The spike gene is a major determinant for the SARS-CoV-2 Omicron-BA.1 phenotype

Barut, Tuba; Halwe, Nico; Taddeo, Adriano; Kelly, Jenna N.; Schön, Jacob; Ebert, Nadine; Ulrich, Lorenz; Devisme, Christelle; Steiner, Silvio; Trüeb, Bettina Salome; Hoffmann, Bernd; Veiga, Inês Berenguer; Leborgne, Nathan Georges François; Moreira, Etori Aguiar; Breithaupt, Angele; Wylezich, Claudia; Höper, Dirk; Wernike, Kerstin; Godel, Aurélie; Thomann, Lisa; Flück, Vera; Stalder, Hanspeter; Brügger, Melanie; Esteves, Blandina I. Oliveira; Zumkehr, Beatrice; Beilleau, Guillaume; Kratzel, Annika; Schmied, Kimberly; Ochsenbein, Sarah; Lang, Reto M.; Wider, Manon; Machahua, Carlos; Dorn, Patrick; Marti, Thomas M.; Funke-Chambour, Manuela; Rauch, Andri; Widera, Marek; Ciesek, Sandra; Dijkman, Ronald; Hoffmann, Donata; Alves, Marco P.; Benarafa, Charaf; Beer, Martin; Thiel, Volker

Variant of concern (VOC) Omicron-BA1 has achieved global predominance in early 2022. Therefore, surveillance and comprehensive characterization of Omicron-BA.1 in advanced primary cell culture systems and multiple animal models is urgently needed. Here, we characterized 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 naïve hamsters, ferrets and hACE2-expressing mice, and in 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 Syrian hamsters, Delta showed dominance over Omicron-BA.1 and in ferrets, Omicron-BA.1 infection was abortive. In mice expressing the authentic hACE2-receptor, Delta and a Delta spike clone also showed dominance over Omicron-BA.1 and an Omicron-BA.1 spike clone, respectively. Interestingly, in naïve K18-hACE2 mice, we observed 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 both Delta and Omicron-BA.1 replication and pathogenicity. Finally, the Omicron-BA.1 spike clone was less well controlled by mRNA-vaccination in K18-hACE2-mice and became 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.



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