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We developed several vaccinia virus (VACV) vaccine candidates for ZIKV based on replication-inducible VACVs (vINDs) expressing ZIKV pre-membrane (prM) and envelope (E) proteins (vIND-ZIKVs). These vIND-ZIKVs contain elements of the <jats:italic>tetracycline<\/jats:italic> operon and replicate only in the presence of tetracyclines. The pool of vaccine candidates was narrowed to one vIND-ZIKV containing a novel mutation in the signal peptide of prM that led to higher expression and secretion of E and production of virus-like particles, which was then tested for safety, immunogenicity, and efficacy in mice. vIND-ZIKV grows to high titers in vitro in the presence of doxycycline (DOX) but is replication-defective in vivo in the absence of DOX, causing no weight loss in mice. C57BL\/6 mice vaccinated once with vIND-ZIKV in the absence of DOX (as a replication-defective virus) developed robust levels of E-peptide-specific IFN-\u03b3-secreting splenocytes and anti-E IgG titers, with modest levels of serum-neutralizing antibodies. Vaccinated mice treated with anti-IFNAR1 antibody were completely protected from ZIKV viremia post-challenge after a single dose of vIND-ZIKV. Furthermore, mice with prior immunity to VACV developed moderate anti-E IgG titers that increased after booster vaccination, and were protected from viremia only after two vaccinations with vIND-ZIKV.<\/jats:p>","DOI":"10.1038\/s41598-021-85951-7","type":"journal-article","created":{"date-parts":[[2021,3,22]],"date-time":"2021-03-22T11:03:43Z","timestamp":1616411023000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Single dose of a replication-defective vaccinia virus expressing Zika virus-like particles is protective in mice"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9141-3246","authenticated-orcid":false,"given":"Brittany","family":"Jasperse","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7295-7547","authenticated-orcid":false,"given":"Caitlin M.","family":"O\u2019Connell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuxiang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paulo H.","family":"Verardi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,3,22]]},"reference":[{"key":"85951_CR1","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1146\/annurev.mi.44.100190.003245","volume":"44","author":"TJ Chambers","year":"1990","unstructured":"Chambers, T. 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