Similar Datasets
Project description:Amino acid changes in two viral proteins drive attenuation of the yellow fever 17D vaccine
| PRJNA1151729 | ENA
Project description:Yellow fever virus, a prototypical member of the Flaviviridae family, is a small single-stranded, positive sense enveloped RNA virus causing viscerotropic, frequently fatal disease. Serial passaging of the virulent YFV Asibi strain in the 1930s yielded the YFV17D strain which remains one of the most effective vaccines ever developed. Remarkably, YFV17D and the virulent parental genome differ only by 68 nucleotides leading to 32 amino acid changes. However, it remains largely unknown which of these sequence differences are responsible for attenuation. Here, we demonstrate that while synonymous mutations are highly conserved across pathogenic YFVs they do not contribute to the characteristic host responses elicited by 17D or virulent viruses. Using a highly modular combinatorial genetic approach we identified key genetic elements in the YFV envelope and non-structural 2A (NS2A) proteins that govern the virus’ ability to spread and suppress host responses.. Introducing these mutations into infectious clones of other YFV genomes results in viral attenuation in vitro and in vivo. Collectively, our results define the genetic basis for YFV17D attenuation and highlight a general approach for creating live-attenuated vaccines for other pathogenic viruses.
2025-05-13 | GSE275507 | GEO
Project description:Yellow fever virus, a prototypical member of the Flaviviridae family, is a small single-stranded, positive sense enveloped RNA virus causing viscerotropic, frequently fatal disease. Serial passaging of the virulent YFV Asibi strain in the 1930s yielded the YFV17D strain which remains one of the most effective vaccines ever developed. Remarkably, YFV17D and the virulent parental genome differ only by 68 nucleotides leading to 32 amino acid changes. However, it remains largely unknown which of these sequence differences are responsible for attenuation. Here, we demonstrate that while synonymous mutations are highly conserved across pathogenic YFVs they do not contribute to the characteristic host responses elicited by 17D or virulent viruses. Using a highly modular combinatorial genetic approach we identified key genetic elements in the YFV envelope and non-structural 2A (NS2A) proteins that govern the virus’ ability to spread and suppress host responses.. Introducing these mutations into infectious clones of other YFV genomes results in viral attenuation in vitro and in vivo. Collectively, our results define the genetic basis for YFV17D attenuation and highlight a general approach for creating live-attenuated vaccines for other pathogenic viruses.
2025-05-13 | GSE275593 | GEO
Project description:Yellow fever virus, a prototypical member of the Flaviviridae family, is a small single-stranded, positive sense enveloped RNA virus causing viscerotropic, frequently fatal disease. Serial passaging of the virulent YFV Asibi strain in the 1930s yielded the YFV17D strain which remains one of the most effective vaccines ever developed. Remarkably, YFV17D and the virulent parental genome differ only by 68 nucleotides leading to 32 amino acid changes. However, it remains largely unknown which of these sequence differences are responsible for attenuation. Here, we demonstrate that while synonymous mutations are highly conserved across pathogenic YFVs they do not contribute to the characteristic host responses elicited by 17D or virulent viruses. Using a highly modular combinatorial genetic approach we identified key genetic elements in the YFV envelope and non-structural 2A (NS2A) proteins that govern the virus’ ability to spread and suppress host responses.. Introducing these mutations into infectious clones of other YFV genomes results in viral attenuation in vitro and in vivo. Collectively, our results define the genetic basis for YFV17D attenuation and highlight a general approach for creating live-attenuated vaccines for other pathogenic viruses.
2025-05-13 | GSE275508 | GEO
Project description:Correlates of immune mediated protection to most viral and cancer vaccines are still unknown. This impedes the development of novel vaccines to incurable diseases such as HIV and cancer. In this study, we have used functional genomics and polychromatic flow cytometry to define the signature of the immune response to the yellow fever (YF) vaccine 17D (YF17D) in a cohort of forty volunteers followed for up to one year after vaccination. We show that immunization with YF17D leads to an integrated immune response that includes several effector arms of innate immunity including complement, the inflammasome and interferons, as well as adaptive immunity as shown by an early T cell response followed by a brisk and variable B cell response. Development of these responses is preceded, as demonstrated in three independent vaccination trials and in a novel in vitro system of primary immune responses (Modular IMmune In vitro Construct (MIMIC) system), by the coordinated up-regulation of transcripts for specific transcription factors including STAT1, IRF7 and ETS2 that are upstream of the different effector arms of the immune response. These results clearly show that the immune response to a strong vaccine is preceded by coordinated induction of masters transcription factors, that lead to the development of a broad, polyfunctional and persistent immune response that integrates all effector cells of the immune system.
