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mRNA Vaccines: What Happens

A question that comes up a lot about mRNA vaccines is what happens at the cellular level after you’re injected with one. The mechanism of any such vaccine is to cause cells to produce a viral protein antigen, but which cells actually do this? It’s also understood that mRNA vaccines tend to act as their own adjuvant and stimulate a further immune response that improves their efficacy – but how does that happen as well?

Let’s dive into some details. But while doing so, I need to note up front that not all of these details are completely known, immunology being what it is. Still, over 25 years of work on the idea of mRNA vaccines have provided a lot of information, which (never forget!) is the only reason that the current vaccines could be developed so quickly. If you remember Tina Turner’s 1986 song “Overnight Sensation”, you’ll have the right idea: after years (decades) of hard work, false starts, and expensive lessons learned, mRNA vaccines for infectious disease were finally ready to come out of nowhere. I’ve linked to this review before (open access), but it’ll give you an idea of how long all this has been in the works.

One thing to note is that such vaccines can have rather different effects if administered through different routes. Here’s a mouse study in 2015 from researchers at Penn and Acuitas (the Vancouver lipid company that’s now partnered with Pfizer and BioNTech for their vaccine), looking at lipid nanoparticle mRNA injected several different ways (intradermally, intraperitoneally, subcutaneously, intramuscularly, and intravenously). They just used the RNA for firefly luciferase as a marker for convenience, because you can inject the mice later on with luciferin (the partner for the enzyme) and just look to see where they light up. For those of you outside the biomedical sciences, I am speaking completely literally.

What they found was that the mRNA injected i.p or i.v. went straight down to the liver, which is not a surprise. You might remember Alnylam, the company developing siRNA therapies – their big success has been targeting rare disorders in the liver, because they’re well aware that that’s where most of their RNA constructs are going to park, anyway. In this mouse model, the mRNA hit the hepatocytes and caused them to make plenty of luciferase, but not for long: at Day 1, the livers were lit up like a used car lot, but by Day 3, everything was gone. At that point, though, there was still some light coming from the sites of injection.

And that’s what you see with the intramuscular dose as well: a good part of the dose goes to the liver, but in that case there’s a substantial effect in the muscle tissue itself, and it’s longer-lasting (out to about a week of protein expression). The subcutaneous and intradermal injections, though, didn’t really show up in the liver at all: the sites of injection light up and keep on going, again, for about a week. This paper didn’t note it, but you would also expect all three of these injections to have some drainage into the lymphatic system as well, which is also important for setting off the immune system. Here’s a 2017 paper from CureVac and Acuitas that demonstrates this in monkeys, though, in the context of experimental vaccines for influenza and for rabies – they could see activation of the innate immune system at the injection site after an intramuscular dose and at the corresponding draining lymph nodes. That’s an important effect with vaccines in general, as you’d imagine, since that’s one of the big sites for antibody maturation and B-cell selection, as mentioned in the last post here. This 2017 paper from the Karolinska Institute, working with GSK, demonstrates this with GSK’s well-known vaccine adjuvant.

And here’s a 2017 paper from the same team at Karolinska along with Moderna, looking at LNP-mRNA influenza vaccines in a primate model as well. They didn’t even bother with intravenous dosing by this point – it’s a comparison between intramuscular and intradermal. It looks like the intradermal dose comes on more quickly in antibody production, but in the end, the two are pretty similar. The paper goes into detail on the rise in the number of germinal centers in the draining lymph nodes, the exact location of all that B-cell selection and the corresponding antibody changes, which argues strongly that the antibody improvements mentioned in yesterday’s post will occur after mRNA vaccination as well. Another 2017 paper from Moderna has more influenza mRNA vaccine data in several animal models, with consistent results – these were the studies leading up to their human trials in this area. In this case, you see protein production at the injection site, in the downstream lymph nodes, and (coming in third), in the spleen (also good news from the immunologic view), and then the liver. All other tissues were much further down the list.

The total amount of protein produced was also estimated in the 2015 paper, and it turns out that the i.v. route actually makes a bit more than the others, shorter duration and all. But overall, you’re almost certainly better going intramuscular – it still has good protein production, and the multiday duration and lymph node involvement are both good for the immune response you’re trying to induce.

