doi:10.1038/s41541-025-01201-1engMata, ElenaBroset, EstherMatute, CarlosStoian, AndreiAdame, SusanaAlejo, TeresaLópez, AlexandreAndrés, BeatrizHeredero, Juande Miguel, DiegoGiménez-Warren, JavierLampaya, VerónicaCasabona, DiegoCalvo, AlbaQuincoces, GemaPeñuelas, IvánGamazo, CarlosUranga, IratxePeña, NatachaArias, MaykelPardo, JuliánMoreno, BernardinoBadiola, JuanMartínez-Oliván, JuanPérez-Herrán, EstherPreserved efficacy of lyophilized SARS-CoV-2 mRNA vaccine incorporating novel ionizable lipids after one year at 25 °CART-2025-144878mRNA vaccines have shown great efficacy against SARS-CoV-2, yet challenges remain in optimizing vaccine components to achieve enhanced immune response and vaccine stability. In this study, we developed CPVax-CoV, a new lyophilized mRNA vaccine that features novel thiolactone-based ionizable lipids and newly designed untranslated regions (UTRs) for enhanced expression. Incorporation of these optimized components into our vaccine candidate CPVax-CoV significantly improved immune responses in mice compared to commercially available mRNA vaccines. Moreover, lyophilized CPVax-CoV has proven to be thermostable, maintaining its biological activity for up to one year at 4 °C and 25 °C after lyophilization, overcoming the cold-chain limitations of current mRNA vaccines. This vaccine demonstrates protective efficacy against ancestral SARS-CoV-2 and the Omicron XBB variant, offering a scalable solution for global distribution and pandemic preparedness. These findings underscore the potential of this platform for future next-generation mRNA vaccine development.2025http://zaguan.unizar.es/record/16229910.1038/s41541-025-01201-1http://zaguan.unizar.es/record/162299oai:zaguan.unizar.es:162299info:eu-repo/grantAgreement/ES/AEI/PID2020-113963RB-I00info:eu-repo/grantAgreement/ES/DGA/B29-20Rinfo:eu-repo/grantAgreement/ES/ISCIII/CB21-13-00087info:eu-repo/grantAgreement/ES/ISCIII/COV20-00308npj Vaccines 10, 135 (2025), 19by-nc-ndhttps://creativecommons.org/licenses/by-nc-nd/4.0/deed.esinfo:eu-repo/semantics/openAccess