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Immunogenicity and protective efficacy of Marburg virus glycoprotein and virus-like particle-forming mRNA-based vaccines.

ABSTRACT: Mounting evidence suggests the high immunogenicity of virus-like particle (VLPs) based vaccines. Although VLP vaccines can be effective, they have not been compared to an envelope glycoprotein (GP)-only vaccine for filoviruses. We conducted a detailed side-by-side comparison of the immunogenicity and protective efficacy of mRNA vaccines encoding for the Marburg virus (MARV) full length GP delivered alone or as a VLP. As expected, co-formulation of the MARV GP and matrix protein VP40 resulted in the formation of VLPs readily detected by electron microscopy after purification from cell supernatants. We vaccinated guinea pigs with a two-component mRNA vaccine encoding for GP and VP40 (from now on referred as VLP vaccine) or a monovalent mRNA vaccine encoding for GP alone. At high vaccine doses, the VLP group demonstrated reduced humoral response as compared to the GP-only group, but both mRNA vaccines fully protected guinea pigs against lethal MARV infection. However, at low doses, GP-only mRNA conferred a 100% protection, whereas the VLP exhibited only a partial protection. In mice the VLP mRNA vaccine was more efficient at inducing GP-specific CD8+ T cells co-expressing IFN-γ and TNF-α, whereas the GP-only mRNA vaccine better induced CD4+ T cells expressing IFN-γ, IL-2 and TNF-α. In addition, in guinea pigs, the VLP vaccine was associated with down-regulation of genes associated with various biological and metabolic processes, including the NF-κB signaling pathway, post-transcriptional silencing of small RNAs, and upregulation of genes involved in the mitochondrial respiratory chain complex. In contrast, the GP-only vaccine upregulated genes involved in interferon signaling. Overall, the VLP mRNA vaccine was less immunogenic and protective, whereas the GP-only mRNA vaccine conferred a robust protection by as little as one µg dose in guinea pigs.

ORGANISM(S): Cavia porcellus

PROVIDER: GSE298124 | GEO | 2025/06/27

REPOSITORIES: GEO

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Project description:Human papilloma (HPV) virus-like particle (VLP) vaccines were recently licensed. Though neutralizing antibody titers are thought to be the main effectors of protection against infection, early predictors of long-term efficacy are not yet defined and a comprehensive understanding of innate and adaptive immune responses to vaccination is still lacking. Here, microarrays were used to compare the gene expression signature in HPV-16 L1 VLP-stimulated PBMC from 17 vaccine and 4 placebo recipients before vaccination, and 1 month after receiving the second immunization. Vaccination with HPV-16 L1 VLP was associated with modulation of genes involved in the inflammatory/defense response, cytokine, interferon and cell cycle pathways in VLP-stimulated PBMC. In addition, there was up-regulation of probesets associated with cytotoxic (GZMB, TNFSF10) and regulatory (INDO, CTLA4) activities. The strongest correlations with neutralizing antibody titers were found for cyclin d2 (CCND2) and galectin (LGALS2). Twenty-two differentially expressed probesets were selected for confirmation by RT-PCR in an independent sample set. Agreement with the microarray data was seen for over two-thirds of these probesets. Up-regulation of immune/defense response genes by VLP, in particular interferon-induced genes was observed in PBMC collected prior to vaccination, with many of these genes being further induced following vaccination. In conclusion, we used gene expression profiling to identify important innate and adaptive response related- genes induced by vaccination with HPV VLP. Further studies are needed to identify gene expression signatures of immunogenicity and long-term protection with potential utility in prediction of long-term HPV vaccination outcomes in clinical trials. Experiment Overall Design: Microarrays (Affymetrix Human Focus) were used to compare the gene expression signature in PBMCs stimulated for 3 days with media alone, Sf9/baculovirus insect cell lysate, and HPV-16 L1 VLP expressed from baculovirus-infected Sf9 insect cells from 17 vaccine and 4 placebo recipients before vaccination, and 1 month after receiving the second immunization (2 months after the initial immunization. Post-vaccination baculovirus sample for Pt078 and pre-vaccination baculovirus sample for Pt082 failed QC.

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Immunogenicity and protective efficacy of Marburg virus glycoprotein and virus-like particle-forming mRNA-based vaccines.

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