Omicron's generally less harmful mechanisms emerge

Adults, at least, seem to be less likely to suffer serious symptoms than with prior SARS-CoV-2 variants

After several weeks of widespread transmission of the Omicron SARS-CoV-2 variant in northern hemisphere countries, far from the equator, in winter, it is clear that Omicron causes less severe disease, on average, in these vulnerable populations, than Delta or previously widely transmitted variants.

This is very good news, but should not be mistaken for a get out of jail free card.

Omicron is extraordinarily transmissible. No other disease has spread to most countries, with 2 day doubling times in some cities, within two months of first being detected.

Omicron’s high degree of escape of immune responses raised by infection with prior variants, or with vaccination, plus its innately higher rate of transmission, mean that vaccination will have little effect on whether people become infected in the next few months.

Vaccination does confer protection against severe disease, to some extent at least - and in 25-hydroxyvitamin D deficient, early treatment deprived, vulnerable populations, this saves many people from harm and death. The safety problems of the mRNA and adenovirus vector COVID-19 “vaccines” currently used in Western nations is a vast topic, which I attempted to cover to some degree in the later updates to:

Omicron rolling updates - it seems to be less virulent than Delta etc.

With the current, extraordinarily rapid, rate of Omicron transmission it is doubtful whether commencing a two injection (plus boosters before long) vaccination program would help much with either resistance to infection or protection from serious disease. The the appropriateness of the vaccination - booster - booster - . . . program is being increasingly questioned. Professor David Livermore, University of East Anglia: dailysceptic.org/the-futility-and-hazards-of-boosterism/.

Rapid 25-hydroxyvitamin D repletion, in days - with bolus (single, high, dose) vitamin D3 is the best option for the great majority of the population with 25-hydroxyvitamin D levels well below the 50 ng/mL (125 nmol/L) their immune system needs. This is just as true for vaccinated as for unvaccinated people. Likewise early treatments. Please see: nutritionmatters.substack.com/p/calcifediol-25-hydroxyvitamin-d-or.

Here is my attempt to summarise some early research which was made available as preprints (not peer reviewed) into Omicron’s mechanisms, to help us understand why it is generally less harmful. To what extent it is less harmful for children is harder to tell, since children are being admitted to hospital with presumably Omicron COVID-19 at an increasing rate, at least in Texas. If this is purely due to the very high prevalence of Omicron, then there may not be anything special about it which threatens to harm children more than prior variants have. However, we can’t yet quantify long-term harm rates for children with any precision, since everything is happening so quickly.

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Peacock et al.

Thomas P. Peacock and 9 colleagues published The SARS-CoV-2 variant, Omicron, shows rapid replication in human primary nasal epithelial cultures and efficiently uses the endosomal route of entry as a bioRxiv preprint: www.biorxiv.org/content/10.1101/2021.12.31.474653v1 on 3rd January.

They confirmed that Omicron continues to use the ACE2 receptor to enter cells, and that it did not use several other receptors they tested. ACE2 [WP] is an enzyme [WP] which catalyses an important reaction in the renin-angiotensin system [WP] which plays a major role in regulating blood pressure. As such, ACE2 is not really a receptor - but it is widely known as such when it is bound to the plasma membrane (AKA cell membrane) [WP], pointing outwards, rather than its unattached, free-floating form.

In their October 2020 article Why is COVID-19 less severe in children? A review of the proposed mechanisms underlying the age-related difference in severity of SARS-CoV-2 infections Petra Zimmermann and Nigel Curtis stated that one of the hypotheses which seek to explain the generally less serious nature of COVID-19 in children is that the degree to which ACE2 is expressed (implicitly on cell membranes) increases with age, as does the expression of the TMPRSS2 protein [WP], which is required for the attached virus cleave the spike protein, which is an essential step by which Delta and prior variants trick the cell into drawing the ACE2 receptor back into the cell, with the virus attached.

In in-vitro [WP], cell-culture, experiments (rather than live animals) Peacock et al. also found that Omicron’s spike protein binds more strongly to human ACE2 than does Delta. They also found that the whole Omicron virus was more adept than previous variants at infecting cells of non-human animals, including those of domestic poultry, horseshoe bats and mice. (Omicron’s potential origins in mice was suggested in late December. Did its many mutations occur in wild mice? Or did they occur in laboratory mice?? Enquiring minds want to know. The enigmatic eugyppius is on the case.)

This suggests that Omicron will infect many non-human species, evolve new mutations there, and so be both harder to eradicate and more likely to evolve variants which could further trouble humans directly, than previous variants.

Syncytia is a cellular state in which multiple normally independent cells, each with their own nucleus, are fused together into a large single cell with multiple nuclei. This can occur naturally and healthily, such as in muscle cells, but can also be pathologically caused by viral infections.

SARS-CoV-2-infected cells typically have some spike proteins sticking out of their cell membrane, just like the virus itself. This is because coronaviruses are enveloped viruses [WP], formed by budding out of the infected cell, taking a portion of the cell’s membrane with them as their outermost layer - with spike proteins sticking outwards.

