Globalist Reality Report

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Has Omicron shifted receptor binding specificity away from deep lung tissue?

Could this be why it appears that Omicron is less severe than other variants?

By Robert W Malone MD, MS
December 15, 2021


HKUMed finds Omicron SARS-CoV-2 can infect faster and better than Delta in human bronchus but with less severe infection in lung

PreRelease of preprint from HKUMed: this paper is currently undergoing peer review https://bit.ly/3GW2t7H
Authors: Dr Michael Chan Chi-wai, John Nicholls, Dr Kenrie Hui Pui-yan, Malik Peiris, Tam Wah-Ching, Professor Leo Poon Lit-man, Professor John Nicholls

Based on current reports, Omicron appears to be associated with three broad characteristics: Vaccine escape (resistance), increased viral replication and reduced disease. In contrast, the preceding dominant variant (Delta) is also associated with vaccine escape, increased viral replication, and increased disease severity compared to preceding dominant circulating variants.

What is going on? How can increased levels of Omicron virus replication be associated with reduced disease? How did so many mutations in the receptor binding domain of Omicron arise, apparently spontaneously? Why do the evolutionary tree plots show that Omicron represents a separate branch from currently circulating viruses? How could so many mutations which confer vaccine resistance suddenly appear? Botswana (and South Africa in general) does not have a very high vaccination rate, so why would a vaccine-resistant virus strain develop in this region. Did someone engineer and release yet another virus? Lots and lots of questions. Very few answers. And then this new press release from the University of Hong Kong arrived today, showing that Omicron replicates more highly in conducting airway cells (bronchus), and less in lung cells. I think that the paper above provides with some important clues that could help us make sense out of this puzzle.

Sometimes I get asked whether the viral mutations occur in the unvaccinated or in the vaccinated. SARS-CoV-2 is a single stranded respiratory RNA virus, and it has a high spontaneous mutation rate. This is a fact which seems to be lost on many “factcheckers”. The answer is that mutations occur in both. The high rate of mutations observed with SARS-CoV-2 occur independently of vaccination status, because they are a consequence of the viral protein which copies the viral genome to make new genomes, and the fact that SARS-CoV-2 is single stranded.

With a single stranded RNA virus, there is not a second strand (of RNA “genes”) that can be used to identify when the polymerase (enzyme that makes new viral RNA genomes) has made a mistake and added the wrong nucleotide (A, U, G or C). So, the ability of the polymerase to “error check” is limited, as there is no second strand copy of the RNA strand being used at the time to manufacture new viral genomes. Nothing to compare to, to figure out which is the “good” gene and which is the “bad” or mutated gene. This results in each infected cell releasing a “swarm” of viral particles, many of which are different from each other. This happens whether or not you are vaccinated, because the vaccines do not prevent you becoming infected or your cells replicating the virus once you are infected.

The question is not whether viral mutations occur with or without vaccination, but rather what natural selection pressures are present to select which viruses survive, infect other cells, and make more copies of themselves. If you have not been vaccinated or infected before, there are a variety of ways that our body, innate immune system (natural antibodies and natural killer cells) and adaptive immunity “select” which viruses do or do not survive to replicate and infect others. This process of repeated selection and replication of the viral particles which are most able to survive in your body causes the genetic characteristics of the “swarm” of viruses infecting you to gradually change – genetically speaking. This is called natural selection of the fittest, and this process happens for everything that uses DNA or RNA to carry information from one generation to the next. This is the process that creates the gradual changes which we call “evolution”. But with viruses, each generation of virus produces a huge number of offspring in a very short period. Viral evolution can happen very fast. Especially with single stranded RNA viruses. And each time the virus swarm “jumps” from one person to the next, the members of the swarm that make the jump encounter a new host. “Host” is a biology term used when talking about parasites. The SARS-CoV-2 virus is a parasite, and you and I are its hosts.

Vaccination with the spike protein of SARS-CoV-2 creates a “selection” force on any swarm of viruses that infect a new host. So does the immunity created by “natural immunity” – the adaptive and innate immune responses that your body is left with after it has been infected and recovered from that infection. Basically, anything that creates an obstacle to the virus infecting a host, replicating, and jumping to another host will drive the virus to evolve to evade that obstacle.

Spike is an interesting protein, and it performs many essential tasks for the virus. One of the most important things that Spike does is to grab onto proteins on the surface of your cells, and then it changes shape and becomes a sort of syringe that injects the RNA genome of the virus into the cell it has grabbed onto. But first it has to grab onto something. That something is a receptor, typically the ACE2 (angiotensin converting enzyme II) protein, that is on the outside of certain types of cells. The part of Spike that does that is called the receptor binding domain (RBD). The primary objective of the genetic Spike vaccines is to cause your body to make antibodies that block the ability of the Spike RBD to bind ACE2. But ACE2 is not just a protein- it is a protein covered with sugar molecules (eg. heavily glycosylated). Changes in the patterns of how these sugar molecules are attached to ACE2 can have a big impact on whether SARS-CoV-2 can infect cells. And changes in the receptor binding domain (RBD) of Spike will not only influence how well it can evade vaccine-induced antibodies, but also how it interacts with ACE2.

What we know about Omicron is that it has many new mutations in the RBD. These mutations are absolutely associated with increased resistance to the effects of vaccine-induced antibodies. But was the development of this cluster of new mutations driven by natural selection due to vaccination? In an area of the world that does not have a very high vaccination rate? That does not make sense.

What if Omicron is the consequence of evolutionary pressure to replicate and infect more efficiently, perhaps to compete with Delta? Or as a consequence of passing between human and animal (cat, ungulate) hosts? What if what has really happened is that Omicron has evolved to change the location where it replicates in our body? What if it has evolved to replicate more in our upper respiratory airway, and less in the deep part of our lung tissues?

Has anything like that ever happened before, perhaps with other respiratory RNA viruses? Like, say, influenza A? Absolutely yes. In general, more severe pandemic influenza strains are often associated with receptor binding mutations that enable them to infect deeper lung tissues, while influenza strains that cause less disease infect upper parts of our respiratory tract. However, viruses that generally infect deep lung may be less infectious to others.

We often seem to fall into simple, binary thinking when considering complicated problems. Left or right-wing politics. Vaccinated or unvaccinated selecting for newly evolved viruses. This can limit our ability to make sense out of the world. But what if what is going on with Omicron is not so much driven by antibodies directed against the Spike RBD, but by selection for shifting the region of the respiratory tract that it infects? Or perhaps, this variant has bounced back and forth between humans and other species, and in so doing it has accumulated mutations which have exploited subtle differences in the ACE2 receptor.

One thing that has always fascinated me about viral evolution (or any evolution, for that matter) is the existence of evolutionary islands. Regions of genetic optimization that may not be the best solution, but which might require genetic changes which are less adaptive for a given environment before they are able to reach a new genetic “island” that is more optimal. Once a population (swarm) of viruses are able to bridge the evolutionary barriers to reach a new “island”, then they have a sort of evolutionary burst that can result in many changes within a short period of time as they evolve to adapt to the new optimum of that “island”. Perhaps what we are seeing with Omicron is the genetic consequence of one of these evolutionary bursts.

This is why this new finding from a team at Hong Kong University is so significant. Because it indicates that what may be most important about Omicron may not be the ability to evade vaccine-induced immunity, but that it has shifted its preferred tissue target for infection and replication to the upper airway instead of deep lung. That could explain why it is more infectious, replicates to higher levels, and yet causes less severe disease.

Let’s hope that is our best gift this Christmas.

Robert W Malone, MD, MS

https://rwmalonemd.substack.com/p/has-omicron-shifted-receptor-binding