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In this study, we evaluated a non-propagating vesicular stomatitis virus (VSV) vector encoding HA and NA antigens of A\/Hamburg\/4\/2009 (H1N1) in a porcine animal model to assess induction of cross-reactive immunity. A single intramuscular immunization elicited high titers of H1N1-neutralizing antibodies and potent N1-sialidase inhibition. A boost with the same single-cycle VSV-vectored H1\/N1 antigens or with a live-attenuated influenza vaccine (LAIV) enhanced inhibitory activity against the antigen-drifted A\/Victoria\/2570\/2019 (H1N1) strain. Vaccination induced N1-specific antibodies that also inhibited avian N1 sialidase and suppressed replication of a bovine-derived H5N1 virus in vitro. Following nasal challenge with a 6:2 reassortant virus encoding drifted HA and NA antigens, vaccinated pigs showed no detectable virus shedding, whereas control animals shed infectious virus. Homologous prime-boost vaccination with the VSV-vectored H1\/N1 antigens conferred protection comparable to the heterologous VSV\/LAIV regimen in the upper respiratory tract. These findings demonstrate that a single-cycle VSV vector encoding both HA and NA induces cross-protective immunity against antigen-drifted influenza viruses, reduces the risk of vaccine mismatch, and may limit infection by zoonotic H5N1 viruses.<\/jats:p>","DOI":"10.1038\/s41541-026-01428-6","type":"journal-article","created":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T04:05:12Z","timestamp":1774670712000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Non-propagating RNA virus-vectored HA\/NA vaccine prevents shedding of antigen-drifted H1N1 influenza virus in pigs"],"prefix":"10.1038","volume":"11","author":[{"given":"Obdulio","family":"Garc\u00eda-Nicol\u00e1s","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Butticaz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robin","family":"Avanthay","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicolas","family":"Ruggli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Artur","family":"Summerfield","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gert","family":"Zimmer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,3,28]]},"reference":[{"key":"1428_CR1","doi-asserted-by":"publisher","first-page":"2694","DOI":"10.1016\/j.jmb.2017.06.015","volume":"429","author":"NC Wu","year":"2017","unstructured":"Wu, N. 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WO2025133030A1), indicating A.S., G.Z., and R.A. as inventors. The invention relates to the heterologous prime-boost vaccine strategy also described in this work. The other authors do not have any competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"104"}}