorbed on the traditional aluminum hydroxide microparticles of around 9.3μm. The potent adjuvant activity of the aluminum hydroxide nanoparticles was likely related to their ability to more effectively facilitate the uptake of the antigens adsorbed on them by antigen-presenting cells. Finally, the local inflammation induced by aluminum hydroxide nanoparticles in the injection sites was milder than that induced by microparticles. Simply reducing the particle size of the traditional aluminum hydroxide adjuvant into nanometers represents a novel and effective approach to improve its adjuvanticity.
| S-EPMC3918952 | biostudies-literature
Project description:We report the application of RNA sequencing technology for high-throughput profiling of the aluminium hydroxide adjuvant mechanism of action in an in vivo experiment on sheep. We mapped about 52 million sequence reads per sample to the sheep genome (build Oar3.1) and identified 21,274 genes in the PBMCs of sheep treated with commercial vaccines or with the adjuvant alone. A total of 2473, 2980 and 429 differentialy expressed genes were identified in the vaccine tf VS vaccine t0, adjuvant tf VS adjuvant t0 and adjuvant tf VS vaccine tf comparisons, respectively. Previously reported genes related to alterations caused by aluminium adjuvant were found differentially expressed, namely: NLRP3, IL1B, IL8, TNF, NFKB2, RELA and RELB. In addition, most of the genes related to apoptosis were up-regulated in both group after treatment. In contrast, other genes related to immune response, inflammatory response and cell-cell signalling were up-regulated in Vac-injected sheep and whereas down-regulated in Adj-injected animals. Taken together, our analysis provides characterization of alterations in the transcriptome caused by the aluminium adjuvant and identifies increased expression of inflammatory cytokines, NF-KB family genes and apoptotic genes.
2018-10-30 | GSE113898 | GEO
Project description:We report the application of miRNA sequencing technology for high-throughput profiling of the aluminium hydroxide adjuvant mechanism of action in an in vivo experiment on sheep. We mapped about 13 million sequence reads per sample to the sheep genome (build Oar3.1) and identified 95 miRNAs in the PBMCs of sheep treated with commercial vaccines or with the adjuvant alone. A total of 3, 6 and 1 differentialy expressed miRNAs were identified in the vaccine tf VS vaccine t0, adjuvant tf VS adjuvant t0 and adjuvant tf VS vaccine tf comparisons, respectively. Furthermore, miRNA target prediction was performed and it was integrated with previous RNA-seq data in the same animals to predict reliable miRNA-mRNA interactions. Previously reported miRNAs related to alterations caused by aluminium adjuvant were found differentially expressed, namely: miR-19b and miR-125b. Within the negatively correlated targets of the differentially expressed miRNAs there are factors that are clearly related with the response to stimulus, RNA binding and cellular response to DNA damage. Taken together, our analysis provides characterization of alterations in the miRNAome caused by the aluminium adjuvant and identifies some targets of the differentially expressed miRNAs which have been previously linked to the immune system. The overrepresentation of genes related to DNA damage stimulus and DNA repair in both groups may be due to miRNA-mediated regulation.
2018-10-30 | GSE113897 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-10-02 | GSE128597 | GEO
Project description:We report the application of miRNA sequencing technology for high-throughput profiling of the aluminium hydroxide adjuvant mechanism of action in an in vivo experiment on sheep. We mapped about 13.1 million sequence reads per sample to the sheep genome (build Oar3.1) and identified 299 miRNAs in the encephalon of sheep treated with commercial vaccines, with the adjuvant alone or with PBS (control group). A total of 2, 38 and 7 differentialy expressed miRNAs were identified in the Vaccine vs. Control, Adjuvant vs. Control and Adjuvant vs. Vaccine comparisons, respectively. Furthermore, miRNA target prediction was performed and it was integrated with previous RNA-seq data in the same animals to predict reliable miRNA-mRNA interactions. Previously reported miRNAs related to brain injury and neurodegenerative diseases were found differentially expressed. Within the negatively correlated targets of the differentially expressed miRNAs there are factors that are clearly related with mitochondria, to maintenance of neuronal polarity and axon growth and to apoptosis. Taken together, our analysis provides characterization of alterations in the miRNAome caused by the aluminium adjuvant alone, while the commercial vaccine not cause great changes, and identifies some targets of the differentially expressed miRNAs which have been previously linked to mitochondrial dysfunction. Aluminum might be causing an imbalance in metal ion levels, among them Mg, in the parietal lobe cortex of animals vaccinated with the adjuvant alone.
