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Developing vaccines that induce immunity against multiple variants and can be rapidly adapted is key to address future threats. In this study, we assessed the immunogenicity and protective efficacy of a non-replicative antibiotic resistance-free DNA vaccine (pPAL) expressing the stabilized spike proteins from the Wuhan and Omicron variants, as well as the conserved nucleoprotein. K18-hACE2 mice received a prime-boost-boost vaccination with three pPAL plasmids encoding the Wuhan spike, Omicron spike, or Wuhan nucleoprotein. The vaccine induced antibody responses against recombinant receptor-binding domains from both spike protein variants and promoted a Th1 bias immune response, as indicated by increased IgG2a\/c levels compared to IgG1. Neutralization antibodies were generated against both SARS-CoV-2 variants. Furthermore, vaccinated mice were protected from a lethal challenge with the Wuhan isolate, showing reduced viral replication in target organs. This study presents a DNA vaccine platform capable of expressing multiple SARS-CoV-2 antigens and inducing robust immunity against different viral variants. This approach offers a promising and adaptable strategy for future SARS-CoV-2 vaccination efforts.<\/jats:p>","DOI":"10.1038\/s41598-025-23919-7","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T15:43:55Z","timestamp":1763135035000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Bivalent SARS-CoV-2 spike immunization with non-replicative antibiotic resistance-free DNA vaccine induces immunity to multiple virus variants"],"prefix":"10.1038","volume":"15","author":[{"given":"Jaime","family":"Larraga","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Nogales-Altozano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laro","family":"Gomez-Marcos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Ruiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco Javier","family":"Loayza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Rivera-Rodr\u00edguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9s","family":"Louloudes-L\u00e1zaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana B.","family":"Carlon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Rodr\u00edguez-Mart\u00edn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Alonso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ver\u00f3nica","family":"Mart\u00edn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro J.","family":"Alcolea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 M.","family":"Rojas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicente","family":"Larraga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noem\u00ed","family":"Sevilla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,14]]},"reference":[{"key":"23919_CR1","doi-asserted-by":"publisher","unstructured":"Deb, P. et al. 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