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

• Published in: Nature communications Vol. 13; no. 1; pp. 5929 - 14
• Main Authors: Barut, G. Tuba, Halwe, Nico Joel, 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.10.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 13/109; 13/51; 14; 14/63; 42; 45; 45/77; 49; 631/326/596/2555; 631/326/596/4130; 64; 64/110; 692/699/255/2514; Animal models; Animals; Cell culture; Cloning; COVID-19; Cricetinae; Dominance; Epithelial cells; Epithelium; Ferrets; gamma-Globulins; Hamsters; Humanities and Social Sciences; Humans; Immunization; Melphalan; Mice; mRNA; multidisciplinary; Mustela; Pathogenicity; Pathogens; Phenotype; Phenotypes; Replication; RNA, Messenger; SARS-CoV-2 - genetics; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - genetics; Vaccination; Vaccines
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-33632-y

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. A comprehensive characterisation of Omicron-BA.1 and VOC Delta in numerous in vitro and in vivo models uncovers the factors that led to its global dominance.