Browse
Submit Data
Databases
API
Help

Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

57 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Reducing cell intrinsic immune responses to mRNA vaccine constructs improves adaptive immune response in mice

ABSTRACT: The response to mRNA vaccines needs to be sufficient for immune cell activation and recruitment but moderate enough to ensure efficacious antigen expression. The choice of the cap structure and use of N1-methylpseudouridine (m1Ψ) instead of uridine, which have been shown to reduce RNA sensing by the cellular innate immune system, has led to improved efficacy of mRNA vaccine platforms. Understanding how RNA modifications influence the cell intrinsic immune response may help in the development of more effective mRNA vaccines. In the current study, we compared mRNA vaccines in mice against influenza virus using three different mRNA formats: uridine-containing mRNA (D1-uRNA), m1Ψ- modified mRNA (D1-modRNA), and m1Ψ-modified mRNA with a cap1 structure (cC1-modRNA). D1-uRNA vaccine induced a significantly different gene expression profile to the modified mRNA vaccines, with an upregulation of Stat1 and RnaseL, and increased systemic inflammation. This correlated with a significantly reduced antigen specific antibody responses and reduced protection against influenza virus infection compared to D1-modRNA and cC1-modRNA. Incorporation of m1Ψ alone without cap1 improved antibodies, but both modifications were required for the optimum response. Therefore, the incorporation of m1Ψ and cap1 alters protective immunity from mRNA vaccines by altering the innate immune response to the vaccine material

INSTRUMENT(S): Illumina HiSeq 4000

ORGANISM(S): Mus musculus

SUBMITTER: Ziyin Wang

PROVIDER: E-MTAB-13194 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

ACCESS DATA

Json Xml

Similar Datasets

N1-methylpseudouridine found within COVID-19 mRNA vaccines produces faithful protein products

Project description:The COVID mRNA vaccines utilize the modified nucleobase N1-methylpseudouridine, in place of canonical uridine, to improve immunogenicity and protein yield. However, relatively few studies have investigated the effect of modified nucleobases on the fidelity of protein translation. Given the interest in the COVID mRNA vaccines, we sought to investigate how N1-methylpseudouridine (and the related modification pseudouridine) is read by ribosomes.

2022-08-18 | PXD029291 | Pride

Immune response genes at the mRNA vaccine delivery sites and draining lymph nodes of rhesus macaques

Project description:mRNA vaccines are emerging as a powerful vaccine platform as they are well-tolerated and scalable. Modified non-replicating mRNA encoding Influenza hemagglutinin and encapsulated in lipid nanoparticles (LNP) induced robust antibody and CD4 T cell responses after intramuscular or intradermal delivery in rhesus macaques. We investigated the local innate immune responses modulating such vaccine-induced immunity at the sites of immunization (skeletal muscle and skin) and their draining lymph nodes (LNs). Rapid mobilization of antigen presenting cells was found at the LNP/mRNA-injection sites and LNs. Dendritic cells efficiently internalized the LNPs, translated the mRNA cargo and upregulated co-stimulatory molecules. In addition, several type I interferon-inducible genes were expressed at the immunization sites and draining LNs. The innate immune activation was transient and resulted in priming of antigen-specific CD4+ T cells exclusively in the vaccine-draining LNs. Collectively, mRNA-based vaccines induce type I interferon-polarized innate immunity and antigen production by antigen presenting cells, which resulted potent vaccine-specific responses.

2017-04-26 | GSE98211 | GEO

Time-dependent enhancement of mRNA vaccines by 4-1BB costimulatory antibodies

Project description:mRNA vaccines have demonstrated efficacy against COVID-19. However, concerns regarding waning immunity and breakthrough infections have motivated the development of next-generation vaccines with enhanced efficacy. In this study, we investigated the impact of 4-1BB costimulation on immune responses elicited by mRNA vaccines in mice. We first vaccinated mice with an mRNA vaccine encoding the SARS-CoV-2 spike antigen like the Moderna and Pfizer-BioNTech vaccines, followed by administration of 4-1BB costimulatory antibodies at various times post-vaccination. Administering 4-1BB costimulatory antibodies during the priming phase did not enhance immune responses. However, administering 4-1BB costimulatory antibodies after 96 hours elicited a significant improvement in CD8 T cell responses, leading to enhanced protection against breakthrough infections. A similar improvement in immune responses was observed with multiple mRNA vaccines, including vaccines against common cold coronavirus, human immunodeficiency virus (HIV), and arenavirus. These findings demonstrate a time-dependent effect by 4-1BB costimulation and provide insights for developing improved mRNA vaccines.

