TY - JOUR T1 - The spike gene is a major determinant for the SARS-CoV-2 Omicron-BA.1 phenotype JF - bioRxiv DO - 10.1101/2022.04.28.489537 SP - 2022.04.28.489537 AU - Tuba Barut AU - Nico Joel Halwe AU - Adriano Taddeo AU - Jenna N. Kelly AU - Jacob Schön AU - Nadine Ebert AU - Lorenz Ulrich AU - Christelle Devisme AU - Silvio Steiner AU - Bettina Salome Trüeb AU - Bernd Hoffmann AU - Inês Berenguer Veiga AU - Nathan Georges François Leborgne AU - Etori Aguiar Moreira AU - Angele Breithaupt AU - Claudia Wylezich AU - Dirk Höper AU - Kerstin Wernike AU - Aurélie Godel AU - Lisa Thomann AU - Vera Flück AU - Hanspeter Stalder AU - Melanie Brügger AU - Blandina I. Oliveira Esteves AU - Beatrice Zumkehr AU - Guillaume Beilleau AU - Annika Kratzel AU - Kimberly Schmied AU - Sarah Ochsenbein AU - Reto M. Lang AU - Manon Wider AU - Carlos Machahua AU - Patrick Dorn AU - Thomas M. Marti AU - Manuela Funke-Chambour AU - Andri Rauch AU - Marek Widera AU - Sandra Ciesek AU - Ronald Dijkman AU - Donata Hoffmann AU - Marco P. Alves AU - Charaf Benarafa AU - Martin Beer AU - Volker Thiel Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/04/28/2022.04.28.489537.abstract N2 - 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.Competing Interest StatementThe authors have declared no competing interest. ER -