The Curious Emergence of Omicron

Part VI: Study Limitations, Concluding Remarks, & Citations

Limitations/Critiques of the Included Studies

Before I finish this post, I do want to point out some criticisms I have for the Wei et. al. study, as well as some points that need clarifying.

With respect to the studies we have examined:

• Most of the studies examined in this series were preprints/preliminary data- The data presented here are some of the first studies on Omicron. Even as I wrote this piece over the course of a week many other papers are likely to have emerged that either support or contradict the information I provided here. Also, take into account that many of these studies were provided in preprint form and are subject to change after peer-review and editing. Considerations should also be made that several of these studies utilized in vitro models and may not parallel results seen in a real-world, clinical setting. Caution needs to be taken when evaluating this studies.

• The actual role of the N501Y mutation is spotty- Although I have written that the N501Y mutation appears to provide greater infectivity, there is some evidence contrary to that. The Wei et. al. researchers have commented that the N501Y mutation does not appear to provide greater binding towards mice ACEII with the likely benefit of the mutation towards escaping antibodies. This presents an issue as to what role the N501Y mutation actually plays in providing better infectivity towards mice, if it even does so. On that front, a lot of liberties have been used in regards to examining this mutation as many researchers have not fully elucidated the cross into mice reservoirs. Hopefully further research will provide more clarity on the matter.

• The type of Omicron variant used in studies matters- We can see with clear evidence that viral evolutionary dynamics depend greatly upon the host. Movement between hosts or serial passage through different species can alter the mutations and binding affinity of SARS-COV2’s spike protein. Care must be made when examining these, and really any studies on SARS-COV2 to understand what type of mutations are being referenced in these studies. A few of the studies I have listed examined samples collected from Botswana as the earliest forms of the variant, although it’s likely that even at the point of sample collection that Omicron may have circulated for some time through humans. If samples are collected from various sources worldwide it is very likely that these variants have passed through many humans and have gained mutations that provide greater binding to human ACEII. Use of these sequences are not likely to provide a proper reference for the earliest progenitor of Omicron. It’s the reason why the researchers in the Wei et. al. study continuously make references and distinctions between pre-outbreak Omicron and post-outbreak Omicron.

With respect to the Wei et. al. study:

• No or very little critique of the human origin hypotheses- Granted, the researchers constructed their study to focus on the animal origin hypothesis, but it would still provide better evidence in favor of their hypothesis if they provided criticisms towards the plausibility of the “cryptic emergence” or immunocompromised patients. Considering that the immunocompromised patients hypothesis is the most widely circulating hypothesis, it would greatly benefit the researchers to address this hypothesis in a manner similar to what I have provided- although I will say that my explanation is both incomplete and highly subjective.

• Selective use of certain studies for SARS-COV2 sequences- The researchers made use of certain databases such as BLASTn. However, several of their sequences were derived from prior studies, such as human SARS-COV2 sequences being derived from the Shan et. al. study. Also, the 3 patients that were used to model chronically ill patients were derived from both this Kemp et. al. study as well as this Truong et. al. study. There are several case studies on chronically infected patients, most of which provide sequencing data throughout these patients’ infections. Why these specific studies were used for their sequencing data should raise a bit of skepticism. Also, take into consideration that more case studies would also provide greater data on prevalent mutations and would provide more consistent data to work from. The use of just 3 patients may not provide the same level of robustness and may not work as a proper reference cohort and the use of these sequences from prior studies are likely to add some biases into the data.

• Statistics and Modeling Galore/ no in vitro or in vivo Assays- This was an area that my friend had many criticisms over with respect to this study, and I can understand why. The researchers relied predominately on statistical models to examine pre-outbreak Omicron’s mutations and their relationship to prior strains. The issue here is that this only provides a predictive, hindsight model as to Omicron’s emergence. No actual in vitro or in vivo assays were conducted, and so no actual tests were done to validate the hypotheses laid out in these studies. When it comes to the modeling results, remember that these too may not reflect results seen using actual cells or animal models. Models heavily rely on variables to create their results and are thus likely to become subject to heavy biases. Remember the issues with the Chen et. al. study I provided in my monoclonal antibody series, and how the results there run counter to several of the results seen in in vitro assays. The studies here provide a framework from which future research can build upon or deconstruct, but on their own they should be met with some level of skepticism.

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Prospective Research Possibilities

We have speculated upon Omicron’s origins, but we haven’t seen any studies to test for this hypothesis.

What makes the original strain so difficult to study is that we really are still unsure what strain of coronavirus it may have emerged from. But let’s say that it came from some bat coronavirus through natural evolution. We still wouldn’t be able to test for an evolutionary pathway that discerns COVID’s ability to jump into human since that would require the use of humans as a host species, something that most people would consider unethical.

Fortunately, Omicron doesn’t present with the same experimental issues. If we assume that the Alpha lineage of SARS-COV2 served as the progenitor strain for Omicron, and we also assume that an Alpha variant jumped into mice and mutated (the evidence presented suggest as much), we certainly would be able to conduct serial passage experiments to validate the assumptions made in the Wei et. al. study. Unlike the original Wuhan strain, researchers will be fully capable of conducting their own animal studies to test and see if the proper mutations arise. Remember that we do have prior evidence of mutations collected from mouse-adapted SARS-COV2, however further studies could be conducted with the hypothesis laid out by the Wei et. al. researchers.