2020-10-02 | GSE128596 | GEO
Project description:We report the application of RNA sequencing technology for high-throughput profiling of the aluminium hydroxide adjuvant mechanism of action in an in vivo experiment on sheep treated with commercial vaccines, with the adjuvant alone or with PBS (control group). We mapped about 74.1 million sequence reads per sample to the sheep genome (build Oar3.1) and after filtering 16,369 genes were expressed, of which 14,387 were annotated genes in Ensembl and 1,982 were candidate lncRNAs. A total of 13, 63 and 76 differentialy expressed genes were identified in the Vaccine vs. Control, Adjuvant vs. Control and Adjuvant vs. Vaccine comparisons, respectively. Previously reported genes related to neuronal development, brain transport and neurotransmission, brain injury and neurodegenerative diseases associated with aluminum were found differentially expressed, namely VCAM1, TRPM4, GDF10 and NTN1.
2020-10-02 | GSE128595 | GEO
Project description:Although patients with Glioblastoma multiforme (GBM) have grave prognosis, significant variability in patient outcome is observed. The objective of this study is to identify a molecular signature for GBM prognosis. We subjected 355 mRNA and microRNA expression profiles to elastic net-regulated Cox regression for identification of an integrated RNA signature for GBM prognosis. A prognostic index (PI) was generated for patient stratification. Survival comparison was conducted by Kaplan-Meier method and a general multivariate Cox regression procedure was applied to evaluate the independence of the PI. The abilities and efficiencies of signatures to predict GBM patient outcome was assessed and compared by the area under the curve (AUC) of the receiver-operator characteristic (ROC). An integrated RNA prognostic signature consisted by 4 protective mRNAs, 12 risky mRNAs, and 1 risky microRNA was identified. Decreased survival was associated with being in the high-risk group (hazard ratio?=?2.864, P<0.0001). The prognostic value of the integrated signature was validated in five independent GBM expression datasets (n?=?201, hazard ratio?=?2.453, P<0.0001). The PI outperformed the known clinical factors, mRNA-only, and miRNA-only prognostic signatures for GBM prognosis (area under the ROC curve for the integrated RNA, mRNA-only, and miRNA-only signatures were 0.828, 0.742, and 0.757 at 3 years of overall survival, respectively, P<0.0001 by permutation test). We describe the first, to our knowledge, robust transcriptome-based integrated RNA signature that improves the current GBM prognosis based on clinical variables, mRNA-only, and miRNA-only signatures.
| S-EPMC4037214 | biostudies-literature
Project description:The heterogeneous composition of vaccine formulations and the relatively low concentration make the characterization of the protein antigens extremely challenging. Aluminum-containing adjuvants have been used to enhance the immune response of several antigens over the last 90 years and still remain the most commonly used. Here, we show that solid-state NMR and isotope labeling methods can be used to characterize the structural features of the protein antigen component of vaccines and to investigate the preservation of the folding state of proteins adsorbed on Alum hydroxide matrix, providing the way to identify the regions of the protein that are mainly affected by the presence of the inorganic matrix. l-Asparaginase from E. coli has been used as a pilot model of protein antigen. This methodology can find application in several steps of the vaccine development pipeline, from the antigen optimization, through the design of vaccine formulation, up to stability studies and manufacturing process.
| S-EPMC6538755 | biostudies-literature