In-depth genome analyses of viruses from vaccine-derived rabies cases and corresponding live-attenuated oral rabies vaccines
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PROVIDER: PRJEB21530 | ENA |
REPOSITORIES: ENA
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Project description:Analyses of viruses from vaccine induced rabies cases and corresponding vaccine batches
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Project description:Enteric fever is a major public health problem and causes numerous deaths annually. Ty21a is the only efficacious oral, live attenuated typhoid vaccine currently licensed for use, however, its mechanism of protection is poorly understood. To address this knowledge gap, we interrogated transcriptional profiles following vaccination with Ty21a and an immunogenic experimental oral live attenuated vaccine, M01ZH09, and related these findings to immunogenicity, and incubation period and disease severity following challenge with Salmonella Typhi four weeks after vaccination. Despite originating from the same parent strain (Ty2), we detected marked differences in the gene expression between both vaccines. Analysis of the transcriptome 7 days after M01ZH09 vaccination implicated transcriptional patterns associated with the cell cycle correlated significantly with humoral immunogenicity 28 days after vaccination. In contrast, significantly induced T and NK cell responses were associated with Ty21a vaccination, and integrative analysis indicated signatures reflecting amino acid metabolism with delayed onset of disease. Stimulation of PBMCs collected from participants prior to and following vaccination with the two vaccine strains in vitro confirmed the superior capacity of Ty21a to induce NK cells, validating gene expression results. These data provide insight into the effects of oral live attenuated typhoid vaccines on the human molecular immune response and underline the involvement of T cell response signatures with protection following challenge.
2017-10-12 | GSE100665 | GEO
Project description:To use proteomic analysis to qualitatively and quantitatively identify mammalian protein components of commercial veterinary vaccines against canine distemper, leptospirosis, borreliosis, and rabies. A total of 25 licensed veterinary vaccines (from 4 different manufacturers) against canine distemper and leptospirosis, borreliosis, and rabies (3 year and 1 year duration of immunity) were analyzed. Duplicate samples from a single lot vial of each vaccine were prepared by acetone precipitation and proteolysis with trypsin and lysC protease mix. Peptides mixtures (one microgram) were analyzed by LC-MS using Orbitrap Fusion Lumos mass spectrometer. LC-MS data were searched against a Bos taurus protein database using MaxQuant to identify and quantify mammalian proteins in the vaccines. Protein classification and network analysis was performed of iIdentified proteins were classified by function and network analysis to visualize interactions. The largest number of mammalian proteins was identified in 3-year rabies vaccines (median 243, range 184-339) and 1 year rabies vaccines (median 193, range 169-350). Borrelia and leptospirosis-distemper (L and D) vaccines had the lowest number of proteins. Rabies vaccines had the largest number of identified proteins in common (316), 33 were unique to 1 year and 44 in 3 year products. Borrelia and L and D vaccines had 16 and 22 uniquely identified proteins, respectively. The protein classifications were primarily as modulators of protein-binding activity, enzymes, transfer/carrier proteins, cytoskeletal proteins, defense or immunity proteins, calcium-binding proteins, and extracellular matrix proteins.
2022-12-06 | MSV000090844 | MassIVE
Project description:Rabies virus (RABV) is a highly neurotropic pathogen that typically leads to mortality of infected animals and humans. The precise etiology of rabies neuropathogenesis is unknown, though it is hypothesized to be due either to neuronal death or dysfunction. Our approach to study the survival and integrity of RABV-infected neurons was to infect Cre reporter mice with recombinant RABV expressing Cre-recombinase (RABV-Cre) to switch neurons constitutively expressing tdTomato (red) to expression of a Cre-inducible EGFP (green), permanently marking neurons that had been infected in vivo. We were able to isolate these previously infected neurons (“infected”) by flow cytometry and assayed their gene expression profiles compared to uninfected cells (“uninfected”) from the same mice.
2012-06-28 | GSE38975 | GEO
Project description:Rabies virus (RABV) is a highly neurotropic pathogen that typically leads to mortality of infected animals and humans. The precise etiology of rabies neuropathogenesis is unknown, though it is hypothesized to be due either to neuronal death or dysfunction. Our approach to study the survival and integrity of RABV-infected neurons was to infect Cre reporter mice with recombinant RABV expressing Cre-recombinase (RABV-Cre) to switch neurons constitutively expressing tdTomato (red) to expression of a Cre-inducible EGFP (green), permanently marking neurons that had been infected in vivo. We were able to isolate these previously infected neurons (“infected”) by flow cytometry and assayed their gene expression profiles compared to uninfected cells (“uninfected”) from the same mice.
2012-06-28 | GSE38970 | GEO
Project description:Although rabies incidence has fallen sharply over the past decades in Europe, the disease is still present in Eastern Europe. Oral rabies immunization of wild animal rabies has been shown to be the most effective method for the control and elimination of rabies. All rabies vaccines used in Europe are modified live virus vaccines based on the Street Alabama Dufferin (SAD) strain isolated from a naturally-infected dog in 1935. Because of the potential safety risk of a live virus which could revert to virulence, the genetic composition of three commercial attenuated live rabies vaccines was investigated in two independent laboratories using next genome sequencing. This study is the first one reporting on the diversity of variants in oral rabies vaccines as well as the presence of a mix of at least two different variants in all tested batches. The results demonstrate the need for vaccine producers to use new robust methodologies in the context of their routine vaccine quality controls prior to market release.
