Development of an in vitro method to assess the immunogenicity of biologics in the prevention of infectious diseases
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PROVIDER: PRJNA1251612 | ENA |
REPOSITORIES: ENA
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Project description:We present a series of preclinical studies focused on developing in vitro 2D and 3D models for assessing immunogenic factors in preventing infectious diseases. Human peripheral blood mononuclear cells (PBMC) and Calu-3 cell lines (bronchial epithelial cells) were used to develop 2D and 3D models. Peptides: Spike-S1-His (S-His), nucleocapsid-His and adjuvants: human adenovirus five serotype-based viral vector (AdV-D24-ICOSL-CD40L), armed with inducible co-stimulator (ICOSL) and CD40 ligand (CD40L), and a vector lacking these transgenes (AdV5/3) were used due to their effective initial interaction with antigen-presenting cells (APC). Studying the potency of biologics in vitro revealed a significant increase in the percentage of CD4+ TCM, CD4+ TEMRA, and CD4+ TEM lymphocyte subpopulations involved in memory cell generation after 24 hours of treatment. Prolonging the exposure for 7 days, a significant increase in CD4+ cells was observed when PBMCs were treated with AdV1 (56.00 ± 0.26% vs. 48.17 ± 1.10%). In contrast, a decrease in CD8+ cells was observed in those treated with AdV1 (37.93 ± 0.35%) compared to AdV1+S-His+N-His (38.47 ± 0.38%) versus the untreated group (44.63 ± 1.07%). A decrease in EMRA was noted when PBMCs were treated with AdV1+S-His+N-His (2.97 ± 0.23% vs. 4.50 ± 0.35%). Moreover, it was pointed out that PBMCs treated with AdV1 alone or in combination with S-His and N-His showed an elevated number of naïve CD4+/CD8+ and SCM CD4+/CD8+ cells. No changes in the number of EMRA CD4+ subpopulations were detected when PBMCs were treated with AdV2 compared with untreated ones (4.27 ± 0.06% vs. 4.50 ± 0.35%). Analysis of the humoral response induced by AdV1, AdV2, S-His, N-His, AdV1+S-His+N-His, and AdV2+S-His+N-His showed that AdV1 alone (4.17 ± 0.25% vs. 3.17 ± 0.06%) and in combination with S-His and N-His (3.87 ± 0.25 vs. 3.17 ± 0.06%) slightly increased the number of CD19+ cells. RNA-Seq analysis of PBMC cells in the 3D model revealed gene overexpression, including FGFR4, associated with the Rap1 pathway in samples exposed to AdV1+S-His+N-His. Thus, the proposed platform's impact on lymphocyte differentiation was confirmed, and cytokine profile analysis in this sample revealed elevated levels of IL-10, IL-12p70, and IL-8. All samples exposed to AdV showed increased levels of IFN-γ. The safety and biodistribution studies of the vaccine platform demonstrated that a 30-day exposure did not impact mice's survival or organ morphology. Exploring the CD40 pathway notably reveals its significant impact on immune cell populations, suggesting potential therapeutic avenues.
2025-09-10 | GSE294796 | GEO
Project description:The efficacy of biologics, such as peptide and protein drugs, is often limited by their short half-lives in vivo. GD2TIF cells expanded in immunocompetent mice without the need for chemotherapeutic conditioning and persisted as a polyclonal population, safely and almost indefinitely. Thus, GD2TIF cells be leveraged as a versatile platform for long-term delivery of biologics. In multiple disease models, GD2TIF cells were proved can be taken as a general platform for long-term delivery of biologics, offering durable therapeutic efficacy with a single infusion.
2025-06-02 | GSE291791 | GEO
Project description:Objectives: To investigate the differences in efficacy and safety between the vector vaccine ChAdOx1 nCoV-19/AZD1222 (Oxford-AstraZeneca) and mRNA-based vaccine mRNA-1273 (Moderna), and evaluate the impact of anti-rheumatic medications on immunogenicity in patients with autoimmune rheumatic diseases (AIRD). Methods: From September 16 to November 15, 2021, we consecutively enrolled participants aged≥20 years with AIRD who received COVID-19 vaccination. The level of serum IgG antibodies to the SARS-Cov-2 receptor-binding domain on the spike protein S1 subunit was quantified by electrochemiluminescence immunoassay at 4-6 weeks after vaccination. The immunogenicity and adverse reactions between ChAdOx1 nCov-19/AZD1222 and mRNA-1273 were compared. Results: Of the 243 rheumatic disease patients who received COVID-19 vaccines, 113 and 130 were immunized with AZD1222 and mRNA-1273, respectively. The anti-SARS-CoV-2 IgG seropositivity rate was 78.8% (89/113) for AZD1222 and 83.1% (108/130) for mRNA-1273. The level of anti-SARS-Cov-2 IgG was higher in patients who received mRNA-1273 than in those who received AZD1222. Prednisolone-equivalent dose >5 mg/day, methotrexate (MTX), non-anti-tumor necrosis factor (TNF)-a biologics, and Janus kinase (JAK) inhibitor use were associated with inferior immunogenicity. All reported adverse reactions were minor. More localized pain at the injection site and less fever and chills were observed in patients receiving mRNA-1273 compared with those receiving AZD1222. Rheumatic disease activities after vaccination remained stable in most patients. Conclusions: mRNA-1273 and AZD1222 vaccines exhibited differential immunogenicity and adverse reaction profiles. Our study findings support temporary discontinuation of daily prednisolone dose >5 mg, MTX, non-anti-TNF-a biologics, or JAK inhibitors after COVID-19 vaccination.
