Evolution of Omicron lineage towards increased fitness in the upper respiratory tract in the absence of severe lung pathology

Arthur Wickenhagen, Meaghan Flagg, Julia R. Port, Claude Kwe Yinda, Kerry Goldin, Shane Gallogly, Jonathan E. Schulz, Tessa Lutterman, Brandi N. Williamson, Franziska Kaiser, Reshma K. Mukesh, Sarah Tol, Brian Smith, Neeltje Doremalen, Colin A. Russell, Emmie Wit () and Vincent J. Munster ()
Additional contact information
Arthur Wickenhagen: National Institutes of Health
Meaghan Flagg: National Institutes of Health
Julia R. Port: National Institutes of Health
Claude Kwe Yinda: National Institutes of Health
Kerry Goldin: National Institutes of Health
Shane Gallogly: National Institutes of Health
Jonathan E. Schulz: National Institutes of Health
Tessa Lutterman: National Institutes of Health
Brandi N. Williamson: National Institutes of Health
Franziska Kaiser: National Institutes of Health
Reshma K. Mukesh: National Institutes of Health
Sarah Tol: National Institutes of Health
Brian Smith: National Institutes of Health
Neeltje Doremalen: National Institutes of Health
Colin A. Russell: University of Amsterdam
Emmie Wit: National Institutes of Health
Vincent J. Munster: National Institutes of Health

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract The emergence of the Omicron lineage represented a major genetic drift in SARS-CoV-2 evolution. This was associated with phenotypic changes including evasion of pre-existing immunity and decreased disease severity. Continuous evolution within the Omicron lineage raised concerns of potential increased transmissibility and/or disease severity. To address this, we evaluate the fitness and pathogenesis of contemporary Omicron variants XBB.1.5, XBB.1.16, EG.5.1, and JN.1 in the upper (URT) and lower respiratory tract (LRT). We compare in vivo infection in Syrian hamsters with infection in primary human nasal and lung epithelium cells and assess differences in transmissibility, antigenicity, and innate immune activation. Omicron variants replicate efficiently in the URT but display limited pathology in the lungs compared to previous variants and fail to replicate in human lung organoids. JN.1 is attenuated in both URT and LRT compared to other Omicron variants and fails to transmit in the male hamster model. Our data demonstrate that Omicron lineage evolution has favored increased fitness in the URT.

Date: 2025
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DOI: 10.1038/s41467-025-55938-3

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