Review 1: "Evolution of Omicron Lineage Towards Increased Fitness in the Upper Respiratory Tract in the Absence of Severe Lung Pathology"

RR:C19 Evidence Scale rating by reviewer:

• Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review: Wickenhagen et al's manuscript "Evolution of Omicron lineage towards increased fitness in the upper respiratory tract in the absence of severe lung pathology" compares the replication and transmission of Omicron variants in both in vivo (hamster) and in vitro (hamster and human epithelial cells) models and demonstrates the fitness evolution of Omicron variants. The project was decently designed and the manuscript was well organized and written. The information of this manuscript is important and provides important implications on predicting the evolution of SARS-CoV-2 variants and developing efficient strategies of preventing SARS-CoV-2 transmission.

The major weakness of this manuscript lies in the Discussion section. Instead of simple summary of findings made in this project, these interesting and important data deserve further analysis and deeper interpretation. For example, the discussion of "selection pressure" mentioned in Lines 274-276, as well as "transmission efficiency" of JN.1 mentioned in Lines 285-286 and lines 309-310, could be expanded by including advances on structure biology and epidemiology, respectively.

One minor issues is that Hamster ACE2 alone data needs to be added as a key control in Figure 1.