2022-05-19 | GSE203081 | GEO
Project description:Diabetes Prevention Program (DPP)
| PRJNA227394 | ENA
Project description:Bacteriophage (phage) therapy is a promising alternative to antibiotics, yet phage-induced immune responses can affect treatment efficacy. However, current methods for assessing phage immunogenicity are limited, hindering the development of safer, more effective therapies. Here, we introduce the Bacteriophage Risk Index (BRI), a novel metric that quantifies phage immunogenic potential based on CpG dinucleotide frequency, motif spacing, and sequence context, key factors influencing Toll-like receptor 9 (TLR9) activation. Applying the BRI to 7,011 phage genomes, we classified them into five risk tiers, revealing substantial immunogenic variability, even among phages targeting the same bacterial host. BRI scores correlated with immune responses in human lung epithelial cells, validating its predictive power. Experimental testing further confirmed this, as exposure of lung epithelial cells to two phages from distinct risk tiers showed that the high-risk phage (Category 4) induced a strong pro-inflammatory response, upregulating CXCL1, CXCL8, IRF7, and TNFAIP3, while the low-risk phage (Category 2) triggered minimal immune activation with limited cytokine expression. These findings confirm that higher BRI scores predict stronger immune responses, providing a robust tool for evaluating phage immunogenicity. By enabling the selection of phages with lower immunogenic potential, the BRI enhances the safety and efficacy of phage therapy while offering a standardized framework for regulatory agencies, clinical researchers, and biologic drug development, with applications extending beyond phage therapy to other immunogenic biologics.
2025-06-16 | GSE293045 | GEO
Project description:Staphylococcus aureus (S. aureus) is one of the most dominant human pathogen, responsible for a variety of chronic and severe infections. As a classic traditional Chinese medicine (TCM) formula, Epidemic Prevention Sachets have been used clinically for centuries to treat infectious diseases. The antimicrobial activity of the essential oil (EO) from Epidemic Prevention Sachets against the S. aureus has not been investigated. In this study, the EO was tested for its antimicrobial activity against S. aureus. We identified that the EOs has high activity against S. aureus. It showed higher activity than the known antibacterial drug combination of Penicillin streptomycin. The same results were demonstrated by transmission electron microscopy. The impact of the EO on transcription of genes from S. aureus was analyzed. SAOUHSC_01002, SAOUHSC_02444, SAOUHSC_00282 and SAOUHSC_00325, which are involved in cation transport (GO:0006812), were significantly affected by the essential oil as defined in the Gene Ontology Biological Process (GO BP), whereas SAOUHSC_00114 and SAOUHSC_03000, which are involved in the protein tyrosine kinase modulator pathway (K19420), were significantly enriched in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Analysis of clusters of orthologous groups (COG) found that there are differences in multiple metabolic pathways, mainly including secondary biosynthesis metabolism, biofilm related genes and energy metabolism. Our study indicates that the essential oil from Epidemic Prevention Sachets is an effective herbal formula against S. aureus.
