Omicron BA. 4, BA. 5 and the road ahead

Non-immunity !

Today’s post will be a rather long one, so have that in mind, it is all about Omicron and the possible future ahead. The posts below are rather pertinent to this, while I won’t dive into details and mention them, the mechanics explained in them are rather impactful.

SARS-CoV-2 - Recombination, Omicron immunity, ADE ?

SARS-CoV-2 Vaccine-escape and virulence alleles on the dynamics of pathogen adaptation

Omicron BA.4, BA. 5 and their consequences

I have covered BA. 4, and BA. 5 for a few weeks now, and I warned if Omicron acquired a specific mutation, L452R it would go off, skyrocketing and dominating the field, because it enables high glycolysis, meaning it will use everything sugar related inside you at an alarming pace, enabling replication like nothing else too. Another of the reasons it will “breakthrough”, is vaccinated or not. One thing I mentioned a couple of times was, that the newer variants would cause severe fatigue, and would cause severe weakness in a lot of the infected (regardless of immunity status btw).

Sadly I can’t find the tweet a nice follower tagged me, but it was an EMS worker from Africa commenting exactly this. BA. 4 and 5 infected are developing severe weakness, their bodies feel like ragdolls. Because of the mutation above, which goes into my recent post about NMN.

Continued Emergence and Evolution of Omicron in South Africa: New BA.4 and BA.5 lineages

Abstract

South Africa’s fourth COVID-19 wave was driven predominantly by three lineages (BA.1, BA.2 and BA.3) of the SARS-CoV-2 Omicron variant of concern. We have now identified two new lineages, BA.4 and BA.5. The spike proteins of BA.4 and BA.5 are identical, and comparable to BA.2 except for the addition of 69-70del, L452R, F486V and the wild type amino acid at Q493. The 69-70 deletion in spike allows these lineages to be identified by the proxy marker of S-gene target failure with the TaqPath™ COVID-19 qPCR assay. BA.4 and BA.5 have rapidly replaced BA.2, reaching more than 50% of sequenced cases in South Africa from the first week of April 2022 onwards. Using a multinomial logistic regression model, we estimate growth advantages for BA.4 and BA.5 of 0.08 (95% CI: 0.07 - 0.09) and 0.12 (95% CI: 0.09 - 0.15) per day respectively over BA.2 in South Africa.

BA.4 and BA.5 have identical spike proteins, most comparable to BA.2. Relative to BA.2, BA.4 and BA.5 have the additional spike mutations 69-70del, L452R, F486V and wild type amino acid at position Q493. Outside of spike, BA.4 has the additional mutations at ORF7b:L11F and N:P151S and a triple amino acid deletion in NSP1:141-143del whilst BA.5 has the M:D3N mutation. Relative to BA.2, BA.5 has additional reversions at ORF6:D61 and nucleotide positions 26858 and 27259. In addition, BA.4 and BA.5 have a nuc:G12160A synonymous mutation in NSP8 that was present in Epsilon (B.1.429) and has arisen in BA.2 in some locations. BA.4 and BA.5 have identical mutational patterns in the 5’ genome region (from ORF1ab to Envelope) yet exhibit genetic divergence in the 3’ region (from M to the 3’ genome end). This suggests that BA.4 and BA.5 may be related by a recombination event, with breakpoint between the E and M genes, prior to their emergence into the general population. This scenario is somewhat similar to the relationship between BA.3 and BA.1/BA.2 which also exhibit apparent ancestral recombination. Using the RASCL pipeline we found no compelling evidence of natural selection acting on the S-genes of viruses in either the BA.4 or BA.5 lineages.

The abstract is pretty straightforward, it refers to them finding the widespread growth of BA. 4, and BA. 5 in South Africa, coming to dominate over BA. 2, and mentioning the different mutations it has compared to the variants before. Mutations are really important to analyze from all perspectives, because some have minimal impact, while others have a really meaningful impact, like the one I discussed before.

