More "domain specific" vaccines and XBB

So many variants

While I work my way through the Galectin-3 piece, here is an… rather ominous update. This is a continuation of this one, but this time no relation to Moderna.

Moderna new "domain specific" vaccine

Some part of me had hopes that only arrogant and/or corrupt American companies would attempt this next step in the futile effort to outrun the incredible pace at which SARS-CoV-2 has been mutating exactly since the introduction of the mRNA and adenovirus-based vaccines.

Apparently, I have levels of optimism I wasn’t aware. I won’t even bother to break down the vaccine sales pitch, I will just point out the potential disaster to come.

An mRNA vaccine with broad-spectrum neutralizing protection against Omicron variant sublineages BA.4/5 -included SARS-CoV-2

Accumulated evidence demonstrated that two-dose Wild type (WT)-based mRNA vaccines effectively induce neutralizing immunity to Delta and Beta, albeit with varying degrees of decline, but had low or completely absent neutralizing antibodies against Omicron2. Therefore, it is imperative to develop an mRNA vaccine against Omicron because of its high infection rate and immune evasion properties. Indeed, a recent study found that Omicron-based mRNA vaccines induced potent neutralizing antibodies against Omicron but could not resist other SARS-CoV-2 variants3. In this study, we prepared and identified a Delta RBD-based mRNA vaccine with broad-spectrum neutralization against SARS-CoV-2 WT, Beta, Delta and Omicron variants. We designed 4 Delta RBD sequences with different UTRs and codon optimizations using Delta’s RBD as the target antigen for the mRNA coding sequence (CDS). The most efficient of these mRNA constructs, mRNA-D2, was selected by Western blotting based on its in vitro expression levels . Western blotting results confirmed that Delta-RBD could be expressed in multiple cell lines in vitro

A triple-RBD-based mucosal vaccine provides broad protection against SARS-CoV-2 variants of concern

The rapid mutation and spread of SARS-CoV-2 variants urge the development of effective mucosal vaccines to provide broad-spectrum protection against the initial infection and thereby curb the transmission potential. Here, we designed a chimeric triple-RBD immunogen, 3Ro-NC, harboring one Delta RBD and two Omicron RBDs within a novel protein scaffold. 3Ro-NC elicits potent and broad RBD-specific neutralizing immunity against SARS-CoV-2 variants of concern. Notably, intranasal immunization with 3Ro-NC plus the mucosal adjuvant KFD (3Ro-NC + KFDi.n) elicits coordinated mucosal IgA and higher neutralizing antibody specificity (closer antigenic distance) against the Omicron variant. In Omicron-challenged human ACE2 transgenic mice, 3Ro-NC + KFDi.n immunization significantly reduces the tissue pathology in the lung and lowers the viral RNA copy numbers in both the lung (85.7-fold) and the nasal turbinate (13.6-fold). Nasal virologic control is highly correlated with RBD-specific secretory IgA antibodies. Our data show that 3Ro-NC plus KFD is a promising mucosal vaccine candidate for protection against SARS-CoV-2 Omicron infection, pathology and transmission potential.

I had picked up this small trend among little over half a dozen papers in the last 12 months in which some researchers argued using other parts of the virus as vaccine targets, to varying degrees of success, I even covered a few promising ones here because of the peculiar and less nocive immune response in comparison to the S protein.

But since Spike-based vaccines are dead in the water, ineffective at best, and clearly harmful at any honest angle you look at it, all companies are now converging on the other easier targets, still in the damn Spike Protein, but arguably “more precise”.

In the Moderna domain-specific piece I argued why that is a bad choice, and I will reiterate here and add some more to it, without going into the molecular and structural aspects of both parts (NTD and RBD).

The NTD is a supersite, a magnet for antibodies to neutralize the virus, since the first wave of Omicron BA. 1 it has been changing with the last two variants (BA. 5 and the ones coming now), it has been changing a lot, around the NTD supersite. A change around it gives it more immune evasive properties, not only in the vaccinated but in unvaccinated (natural immunity) too. Using this part of the virus will inevitably fuel mutations at an alarming pace that will get all “experts” by surprise and bite people in the ass.

RBD is a minor problem in normal circumstances (natural infection, and to some extent breakthrough infection among the vaccinated), but as a vaccine target, it is two for the price of one. The molecular mimicry of other pathogens guarantees a potent immune response, basically an immunological inflammatory bomb. The RBD is also a target of antibodies in the unvaccinated, it confers good protection (this is the reasoning behind using it as a vaccine target from a superficial, simplistic perspective), but the antibody response in vaccinated is pretty weak to non-existent.

Major changes in the RBD will aid the virus immune evasion and inflammatory creation. A subscriber asked me to cover XBB given the talks around some circles about its possible pathogenicity. XBB is not the only new variant that has concerned some researchers and people, but here is the quick and dirt of it.

Kudos to whoever created the image

The H655Y was responsible for changing how Omicron entered cells and some argue it is what conferred its lower pathogenicity. But it is also one that confers great transmissibility. P681H increases the cleavage of the Spike. N754K creates a possible new cleavage site, changing how the virus behaves. D796Y is one that confers immune evasion. Other changes are mutations that they will confirm are drug-resistance changes. Here is a good Twitter thread from one of the authors of the paper himself.

Yunlong Richard Cao @yunlong_cao

XBB's superior antibody escaping capability not only comes from the convergent RBD mutations, it's NTD mutations, V83A and 144-deletion, are also extremely good at escaping NTD-targeting neutralizing antibodies.

If you live in the Northern Hemisphere, I highly HIGHLY recommend you to go and buy Bromhexine. I don’t know where the winds will shift, and I have always been one to operate from “better safe than sorry”.

The Galectin piece will take a couple of days to get done, maybe Friday or latest Saturday, so maybe nothing from me until then, or unrelated things like supply chain/logistics, the other things I cover.

Appreciate all the support from my subscribers and people who use KoFi, without your support I wouldn’t be able to do this.