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Construction and Immunogenicity of Modified mRNA-Vaccine Variants Encoding Influenza Virus Antigens.

ABSTRACT: Nucleic acid-based influenza vaccines are a promising platform that have recently and rapidly developed. We previously demonstrated the immunogenicity of DNA vaccines encoding artificial immunogens AgH1, AgH3, and AgM2, which contained conserved fragments of the hemagglutinin stem of two subtypes of influenza A-H1N1 and H3N2-and conserved protein M2. Thus, the aim of this study was to design and characterize modified mRNA obtained using the above plasmid DNA vaccines as a template. To select the most promising protocol for creating highly immunogenic mRNA vaccines, we performed a comparative analysis of mRNA modifications aimed at increasing its translational activity and decreasing toxicity. We used mRNA encoding a green fluorescent protein (GFP) as a model. Eight mRNA-GFP variants with different modifications (M0-M7) were obtained using the classic cap(1), its chemical analog ARCA (anti-reverse cap analog), pseudouridine (Ψ), N6-methyladenosine (m6A), and 5-methylcytosine (m5C) in different ratios. Modifications M2, M6, and M7, which provided the most intensive fluorescence of transfected HEK293FT cells were used for template synthesis when mRNA encoded influenza immunogens AgH1, AgH3, and AgM2. Virus specific antibodies were registered in groups of animals immunized with a mix of mRNAs encoding AgH1, AgH3, and AgM2, which contained either ARCA (with inclusions of 100% Ψ and 20% m6A (M6)) or a classic cap(1) (with 100% substitution of U with Ψ (M7)). M6 modification was the least toxic when compared with other mRNA variants. M6 and M7 RNA modifications can therefore be considered as promising protocols for designing mRNA vaccines.

SUBMITTER: Starostina EV

PROVIDER: S-EPMC8147809 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundBladder cancer (BLCA) is one of the most prevalent urinary system malignancies, with high mortality and recurrence. The present study aimed to identify potential tumor antigens for mRNA vaccines in BLCA and patient subtypes suitable for different immunotherapy.MethodsGene expression profiles, mutation data, methylation data, and corresponding clinical information were obtained from the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and ArrayExpress databases. Immunohistochemical staining of microarrays was performed to assess protein expression levels of IGF2BP2 and MMP9. Differential gene analysis, survival analysis, correlation analysis, consensus clustering analysis, and immune cell infiltration analysis were conducted using R software. Finally, the R package "immcluster" was used based on Combat and eXtreme Gradient Boosting algorithms to predict immune clusters of BLCA samples.ResultsTwo mutated, amplified, and over-expressed tumor antigens, IGF2BP2 and MMP9, were found to be associated with clinical outcomes and the abundance of antigen-presenting cells (APCs). Subsequently, three immune subtypes (BIS1, BIS2, and BIS3) were defined in the BLCA cohort. BIS3 subtype exhibited an "active" immune phenotype, while BIS1 and BIS2 subtypes have a "suppressive" immune phenotype. Patients in BIS1 and BIS2 had a poor prognosis compared to BIS3. BIS3 had a higher score in checkpoints or immunomodulators (CP) and immunophenoscore (IPS), while BIS1 and BIS2 scored higher in major histocompatibility complex-related molecules (MHC molecules). Meanwhile, BIS2 and BIS3 had a significantly higher tumor mutational burden (TMB) compared to patients with BIS1. Finally, the "immcluster" package was applied to the dataset, which has been shown to accurately predict the immune subtypes of BLCA samples in many cohorts.ConclusionsIGF2BP2 and MMP9 were potential antigens for developing mRNA vaccines against BLCA. The results in the present study suggested that immunotherapy targeting these two antigens would be suitable for patients falling under the BIS2 subtype. R package "immcluster" could assist in screening suitable BLCA patients for antitumor therapy.

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Construction and Immunogenicity of Modified mRNA-Vaccine Variants Encoding Influenza Virus Antigens.

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