The syncytia trouble begins when a protruding spike protein of an infected cell B is attracted to and binds to an ACE2 receptor on an uninfected cell A. (This attraction is an electrostatic attraction due to positive and negative charges on particular parts of both the spike protein and ACE2, coming close to each other, and so creating an attractive force, as part of the close physical match between the surfaces of the two proteins. These are not strong, covalent, bonds like those which bond atoms into molecules. They are more gentle, but collectively, the stronger they are, the longer they hold the spike and ACE2 molecules together, despite the thermal vibration inherent in all matter which would otherwise cause them to be jostled apart.)

Lin et al. described this nasty process in May 2021: www.nature.com/articles/s41418-021-00795-y:

The spike and ACE2 proteins are attracted to each other and this leads to the cell membranes of the two lung cells in the above diagram being drawn together, and fusing. The result is a larger cell-like structure - which could be extended with further unions - a syncytia. The article mentions syncytia with up to 20 nuclei.

This process, found mostly in severe COVID-19 - and surely partly or largely causing to the severity itself - enables these larger cell-like structures to engulf the lymphocytes which our immune system sends to kill infected cells. This induces a state of lymphopenia - a shortage of lymphocytes. Lin et al. mention that the anti-depressant drug fluvoxamine - a promising treatment for COVID-19, though I think for later stages of the disease, rather than early treatment - may inhibit one of the processes which facilitates the formation of syncytia.

The good news from Peacock et al. is that Omicron seems to be less likely to cause syncytia than prior variants, despite their expectation that this would not be the case.

Peacock et al. also found that the Omicron SARS-CoV-2 virus can enter cells without relying on the expression of both ACE2 and TMPRSS2, by using the ACE2 and “the endosomal pathway”, which does not require TMPRSS2.

Endosomes [WP] are a system for handling material engulfed by the cell membrane from outside the cell, and sealed up in a portion of this membrane like a bubble. The system is designed to degrade the engulfed material, so this is a pathway to cellular entry which has long evolved to thwart the ability of invading viruses or other pathogens to infect the cell.

Omicron’s ability to use this endosomal pathway, to a much greater degree than prior variants, indicates that it has evolved significant protection against the efforts of the cell to to stop the virus releasing its RNA [WP] into the cytosol [WP] (main body, but not including the nucleus [WP] or mitochondria[WP]) of the cell - where it programs the mitochondria to make viral proteins and so produce numerous copies of the virus.

Here we show that Omicron virus replicates extremely rapidly within primary cultures of nasal epithelial cells [WP - that line the skin, surfaces of organs and blood vessels], even more so than Delta, which itself replicated faster than any previously characterised variants. We propose that Omicron achieved this rapid replication rate by becoming less specialised in terms of its cellular tropism [WP - the pattern of which cells can be infected].

Earlier SARS-CoV-2 isolates [variants] were limited in their tropism by their requirement for cell surface entry using the TMPRSS2 protease, and it appears subsequent variants, such as Alpha and Delta, became even more heavily reliant.

However only a low proportion of cells in the upper respiratory tract express both ACE2 and TMPRSS2. Here we show that Omicron has adapted to additionally use the ubiquitous endosomal pathway for entry, thus expanding the number of cell types it can infect, as single cell RNA seq data indicates that seven times more cells in the nose express both ACE2 and the ubiquitous endosomal cathepsin proteases than co-express ACE2 and TMPRSS2.

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Brian J. Willett et al.

29 authors contributed to this 59 page preprint, released on 3rd January: The hyper-transmissible SARS-CoV-2 Omicron variant exhibits significant antigenic change, vaccine escape and a switch in cell entry mechanism, www.medrxiv.org/content/10.1101/2022.01.03.21268111v1. Figure 1C (reproduced at the start of the article you are reading) depicts the divergence of SARS-CoV-2 variants compressed into a flat, radial, diagram, with Omicron’s genetic origins being unrelated to almost all of the numerous branches - linking back to the earliest months of the spread and mutation of the earliest variants.

Willett et al. tested the ability of Delta, D614G [WP] (an early 2020 variant from Wuhan) and Omicron to create syncytia:

The Delta variant exhibited the highest levels of cell fusion followed by Wuhan D614G. Interestingly, the Omicron variant failed to promote fusion.

They also found that the number of Omicron viruses in lung epithelial cell culture after 72 hours was “at least an order of magnitude” (a factor of 10) less than that of Delta and D614G. Indeed, at the right of Fig 5D, we see Omicron numbers are about 1/50th of those of Delta and D614G:

Although Omicron has more mutations, with respect to the original Wuhan strain, than most other variants, the changes to protein structure are still rather small in the scheme of things.

The mechanisms by which Omicron’s mutations prevent it from forming syncytia to any significant degree are not reported in these article, and it is probably to early for them to be understood.

