Immunogenicity and protective efficacy of Marburg virus glycoprotein and virus-like particle-forming mRNA-based vaccines.
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PROVIDER: PRJNA1268395 | ENA |
REPOSITORIES: ENA
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Project description: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.
2025-06-27 | GSE298124 | GEO
Project description:Marburg virus, a member of the Filoviridae, is the causative agent of Marburg virus disease (MVD), a hemorrhagic fever with a case fatality rate of up to 90%. Acute kidney injury is common in MVD and is associated with increased mortality, but its pathogenesis in MVD remains poorly understood. Interestingly, autopsies show the presence of viral proteins in different parts of the nephron, particularly in proximal tubular cells (PTC). These findings suggest a potential role for the virus in the development of MVD-related kidney injury. To shed light on this effect, we infected primary human PTC with Lake Victoria Marburg virus and conducted transcriptomic analysis at multiple time points. Unexpectedly, infection did not induce marked cytopathic effects in primary tubular cells at 20 and 40 hours post infection. However, gene expression analysis revealed robust renal viral replication and dysregulation of genes essential for different cellular functions. The gene sets mainly downregulated in PTC were associated with the targets of the transcription factors MYC and E2F, DNA repair, the G2M checkpoint, as well as oxidative phosphorylation. Importantly, the downregulated factors comprise PGC-1α, a well-known factor in acute and chronic kidney injury. By contrast, the most highly upregulated gene sets were those related to the inflammatory response and cholesterol homeostasis. In conclusion, Marburg virus infects and replicates in human primary PTC and induces downregulation of processes known to be relevant for acute kidney injury as well as a strong inflammatory response.
2024-02-14 | GSE226148 | GEO
Project description:Marburg virus is a genetically simple RNA virus that causes a severe hemorrhagic fever upon infection in humans and non-human primates. The mechanism of how this pathogenesis comes about is not well understood, but it is well accepted that pathogenesis is significantly driven by a hyperactive immune response. To better understand the overall response to Marburg virus challenge, we undertook a transcriptomic analysis of immune cells circulating in the blood following aerosol exposure of cynomolgus macaques to a lethal dose of Marburg virus. Using two-color microarrays, we analyzed the transcriptome of peripheral blood mononuclear cells that were collected throughout the course of infection from 1 to 9 days postexposure, representing the full course of the infection. The host response to aerosolized Marburg was evident at 1 day post-exposure. The response followed a 3-phase response that was led by a robust innate immune response. Analysis of cytokine transcripts that were overexpressed during infection indicated that previously unanalyzed cytokines are likely induced in response to exposure to Marburg virus, and further suggested that the immune response may favor a Th2 response that would hamper the development of an effective antiviral immune response. Late infection events included the upregulation of coagulation associated factors. These findings suggest new avenues for investigating the pathogenesis of Marburg virus infection and provide rich dataset of factors expressed throughout the course of infection that can be investigated as markers of infection and targets for therapy. RNA was isolated from a total of 30 PBMC samples from 15 cynomologus macaques infected with Marburg Virus. Samples were obtained at sequential timepoints post-infection, and included a pre-infection specimen from each animal. These samples were then processed and hybridized onto the Agilent 2-color arrays.
2015-05-11 | E-GEOD-58287 | biostudies-arrayexpress
Project description:Marburg virus is a genetically simple RNA virus that causes a severe hemorrhagic fever upon infection in humans and non-human primates. The mechanism of how this pathogenesis comes about is not well understood, but it is well accepted that pathogenesis is significantly driven by a hyperactive immune response. To better understand the overall response to Marburg virus challenge, we undertook a transcriptomic analysis of immune cells circulating in the blood following aerosol exposure of cynomolgus macaques to a lethal dose of Marburg virus. Using two-color microarrays, we analyzed the transcriptome of peripheral blood mononuclear cells that were collected throughout the course of infection from 1 to 9 days postexposure, representing the full course of the infection. The host response to aerosolized Marburg was evident at 1 day post-exposure. The response followed a 3-phase response that was led by a robust innate immune response. Analysis of cytokine transcripts that were overexpressed during infection indicated that previously unanalyzed cytokines are likely induced in response to exposure to Marburg virus, and further suggested that the immune response may favor a Th2 response that would hamper the development of an effective antiviral immune response. Late infection events included the upregulation of coagulation associated factors. These findings suggest new avenues for investigating the pathogenesis of Marburg virus infection and provide rich dataset of factors expressed throughout the course of infection that can be investigated as markers of infection and targets for therapy.
