The Negatives of Positive Feedback

Rogue Waves in a Complex System

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Long before Omicron was deemed the most rapidly transmitting virus in human history, I described a positive feedback loop between the rate of evolution and transmissibility, with the potential for increases in transmissibility due to several micro, macro, viral, and host factors that would accelerate this process. These factors manifest greater synchrony and therefore amplitude of waves from increased travel due to lessened travel restrictions (which would increase the number of humans a single person contacts and therefore R), greater Ace2 affinity of Spike, and greater amount of infections per unit time. In turn, this greater amount of infections from these advantages would accelerate evolution, making waves have greater amplitude and frequency.

This rate of evolution has its advantages for the virus. Thanks to rapid evolution, raw increases in transmissibility by virtue of ACE2 binding affinity increases can be realized. Let me show you an example:

When you increase the virus’ binding to the receptor like this you can reasonably expect greater transmissibility. But when does the positive feedback stop? Well, let me introduce you to rbd-62. Basically, they simply passaged sars cov 2 spike in cells in a dish and allowed the best-binding spike compete and refine. At the end of the experiment, they made a spike that had greater affinity for spike than many of our best-binding antibodies had for spike. So there was a clear thermodynamic trajectory for spike to get better.

What does this mean clinically? One virologist claimed that an ultra-affinity spike would be incompetent because once bound to its target, it would not be able to function in the cell it had infected. However, I disagree, and you can see why in this preprint where pseudovirus with extreme ace2 affinity was still viable and fusogenic.

Therefore, we can expect large increases in “transduction efficiency” in a dish and “transmissibility” among the population, which would lead to more evolution. Increases in thermodynamic favorability allow for different conformations of spike that can “tradeoff” a bit of thermodynamic stability for sera-evasiveness. In short terms, the virus has plenty of ways to optimize fitness, and an interesting thing is, as it adopts a more rbd-62 like form there is inherent sera evasion that comes with the new shape. You can bet on more evolution.

I wasn’t 100% on the mark Oct ‘21 though, because I said, at that time the virus was increasing virulence. It did as far as Delta goes, but early Omicron was not as virulent as Delta. However, Omicron has reacquired a few of the virulent features of Delta and can surpass them with a more polybasic furin cleavage site. We should also think of Omicron not as a linear development from Delta, or as a progression, but rather as a separate, more “fit” variant of SARS Cov 2, where less fusogenicity of Omicron was a matter of happenstance and unlikely fitness. Indeed, Omicron is increasing its fusogenicity. The time indeed to intervene to prevent another wave is at the point of waning (or nullified) antibody-mediated immunity. Since variants can emerge that effectively nullify antibody-mediated immunity like the variant XBB, (which is one to watch) we can be caught quickly by surprise.

If SARS Cov 2 lineages were named by serological distinction (how well antibodies from one infection can bind another) I would call XBB SARS Cov 3.

What does this all mean? We have much more evolution to go, and even more positive feedback from the evolution, transmissibility, and sera-evasion feedback loop.

Good luck out there.

AJ