ArticlePLoS pathogens2015
Identification of the Mechanisms Causing Reversion to Virulence in an Attenuated SARS-CoV for the Design of a Genetically Stable Vaccine.
Article in PLoS pathogens, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 109 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
109 citing papers in PubMed, 1 synthesis or guideline pooled it, 172 citations in OpenAlex.
- The Reassessed Potential of SARS-CoV-2 Attenuation for COVID-19 Vaccine Development-A Systematic Review.Viruses · 2022Pooled it
- Reverse genetics strategies for coronaviruses: platform construction and applications in vaccine development.Virus genes · 2026Review
- Molecular and phenotypic characterization of SG9R-likeFrontiers in veterinary science · 2026Article
- Characterization of Gene Expression Suppression by Bovine Coronavirus Non-Structural Protein 1.Viruses · 2025Article
- Development of viral infectious clones and their applications based on yeast and bacterial artificial chromosome platforms.Molecular biomedicine · 2025Review
- SIRT2 suppresses aging-associated cGAS activation and protects aged mice from severe COVID-19.Cell reports · 2025Article
- Regulation of protein thermal stability and its potential application in the development of thermo-attenuated vaccines.Engineering microbiology · 2024Article
- PDZ2-conjugated-PLGA nanoparticles are tiny heroes in the battle against SARS-CoV-2.Scientific reports · 2024Article
- Human coronavirus NL63 nsp1 induces degradation of RNA polymerase II to inhibit host protein synthesis.PLoS pathogens · 2024Article
- Inhibition of mRNA nuclear export promotes SARS-CoV-2 pathogenesis.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Swine acute diarrhea syndrome coronavirus Nsp1 suppresses IFN-λ1 production by degrading IRF1 via ubiquitin-proteasome pathway.Veterinary research · 2024Article
- Canine distemper virus infection of vaccinal origin in a 14-week-old puppy.Journal of veterinary diagnostic investigation : official publication of the American Association of Veterinary Laboratory Diagnosticians, Inc · 2024Article
- Multiple Lines of Evidence Support 199 SARS-CoV-2 Positively Selected Amino Acid Sites.International journal of molecular sciences · 2024Article
- A short sequence in the tail of SARS-CoV-2 envelope protein controls accessibility of its PDZ-binding motif to the cytoplasm.The Journal of biological chemistry · 2024Article
- Antiviral responses versus virus-induced cellular shutoff: a game of thrones between influenza A virus NS1 and SARS-CoV-2 Nsp1.Frontiers in cellular and infection microbiology · 2024Review
- Vaccine skepticism and vaccine development stages; inoculation from "cowpox" lesion to the current mRNA vaccine of COVID-19: review.Therapeutic advances in vaccines and immunotherapy · 2024Review
- An Evolutionarily Conserved Strategy for Ribosome Binding and Host Translation Inhibition by β-coronavirus Non-structural Protein 1.Journal of molecular biology · 2023Article
- Deletion of a 7-amino-acid region in the porcine epidemic diarrhea virus envelope protein induces higher type I and III interferon responses and results in attenuationJournal of virology · 2023Article
- An evolutionarily conserved strategy for ribosome binding and inhibition by β-coronavirus non-structural protein 1.bioRxiv : the preprint server for biology · 2023Article
- Different electrostatic forces drive the binding kinetics of SARS-CoV, SARS-CoV-2 and MERS-CoV Envelope proteins with the PDZ2 domain of ZO1.Scientific reports · 2023Article
49 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
A SARS-CoV lacking the full-length E gene (SARS-CoV-∆E) was attenuated and an effective vaccine. Here, we show that this mutant virus regained fitness after serial passages in cell culture or in vivo, resulting in the partial duplication of the membrane gene or in the insertion of a new sequence in gene 8a, respectively. The chimeric proteins generated in cell culture increased virus fitness in vitro but remained attenuated in mice. In contrast, during SARS-CoV-∆E passage in mice, the virus incorporated a mutated variant of 8a protein, resulting in reversion to a virulent phenotype. When the full-length E protein was deleted or its PDZ-binding motif (PBM) was mutated, the revertant viruses either incorporated a novel chimeric protein with a PBM or restored the sequence of the PBM on the E protein, respectively. Similarly, after passage in mice, SARS-CoV-∆E protein 8a mutated, to now encode a PBM, and also regained virulence. These data indicated that the virus requires a PBM on a transmembrane protein to compensate for removal of this motif from the E protein. To increase the genetic stability of the vaccine candidate, we introduced small attenuating deletions in E gene that did not affect the endogenous PBM, preventing the incorporation of novel chimeric proteins in the virus genome. In addition, to increase vaccine biosafety, we introduced additional attenuating mutations into the nsp1 protein. Deletions in the carboxy-terminal region of nsp1 protein led to higher host interferon responses and virus attenuation. Recombinant viruses including attenuating mutations in E and nsp1 genes maintained their attenuation after passage in vitro and in vivo. Further, these viruses fully protected mice against challenge with the lethal parental virus, and are therefore safe and stable vaccine candidates for protection against SARS-CoV.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.