Barut, Güliz TubaGüliz TubaBarut0000-0002-3863-0775Halwe, Nico JoelNico JoelHalweTaddeo, AdrianoAdrianoTaddeo0000-0003-3281-1548Kelly, Jenna NicoleJenna NicoleKellySchön, JacobJacobSchönEbert, NadineNadineEbertUlrich, LorenzLorenzUlrichDevisme, ChristelleChristelleDevismeSteiner, SilvioSilvioSteiner0000-0003-1999-1425Trüeb, Bettina SalomeBettina SalomeTrüebHoffmann, BerndBerndHoffmannBerenguer Veiga, Inês MargaridaInês MargaridaBerenguer Veiga0000-0001-8554-790XLeborgne, Nathan Georges FrançoisNathan Georges FrançoisLeborgneAguiar Moreira, EtoriEtoriAguiar MoreiraBreithaupt, AngeleAngeleBreithauptWylezich, ClaudiaClaudiaWylezichHöper, DirkDirkHöperWernike, KerstinKerstinWernikeGodel, AurélieAurélieGodelThomann, Lisa JaneLisa JaneThomannFlück, VeraVeraFlückStalder, HanspeterHanspeterStalderBrügger, MelanieMelanieBrügger0000-0003-3810-7682Oliveira Esteves Criblez, Blandina IsabelBlandina IsabelOliveira Esteves CriblezZumkehr, BeatriceBeatriceZumkehrBeilleau, Guillaume Francois FredericGuillaume Francois FredericBeilleauKratzel, AnnikaAnnikaKratzelSchmied, Kimberly ShadiaKimberly ShadiaSchmiedOchsenbein, SarahSarahOchsenbeinLang, Reto MarioReto MarioLangWider, ManonManonWiderMachahua Huamani, Carlos EstebanCarlos EstebanMachahua HuamaniDorn, PatrickPatrickDornMarti, ThomasThomasMarti0000-0003-3005-220XFunke-Chambour, ManuelaManuelaFunke-ChambourRauch, AndriAndriRauch0000-0001-5297-6062Widera, MarekMarekWideraCiesek, SandraSandraCiesekDijkman, RonaldRonaldDijkman0000-0003-0320-2743Hoffmann, DonataDonataHoffmannAlves, MarcoMarcoAlvesBenarafa, CharafCharafBenarafa0000-0002-2049-7769Beer, MartinMartinBeerThiel, Volker EarlVolker EarlThiel2024-10-112024-10-112022-10-07https://boris-portal.unibe.ch/handle/20.500.12422/87977Variant of concern (VOC) Omicron-BA.1 has achieved global predominance in early 2022. Therefore, surveillance and comprehensive characterization of Omicron-BA.1 in advanced primary cell culture systems and animal models are urgently needed. Here, we characterize Omicron-BA.1 and recombinant Omicron-BA.1 spike gene mutants in comparison with VOC Delta in well-differentiated primary human nasal and bronchial epithelial cells in vitro, followed by in vivo fitness characterization in hamsters, ferrets and hACE2-expressing mice, and immunized hACE2-mice. We demonstrate a spike-mediated enhancement of early replication of Omicron-BA.1 in nasal epithelial cultures, but limited replication in bronchial epithelial cultures. In hamsters, Delta shows dominance over Omicron-BA.1, and in ferrets Omicron-BA.1 infection is abortive. In hACE2-knock-in mice, Delta and a Delta spike clone also show dominance over Omicron-BA.1 and an Omicron-BA.1 spike clone, respectively. Interestingly, in naïve K18-hACE2 mice, we observe Delta spike-mediated increased replication and pathogenicity and Omicron-BA.1 spike-mediated reduced replication and pathogenicity, suggesting that the spike gene is a major determinant of replication and pathogenicity. Finally, the Omicron-BA.1 spike clone is less well-controlled by mRNA-vaccination in K18-hACE2-mice and becomes more competitive compared to the progenitor and Delta spike clones, suggesting that spike gene-mediated immune evasion is another important factor that led to Omicron-BA.1 dominance.en600 - Technology::630 - Agriculture500 - Science::570 - Life sciences; biology600 - Technology::610 - Medicine & healtharticle10.48350/1736123620733410.1038/s41467-022-33632-y