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The emergence of SARS-CoV2 variants of concern (VoCs) and evidence that existing vaccines that were designed to protect from the original strains of SARS-CoV-2 may have reduced potency for protection from infection against these VoC is driving continued development of second-generation vaccines that can protect against multiple VoC. In this report, we evaluated an alphavirus-based replicating RNA vaccine expressing Spike proteins from the original SARS-CoV-2 Alpha strain and recent VoCs delivered in vivo via a lipid inorganic nanoparticle. Vaccination of both mice and Syrian Golden hamsters showed that vaccination induced potent neutralizing titers against each homologous VoC but reduced neutralization against heterologous challenges. Vaccinated hamsters challenged with homologous SARS-CoV2 variants exhibited complete protection from infection. In addition, vaccinated hamsters challenged with heterologous SARS-CoV-2 variants exhibited significantly reduced shedding of infectious virus. Our data demonstrate that this vaccine platform can be updated to target emergent VoCs, elicits significant protective immunity against SARS-CoV2 variants and supports continued development of this platform.<\/jats:p>","DOI":"10.7554\/elife.75537","type":"journal-article","created":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T06:00:19Z","timestamp":1645509619000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.75537","source":"Crossref","is-referenced-by-count":35,"title":["SARS-CoV2 variant-specific replicating RNA vaccines protect from disease following challenge with heterologous variants of concern"],"prefix":"10.7554","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8233-8176","authenticated-orcid":true,"given":"David W","family":"Hawman","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and 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