@article{203451,
  keywords = {highlighted},
  author = {Jiayu Zhang and Elizabeth Chavez and Melina Winkler and Jianche Liu and Sebastian Carver and Aaron Lin and Abhishek Biswas and Tomokazu Tamura and Anna Tseng and Danyang Wang and Aaron Benhamou and Aoife Connell and Mao Matsuo and Jack Norton and Devin Kenney and Britt Adamson and Ralph Kleiner and Benjamin Burwitz and Nicholas Crossland and Florian Douam and Alexander Ploss},
  title = {Amino acid changes in two viral proteins drive attenuation of the yellow fever 17D vaccine},
  abstract = {<p>The live-attenuated yellow fever 17D vaccine strain differs genetically only minimally from its virulent parent. However, it remains unclear which sequence differences lead to virulence or attenuation. Here we demonstrate, using SHAPE-MaP, that these mutations do not induce global RNA structure changes and show that protein sequence mutations are mostly responsible for the phenotypic differences between 17D and virulent YFV. Using a highly modular, combinatorial genetic approach, we identified key mutations in the envelope (E) and non-structural 2A (NS2A) proteins that increase 17D{\textquoteright}s ability to spread and enhance host antiviral responses. Introducing these mutations into infectious clones of virulent YFV genomes results in viral attenuation in vitro and in two mouse models. Collectively, our results define the genetic basis for 17D attenuation and highlight a potentially general approach for creating live-attenuated vaccines by introducing mutations resulting in similar phenotypic changes in other pathogenic viruses.</p>},
  year = {2025},
  journal = {Nature Microbiology},
  volume = {10},
  pages = {1902-1917},
  month = {07/2025},
  issn = {2058-5276},
  doi = {10.1038/s41564-025-02047-y},
  language = {eng},
}