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

  1. Tuba Barut
  2. Nico Joel Halwe
  3. Adriano Taddeo
  4. Jenna N. Kelly
  5. Jacob Schön
  6. Nadine Ebert
  7. Lorenz Ulrich
  8. Christelle Devisme
  9. Silvio Steiner
  10. Bettina Salome Trüeb
  11. Bernd Hoffmann
  12. Inês Berenguer Veiga
  13. Nathan Georges François Leborgne
  14. Etori Aguiar Moreira
  15. Angele Breithaupt
  16. Claudia Wylezich
  17. Dirk Höper
  18. Kerstin Wernike
  19. Aurélie Godel
  20. Lisa Thomann
  21. Vera Flück
  22. Hanspeter Stalder
  23. Melanie Brügger
  24. Blandina I. Oliveira Esteves
  25. Beatrice Zumkehr
  26. Guillaume Beilleau
  27. Annika Kratzel
  28. Kimberly Schmied
  29. Sarah Ochsenbein
  30. Reto M. Lang
  31. Manon Wider
  32. Carlos Machahua
  33. Patrick Dorn
  34. Thomas M. Marti
  35. Manuela Funke-Chambour
  36. Andri Rauch
  37. Marek Widera
  38. Sandra Ciesek
  39. Ronald Dijkman
  40. Donata Hoffmann
  41. Marco P. Alves
  42. Charaf Benarafa
  43. Martin Beer
  44. Volker Thiel
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Abstract

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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