The second paragraph and the rest of the paper discuss the mutations more in-depth, but they don’t jump to any conclusions about the impact the mutations will have. But one part in specific is the recombination, where they proposed recombination might be one of the sources of the evolution of both newer variants, and of course, selective pressure.

Omicron sub-lineages BA.4/BA.5 escape BA.1 infection elicited neutralizing immunity

Abstract

The SARS-CoV-2 Omicron (B.1.1.529) variant first emerged as the BA.1 sub-lineage, with extensive escape from neutralizing immunity elicited by previous infection with other variants, vaccines, or combinations of both1,2. Two new sub-lineages, BA.4 and BA.5, are now emerging in South Africa with changes relative to BA.1, including L452R and F486V mutations in the spike receptor binding domain. We isolated live BA.4 and BA.5 viruses and tested them against neutralizing immunity elicited to BA.1 infection in participants who were Omicron/BA.1 infected but unvaccinated (n=24) and participants vaccinated with Pfizer BNT162b2 or Johnson and Johnson Ad26.CoV.2S with breakthrough Omicron/BA.1 infection (n=15). In unvaccinated individuals, FRNT50, the inverse of the dilution for 50% neutralization, declined from 275 for BA.1 to 36 for BA.4 and 37 for BA.5, a 7.6 and 7.5-fold drop, respectively. In vaccinated BA.1 breakthroughs, FRNT50 declined from 507 for BA.1 to 158 for BA.4 (3.2-fold) and 198 for BA.5 (2.6-fold). Absolute BA.4 and BA.5 neutralization levels were about 5-fold higher in this group versus unvaccinated BA.1 infected participants. The observed escape of BA.4 and BA.5 from BA.1 elicited immunity is more moderate than of BA.1 against previous immunity1,3. However, the low absolute neutralization levels for BA.4 and BA.5, particularly in the unvaccinated group, are unlikely to protect well against symptomatic infection4.This may indicate that, based on neutralization escape, BA.4 and BA.5 have potential to result in a new infection wave.

Before someone else comments, there are quite a few published papers that go with the motions, and even when their own finding points toward bad outcomes from the vaccines, they will still push them. Otherwise, I suspect they wouldn’t be published.

Here the authors isolated BA. 4 and 5 and tested it against the “immunity” elicited in unvaccinated and Pfizer/J&J vaccinated individuals. I will kindly disregard some of their points for obvious reasons, given the mountain of evidence against it, but the point of my sharing and analyzing this paper was simple. Like Omicron (BA.1) breaking through the vaccinated like a hot knife through butter, newer variants will do the same, in both vaccinated and unvaccinated. My opinions are well known by now about breakthrough infections, and their cost (taxing the body, and slowly chipping the infected).

BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron BA.1 infection

Abstract

Recent emergence of SARS-CoV-2 Omicron sublineages BA.2.12.1, BA.2.13, BA.4 and BA.5 all contain L452 mutations and show potential higher transmissibility over BA.2. The new variants’ receptor binding and immune evasion capability require immediate investigation, especially on the role of L452 substitutions. Herein, coupled with structural comparisons, we showed that BA.2 sublineages, including BA.2.12.1 and BA.2.13, exhibit increased ACE2-binding affinities compared to BA.1; while BA.4/BA.5 shows the weakest receptor-binding activity due to F486V and R493Q reversion. Importantly, compared to BA.2, BA.2.12.1 and BA.4/BA.5 exhibit stronger neutralization escape from the plasma of 3-dose vaccinees and, most strikingly, from vaccinated BA.1 convalescents. To delineate the underlying evasion mechanism, we determined the escaping mutation profiles, epitope distribution and Omicron sub-lineage neutralization efficacy of 1640 RBD-directed neutralizing antibodies (NAbs), including 614 isolated from BA.1 convalescents. Interestingly, post-vaccination BA.1 infection mainly recalls wildtype-induced humoral memory and elicits antibodies that neutralize both wild-type and BA.1. These cross-reactive NAbs are significantly enriched on non-ACE2-competing epitopes; and surprisingly, the majority are undermined by R346 and L452 substitutions, namely R346K (BA.1.1), L452M (BA.2.13), L452Q (BA.2.12.1) and L452R (BA.4/BA.5), suggesting that R346K and L452 mutations appeared under the immune pressure of Omicron convalescents. Nevertheless, BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1 but do not respond to wild-type SARS-CoV-2, due to the high susceptibility to N501, N440, K417 and E484. However, these NAbs are largely escaped by BA.2 sublineages and BA.4/BA.5 due to D405N and F486V, exhibiting poor neutralization breadths. As for therapeutic NAbs, LY-CoV1404 (Bamlanivimab) and COV2-2130 (Cilgavimab) can still effectively neutralize BA.2.12.1 and BA.4/BA.5, while the S371F, D405N and R408S mutations carried by BA.2/BA.4/BA.5 sublineages would undermine most broad sarbecovirus NAbs. Together, our results indicate that Omicron can evolve mutations to specifically evade humoral immunity elicited by BA.1 infection. The continuous evolution of Omicron poses great challenges to SARS-CoV-2 herd immunity and suggests that BA.1-derived vaccine boosters may not be ideal for achieving broad-spectrum