Both the Pfizer/BioNTech and Moderna vaccines are being given i.m., so if you’d like to know what parts of your body are producing the coronavirus Spike protein antigen, the answer seems to be the muscle tissue at the site of injection, the lymphatic tissue downstream in your armpit on that side, your spleen, and (for the first day or two) your liver. The bulk of the Spike that you’re going to make is probably made in the first two or three days, anyway, from what we can see from the animal models. My wife was just saying that it’s too bad that we don’t have a luciferase-style readout built in for us humans as well – she’s enthusiastic about being able to watch a green glow coming from under her skin to know that the vaccine is doing its job, but freely admits that this would probably set off a lot of lunatic conspiracy theories as well.

Let me finish off with another paean to experimentation. If you’ve had a chance to look at those papers referenced along the way, you’ll see that many of them make comparisons to other vaccine technologies. This 2018 one from Penn, Duke, Acuitas and others is especially clear on that point. What you can see is that it was already becoming apparent that the mRNA platform had great promise for inducing strong, wide-ranging immune responses – stronger, in fact, than many comparator techniques. The work that had been done over the years on formulations, RNA modifications and other techniques was paying off just in time for the current pandemic. mRNA vaccination was in exactly the right stage for things to take off with a good expectation of success.

It wasn’t always that way. I mentioned the innate immune system before, and without getting too far into the weeds, it has to be noted that getting the balance right between that innate response and the adaptive response is a key for any vaccine technology. You’d like to have the innate system in play, but if you set it off too strongly with either an mRNA or viral vector vaccine, you can actually damage your total antigen production (and the subsequent adaptive antibody response) due to attacks on the vaccine species themselves.

It is not totally obvious how you strike that balance, though: the innate immune system works through a whole army of receptors – a long list of toll-like receptors (TLRs), RIG-I and the other pattern-recognition receptors and proteins, such as MDA5, LGP2 and more. This is all an elaborate sentry system that is watching for weirdo DNA and RNA species as a sign of viral infection, and is ready to bat them down through a whole list of counterattacks. So to get a good RNA vaccine, you frankly have to make it work like a particularly stealthy virus, and not trip every single alarm before your payload gets a chance to enter the cells. But as mentioned, some activation of the innate system is needed to get the adjuvant boost. A lot of that work has to be done empirically, which is why we’ve seen so many RNA and DNA formulation ideas over the years. None of these have been stupid ideas (far from it) but some of them work better than others, and the current lipid nanoparticle ones are the current state of the art – the LNPs themselves activate the innate immune system, but in a way that doesn’t seem to trigger too much of a self-defeating cytokine response. It’s a useful enough effect that they’re being proposed as adjuvant additions to other, more traditional vaccines for that effect alone. This effect had to be discovered by hard work and repeated testing; you’re not going to whiteboard your way past mammalian immunology, not for a long time yet. . .

Update: if you’d like to know more about the supply chain for the lipids and RNA in making these vaccines, here is an excellent place to find out the details.

96 comments on “mRNA Vaccines: What Happens”

  1. Dr. Seymour Tushi says:

    More ammo for the “Bill Gates Wants To Make Our Babies Glow” crowd

    1. Ross Presser says:

      So this blog here made me curious about how luciferase might have actually been used in humans. Unfortunately, Googling for “luciferase in humans” has results totally polluted by that crowd you just mentioned, as well as those who can’t get past the fact that “enzyme that produces light” is similar to a name for Satan. (headbang)

      1. Alec Kynes says:

        These people shouldn’t come to the Netherlands.

        A “lucifer” is what we call a matchstick.

        1. Chris Phillips says:

          Fascinating. Just as we did in the UK a century ago:
          “While you’ve a lucifer to light your fag, smile, boys, that’s the style.”

          1. Charles H. says:

            US version:
            As long as you’ve a lucifer to light your fag,
            Smile, Smile, Smile.

        2. BART says:

          it makes perfect sense as all three a match (lucifer) Lucifer and LUCIFERasis derive from the same LUCIDO – bright, luminescent, the one producing light

          1. Robert Farquharson says:

            In the case of Lucifer the meaning is light bearer. He was not the light but the bearer of it. He gave up that job long ago!

      2. M says:

        I think those people are in need of some restraint.

        1. Andrew Murray says:

          Actually they are in need of a good classical education

          1. Robin Hoffman says:

            Agreed!

        2. Alan Mushnick says:

          Pleased to meet you!

      3. Daniel Neely says:

        Well if they understood why the enzyme is named that, they wouldn’t be so excited about seeing lights at the end of tunnels after near death experiences…

      4. Gilad Ben-Yossef says:

        Well, the etymology of Lucifer from old English literally means morning star, or “bringer of light”

        1. confused says:

          It’s originally Latin, actually (‘lucifer’ means ‘light bearer’ derived from ‘lux’), but yes, it was originally a name for Venus as a morning star (equivalent to the Greek name ‘Phosphoros’ which also means ‘light bearer’).

