December 19, 2021

Q&A #06 - Geert and John’s email exchange of thought and ideas about the Omicron articles

Discussed articles

- ‘Omicron: The calm before the tsunami?
- ‘Continued mass vaccination will only push the evolutionary capacity of SARS-CoV-2 Spike protein
   beyond the Omicron version


Dear John,

I think that after this, I am going to keep quiet (in terms of articles) for a little while.
I am beyond worried about mass vax against Omicron.
I cannot emphasize enough how a complete lack of understanding of viral evolution is now dominating the scene.

The article is about one page. Could you please do me a favor and review it? Txs!!


Is it truly our last chance? Or will the cycle repeat itself, cause waves of severe disease/death with new vaccines rolled out, then further mutation resulting in another escape strain from those vaccines, thereby resetting back to innate immunity again, and on and on?


Remember: ‘Continued mass vaccination will only push the evolutionary capacity of SARS-CoV-2 Spike protein beyond the Omicron version’ – allosteric mutations and ADE, remember?

It’s ADE that is going to tip the balance in the wrong and irreversible direction. ADE in vaccinees will provide the virus with exceptional virulence and make it resemble Marek in unvaccinated…this means natural selection against all those whose innate immunity got messed up.


Ah ok now I believe understand... Enough mutation in RBD of S specifically allows for the “reset” because there is no longer binding/recognition by previous antibodies. Allosteric mutation on the other hand results in binding of previous antibodies, but no longer blocking entrance via ACE2 and potentially allowing infection of other immune cells (macrophages etc) via Fc receptors. Is that right?


The only correction, John, is that the altered binding site does not need to be an Fc receptor on macrophages. It can basically bind to other domains on permissive host cells. As we already know, SC-2 is not strictly bound to entering the cell via Ace-2 (although this is still the preferred receptor). A cell has many surface determinants that could serve as a receptor for an altered binding site…


Yes, I do remember you talking about the alternative receptor sites.
And this *could* have happened with another subvariant of Delta... But now that Omicron appears to be rapidly taking over, it would likely happen with an Omicron sublineage? 
I’m curious if there is a way of calculating probability of an allosteric mutation leading to this outcome versus the probability of another set of mutations in RBD leading to another Omicron-style variant down the road?


Computational biology is not my strength!

Anyway, it’s reasonable to postulate that when one administers a vaccine that induces Abs to all of the mutated neutralizing epitopes at once (which we never did with the Wuhan-based vaccines as they were already facing variants right from start), one will drive natural selection of mutants that have a dramatic impact on that life-threatening ‘attack’. I am convinced that this is only going to be possible via a substantial antigenic SHIFT (instead of drift) and that it will need to involve allosteric mutations to basically bypass the current RBD which has now (i.e., upon anti-Omicron vax) fallen prey to a multitude of effective neutralizing Abs. I don’t think there is any probability that further changes in RBD could occur fast enough to bypass Omicron vaccine-induced Abs as there is always a fitness cost to pay for a mutation and it takes time to overcome the ‘valley of fitness cost’. As you will appreciate, all of the mathematical models used so far, even the most sophisticated ones, have miserably failed. That’s because they’re only as good as the assumptions are…


Wonderful explanation - thank you. 

I just assumed the "antigenic shift" necessary to bind other receptor sites (from allosteric mutations or otherwise) would require a MUCH larger fitness cost than that which is necessary to rework RBD once again (similar to what happened with Omicron) - I guess that wouldn't be the case?

I would think modifying the "key" (changes to RBD) but still binding to the same "lock" (ACE2) would be much easier than selecting a new lock altogether!
Or, perhaps you're stating that one of these other receptor sites that's already in use (albeit relatively inconsequential) by SARS-CoV-2 then becomes the preferred point of entry?

Sorry for the drawn-out mental exercise.  Perhaps it will help you in crafting future statements that may address this!


Txs, John, for your feedback. The fitness cost is pretty high if you want to implement changes within a narrow domain (RBD) that is also subject to physicochemical/ steric constraints for binding to a specific receptor (Ace-2). On the contrary, any mutation that enhances binding to another cell surface determinant (that is already in use, at least to some extent) will not be facing these constraints as it doesn’t need to deal with any of the (previously) neutralizing Abs (those can just bind as before).

That’s why I am beyond fearful that the catastrophe (ADE) could occur very fast after mass vax with anti-Omicron starts.

