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The controversial live attenuated virus vaccine Dengvaxia has boosted the pursuit of subunit vaccine approaches, and nonstructural protein 1 (NS1) has recently emerged as a promising candidate. However, we found that NS1 immunization or passive transfer of NS1 antibodies failed to confer protection in symptomatic dengue mouse models using two non\u2013mouse-adapted DENV2 strains that are highly virulent. Exogenous administration of purified NS1 also failed to worsen in vivo vascular leakage in sublethally infected mice. Neither method of NS1 immune neutralization changed the disease outcome of a chimeric strain expressing a vascular leak-potent NS1. Instead, virus chimerization involving the prME structural region indicated that these proteins play a critical role in driving in vivo fitness and virulence of the virus, through induction of key proinflammatory cytokines. This work highlights that the pathogenic role of NS1 is DENV strain dependent, which warrants reevaluation of NS1 as a universal dengue vaccine candidate.<\/jats:p>","DOI":"10.1084\/jem.20191548","type":"journal-article","created":{"date-parts":[[2020,5,14]],"date-time":"2020-05-14T02:21:32Z","timestamp":1589422892000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":33,"title":["Relative contribution of nonstructural protein 1 in dengue pathogenesis"],"prefix":"10.1084","volume":"217","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6775-2037","authenticated-orcid":true,"given":"Pei Xuan","family":"Lee","sequence":"first","affiliation":[{"name":"Infectious Disease Programme and Department of Microbiology & Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 1"},{"name":"Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore 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