Moderna new "domain specific" vaccine

Subtly designing a plague

My mitochondria-related piece is taking longer than expected to write not because it is extensive, it is just complex, didn’t expect to write anything today yet, but the opportunity presents itself sometimes. I won’t break down this paper as I usually do, because I don’t see a point.

Now is a good time to remind anyone of this.

Current mRNA is almost "unfixable"

The immune response your body produces from mRNA is hardcoded in you, you can’t simply bypass it. And as anyone remembers, the mRNA vaccines produce a strong Th17 response, a highly inflammatory immune state linked to dozens of diseases and autoimmunity. And the following will be even more important.

The shift in mRNA elicited immunity

The multiple vaccinated antibody response is shifting towards a less inflammatory, less neutralizing subclass, IgG4. If you didn’t read my Many faces of SARS-CoV-2 proteins, you will understand shortly.

Development of SARS-CoV-2 mRNA vaccines encoding spike N-terminal and receptor binding domains

With the success of mRNA vaccines against coronavirus disease 2019 (COVID-19), strategies can now focus on improving vaccine potency, breadth, and stability. We present the design and preclinical evaluation of domain-based mRNA vaccines encoding the wild-type spike-protein receptor-binding (RBD) and/or N-terminal domains (NTD). An NTD-RBD linked candidate vaccine, mRNA-1283, showed improved antigen expression, antibody responses, and stability at refrigerated temperatures (2-8°C) compared with the clinically available mRNA1273, which encodes the full-length spike protein. In mice administered mRNA-1283 as a primary series, booster, or variant-specific booster, similar or greater immune responses and protection from viral challenge were observed against wild-type, beta, delta, or omicron (BA.1) compared with mRNA-1273 immunized mice, especially at lower vaccine dosages. These results support clinical assessment of mRNA-1283 (NCT05137236)

So Moderna basically wants to engineer a perfect immune evasive variant by the looks of it. Why is that ? Simple, a lot of the new mutations in the newest Variants of Concern, variants that are going through convergent evolution, have plenty of mutations around the NTD supersite.

The problems here are two-fold. An antigenic supersite is what the name implies, a place with potent antigenicity, for your antibodies to do their work, and this is how they are pulling the same trick as they did with the Spike Protein and keeping the FCS, SEB insert. Because a supersite for antibodies guarantees a strong immune response, it will also become a magnet for mutations. Most natural antibodies are targeted to this region.

The second is the Galectin-fold. I still need to write my Galectin piece, but for now, remember that most vaccinated persons are shifting their IgGs (antibodies) toward IgG4. See the image below.

The RBD is even worse, with antigen mimics from all of these diseases, which has been one of my arguments for over a year on why there is such a strong presence of Th17 in many vaccinated persons, and why this disease presents as everything. (Because the antigen of a specific disease will give you an immune response for that specific disease)

Source

Do not be mistaken, all of these companies are data-mining social media for information at an alarming scale, so they are fully aware of all the different problems mRNA-LNP face, from your own body competing to avoid translating (the process in which the mRNA instructs your cells to produce the Spike Protein), to what actually the cells are producing, because there is no biological possibility it is 100% perfect 100% of the time (in fact, most of the experts I talked to agree 30% is a good “guesstimate”).

The idea behind the change, is shorter length> fewer translational problems> fewer problems with protein quality, and everything else. There are also hidden things inside the S2, removing it abrogates the chances of further “injury”, since the Spike is truly nature’s biggest “hit and run”.

Spike protein S2 enhances amyloid-β production

Some highlights for future reference, when this inevitably backfires at some level.

Compared with mRNA-1273–vaccinated mice, those vaccinated with mRNA-1284 and mRNA1285 (both 1 µg) produced higher interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) expression when CD4+ T-cells were stimulated with the S1 or RBD peptide pool; similar results were observed in CD8+ T-cells, when stimulated with the S1 or RBD peptide pool including those from mice vaccinated with mRNA-1283.

Overall, the greatest variant-specific nAb fold increases were observed in groups administered matched variant boosters for both mRNA-1273 and mRNA-1283, supporting the use of variant-matched boosters

D614G and BA.1 viral N gene RNA copies were similarly low in mRNA-1273 and mRNA-1283–vaccinated mice. A lower level of protection was observed against BA.1 than D614G, regardless of vaccine or dose

The best, for last.

demonstrating the ability of these vaccines to induce rapid antigen expression lasting several days at levels greater than mRNA-1273, even at lower doses

That is exactly what I want, persistent antigen production, with a highly inflammatory immune response hardcoded in my physiology, all over my body, regardless of dosage.

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