In Regards to Omicron

A few comments and open discussion.

Minor correction: On my post about Ba.4/Ba.5 I made a comment that we should look into older monoclonals for current utilize with this new subvariant. However, after thinking about it further I believe that remark was too premature based on the tiny data provided. In order to make such an argument there would need to be further analysis of the epitopes being targeted by the monoclonals (Eli Lily’s and Regeneron). I think I jumped the shark based on the comment made in the Forbes article. So as of now consider this hypothesis shelved until further evidence can be found to substantiate it.

Going into my post on Ba.4/Ba.5 I wanted to make some remarks about the complexities of immunity and how simple analyses or assumptions may not tell us much about anything.

But I also want to use this post to discuss a few things in regards to Omicron and generally the atmosphere surrounding COVID as it exists currently. This post will feel a little bit scrambled since it will likely come together as I form my thoughts, so please bear with me and let’s venture forward.

Because the immunity section was going to end up becoming super long, I decided to split this article up and save the immunity section for the future. Apologies for those looking forward to it! It should be out within a day or two.

The Omicron Enigma

Just like many people out there I was infected with Omicron, and at the time was the only SARS-COV2 infection that I received (at least as far as I am aware of). Nearly everyone from both naturally immune and vaccinated was able to get COVID, and because of that it caught people off guard.

Because of this, it’s rather strange how much of Omicron has been memory-holed.

At the time I wrote a few pieces on Omicron and its emergence, with the general hypothesis in the scientific community being that it was some offshoot of Alpha from long ago, or it may have come from animal reservoirs. In general, we didn’t know where it came from at the time, nor do we know about its origins now.

Considering how the emergence of SARS-COV2 called into question gain-of-function research and possible lab leaks, it only seemed plausible that people consider Omicron itself to be of lab origin.

Brian Mowrey of Unglossed has raised this hypothesis based on the mutation rate, as well as both Ba.1 and Ba.2 emerging at the same time (Ba.1 was able to outcompete Ba.2 until later on).

The Ba.1 and Ba.2 being different variants that emerged separate is very interesting. It alludes to the fact that there may have been a lot of noise that came about during the emergence of Omicron- sounds a bit too familiar to the initial coverage of COVID, right?

In one study by Mykytyn, et. al.¹ researchers conducted antigenic cartography through utilizing pseudovirus particles expressing different spike proteins and infecting in vitro cells. Antigenic cartography maps the different responses of cells to the virus and generally provides some insight into the relationship between different variants. The results suggest that, not only are Omicron Ba.1 and Ba.2 very antigenically different than prior variants, but that they are themselves distinct from one another, suggesting either a divergence from a common ancestor or two independent emergences of each variant.

From Mykytyn, et. al. An antigenic map is shown above based on responses to various spike proteins. Note that many prior variants clump nearby one of the original variants (D614G). However, both Ba.1 and Ba.2 are fairly separate from the other strains. More importantly, Ba.1 and Ba.2 are distinct from one another as well.

And the researchers provide this comment in regards to results of their neutralization results. Keep in mind that these neutralization assays come with many caveats, but on the basis of being consistent they at least follow the similar design of other studies:

Similar to pseudovirus data, we observed a reduction in neutralization titers of Omicron BA.1 sera against all other variants (2.4 to 9 fold compared to homologous) and poor neutralization of Omicron BA.1 by all non-homologous sera (8 to 112 fold reduction). In addition, Omicron BA.2 was also poorly neutralized by all sera (7 to 114 fold reduction), including Omicron BA.1 (8 fold reduction). Although Omicron BA.1 and Omicron BA.2 possess many overlapping mutations in S, the differences between the variants were sufficient to prevent efficient cross-neutralization. In agreement, our study shows that antibodies elicited against the original SARS-CoV-2 cluster do not neutralize Omicron BA.1 well, and vice-versa.

All this to say, Omicron essentially threw a wrench into everyone’s working model of COVID. No longer could we make the case that natural immunity was better than vaccinated immunity- everyone was getting sick regardless because the virus had mutated so extensively that it evaded nearly all prior immunity.

