Spike protein shape and vaccine failure

The Surprising Impact of Protein Shape on Immune Response

A recent trend in my Substack as of the last few weeks is significant papers being published that either lead me to refine and further advance certain lines of inquiry or prove evidence to older propositions, therefore helping “make my case” or in fancier words “giving evidence to my hypotheses (plural)”. This will be lighter on the science but very heavy on significance and “impact”.

I have written and somewhat forecasted the surfacing, general (immune) response, and the shifts in many variants, but after a while, I decided to focus my efforts on other avenues since variant chasing might generate clicks, and get you subscribers, but it is intellectually void (plus you are just fueling the fear hamster wheel). To understand some of the points I am about to make these are good reference substacks, but I will summarize it anyway.

Spike Protein as a endotoxin delivery system

Another HIV "piece" in the Spike Protein

Spike Protein, novel binding sites and coagulopathy

But for quite a substantial amount of 2022 one mild criticism of mine towards researchers was how they left many mutations “uncategorized” meaning a mutation occurred, but we didn’t have much or any data on its effect. Mild by the fact that I do understand the decision to follow significant or impactful mutations such as L452R a mutation that directly affected SARS2 replication rate, and others mutations since they clearly give the virus an absurd advantage over the “older” variants. From a pandemic perspective, these mutations have more weight than others. Below is the most pertinent quote from one of the Substacks above.

It is safe to just say it now that there are cryptic functions all over the Spike Protein sequence, and depending on its conformation (shape) it either “activates” said function, or remains buried, without doing much. Other aspects of my stupid observation and research do apply but I would get way ahead of myself for now. Non-canonical proteins have more functions and are often much overlooked by researchers than canonical ones too, a topic to delve into if you like this subject matter.

This is important to keep in mind. Spike Protein. Shape. Sequence (amino acids), function.

A paper was uploaded today on the Biorxiv server, a pre-print website, where you can upload your research before it gets peer-reviewed, I will cover it briefly. In this paper the authors used a new vaccine platform, using ferritin at a nanoscale. Ferritin nanoparticles are a promising nanomaterial for many applications, sadly vaccines being one of the most applicable ones.

They based their vaccine (named DCFHP) on the Wuhan Spike sequence, but they decided to investigate what the immune response using other variants of Spike would be.

Here we report the expression, purification, thermal stability, and immunogenicity profiles of these vaccine candidates. While the expression of all vaccine candidates in mammalian cells was similar, size-exclusion chromatography (SEC) indicated differences in the homogeneity of the purified nanoparticles. In addition, different vaccine candidates exhibited substantially different thermal unfolding profiles, as determined by differential scanning fluorimetry (DSF). Strikingly, immunization with a vaccine candidate based on a particular VOC did not always elicit the highest neutralization titers against that VOC. Indeed, overall, immunization with the original DCFHP, based on the Wuhan-1 strain, elicited the most cross-reactive neutralizing titers. Our results highlight that some variant-specific vaccine candidates may be suboptimal future vaccines.

In addition, the thermal melting transitions of the DCFHP-variants were different from those observed with DCFHP (Figure 5), suggesting that protein stability is impacted. Most strikingly, the ability of DCFHP-variants to elicit neutralizing antisera in mice was generally inferior to that of DCFHP – measured not only against the WT virus, but also against the corresponding VOCs (Figures 7, 8).

Taken together, our results indicate that, at least in the background of DCFHP, predicting the effect of mutations on the immunogenicity of vaccine variants is not as straightforward as what one would anticipate for introducing amino acid substitutions into a rigid protein. Rather, it appears likely that these mutations are impacting the structural integrity of the spike protein and/or exposing non-neutralizing epitopes, with consequences for immunogenicity. This result is particularly striking given that these immunizations were done with purified, homogenous nanoparticles – utilizing a platform amenable to protein purification, unlike some other vaccine platforms. Earlier studies have reported that the SARS-CoV-2 spike is dynamic, and not a rigid protein. Taken together, these results suggest that, for the creation of optimal vaccines against VOCs, it may be important to profile each mutation individually for their impact on protein structure and immunogenicity

As some would expect, mutations not only affect function but also affect immunogenicity especially when used as a vaccine, something I wrote months before they even proposed using Omicron as a vaccine, since Omicron itself was a very poor vaccine target, particularly the reason they decided for the bivalent booster.

All the paragraphs quoted above are important but the really impactful section is the one citing thermal melting transitions, meaning in simpler terms how a protein behaves when it is heated this can change its shape, and here they found the spike loses its structure and its prior behavior (its thermal “stability”) with the mutations, losing its shape. The thermal stability of the Spike Protein produced by novel vaccine platforms was brought up early by me and a few others, and I had greater worry about this because I was very aware of how “multifunctional” the Spike Protein is. There is no guarantee of proper immunogenicity, but this goes far beyond just an immune response.

This is evidence that misshapen Spike Protein is being produced, do you the quote from one of my substacks ? The shape of a protein is important, and we do not know to this very day what the original mRNA vaccine produced, and misshapen Spike will produce non-canonical signaling. Non-canonical means unknown or yet to be researched, we do not have a clue what is being exposed to the body when the Spike is misshapen, and that can influence the adverse effects heavily.

Beyond a non-canonical response, misshapen proteins especially the Spike Protein are soluble proteins. Depending on the context, such as the one here, you can interpret soluble Spike Protein (sSP) as a “floating” protein, depending on its shape it maintains a lot of the functions of the Spike Protein but it is floating in fluid and potentially bloodstream, and here is where the fact that the SP can pierce membranes on its on comes into play.

Various sections of the Spike Protein can interact with other receptors in a myriad of cells, the Spike Protein (especially with the proline modifications), misshapen, or not become an endotoxin magnet. The Spike also has other cleavage sites.

Given my history of brain and neurological injuries, I have always paid more attention to the effects of the virus and its impact on our metabolism in regard to the brain. And ever since I found an over-representation of the Kynurenine Pathway in response to the virus, and all the different impacts the virus can exert via a dozen different pathways on neurological health, I “forecasted” that a massive drop in cognitive capacity would occur. What we just discussed here plays a very significant role in this.

And as I expected, many countries will use different excuses to position themselves to gobble up any competently cognitive talent as fast as they can before the cognitive decline affects the country's economy and functions too hard.

South Korea boosts visas for skilled workers amid labor shortages

South Korea aims to issue a record number of visas for foreign skilled workers this year, as the justice minister announced on Wednesday a fifteen-fold increase in the annual quota to 30,000 in order to help companies overcome staffing shortages.

Canada is also changing its laws, especially in regard to tech workers. A war for cognitive talent is about to be set off.

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