Now, this is the most interesting paper of all, and I think relatively new one. Bear in mind the vaccinated here are all vaccinated with CoronaVac, inactivated, time-tested way of creating vaccines, I sometimes joke it is useless but harmless. Again, the authors pay attention to new variants of concern dominating over the old ones, and the impact certain mutations have on the binding of human ACE2.

To simplify all the complex molecular biology, and science-speak, BA.2.12.1 (the one currently growing and dominating Europe, and if I recall correctly the US), and BA. 4 and 5 both escape the antibodies elicited by 3 doses of the vaccine and also by people infected with BA. 1 and vaccinated. Meaning your body is still recalling the wild-type (Wuhan strain) spike, even when you are vaccinated with the whole (dead) virus, the explanation is pretty simple, and I covered it already. A lot of potent antigenic sites (the things that make your body produce an immune response) from other pathogens. Immune imprinting is happening with all vaccines, the only debatable part would be, at what level.

The mutations of all the new “variants” “suggesting that R346K and L452 mutations appeared under the immune pressure of Omicron convalescents.”

BA. 1 antibodies specific antibodies can neutralize BA. 1 but not ancestral (Wuhan) SARS-CoV-2 because of specific differences in amino acids.

The closing of the abstract is the most important part because it doesn’t apply only to this paper, or this vaccine, but to the whole vaccination effort. As of now, Omicron is evolving to evade specific types of immune responses.

while the S371F, D405N and R408S mutations carried by BA.2/BA.4/BA.5 sublineages would undermine most broad sarbecovirus NAbs. Together, our results indicate that Omicron can evolve mutations to specifically evade humoral immunity elicited by BA.1 infection. The continuous evolution of Omicron poses great challenges to SARS-CoV-2 herd immunity and suggests that BA.1-derived vaccine boosters may not be ideal for achieving broad-spectrum

Humoral immunity basically means antibodies, producing non-neutralizing antibodies in every vaccinated person is putting selective pressure on the virus to continuously evolve to evade humoral immunity (your faster immune response), making it more difficult to deal with. The closing statement is the most important one, and I already covered it, there won’t be an Omicron vaccine because of everything discussed so far, and more. Doing so would only make things worse.

Let’s dig deeper into the paper.

However, we found that BA.2 sub-variants BA.2.13 and 13 BA.2.12.1 showed increased immune evasion capability than BA.2, with BA.2.12.1 stronger than 14 BA.2.13; while BA.4/BA.5 confers even stronger antibody escape. The drop in 15 neutralization efficacy is more severe in the plasma obtained from individuals infected by BA.1 16 who had received 3-dose CoronaVac before infection

As I mentioned above, immune imprinting is happening even when you are not producing a highly inflammatory protein by the hundreds of billions, and even old-type vaccines using “whole dead virus” have a similar effect of making your body remember the old spike, and not “learn” the new one, adding fuel to the fire, since it can evade a lot of your antibodies.

