The spike gene is a major determinant for the SARS-CoV-2 Omicron-BA.1 phenotype
G. Tuba Barut, Nico Joël Halwe, Adriano Taddeo, Jenna N. Kelly, Jacob Schön, Nadine Ebert, Lorenz Ulrich, Christelle Devisme, Silvio Steiner, Bettina Salome Trüeb, Bernd Hoffmann, Inês Berenguer Veiga, Nathan Georges François Leborgne, Étori Aguiar Moreira, Angele Breithaupt, Claudia Wylezich, Dirk W. Höper, Kerstin Wernike, Aurélie Godel, Lisa Thomann, Vera Flück, Hanspeter Stalder, Melanie Brügger, Blandina I. Oliveira Esteves, Béatrice Zumkehr, Guillaume Beilleau, Annika Kratzel, Kimberly Schmied, Sarah Ochsenbein, Reto M. Lang, Manon Wider, Carlos Machahua, Patrick Dorn, Thomas M. Marti, Manuela Funke-Chambour, Andri Rauch, Marek Widera, Sandra Ciesek, Ronald Dijkman, Donata Hoffmann, Marco P. Alves, Charaf Benarafa, Martin Beer, Volker Thiel
Abstract
Variant 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.