Schön, JacobJacobSchönBarut, Güliz TubaGüliz TubaBarut0000-0002-3863-0775Trüeb, Bettina SalomeBettina SalomeTrüebHalwe, Nico JoelNico JoelHalweBerenguer Veiga, Inês MargaridaInês MargaridaBerenguer Veiga0000-0001-8554-790XKratzel, AnnikaAnnikaKratzelUlrich, LorenzLorenzUlrichKelly, Jenna NicoleJenna NicoleKellyBrügger, MelanieMelanieBrügger0000-0003-3810-7682Wylezich, ClaudiaClaudiaWylezichTaddeo, AdrianoAdrianoTaddeo0000-0003-3281-1548Aguiar Moreira, EtoriEtoriAguiar MoreiraTúrós, Péter DemeterPéter DemeterTúrósGrau Roma, LlorençLlorençGrau RomaAhrens, Ann KathrinAnn KathrinAhrensSchlottau, KoreKoreSchlottauBritzke, TobiasTobiasBritzkeBreithaupt, AngeleAngeleBreithauptCorleis, BjörnBjörnCorleisKochmann, JanaJanaKochmannOliveira Esteves Criblez, Blandina IsabelBlandina IsabelOliveira Esteves CriblezAlmeida, LeaLeaAlmeidaThomann, Lisa JaneLisa JaneThomannDevisme, ChristelleChristelleDevismeStalder, HanspeterHanspeterStalderSteiner, SilvioSilvioSteiner0000-0003-1999-1425Ochsenbein, SarahSarahOchsenbeinSchmied, Kimberly ShadiaKimberly ShadiaSchmiedLabroussaa, FabienFabienLabroussaaJores, JörgJörgJores0000-0003-3790-5746V'kovski, PhilipPhilipV'kovskiCmiljanovic, VladimirVladimirCmiljanovicAlves, MarcoMarcoAlvesBenarafa, CharafCharafBenarafa0000-0002-2049-7769Ebert, NadineNadineEbertHoffmann, DonataDonataHoffmannBeer, MartinMartinBeerThiel, Volker EarlVolker EarlThiel2024-10-262024-10-262024-08https://boris-portal.unibe.ch/handle/20.500.12422/179140Approved vaccines are effective against severe COVID-19, but broader immunity is needed against new variants and transmission. Therefore, we developed genome-modified live-attenuated vaccines (LAV) by recoding the SARS-CoV-2 genome, including 'one-to-stop' (OTS) codons, disabling Nsp1 translational repression and removing ORF6, 7ab and 8 to boost host immune responses, as well as the spike polybasic cleavage site to optimize the safety profile. The resulting OTS-modified SARS-CoV-2 LAVs, designated as OTS-206 and OTS-228, are genetically stable and can be intranasally administered, while being adjustable and sustainable regarding the level of attenuation. OTS-228 exhibits an optimal safety profile in preclinical animal models, with no side effects or detectable transmission. A single-dose vaccination induces a sterilizing immunity in vivo against homologous WT SARS-CoV-2 challenge infection and a broad protection against Omicron BA.2, BA.5 and XBB.1.5, with reduced transmission. Finally, this promising LAV approach could be applicable to other emerging viruses.en600 - Technology::630 - Agriculture600 - Technology::610 - Medicine & healtharticle10.48350/1989943899751810.1038/s41564-024-01755-1