As another example, take this excerpt from Willet, et. al.² for another idea of how evasive Ba.1 was be relating the mutations to immune invasion:

Within the spike protein, BA.1 and BA.2 sub-lineages share 21 amino acid mutations with 12 distinct mutations in BA1 and 6 in BA.2. BA.2 lacks the 69,70 deletion present in BA.1. The G339D, N440K, S477N, T478K, Q498R and N501Y mutations (present in BA.1 and BA.2) enhance binding of spike to the human ACE2 receptor, while combinations such as Q498R and N501Y may enhance ACE2 binding additively19. Deep mutational scanning (DMS) estimates at mutated sites are predictive of substantially reduced monoclonal and polyclonal antibody binding and altered binding to human ACE2 (Fig. 1b)20. Fourteen mutations in Omicron (K417N, G446S (BA.1), E484A, Q493R, G496S (BA.1), Q498R and to a lesser extent, G339D, S371L/F (BA.1/BA.2), S373P, N440K, S477N, T478K, N501Y and Y505H) may affect antibody binding on the basis of a calculated escape fraction (a quantitative measure of the extent to which a mutation reduces polyclonal antibody binding by DMS). Seven Omicron RBD mutations (K417N, G446S(BA.1), E484A, Q493R, G496S(BA.1), Q498R and N501Y) have been previously shown to be associated with decreased antibody binding, importantly falling in epitopes corresponding to three major classes of RBD-specific neutralizing antibodies (nAbs).

So there was a general expectation that nearly no one would be “fully” protected from Omicron, and as I recall the general sentiment at the time was to say that Omicron almost created an even playing field for the world. We were starting at square one, and fortunately for most us Omicron was mild so there was a general sentiment that this would be the beginning of the end for COVID.

But how many people reading this actually remember that this was a thing; that we (rightfully) took Omicron as some measure of immunity reset for the world? Why was it that there was no reworking of our understanding of COVID in the wake of Omicron?

Instead, it appeared that many eventually settled into Omicron and viewed it as a continuation of Delta, even thought it contained several dozen new mutations that absolutely does not follow the typical mutation rate one would expect for a naturally occurring virus (as natural as a virology lab in Wuhan can be considered natural).

Again, compare the mutations found in the spike protein of Alpha, Beta, Delta, and Omicron using the chart below from Lippi, et. al.³ Then compare the chart from Wednesday showing the mutations between Ba.1/Ba.2 and other subvariants of Omicron⁴.

From Lippi, et. al. Compare all of the spike mutations that came about in prior variants and compare them to Ba.1 (B.1.1.529). Note that the 15 mutations within the RBD alone for Ba.1 (in red) are far greater than the number of mutations in the entire spike protein of other variants. The number of mutations should raise questions as to how these mutations arose.

Such a high degree of mutations (Note: there are more mutations in Ba.1’s receptor binding domain than there are mutations in the spike protein of other variants) requires some degree of contextualization, and one that takes into account how to go about parsing this high degree of mutations.

Do we try to find reasons to suggest why these mutations came about? Some suggest zoonotic jump from mice and rats as an explanation as to why these mutations in particular came about, yet there hasn’t been any evidence of mouse zero running about in South Africa. It may be from an immunocompromised individual, but that doesn’t explain why mutations that confer greater transmissibility yet lower virulence would be favored unless the net fitness favored these mutations, as well as why surveillance somehow did not see the emergence of some ancestral lineage (if the patient received longterm treatment). Both hypotheses don’t also take into account how both Ba.1 and Ba.2 emerged around the same time yet are so distinct from one another. That would generally leave us with a lab-based theory, whether released intentionally or a possible leak. In all cases though, it doesn’t follow the typical route through human serial passage, and so does it seem appropriate to include Omicron into the human evolutionary model?

This creates a host of problems, mostly because Omicron means that we can’t draw a line from Delta to Omicron- we can’t connect the dots and follow an evolutionary progression from one variant to another. In fact, this may be considered the improper inclusion of Omicron, and yet it appears to be happening everywhere.

Many models on COVID now just include Omicron rather than treating it as a separate entity to which we don’t know the origins of. Hypotheses now work around Omicron’s more transmissible yet reduced virulent nature to extrapolate assumptions. Now that Ba.4 and Ba.5 are appearing with greater virulence, it’s suddenly as if the Delta→ Ba.1/Ba.2 → Ba.4/Ba.5 line of viral progression is somehow something that was predicted for by several, as if they somehow knew that a variant like Omicron would arise when many have raised concerns about possible lab origins for this variant.