          1. Liang Jiang says:

            culture has the magic of making unrelated things relevant. Morning star (a weapon/ a celestial body), Venus (a goddess/ a planet), Lucifer (a demon/ match stick)
            These things relate in mysterious ways. the demon Lucifer has a crown that signifies morning star, but so does the statue of liberty and the god Apollo.

      5. albegadeep says:

        Ironically, the Biblical reference isn’t to Satan at all, but to the king of Babylon (possibly Nebuchadnezzar) as clearly indicated at the start of the passage. But lots of folks don’t actually read the context.

        1. confused says:

          I think this is a result of allegorical/typological interpretation of the verse, but Lucifer as a name for Satan became established enough that it persists in churches/communities that are a lot less into allegorical interpretation than the medieval Church was.

        2. Suzanne Spiers says:

          Lucifer was the biblical angel who was cast out of heaven for wanting to be equal in power an authority to God. He was the most beautiful angel of all and when he was cast out of heaven, 1/3 of the heavenly host went with him and these are currently known as demons.

          Lucifer now has a good many other names, one of which is Satan which means the deceiver.

      6. Take a look at the paper ‘Developing mRNA-vaccine technologies’ by Thomas Schlake et al. in RNA Biology (www.landesbioscience.com) and also the paper ‘Cationic liposome-mediated RNA transfection’ by Robert Malone et al. in Proc. Natl. Acad. Sci USA (1989)
        Hope it will help

    2. Michael says:

      I’m sure the enzyme “luciferase” won’t cause any concerns, either.

    3. sgcox says:

      For glowing green you need GFP, not Luciferase.

      1. Marko says:

        These days you don’t have to settle for one color. There are both multicolor luciferase and GFP assays.

        It’s a regular Gay Pride Day in the lab, every day.

      2. Roland says:

        COVID-19 Vaccine
        Vial contains 5 doses of 0.3ml
        For intramuscular use
        NOT for use in facial muscles
        Colours may vary

        (thanks for another fascinating explanation Derek)

    4. Dianne MacKay says:

      So how or will scientists study the long term effects of the mRNA vaccines?

      1. Yusef Asabiyah says:

        That’s the first intelligent comment I’ve read here. As I read all the above, it was as if the most important thing in all this is that there are “conspiracy theory” nuts out there who can’t understand what’s going on.

        I really do not know how it is possible to vaccinate the world population without asking and answering this question FIRST. Maybe everything will be okay, but it frightens me if it is not okay.

        I do understand expediency was important in this instance, but I also have a fear of expediency being of too much importance in any scientific endeavor. I have noticed expediency leading to mistakes in both my own and my colleagues’ work. A little more time and a more careful review could have prevented embarrassment.

        But I am very conservative, very risk averse, and possibly weak kneed. I hope that’s all my trepidations are based on– lack of courage.

  2. Esther van de Vosse says:

    Hi, this is a very good review of the current literature, thank you! I have read many of the articles mentioned and also searched specifically for whether the muscle cells themselves express the Spike protein but did not find anything that suggests that (you mention ‘muscle tissue’ which does not necessarily mean muscle cells). I expect it would be APCs (mainly monocytes) that express the Spike protein. Did you find a ref for expression in muscle cells? if so, can you please let me know which one that is? Thank you!

  3. DJK says:

    Excellent article.. Does anyone want to speculate about what might happen if one follows a dose of an adenovirus vaccine(J&J) with a dose of an mRNA vaccine?

  4. Marko says:

    The Moderna folks have done work on optimizing the secondary structure of the mRNA coding sequence so as to extend in vivo half-life. It turns out that you gain more in protein expression overall by increasing mRNA half-life than you could gain by boosting the translation rate, and high translation rates may lead to shorter half-life :

    mRNA structure regulates protein expression through changes in functional half-life

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883848/

    Depending on how successful they’ve been with this, and how mRNA half-life varies with cell type, etc. , expression of spike protein may be going on at some sites for considerably longer than we might expect.

    More transparency on this, as well as on the issue of LNP trafficking and uptake, would certainly be welcome.

  5. Josef Kovacs says:

    This article seems a good, partial response to an interesting discussion on your previous blog article: https://blogs.sciencemag.org/pipeline/archives/2021/01/11/rna-vaccines-and-their-lipids

    Can you elaborate more w.r.t. JW Ulm’s query regarding data on what other cells in the body may end up producing the spike proteins? and the BBB?