2025-05-17 | GSE296946 | GEO
Project description:Crohn's disease and ulcerative colitis are chronic inflammatory disorders of the gastrointestinal tract. Treatment options include biologic therapies; however, a proportion of patients lose response to biologics, partly due to the formation of anti-drug antibodies (ADAbs). Concomitant immunosuppressive agents reduce the development of ADAbs. This review article aims to assess the immunogenicity of biologic therapies and their clinical implications. A comprehensive literature search was conducted for articles published January 2009 to August 2015 reporting immunogenicity to adalimumab (ADM), certolizumab pegol (CZP), golimumab, infliximab (IFX), ustekinumab, and vedolizumab in inflammatory bowel disease (IBD). Eligible articles were reviewed and quality assessed by independent reviewers. Overall, 122 publications reporting 114 studies were assessed. ADAbs were reported for all agents, but the percentage of patients developing ADAbs was extremely variable, with the highest (65.3%) being for IFX administration to patients with IBD. ADAb presence was frequently associated with a reduction in primary efficacy and a loss of response, and, for IFX, an increase in adverse events (AEs). Lower serum levels of ADM, CZP and IFX were seen in ADAbs-positive rather than ADAbs-negative patients; pharmacokinetic data were unavailable for other therapies. Little information was available regarding the timing of ADAb development; studies reported their detection from as early as 10-14 days up to months after treatment initiation. Biologic therapies carry an intrinsic risk of immunogenicity, although reported rates of ADAbs vary considerably. The clinical implications of immunogenicity are a concern for effective treatment; further research, particularly into the more recently approved biologics, is required.
| S-EPMC5784568 | biostudies-literature
Project description:Breast cancer prevention with liquiritigenin
| PRJNA926640 | ENA
Project description:Immune checkpoint blockade (ICB) therapy is a cornerstone of oncologic treatment for patients with advanced stage non-small cell lung cancer (NSCLC) and other malignancies. Neoantigen immunoediting drives ICB efficacy, yet the fundamental physiochemical characteristics of neoantigens and how neoantigen immunogenicity shapes treatment response remains poorly understood. To help address these questions, a prospective clinical trial of NSCLC patients treated with nivolumab was conducted. We assessed genomic alterations in tumors from 58 patients and performed large-scale neoepitope immunogenicity analyses, before and during treatment (CheckMate153, CA209-153). Tumors were analyzed by whole-exome and transcriptome sequencing. In responding patients, loss of mutation and neoantigen burden early during therapy associated with clinical benefit. We evaluated the immunogenicity of 1,453 candidate neoantigens and identified 502 neopeptides that bound to MHC I and 196 neopeptides that were immunogenically recognized by T cells in the setting of nivolumab treatment. These T cell reactive neoantigens were differentially present in clonal populations that underwent distinctive evolutionary trajectories across responders and nonresponders. Mapping these neoantigens to tumor clonal dynamics and clinical response revealed strong selection against immunogenic neoantigen harboring clones compared to non-immunogenic clones. Using this large collection of neoantigens, we identified position specific amino acid features related to immunogenicity, which we used to develop and validate an immunogenicity score. Changes in the genomic and neoantigen immunogenicity landscapes were accompanied by temporal changes in the tumor microenvironment. Nivolumab-induced microenvironmental evolution in NSCLC shared some similarities with that in melanoma, yet critical differences in immunologic programs were apparent from comparative network analysis between tumor types. This study provides unprecedented molecular portraits of the neoantigen landscapes underlying nivolumab’s mechanism of action.
| EGAS00001007509 | EGA
Project description:Immune checkpoint blockade (ICB) therapy is a cornerstone of oncologic treatment for patients with advanced stage non-small cell lung cancer (NSCLC) and other malignancies. Neoantigen immunoediting drives ICB efficacy, yet the fundamental physiochemical characteristics of neoantigens and how neoantigen immunogenicity shapes treatment response remains poorly understood. To help address these questions, a prospective clinical trial of NSCLC patients treated with nivolumab was conducted. We assessed genomic alterations in tumors from 58 patients and performed large-scale neoepitope immunogenicity analyses, before and during treatment (CheckMate153, CA209-153). Tumors were analyzed by whole-exome and transcriptome sequencing. In responding patients, loss of mutation and neoantigen burden early during therapy associated with clinical benefit. We evaluated the immunogenicity of 1,453 candidate neoantigens and identified 502 neopeptides that bound to MHC I and 196 neopeptides that were immunogenically recognized by T cells in the setting of nivolumab treatment. These T cell reactive neoantigens were differentially present in clonal populations that underwent distinctive evolutionary trajectories across responders and nonresponders. Mapping these neoantigens to tumor clonal dynamics and clinical response revealed strong selection against immunogenic neoantigen harboring clones compared to non-immunogenic clones. Using this large collection of neoantigens, we identified position specific amino acid features related to immunogenicity, which we used to develop and validate an immunogenicity score. Changes in the genomic and neoantigen immunogenicity landscapes were accompanied by temporal changes in the tumor microenvironment. Nivolumab-induced microenvironmental evolution in NSCLC shared some similarities with that in melanoma, yet critical differences in immunologic programs were apparent from comparative network analysis between tumor types. This study provides unprecedented molecular portraits of the neoantigen landscapes underlying nivolumab’s mechanism of action.
| EGAS00001007508 | EGA