Researchers could utilize serial passage of Alpha through laboratory mice that are either immunocompetent or immunocompromised, collect nasal samples and sequence the virus’ genome. If researchers arrive at the same conclusions as the ones presented here we could conclude that Omicron most likely emerged from mice.

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Final Thoughts on Omicron (For Now)

We’ve gone over plenty of information here, but the evidence appears to point towards a possible mouse origin for Omicron.

The sequence of events are likely to be the following:

1. SARS-COV2, which has circulated within the human population for several months, eventually receives an N501Y mutation within its RBD with the emergence of the Alpha variant.

2. This mutation provides SARS-COV2 the ability to pass successfully into mice as it provides greater infectivity in mice.

3. Now within mice reservoirs, SARS-COV2 continues to mutate, gathering more mutations (such as the Q493R and Q498R mutations) that provide better binding to mice ACEII receptors.

4. Eventually, this variant that has circulated within mice reservoirs eventually jumps back into human hosts and begins to spread globally.

So far this is the extent of the events that we can outline, although we can clearly see that it is not complete and provides several more questions. For instance, we would have to assume that at no point did a progenitor of Omicron make a jump into humans and possibly spread a different variant before the emergence of Omicron, although this may be plausible if there was a lack of robust surveillance for SARS-COV2 mutations, akin to the “cryptic emergence” hypothesis the researchers alluded to in their introduction. By that same notion, we also don’t know how mice served as the animal reservoir, considering that other mammals such as white-tailed deer have also tested positive for COVID. It is interesting to see Omicron showing great binding affinity for both humans and camels, especially considering that camels appear to serve as reservoirs for MERS-COV and sources of animal-to-human transmission of the virus.

And it’s from this perspective that the researchers provide a word of caution. Regardless of whether mice were the actual origins of Omicron, there’s no denying the ability for SARS-COV2, or really many viruses to jump in between species. Even as Omicron appears to be far more mild in disease compared to prior variants, concerns may still remain that Omicron may mutate to become more severe, or that SARS-COV2 can find other animal reservoirs that don’t provide us with the same reduced illness that Omicron has. The last figure from the Wei et. al. study provides a clear picture that several other mammals show strong binding affinity to Omicron’s RBD, suggesting that there may be some shared nature of ACEII structure across several mammalian species and may operate to provide the ability for SARS-COV2 to jump between species.

Humans represent the largest known reservoir of SARS-CoV-2, and frequently come in contact with other animals, including livestock animals, pets, or wild animals that invade homes searching for food and shelter. Given the ability of SARS-CoV-2 to jump across various species, it appears likely that global populations will face additional animal-derived variants until the pandemic is well under control. Our study thus emphasizes the need for viral surveillance and sequencing in animals, especially those in close contact with humans. Furthermore, computational characterization of the spike RBD in animals and identification of their potentials to interact with human ACE2 will likely help to prevent future outbreaks of dangerous SARS-CoV-2 variants.

Even to this day the questions about the origins of Omicron are still being debated. More credence has been presented in regards to the idea of the lab-leak hypothesis, although we still have yet to be provided with definitive evidence. Now, we are left to question the origins of Omicron.

Could Omicron have emerged through our close relationship with animals such as mice? Or, even more specifically, could the use of mice as models for testing therapeutics and different COVID variants provide the avenues for eventual passage into mice? I have raised this question in regards to the use of transgenic mice, especially if transgenic mice were genetically engineered to express both murine ACEII and human ACEII receptors. Not only that, but in some sense the laboratory setting may also provide the appropriate variables for SARS-COV2 infected mice to spread the virus to other laboratory mice. Even just a few weeks ago there was a report of a Taiwanese scientist testing positive for COVID after being bitten by a lab mouse, raising questions with Taiwanese officials as to how that was possible especially considering that Taiwan continues to have stringent border laws in light of COVID.

One has to wonder if the utilization of mice models for the sake of our benefit could, in some manner, provide avenues for “gain-of-function”, or possibly “loss-of-function” in the case of Omicron.

Nonetheless, although Omicron has shown to be far more infectious and transmissible with reduced virulence, caution has to be taken that Omicron may not at some point find a middle ground for both transmissibility and virulence after many passages through human hosts. We can see that when examining post-outbreak Omicron variants which have picked up mutations in favor of human ACEII receptors. The extent to which the mutations may eventually garner greater virulence is up to debate for now, but just as likely Omicron is to become more virulent there is still a possibility that Omicron moves so quickly through the population that it may eventually burn itself out and remove itself from circulation.

For now, Omicron continues to spread and infect hundreds of thousands of people globally without the same level of severity as Delta. In fact, it seems that reaching the end of the pandemic may actually be a reality within a few months. Nonetheless, as it continues to spread we are left to ponder on Omicron’s origins, drawing parallels to SARS-COV2’s questionable origins and emergence as well.

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Citations

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18. Chen J, Wang R, Gilby NB, Wei GW. Omicron (B.1.1.529): Infectivity, vaccine breakthrough, and antibody resistance. Preprint. ArXiv. 2021;arXiv:2112.01318v1. Published 2021 Dec 1.