Makes sense?
If not, do let me know!


Makes sense! I was unaware that there were already other sites that SARS-CoV-2 latches onto... So I thought those recepting binders would have to evolve "from scratch". Now that I know they already exist, and just have to be improved upon, this makes complete sense!


Yes! So, indeed, the requirements for receptor-mediated entry of CoVs are not very stringent!


I still have few other quick questions.

Why would this "immune reset" with Omicron result in mild/moderate disease initially (due to innate immunity being "reactivated") when the original Wuhan outbreak started off bad right off the bat... Is this because of some level of pre-existing "herd immunity" and innate immune training to SC2?


Omicron should not be a problem for the unvax’ed whose innate immunity got meanwhile well trained. Older vax’ed age groups have revealed lower case rates (according to PHE) than younger age groups which suggests enhanced affinity of innate Abs (must have been acquired prior to vaccination). Younger vax’ed age groups have high titers of naïve Abs. When set free, those can easily deal with variants (that’s why no youngsters or children got the disease at the beginning of the pandemic). Of course, there are still the people with underlying diseases, most of whom have been jabbed. They cannot rely on their innate Abs and yes, I expect a relatively high case fatality rate in those (unless treated) but of very short duration as a steep incline of infectivity (due to high level of infectiousness) would be followed by a steep decline (due to massive elimination of the virus by a large cohort of +/- simultaneously asymptomatically/ mildly infected individuals.


This clears that up great - thank you.
Next question: Why the assumption that a new host entry mechanism would result in significantly more severe disease than that which was the case with ACE2? I understand how traditional ADE (via Fc receptors) can amplify disease... But this would simply be a new entry site, not an additional added mechanism, correct?


Omicron would still have the same entry site (Ace-2) as neutralizing Abs don’t bind. It’s only when allosteric mutations occur (new variant) that vaccinal Abs raised against Omicron S-based vaccine will bind to RBD (no longer capable of mediating viral entry) of this new variant and cause ADE. So severity depends on ADE not on mechanism of cell entry.


‘…vaccinal Abs raised against Omicron S-based vaccine…’ Still a bit confused on this part. So an allosteric mutation would potentially prevent the virus from entering cells via ACE2 altogether, but Omicron S-based vaccinal antibodies would still bind to it (just no longer neutralizing)?




So the virus would then infect immune cells specifically? (That's why I was curious why the FcyR receptor wouldn't be involved?)


I’ve not been taking a deep dive into the mechanistic details of ADE. However, what I can say is that non-neutralizing Abs that bind with high affinity to the virus will precipitate its entry into host cells. I am not sure this mechanism (exclusively) occurs through FcyR on macrophages/ dendritic cells. Of course, these receptors are expressed on those cells and they bind of course to immunoglobulins. But I do not rule out that coating of virus particles with immunoglobulins that don’t neutralize, could suffice to cause non-receptor-mediated viral entry into host cells….. Anyway, the outcome of all this is enhanced/ exacerbated pathogenicity…

Thank you Geert and John.

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Geert Vanden Bossche received his DVM from the University of Ghent, Belgium, and his PhD degree in Virology from the University of Hohenheim, Germany. He held adjunct faculty appointments at universities in Belgium and Germany. After his career in Academia, Geert joined several vaccine companies (GSK Biologicals, Novartis Vaccines, Solvay Biologicals) to serve various roles in vaccine R&D as well as in late vaccine development.

Geert then moved on to join the Bill & Melinda Gates Foundation’s Global Health Discovery team in Seattle (USA) as Senior Program Officer; he then worked with the Global Alliance for Vaccines and Immunization (GAVI) in Geneva as Senior Ebola Program Manager. At GAVI he tracked efforts to develop an Ebola vaccine. He also represented GAVI in fora with other partners, including WHO, to review progress on the fight against Ebola and to build plans for global pandemic preparedness.

Back in 2015, Geert scrutinized and questioned the safety of the Ebola vaccine that was used in ring vaccination trials conducted by WHO in Guinea. His critical scientific analysis and report on the data published by WHO in the Lancet in 2015 was sent to all international health and regulatory authorities involved in the Ebola vaccination program. After working for GAVI, Geert joined the German Center for Infection Research in Cologne as Head of the Vaccine Development Office. He is at present primarily serving as a Biotech / Vaccine consultant while also conducting his own research on Natural Killer cell-based vaccines.


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