mRNA Vaccines and Immunopathology

ChrisPrattAlphaRaptr - [original thread]

I'm reluctant to dive into another argument considering that I'm already neglecting to reply to other people who deserve it elsewhere, but this seems important.

These are top class scientists raising concerns in their area of expertise about the vaccine. Ulms is postdoc cedar Sinai and genetics resident at upmc and harvard med phd. Goh Kiang Hua, MD, is a consultant general surgeon and Fellow of the Royal College of Surgeons (FRCS).

If that's your bar for top class scientist, you've got one right here with a more relevant specialty and equivalent experience to the post-doc. Note that neither surgery or genetics are vaccinology/immonology or even infectious disease. Note that (presumably) the last time the surgeon would have learned about vaccines/immunology would have been in medical school in the 80s. Not to throw shade on either of their credentials/knowledge; just to underline that specialties can be very different and the knowledge base of a geneticist is very different from an infectious disease specialist or immunologist.

Although there have been past studies on the cellular localization of LNPs (more on this below), different LNP formulations would enter different cell types, Dr. Ulm stated, so “we don’t know where in the body they’re going,”

This is probably important to know for scientists studying the immune response, but I'm very skeptical it matters for recipients of the vaccine/adverse events?

that seems to mean that people who get the mRNA vaccines are going to have a much greater range of cells and tissues vulnerable to cytotoxic [T-cell] attack…with side effects that may not manifest for years (with cumulative damage and chronic inflammation).

At first glance this is nonsense. mRNA is short lived, and the idea that mRNA would specifically persist and continue to make protein in the brain for years is silly. It turns out the medium article misrepresented what Ulm was trying to say:

There is potential for enhanced immunostimulatory impact through this process, but also elevated risk of cytotoxic, inflammatory, and autoimmune effects, even more so if the liposomal particles can traverse the blood-brain barrier to enter, for example, motor neurons or oligodendrocytes (the glial cells targeted in multiple sclerosis). These effects, in turn, depend critically on the organ and tissue profile of the cells that receive the LNPs, translate the mRNA payload, and dock the antigenic protein on MHC-I cell-surface molecules. This is doubly true in the case of COVID-19 in light of the still-evolving picture of SARS-CoV-2 immunology. Immune responses appear to be incremental and fleeting, both for natural and vaccine-mediated immunity, suggesting a likely need for multiple boosters after an initial inoculation. Therefore, if cytotoxic responses to integral tissues are transpiring through MHC-I-mediated presentation of SARS-CoV-2 spike protein, the effects may be at first subclinical, manifesting fully only after successive immunizations over months or years.

tl;dr - if you generate some covid CD8s in early vaccines, after years of repeated LNP boosters you might accumulate sufficient CD8s to cause immunopathology. Note that B cells generating protective neutralizing antibodies almost certainly wouldn't have this concern, meaning that it wouldn't be a problem for the initial shots people are getting now. It would also be pretty obvious as we'd notice significant autoimmunity shortly after receiving the booster so we'd catch it very early in clinical trials.

What doesn't make sense is why they're suggesting immunopathology in the brain when it is 'immunoprivileged' (sort of), and, more importantly, the concentration of protein production is presumably at least 5 orders of magnitude higher at the site of injection and in draining lymph nodes. If anything, expect immunopathology in the muscle. This kind of experiment was almost certainly done in animal models early on and an answer should be out there, I just don't have time to dig through those papers right now.

They also don't mention that we've never had a vaccine that generated robust CD8 mediated immunity. You need to get the antigen and adjuvant into a specific class of antigen-presenting cell to prime them properly. There's also the relatively poorly understood issue that they typically return to where they are primed; if you're vaccinated and primed in the arm the CD8s typically won't spontaneously travel to the brain. Overall, I'm confused why they focused on the brain aside from shock value.

The surgeon then mentioned cases of immune thrombocytopenia — a life-threatening blood clot or platelet disorder — occurring shortly after mRNA vaccination. While no causative link has been confirmed, he considered that maybe the LNPs had carried the mRNA vaccine into the megakaryocytes (platelet-producing cells) in the bone marrow. The megakaryocytes then express the spike protein, only to be marked for destruction by cytotoxic T-cells. Platelets then become deficient, causing thrombocytopenia. Of course, he emphasized that these are just speculations.

You often get ITP in scenarios of strong immune activation. It's poorly understood, but that statement is making a big stretch; if those patients had lots of CD8s from, say, a previous infection, why would they specifically damage megakaryocytes and not the muscle or surrounding tissue actually expressing large amounts of spike protein?

I used to work in gene therapy and recall how we’d obsess on tissue tropism for our vectors before considering clinical trials, so I’m bewildered that this information seems almost absent for an almost entirely new vaccine modality…Without knowing more about the specific LNP formulations and their cellular and tissue trafficking patterns, we just can’t say much of anything with certainty.

Gene therapy and mRNA vaccines are a poor comparison to make (although I suspect Ulm knows this and the journos optimized for shock value). One is permanently editing the genome and will produce those proteins for the rest of your life. Moreover, there's the concern that if you stick a gene therapy vector into a rapidly dividing cell and it inserts into the wrong place in the genome you can get cancer, which was actually seen with pretty high probability in the very early trials. mRNA vaccines transiently produce spike protein on the order of days-weeks.

I could provide a better researched answer if I had time to read some of the older LNP papers which almost certainly looked at these questions in animal models.