{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T19:17:32Z","timestamp":1787167052884,"version":"build-2736575974"},"reference-count":45,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T00:00:00Z","timestamp":1753920000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["OD029608"],"award-info":[{"award-number":["OD029608"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Vaccines have done more to improve the health of humankind over the past century than almost any other technology. Among vaccines, the live-attenuated yellow fever (YF) vaccine (17D) is highly effective, providing long-lasting immunity against yellow fever virus (YFV) infection with a single dose. Developed in the 1930s through extensive serial passage of the virulent YFV-Asibi strain through mouse and chicken embryonic tissue, 17D acquired several mutations that render it attenuated in humans and non-human primates. Over the past century, 17D has become a widely studied immunogen and has also been developed into a vaccine platform for other pathogens. Despite this, most studies of 17D have focused exclusively on the host, without clearly defining the virus-intrinsic features of attenuation. Consequently, the genetic determinants of 17D attenuation remain unknown and are assumed to be multigenic. Here, we leverage the hamster host, which recapitulates many important features of human YF disease, to understand the genetic basis of 17D attenuation. We developed a YFV reverse genetics system and generated hamster-adapted Asibi\/17D chimeric viruses, discovering that viruses containing 17D-derived mutations in the viral gene NS2B were significantly attenuated in the hamster. Further analysis revealed that the two non-synonymous mutations in NS2B that distinguish 17D from Asibi, I37L and I109L, act cooperatively to mediate attenuation, with both mutations required to fully prevent key features of YF disease including liver injury and coagulopathy. These findings establish NS2B as an important and unexpected determinant of YFV-17D attenuation in vivo. In addition to the implications of these findings for improving the efficacy and safety of the 17D vaccine platform, this discovery also provides a new direction for understanding more generalized principles and mechanisms of durable vaccine-induced immunity.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013373","type":"journal-article","created":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T17:43:16Z","timestamp":1753983796000},"page":"e1013373","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Two mutations in NS2B are responsible for attenuation of the yellow fever virus (YFV) vaccine strain 17D"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0190-500X","authenticated-orcid":true,"given":"Xueer","family":"Qiu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6560-9680","authenticated-orcid":true,"given":"Adam L.","family":"Bailey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,7,31]]},"reference":[{"key":"ppat.1013373.ref001","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.64670","article-title":"The global burden of yellow fever","volume":"10","author":"KA Gaythorpe","year":"2021","journal-title":"Elife"},{"issue":"5","key":"ppat.1013373.ref002","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pmed.1001638","article-title":"Yellow fever in Africa: estimating the burden of disease and impact of mass vaccination from outbreak and serological 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