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Project description:Porcine epidemic diarrhea virus (PEDV) is a deadly coronavirus for neonatal piglets and no effective vaccines are available. Transcriptional regulatory sequences (TRSs) are critical in regulating coronavirus discontinuous transcription. Also, TRSs contribute to a high recombination rate of coronaviruses, leading to difficulty in developing safe live vaccines. We hypothesize that recoding the TRS core sequences (TRS-CS) of PEDV can make the recombination impossible between the engineered vaccine virus and field strains or wildtype viruses. We used an infectious clone-derived reporter PEDV, dORF3-EGFP, as the backbone to generate a remodeled TRS (RMT) mutant that carries the recoded leader and body TRS-CSs. The RMT and dORF3-EGFP showed comparable replication efficiency in Vero cells. However, the incompatibility between the rewired and wildtype TRS-CSs led to few EGFP in RMT-infected cells. Furthermore, RMT and dORF3-EGFP had a similar attenuated phenotype, replication efficiency, and protective immunogenicity in neonatal pigs. RNA sequencing analysis indicated that EGFP transcription directed by the heterogenous TRS-CSs was significantly reduced to an extremely low level. Meanwhile, recombinant viruses were not detected in Vero cells and in pigs that were co-infected with RMT and a PEDV S-INDEL strain, Iowa106. In vitro and in vivo passaging of the RMT did not result in reversion mutations in the rewired TRS-CSs, introduced gaps, and disrupted wildtype TRSs. In summary, the RMT mutant was resistant to recombination and genetically stable and can be further optimized (e.g., deletion of the EGFP) to serve as a platform to develop safe PEDV live attenuated vaccines.
2023-11-04 | GSE246991 | GEO
Project description:Analysis of patterns of nucleotide sequence diversity in wild-type rabies virus (RABV) genomes and in the SAD live attenuated oral vaccine lineage was used to test for the relaxation of purifying selection in the latter and provide evidence regarding the genomic regions where such relaxation of selection occurs. The wild-type sequences showed evidence of strong past and ongoing purifying selection both on nonsynonymous sites in coding regions and on non-coding regions, particularly the start, end and 5' UTR regions. SAD vaccine sequences showed a relaxation of purifying selection at nonsynonymous sites in coding regions, resulting a substantial number of amino acid sequence polymorphisms at sites that were invariant in the wild-type sequences. Moreover, SAD vaccine sequences showed high levels of mutation accumulation in the non-coding regions that were most conserved in the wild-type sequences. Understanding the biological effects of the unique mutations accumulated in the vaccine lineage is important because of their potential effects on antigenicity and effectiveness of the vaccine.
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Project description:It is well established that the pathogenicity and pathology of rabies virus (RABV) varies according to the variant, but the exact mechanism for this is still not completely known. In this study, the gene expression profile in brains of mice infected with virus isolated from a human case of dog rabies (V2) or vampire bat-acquired rabies (V3) were analyzed in experimental condition. In total, 138 array probes associated with 120 genes were differentially expressed between mice inoculated with V2 and the control mice at day 10 post-inoculation. A single probe corresponding to an unannotated gene was identified in V3 versus control mice. Gene ontology (GO) analysis revealed that all of the genes up-regulated in mice inoculated with V2 were involved in the biological process of immune defense against pathogens. Although both variants being considered pathogenic, inoculation in exactly same condition generated particular results regarding gene expression, more likely to differences in pathogenesis between dog and bat-related variants, already considered in other studies. This study was the first to demonstrate the global gene expression in experimental rabies infection due to V3 wild-type rabies virus, which reservoir is the vampire bat Desmodus rotundus, an important transmitter of rabies for humans and production animals in Latin America.
2022-02-28 | E-MTAB-11414 | biostudies-arrayexpress
Project description:Influenza B virus (FLUBV) is a major respiratory pathogen of humans. Seasonal influenza vaccines include either one or both FLUBV lineage strains, Victoria, and Yamagata. Vaccine mismatch occurs frequently, particularly in countries where vaccines contain only one of the lineages. We have previously described the safety and efficacy of modified live attenuated FLUBV vaccines based on either virus with rearranged genomes (FluB-RAM and FluB-RANS) or carrying a PB1 segment with a combination of temperature sensitive mutations and a C-terminal HA tag (FluB-att). We compared side by side the immunological responses in female and male DBA/2J mice vaccinated with either one of these vaccines and those with isogenic backgrounds encoding a chimeric HA segment carrying an N-terminal peptide encoding the IgA inducing peptide (IGIP). Recombinant viruses with or without the IGIP modification were genetically stable over multiple passages in eggs. In mice, introduction of IGIP improved attenuation of the vaccine candidates, particularly for the FluB-RAM/IGIP compared with the non-IGIP FluB-RAM counterpart. In a prime-boost regime, mice were completely protected against lethal challenge with a homologous FLUBV strain. Recombinant viruses induced antibodies against HA considered of protective value. Antibodies against NA and NP were readily detected. Compared to male mice and regardless of the vaccine used, female mice showed a clear trend towards enhanced humoral and cross-reactive IgG and IgA anti-HA responses as well as against NA and NP. The presence of IGIP in the vaccine resulted in an overall trend towards reduced anti-HA responses but enhanced anti-NA and anti-NP responses, particularly of the IgA isotype. Mucosal and serological responses two weeks after challenge showed similar trends with clear differences observed based on sex, vaccine backbone, and whether the vaccine carried the IGIP modification. These findings are significant for the development of universal influenza vaccines.
2023-05-01 | GSE205172 | GEO