2015-05-11 | GSE58287 | GEO
Project description:Ebola virus (EBOV) and Marburg virus (MARV) are zoonotic filoviruses that cause hemorrhagic fever in humans. Bat species in both Chiropteran suborders host filoviruses, suggesting that bats may have coevolved with this viral family. Correlative data implicate bats as natural EBOV hosts, but neither a full-length genome nor an EBOV isolate has been found in any bats sampled. Here, we modelled filovirus infection in the Jamaican fruit bat (JFB), Artibeus jamaicensis. Bats were inoculated with either EBOV or MARV through a combination of oral, intranasal, and subcutaneous routes. EBOV-infected bats supported systemic virus replication and shed infectious virus orally. In contrast, MARV replicated only transiently and was not shed. In vitro, JFB cells replicate EBOV more efficiently than MARV, and MARV infection induced innate antiviral responses that EBOV efficiently suppressed. Experiments using VSV pseudoparticles or replicating VSV expressing the EBOV or MARV glycoprotein demonstrated an advantage for EBOV entry and replication early, respectively, in JFB cells. Overall, this study describes filovirus species-specific phenotypes for both JFB and their cells.
2025-03-02 | GSE288891 | GEO
Project description:Transcriptomics of Marburg virus-infected proximal tubular cells
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Project description:The Schmallenberg virus (SBV) is an orthobunyavirus that causes abortions, stillbirths, and congenital defects in pregnant sheep and cattle. Inactivated or live attenuated vaccines have been developed in endemic countries, but there is still interest in the development of SBV vaccines that would allow Differentiating Infected from Vaccinated Animals (DIVA). Therefore, an attempt was made to develop novel DIVA-compatible SBV vaccines using SBV glycoproteins expressed in baculovirus. All vaccines and phosphate buffered saline (PBS) controls were prepared with adjuvant and administered subcutaneously to cattle at 6 month of age. The first trial included 2 groups of animals vaccinated with either carboxyl-terminus glycoprotein (Gc) or PBS and boosted after 2 weeks. In the second trial, 3 groups of cattle were administered either Gc, Gc and amino-terminus glycoprotein (Gn), or PBS with a booster vaccination after 3 weeks. The animals were challenged with SBV 9 days after the booster vaccination in the first study, and 3 weeks after the booster vaccination in the second study. Using a SBV Gc-specific enzyme-linked immunosorbent assay, antibodies were first detected in serum samples 14 days after the first vaccination in both trials, and peaked on days 7 and 9 after the booster in the first and second trials, respectively. Low titers of neutralizing antibodies were detected in serum from only 3/6 and 2/4 animals in the first and second trial, respectively, at 14 days after the first vaccination. The titers increased 2 to 3-fold after the booster vaccination. SBV-specific RNA was detected in the serum and selective tissues in all animals after SBV challenge independent of vaccination status. The SBV candidate vaccines neither prevented viremia nor conferred protection against SBV infection.
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Project description:The Marburg virus (MARV), belonging to the Filoviridae family, poses a significant global health threat, emphasizing the urgency to develop Marburg virus-like particle (VLP) vaccines for outbreak mitigation. The virus's menacing traits accentuate the need for such vaccines, which can be addressed by VLPs that mimic its structure safely, potentially overcoming past limitations. Early Marburg vaccine endeavors and their challenges are examined in the historical perspectives section, followed by an exploration of VLPs as transformative tools, capable of eliciting immune responses without conventional risks. Noteworthy milestones and achievements in Marburg VLP vaccine development, seen through preclinical and clinical trials, indicate potential cross-protection. Ongoing challenges, encompassing durability, strain diversity, and equitable distribution, are addressed, with proposed innovations like novel adjuvant, mRNA technology, and structure-based design poised to enhance Marburg VLP vaccines. This review highlights the transformative potential of Marburg VLPs in countering the virus, showcasing global collaboration, regulatory roles, and health equity for a safer future through the harmonious interplay of science, regulation, and global efforts.
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2019-06-20 | GSE132998 | GEO
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