Likewise the mechanisms by which these mutations greatly reduce the proclivity of the virus to replicate in the lungs are probably not yet known.

Both these changes are extremely welcome.

If one were designing a virus to put the pharmaceutical companies’ COVID-19 vaccine operations out of business, one would need it to be firstly more infectious than all current variants and secondly much less likely to cause serious disease.

This great attenuation of growth in lung tissue in-vitro experiments is not necessarily a result of the inability of Omicron to create syncytia - since syncytia reduce efforts of the immune system to kill infected cells, and there is presumably no active immune response in the in-vitro cell cultures which were used in these experiments.

Willett et al. make a bolder statement than Peacock et al. regarding Omicron’s increased ability to enter the cell via the endosomal route. They describe it as a complete switch from the original (including Delta) ACE2 + TMPRSS2 route to the ACE2 only endosymal route:

. . . this pattern was completely reversed, suggesting a binary switch from cell surface to endosomal fusion; . . .

These data indicate that, whilst Delta is optimised for fusion at the cell surface, Omicron preferentially achieves entry through endosomal fusion; this biological about-face may impact transmission, cellular tropism and pathogenesis. Moreover, this switch away from TMPRSS2-mediated activation offers a mechanistic explanation for reduced syncytia formation by Omicron infected cells.

Willett et al. researched, the protective effects of vaccination against Omicron infection, but not severity of infection. Currently used mRNA and adenovirus vector “vaccines” raise narrow immunity only to prominent part of the spike protein, some of which are specific to the early 2020 model spike protein still used in these products, not to any other viral proteins, and in a manner which is very limited regarding mucosal immunity - the most powerful part of the immune responses to respiratory pathogens, which occurs in the nasal passages.

It is widely recognised that natural infection with a virus generally - perhaps always - raises stronger, broarder, longer lasting, immune responses than any responses which can be induced by vaccination alone. So I don’t accept the veracity of the final part of their statement:

We also show that immunity from natural infection (without vaccination) is more protective than two doses of vaccine but inferior to three doses.

Booster vaccine injections evidently do raise immunity very significantly compared to the effects of the first two doses, but as far as I know, no sequence of vaccinations, especially not involving the nasal passages, using only the spike protein, and using an out-of-date spike protein compared to current variants, can generate a better, longer-lasting immune response than that which results from natural infection.

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A month ago, all we knew was that Omicron was highly infectious and seemed to be causing less harm than Delta in South Africa. That was in summer, with higher vitamin D levels and widespread use of ivermectin and probably other treatments than in the vulnerable populations of the USA, the UK and other densely populated countries entering winter.

Now we have both observational and mechanistic evidence to reasonably conclude that Omicron is generally less likely to cause serious harm - which typically involves the lungs - than Delta and prior variants.

However, it is still early days. This is a bugger of a virus, and there is a great deal of variation in how it infects individuals. There may be all sorts of neurological effects, for some people at least. The nasal passages are worryingly close to the brain. A nurse once told me of her fiancee, who had a herpes simplex infection in his nasal passages, which got into his brain and killed him. (Low 25-hydroxyvitamin D causes worse herpes virus infections - so this tragedy could probably have been easily avoided.)

Every effort with vitamin D and early treatment is worthwhile - since the virus is a crapshoot and these approaches are genuinely safe and effective.

The vaccines are not as safe as generally assumed, and they are not very effective. However, their effectiveness against severe disease is a lifesaving matter in whole populations of low 25-hydroxyvitamin D people, who have been egregiously, criminally, denied both good nutrition and early treatment by their governments, public health officials and the majority of the medical profession - all of whom seem to be dancing to the beat of multinational pharmaceutical companies. (These companies do, at times, produce excellent products - but more often they suppress access to simpler, better, approaches to the health problems they provide expensive drugs and vaccines for.)

There are numerous aspects to the COVID Vaccine Civil Wars, which arose only in the last year and have already driven deep divisions between millions of people in ways which never could have been anticipated.

These wars are not at all over - though with most people likely to get real, lasting, immunity from Omicron infection in the next few months (who haven’t attained this earlier by infection with Delta and earlier variants), there is no reason at all for such people to keep getting vaccinated. Furthermore, vaccination after infection typically leads to worse adverse reactions.

The vaccines should never have been widely deployed. From the start, 25-hydroxyvitamin D repletion was always the most important way of tackling the pandemic. Yet now, two years later, we still find it hard to get anyone to pay attention to this. Most think they already know what needs to be known about this little vitamin (and in the UK they pronounce the first syllable of this word like little rather than lively). Everyone knows we are having this great global crisis, with trillions of dollars being spent in desperate efforts to save humanity. They cannot imagine that most people’s immune systems are crippled - and always have been - due to lack of a gram of vitamin D3 every 22 years (5000 IU/day for 70kg bodyweight).

I will try to give an account of what is going on, but the whole global situation dwarfs any individual’s ability to follow or write about. One thing is for sure, if you keep reading this Substack, you are going to get very sick of the word egregious.