2008-12-01 | GSE13699 | GEO
Project description:The molecular basis of attenuation for live-attenuated vaccines is poorly understood. The yellow fever (YF) 17D vaccine virus was derived from the wild-type, parental strain Asibi virus by serial passage in chicken tissue and has proven to be a very safe and efficacious vaccine. We have previously shown that wild-type Asibi is a typical RNA virus with high genetic diversity, while the 17D vaccine virus has very little genetic diversity. To investigate this further, we treated Asibi and 17D viruses with ribavirin, a GTP analog with strong antiviral activity that increases levels of mutations in the viral genome. As expected, ribavirin treatment introduced mutations into the Asibi virus genome at a very high frequency and decreased viral infectivity while, in contrast, the 17D vaccine virus was resistant to ribavirin, as treatment with the antiviral introduced very few mutations into the genome, and viral infectivity was not lost. The results were confirmed for another YF wild-type parental and vaccine pair, a wild-type French viscerotropic virus and French neurotropic vaccine. Using recombinant Asibi and 17D viruses, ribavirin sensitivity was located to viral nonstructural genes. Thus, two live-attenuated YF vaccine viruses are genetically stable even under intense mutagenic pressure, suggesting that attenuation of live-attenuated YF vaccines is due, at least in part, to fidelity of the replication complex resulting in high genetic stability.IMPORTANCE Live-attenuated viral vaccines are highly safe and efficacious but represent complex and often multigenic attenuation mechanisms. Most of these vaccines have been generated empirically by serial passaging of a wild-type (WT) virus in cell culture. One of the safest and most effective live-attenuated vaccines is yellow fever (YF) virus strain 17D, which has been used for over 80 years to control YF disease. The availability of the WT parental strain of 17D, Asibi virus, and large quantities of clinical data showing the effectiveness of the 17D vaccine make this WT parent/vaccine pair an excellent model for investigating RNA virus attenuation. Here, we investigate a mechanism of 17D attenuation and show that the vaccine virus is resistant to the antiviral compound ribavirin. The findings suggest that attenuation is in part due to a low probability of reversion or mutation of the vaccine virus genome to WT, thus maintaining a stable genotype despite external pressures.
| S-EPMC6805994 | biostudies-literature
Project description:To better understand how innate immunity to vaccination can lead to lasting protective immunity, we have used systemic bioinformatics approaches to define the signature of the yellow fever specific immune response in a cohort of 21 volunteers.
2017-06-25 | GSE82152 | GEO
Project description:The yellow fever virus 17D (YFV-17D) live attenuated vaccine is considered one of the successful vaccines ever generated associated with high antiviral immunity, yet the signaling mechanisms that drive the response in infected cells are not understood. Here, we provide a molecular understanding of how metabolic stress and innate immune responses are linked to drive type I IFN expression in response to YFV-17D infection. Comparison of YFV-17D replication with its parental virus, YFV-Asibi, and a related dengue virus revealed that IFN expression requires RIG-I-like Receptor signaling through MAVS, as expected. However, YFV-17D uniquely induces mitochondrial respiration and major metabolic perturbations, including hyperactivation of electron transport to fuel ATP synthase. Mitochondrial hyperactivity generates reactive oxygen species (mROS) and peroxynitrite, blocking of which abrogated IFN expression in non-immune cells without reducing YFV-17D replication. Scavenging ROS in YFV-17D-infected human dendritic cells increased cell viability yet globally prevented expression of IFN signaling pathways. Thus, adaptation of YFV-17D for high growth uniquely imparts mitochondrial hyperactivity generating mROS and peroxynitrite as the critical messengers that convert a blunted IFN response into maximal activation of innate immunity essential for vaccine effectiveness.
| S-EPMC11398391 | biostudies-literature
Project description:Yellow fever virus (YFV) is a mosquito-borne flavivirus that causes over 109,000 severe infections and over 51,000 deaths annually in endemic areas of sub-Saharan Africa and tropical South America. The virus has a transmission cycle involving mosquitoes and humans or non-human primates (NHPs) as the vertebrate hosts. Although yellow fever (YF) is prevented by a live attenuated vaccine (strain 17D), recent epidemics in Angola, the Democratic Republic of the Congo (DRC), and Brazil put great pressure on vaccine stockpiles. This resulted in the World Health Organization (WHO) and Pan American Health Organization (PAHO) implementing, on an emergency basis only, off-label dose-sparing techniques and policies during 2016-2018 to protect as many people in DRC and Brazil as possible from disease during unexpected large outbreaks of YF. Subsequently non-inferiority studies involving full doses compared to fractional doses indicated promising results, leading some policy-makers and scientists to consider utilizing YF vaccine fractional doses in non-emergency scenarios. Although the additional data on the immunogenicity and safety of fractional doses are promising, there are several questions and considerations that remain regarding the use of fractional doses, including differences in the initial antibody kinetics, differences in the immune response in certain populations, and durability of the immune response to fractional doses compared to full doses. Until the remaining knowledge gaps are addressed, full doses instead of fractional doses should continue to be used unless there are insufficient doses of the vaccine available to control outbreaks of YF.
| S-EPMC10640814 | biostudies-literature
Project description:The yellow fever (YF) 17D vaccine is a live attenuated virus. Three-dimensional (3D) homology modeling of the E protein structure from YF 17D virus and its comparison with that from tick-borne encephalitis virus revealed that it is possible to accommodate inserts of different sizes and amino acid compositions in the flavivirus E protein fg loop. This is consistent with the 3D structures of both the dimeric and trimeric forms in which the fg loop lies exposed to solvents. We demonstrate here that YF 17D viruses bearing foreign humoral (17D/8) and T-cell (17D/13) epitopes, which vary in sequence and length, displayed growth restriction. It is hypothesized that interference with the dimer-trimer transition and with the formation of a ring of such trimers in order to allow fusion compromises the capability of the E protein to induce fusion of viral and endosomal membranes, and a slower rate of fusion may delay the extent of virus production. This would account for the lower levels of replication in cultured cells and of viremia in monkeys, as well as for the more attenuated phenotype of the recombinant viruses in monkeys. Testing of both recombinant viruses (17D/8 and 17D/13) for monkey neurovirulence also suggests that insertion at the 17D E protein fg loop does not compromise the attenuated phenotype of YF 17D virus, further confirming the potential use of this site for the development of new live attenuated 17D virus-based vaccines.
| S-EPMC1143750 | biostudies-literature