If Omicron does have a mouse origin, then what could be next?

Wei and colleagues at the Chinese Academy of  Sciences in Beijing published a paper in the Journal of Genetics and Genomics on Dec. 24, 2021, titled “Evidence for a mouse origin of the SARS-CoV-2 Omicron variant.” In this paper, they reported:

“Mutations in the Omicron spike protein significantly overlapped with SARS-CoV-2 mutations known to promote adaptation to mouse hosts, particularly through enhanced spike protein binding affinity for the mouse cell entry receptor. Collectively, our results suggest that the progenitor of Omicron jumped from humans to mice, rapidly accumulated mutations conducive to infecting that host, then jumped back into humans, indicating an inter-species evolutionary trajectory for the Omicron outbreak.”

Multiple publications since 2020 have reported on mouse-adapted SARS-CoV-2. Some of these studies involved passaging SARS-CoV-2 isolates of human origin in mice for 6, 10 or up to 30 passages, and then observing genetic mutations and changes in transmissibility and/or virulence in different species of mice. This work was reported from, for example, the USA (North Carolina, Iowa), France (Paris) and China (Harbin, Beijing, Wuhan, Shanghai).

Cameroni and international colleagues posted a manuscript on bioRxiv on Dec. 14, 2021, in which they reported experimental evidence that the Omicron receptor binding domain (RBD) “binds with increased affinity to human ACE2 and gains binding to mouse ACE2.” They concluded: “Collectively, these findings suggest that mutations in the RBD of Omicron may have enabled adaptation to rodents as well as contributed to potentially increased transmission in humans.”

Earlier, Telenti and colleagues published a perspective titled “After the pandemic: perspectives on the future trajectory of COVID-19”in Nature on July 8, 2021. In a subsection on “interspecies spread” they wrote:

“New variants that can be transmitted back to humans in an interspecies ‘ping pong’ of infections could contribute to further SARS-CoV-2 diversification, as it is the case for influenza A viruses [boldface added]. Infection and propagation of SARS-CoV-2 in nonhuman species could lead to sequence alterations, interspecies transmission and adaptations that could compromise human immunity or affect virulence and that could diminish binding to monoclonal antibodies that are in clinical use.”  

If the hypothesis that Omicron does have a mouse origin is plausible, then what other mouse-related variants might exist in the near future? A worse-than-Omicron variant of concern would be one that is still highly transmissible and could also evade enough T-cell immunity to cause increased virulence. In theory, this variant might arise by a recombination event or perhaps prolonged interspecies “ping-ponging” between humans and mice.