This suggests that certain21 BA.2 mutations may specifically evade broad sarbecovirus neutralizing antibodies which are 22 substantially enriched in vaccinated SARS convalescents20. Together, these observations indicate 23 that the newly emerged BA.2.13, BA.2.12.1 and BA.4/5 display stronger and distinct humoral 24 immune evasion than BA.1 and BA.2.

The authors go to further delineate the specific antibody response and groups, and how each mutation impacts, to explain the effective immune evasion of all variants discussed here.

These broad NAbs in groups A, B and C are also shown to be enriched in individuals who received a booster dose of mRNA vaccines , which probably accounts for the high plasma neutralizing activity of 3 dose mRNA vaccinees against Omicron variants. Nevertheless, BA.1-stimulated groups B and C NAbs were significantly evaded by BA.4 due to F486V and L452R, concordant with results from DMS

This will be important in a few sentences, the same natural antibodies “enriched” by the mRNA and “effective” (heh) against Omicron are significantly evaded by BA.4 (and 5 probably) due to those specific mutations. Bear in mind this, high plasma antibodies in mRNA vaccinated.

In this study, we showed that Omicron is continuously evolving under immune pressure, and rationalized the appearance of R346K (BA.1.1) and L452 substitutions. Unlike when Omicron first appeared, now Omicron sublineages have started to target the humoral immunity induced by Omicron itself, including the humoral immunity induced by post-vaccination Omicron infection.

This poses a great challenge to the currently established herd immunity through WT-based 1 vaccination and BA.1/BA.2 infection. Similarly, this observation also suggests that Omicron BA.1-based vaccine may not be the ideal antigen for inducing broad-spectrum protection against 3 emerging Omicron sublineages.

If you are a few months old readers (or a couple of years Twitter follower) none of this will be new, Omicron, as expected, is now evolving to evade the fixated immune response from the vaccines, with a similar mutation Delta acquired and caused breakthrough infections by the bucketload, mutations that Delta did not acquire naturally, it was from selective pressure from you know exactly what.

Nice presentations of all the changes in all the new variants!

Omicron as a vaccine has a very poor antigenicity, and a very poor “irritating ability” towards your body, it only works “as a live vaccine” if you are previously unvaccinated, and when you are vaccinated, your immune memory it simply stays fixated on the old spike from the Wuhan strain, producing a lot of non-neutralizing antibodies, putting selective pressure that produces new, more immune evasive competent variants, and causing low grande long term inflammation. Because when you don’t have a very broad neutralizing immune response, the body will use the antibodies to infect other types of cells and cause different types of apoptosis (ferroptosis and pyroptosis being the preferred ones).

Paxlovid, like Pfizer's own vaccine, is one of the worst products designed recently, it does nothing against the viral infection, and I would deduce, by my observations, it will create new mutations, not seen before in any of the other variants. Time will tell what these variants with these new mutations will do, I can safely extrapolate they will cause more immune dysfunction, and more “chronic” Covid because you are putting selective pressure on the virus to stay still for days and go back with a vengeance.

Be advised that Omicron, especially the new variants, is impacting and hitting the gut pretty hard, and symptoms might last up to 4 weeks after the infection, similar to what Alpha did, Alpha used to hit the gut pretty hard, and last 2-3 weeks. Gut health should be one of your focuses, among everything I covered before to make your physiology ready to handle the virus.

I am better at forecasting than most people, especially “scientists”, and I don’t see highly concerning developments, for now, just trends to keep an eye on, if you take care of yourself, these should not be a problem, just a hindrance for a couple of weeks, because the new variants will create new waves.

And you should oppose the high-income hypochondriacs because some countries and a portion (the wealthy, insane, mentally unstable portion) of the population will demand more restrictive measures. Never thought I would live to see the day the “wealth” would ask the State to make them slaves.

I have more to share, but this is enough for now. Maybe I will send a couple of shorter emails in the next few days, writing about just single papers that I find interesting or pertinent.

Take care of yourselves, your health, and your loved ones, bumpy road ahead.

Deep appreciation for all the supporters!