It’s even strange seeing many people remark that Ba.4 and Ba.5 are now the time where immune escape is happening, especially since immune escape was happening as soon as Omicron emerged and is not exclusive to this current subvariant. Again, more memory-holing appears to be at play here. Granted, there is an argument to be made that the combination of mutations found within Ba.4/Ba.5 are what makes the immune escape, but since this appears to be the general progression of viruses that find niches within humans (i.e. mutate to evade immunity), this may not be a surprise more than something that should be expected.

Even with this steelman, there are a few questions (as raised by Brian Mowrey) as to whether Ba.4/Ba.5 are actually distinct from Ba.2 as well⁵.

Omicron has become a conundrum for the scientific community and many others, yet it’s treated as if it’s not the anomaly that it should be designated.

It’s as if Omicron is being treated as the estranged child that has been welcomed into the COVID family, not some random stranger that appeared at the family picnic and eats all of the coleslaw and macaroni salad while Auntie Alpha looks on wondering who’s kid this is that just appeared out of nowhere.

In that regard, it doesn’t quite make sense how Omicron has inserted itself so seamlessly into the COVID discourse. Instead, it may be more viable to consider Omicron and Wuhan as completely separate viruses (to a degree), if not for the difficulty of figuring out exactly what to do with Omicron. This does raise problems of its own, but it should at least emphasize the fact that Omicron’s analysis may be biased by our analyses of prior variants.

There’s likely more I intend to say here that I can’t think of at the moment, but keep in mind that when parsing the information we should remember the strange emergence of Omicron and factor that into our working model, rather than disregard it’s sudden appearance and act as if it was just the normal state of affairs.

With that, I would like to know what you all think about Omicron given everything that has been going on.

Do you think Omicron emerged from animal reservoirs, or emerged from an immunocompromised individual? Or is there a possibility that Omicron, similar to the original Wuhan, may have emerged from a lab?

How do we contextualize the enigma that is Omicron? How do we relate it to prior variants, or should we consider it completely separate? If we do include Omicron with respect to variants such as Delta, how do we rationalize the high number of mutations that have still not been fully answered?

Consider these questions, and any other questions and think about opening up some discussion about what’s going on. I’ll try to release my immunity post either tomorrow or Sunday, so please be on the lookout for that!

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1. Omicron BA.1 and BA.2 are antigenically distinct SARS-CoV-2 variants

Anna Z. Mykytyn, Melanie Rissmann, Adinda Kok, Miruna E. Rosu, Debby Schipper, Tim I. Breugem, Petra B. van den Doel, Felicity Chandler, Theo Bestebroer, Maurice de Wit, Martin E. van Royen, Richard Molenkamp, Bas B. Oude Munnink, Rory D. de Vries, Corine GeurtsvanKessel, Derek J. Smith, Marion P. G. Koopmans, Barry Rockx, Mart M. Lamers, Ron Fouchier, Bart L. Haagmans

bioRxiv 2022.02.23.481644; doi: https://doi.org/10.1101/2022.02.23.481644

2. Willett, B.J., Grove, J., MacLean, O.A. et al. SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway. Nat Microbiol (2022). https://doi.org/10.1038/s41564-022-01143-7

3. Lippi, G., Mattiuzzi, C. & Henry, B. (2022). Updated picture of SARS-CoV-2 variants and mutations. Diagnosis, 9(1), 11-17. https://doi.org/10.1515/dx-2021-0149

4.

From Hachmann, et. al. Note that both Ba.1 and Ba.2 contain dozens of different mutations. However, sublineages of Ba.2 only carry a few mutations onward.

Hachmann, N. P., Miller, J., Collier, A. Y., Ventura, J. D., Yu, J., Rowe, M., Bondzie, E. A., Powers, O., Surve, N., Hall, K., & Barouch, D. H. (2022). Neutralization Escape by SARS-CoV-2 Omicron Subvariants BA.2.12.1, BA.4, and BA.5. The New England journal of medicine, 387(1), 86–88. https://doi.org/10.1056/NEJMc2206576

5. Both Ba.1 and Ba.2 were detected and sequenced in November 2021. Ba.4 and Ba.5 were detected in January, although there is a possibility of their existence from earlier on. Remember that these strains are all derived from similar geographical regions, which would at least lend some value to the idea that all of the sublineages of Omicron may have come about around similar times rather than from one another.

https://www.nicd.ac.za/omicron-lineages-ba-4-and-ba-5-faq/