Persisting immunological differences after SARS2 vaccination

One of those questions that has been on my mind, is whether vaccination against SARS2 really triggers some sort of persisting immunological abnormality in regards to how the body responds to this virus. It’s tempting to assume that after sufficient breakthrough infections and waning of the vaccine, everyone just deals with it in the same way.

This however, is not the case. The immune response remains fundamentally different. Specifically, what you see after vaccination is that the body deploys a strong CD8+ T cell response against SARS2. On the other hand, in people who remain unvaccinated, the T cell response is dominated by CD4+ T cells.

They’re looking here at young donors aged 27 on average, all of whom had mild infections, 181 days ago on average. Two of their donors are unvaccinated and those donors show a different immune response, with a CD4+ dominant ratio:

The overall CD4+IFN-γ+/CD8+IFN-γ+ ratio decreased after the enrichment process to 1.84 ± 2.17, with donors 3 and 5 maintaining their CD4+IFN-γ+ predominance (Fig 5E). Interestingly, these donors are the only subjects in the study group that were not vaccinated, so we performed a Fisher exact test to characterize this association. We found that the CD4+IFN-γ+/CD8+IFN-γ+ ratio is strongly associated with the vaccination status (P < 0.001), showing that unvaccinated subjects present a higher CD4+IFN-γ+/CD8+IFN-γ+ ratio.

The unvaccinated donors showed a much weaker CD8+ T cell response:

When analyzed individually, donors 3 and 5 showed much lower cytotoxic potential, with marginal difference between SARS-CoV-2-pulsed blasts and unstimulated blasts. As mentioned before, these donors had larger quantities of specific CD4+ cells compared with specific CD8+.

So there is a persisting immunological difference. The immune system is just responding in a different manner. Is that a good thing, or a bad thing? Well, these CD8+ T cells will have to do the job of killing infected cells for vaccinated people. These cells depend on whatever small peptide an infected cell is displaying in its MHC molecule. As long as that remains the case, there’s a relatively simple way for the virus to escape them: Stop the infected cell from displaying the peptide in its MHC molecule.

This may not be necessary however, if the B cells respond with IgG4 antibodies against the virus. These antibodies would bind to the peptide in the MHC molecule, stopping the CD8+ T cells from doing their job.

Keep in mind, the CD4+ T cells are there for a reason. After infection they have the job of activating NK cells too. The Interleukin-2 released by these Spike targeting CD4+ T cells also has an important job: It tells NK cells to proliferate themselves.

So if the CD8+ T cells are not doing the job for the unvaccinated, how is their immune system responding? Well, the NK cells have various receptors, some of which bind to Spike. An example is NKG2D. This receptor is upregulated in NK cells seen in blood after infection.

However, keep in mind, your blood is supposed to be sterile, unless things are really going wrong. The NK cells migrate to the tissues where the virus shows up, like the lungs. So when you see a sudden decline in certain receptors in the NK cells in blood, that’s an indicator that those NK cells have moved into the relevant tissues to do their job. You see a significant decline in convalescent donors in NK cells with the NKp46 receptor, especially after severe infections. Other studies also find that NKp30 and NKp46 are important in eliminating the virus.

So if you follow what I’ve explained here, it would seem that in vaccinated people, CD8+ T cells tend to do the job of killing infected cells, whereas in unvaccinated people NK cells perform this job. This matters for a number of reasons. It’s the NK cells that have to do the job of eliminating the macrophages in the lungs where the virus persists. When they fail to do this, the virus persists.

The NKp46 receptor is known to be very important, in generating variant independent immunity to influenza. Influenza constantly mutates its hemagglutinin, but no matter how it mutates, it still needs to be able to bind to sialic acids. The NKp46 receptor is full of sialic acids, so despite the constant mutations, the NK cells can find the influenza virus infected cells. SARS2’s Spike similarly binds to sialic acids.

You would expect it to follow from this, that over time, as genetic diversity of the virus continues to increase, the natural variant-independent response will perform increasingly better than the variant-dependent response induced by vaccination.

Most people seem to forget that the immune system is characterised by constrained space. You can’t have your kidneys or your skin or any other organ full of white blood cells. This undermines the function of such organs.

The NK cells that work against SARS2 should generally also work against the other most dominant respiratory viruses, like influenza.

Through mass vaccination we’re forcing the CD8+ T cells to do the job these NK cells would normally be doing. And whereas the NK cells maintain their effectiveness despite growing genetic diversity of Spike, there’s now clear evidence of widespread T cell exhaustion in the population.

The impact of this problem will reveal itself as the circulating genetic diversity of the virus increases. You will need more and more CD8+ T cells, to do the same job as a given number of NK cells do.

The most important thing to take away from this is that there are persistent differences in the immune response between vaccinated and unvaccinated people. The IgG4 response has been discussed at length by me and others, but the CD8+ T cell dominant response in the vaccinated has to be kept in mind too.

The eventual outcome of this is the unravelling of the human immune system. That’s a big claim to make, but all the signs are there: The IgG4 response, the elevated level of T cell exhaustion that can now be observed in most of the population, the long COVID cases that increase with every new wave.

It seems that cannabidiol causes a shift in the body’s lymphocyte population, with a reduction in B cells and T cells, while NK cells are increased. THC is known to increase T cell apoptosis. It’s known that heavy cannabis use leads to better outcomes in HIV.

Cannabinoids are the closest thing I’ve seen to a solution.