2024-09-04 | GSE260817 | GEO

Blood transcriptome profiling reveals distinct gene networks induced by mRNA vaccination against COVID-19

Project description:Messenger RNA (mRNA) vaccines represent a new class of vaccines that has been shown to be highly effective during the COVID-19 pandemic and that holds great potential for other preventative and therapeutic applications. Understanding the underlying mechanisms of the immune responses induced by this novel vaccine type and their relation to vaccine responses might help to further refine and optimize future vaccine design. In this study, we conducted an in-depth analysis of the blood transcriptome before and 24h after second and third vaccination with licensed mRNA vaccines against COVID-19 in humans, following a prime vaccination with either mRNA or ChAdOx vaccines. Utilizing an unsupervised weighted gene correlation network analysis, we identified distinct gene networks of co-varying genes characterized by either an expressional up- or down-regulation in response to vaccination. Down-regulated networks were associated with cell metabolic processes and regulation of transcription factors, while up-regulated networks were associated with myeloid differentiation, antigen presentation, and antiviral, interferon-driven pathways. Within this interferon-associated network, we identified highly connected hub genes such as STAT2 and RIGI, potentially playing important regulatory roles in the vaccine-induced immune response. The expression profile of this network significantly correlated with S1-specific IgG levels at the follow-up visit in vaccinated individuals. Those findings could be corroborated in an independent cohort of mRNA vaccine recipients. Collectively, insights from this study might contribute to current research endeavors aimed at further enhancing/ or optimizing vaccine-induced immunity.

2024-01-29 | GSE247401 | GEO

CLIP of mRNA capping enzyme CMTR1 in Drosophila melanogaster

Project description:The mRNA cap structure consists of the m7G "cap0" linked to the 5'-most nucleotide of the initial mRNA. The first two nucleotides of mRNA can be 2'-O-Ribose modified to form cap1 or cap2 structures. Here, mRNA was sequenced after CLIP with tagged recombinant CMTR1 and compared to input RNA.

2021-12-18 | GSE181321 | GEO

CLIP of mRNA capping enzyme CMTR2 in drosophila melanogaster

2021-12-18 | GSE138868 | GEO

A systems immunology study comparing innate and adaptive immune responses in adults to COVID-19 mRNA (BNT162b2/mRNA-1273) and adenovirus vectored vaccines (ChAdOx1-S)

Project description:We longitudinally profiled plasma proteomes in 54 adults vaccinated with the BNT162b2 (Pfizer-BioNTech) or ChAdOx1-S (Oxford-AstraZeneca) vaccines. Blood was collected pre-vaccination (V0) and 1-7 days after the 1st doses (BNT162b2 or mRNA-1273, V1) to assess innate and early adaptive responses. We identified key differences in the immune responses induced by the ChAdOx1-S and BNT162b2 vaccines that were correlated with subsequent antigen-specific antibody and T cell responses or vaccine reactogenicity. We observed that vaccination with ChAdOx1-S but not BNT162b2 induced a memory-like response after the first dose, which was correlated with the expression of several proteins involved in complement and coagulation. The COVID-19 Vaccine Immune Responses Study (COVIRS) thus represents a major resource to understand the immunogenicity and reactogenicity of these COVID-19 vaccines.

2023-03-01 | PXD036608 | Pride

Transcriptome atlas of injection site response reveals initial mechanisms of mRNA vaccine immunity

Project description:Precise immunological mechanisms of mRNA vaccines have still not been fully elucidated, especially the initial immune responses at the injection site. Here, by constructing a single-cell atlas of injection site responses of mRNA vaccine, we show that stromal inflammatory responses and type I interferon responses dominate initial transcriptional reactions elicited by mRNA vaccines at the injection site. Tracking down the fates of the delivered mRNA revealed that injection site fibroblasts are highly enriched with the delivered mRNA, and they express IFN-β specifically in response to the mRNA component, not to the LNP. Accordingly, migratory dendritic cells highly expressing interferon stimulated genes (mDC_ISG) were found specifically in muscle and draining lymph nodes of mRNA vaccine injected mice, compared to the empty LNP injected mice. Co-administration of IFN-β and LNP robustly induced mDC_ISGs at the injection site and substantially enhanced antigen-specific CD8 T cell responses. Collectively, these data elucidate earliest mechanisms of the mRNA vaccine and highlight the underappreciated immunogenic role of the mRNA component in the mRNA vaccine.

2023-12-14 | GSE239574 | GEO

Systems biology analysis reveals distinct molecular signatures promoting immune responsiveness to the BNT162b COVID-19 vaccine [scRNA-seq]

Project description:Human immune responses to COVID-19 vaccines display a large heterogeneity of induced immunity and the underlying immune mechanisms for this remain largely unknown. Using a systems biology approach, we longitudinally profiled a unique cohort of female high and low responders to the BNT162b vaccine, who were known from previous COVID-19 vaccinations to develop maximum and minimum immune responses to the vaccine. We utilized high dimensional flow cytometry, bulk and single cell mRNA sequencing and 48-plex serum cytokine analyses. We revealed early, transient immunological and molecular signatures that distinguished high from low responders and correlated with B and T cell responses measured 14 days later. High responders featured a distinct transcriptional activity of interferon-driven genes and genes connected to enhanced antigen presentation. This was accompanied by a robust cytokine response related to Th1 differentiation. Both transcriptome and serum cytokine signatures were confirmed in two independent confirmatory cohorts. Collectively, our data contribute to a better understanding of the immunogenicity of mRNA-based COVID-19 vaccines, which might lead to the optimization of vaccine designs for individuals with poor vaccine responses.

2024-01-29 | GSE246937 | GEO

Systems biology analysis reveals distinct molecular signatures promoting immune responsiveness to the BNT162b COVID-19 vaccine [bulk RNA-seq]

2024-01-29 | GSE246525 | GEO