    1. Natasha Nolan says:

      I see that JW Ulm’s very detailed concerns and the thread following, have been removed. Hmm

  6. John says:

    What happens to the cells involved in the production of the antigen? Does the mRNA eventually decay and the production stops, or does the immune system start destroying those cells as a way to stop the foreign particles from being produced?

    1. DrMAD says:

      Great questions. The understanding from ID experts is that the cell is destroyed. Maybe that is why muscle soreness is one of the main side effects. After my second Pfizer dose my whole arm mess sore for about 48 hours.

    2. Miguel Dominguez says:

      Great questions. The understanding from ID experts is that the cell is destroyed. Maybe that is why muscle soreness is one of the main side effects. After my second Pfizer dose my whole arm mess sore for about 48 hours.

  7. Jason Chang says:

    Great easy to read article on a complex topic thank you

  8. Doug H MD says:

    “My wife was just saying that it’s too bad that we don’t have a luciferase-style readout built in for us humans as well –”
    I would settle for human studies of the same…None? why?

    1. John Wayne says:

      People are too big. While expressed luciferase can be prompted to glow, that light doesn’t penetrate infinitely through tissues. Mice are small enough to study. For people, you could only look at things closer to the surface of your skin.

      Another practical problem is that the detectors built for this are sized for lab animals. Dosing people with curiosity reporters is probably a tougher sell to ethics boards, but it probably could be done.

      1. Yvar says:

        However, ex vivo bioluminescence imaging through a blood draw or biopsy is truly possible, and already shown by Sam Gambhir in one of his final publications. Current thought in the molecular imaging community is if you’re going to pull out cells and genetically manipulate them before reinjecting, might as well put non-immunogenic trackers in them (fluorescent, bioluminescent and PET when possible).

        https://www.ncbi.nlm.nih.gov/pubmed/30886438

  9. Barry says:

    How strongly you provoke the innate immune response will determine whether you have made a vaccine at all, or have (perversely) tolerized the host to the foreign (viral) protein. If you wipe out the TLR agonism of your mRNA (modified bases), you no longer have an adjuvant; you no longer have a vaccine

    https://science.sciencemag.org/content/371/6525/145

  10. Ken says:

    “but freely admits that this would probably set off a lot of lunatic conspiracy theories as well.”

    Sadly you don’t need a green glow to set off lunatic conspiracy theories. Though I am amused by the number of people jokingly (I hope) saying “I got the vaccine, how long until I grow the extra toes?”

  11. John A says:

    If certain cells (muscle, liver, spleen) express spike protein and are then presumably destroyed by the immune system, can those cells be regenerated? Or are we permanently losing muscle and liver tissue each time we inject an mRNA vaccine?

    1. Barry says:

      If the cells transformed by mRNA vaccines and destroyed by our T-cell response are hepatocytes, we replace them easily. If they’re neurons of the CNS, we may not replace them at all.In between are other cells. Striated muscle is a little odd in that cells fuse into multinucleated syncytia (so how one counts muscle cells is kinda fuzzy). But injecting an mRNA muscle into a deltoid muscle should not result in permanent loss of muscle mass or function.

      1. Rando says:

        Does the CNS include the brain? Can the lipids get through the BBB?

        1. Tim Mackey MS MD FAAP says:

          Early studies of LNP was to enhance neurological medications across the blood brain barrier. They where quite successful so there is a potential for a very small portion of vaccine making it into the CNS.

          1. Doug H MD says:

            not potential. It has been shown. but as you say the amounts are TINY

      2. Mammalian scale-up person says:

        If I recall correctly from Ye Olden Dayes of working on BMPs, muscle tissue remodels itself amazingly quickly – you can gain or lose a considerable amount within a few weeks, just by sitting around not moving much or by diligent time in the gym with a trainer. How much and how quickly you gain or lose is governed mostly by hormone levels (obviously), age, genetic luck and diet. Even people who lose a very substantial amount of muscle tissue through, for example, being comatose, manage to gain it back in time. Immune system remodeling has very little to do with it.

        1. Glen Mangseth says:

          If I remember y muscle physiology correctly, the number of cells comprising a muscle are relatively fixed from birth. Muscles increase and decrease in size by changes in the volume of those muscle cells, not the number. Training increases the cross section of muscle cells through the addition of more myofibrils (actin and myosin, components of the contractile mechanism).

  12. daksya says:

    What are the advantages and drawbacks to partitioning a dose into multiple modes and locations during a vaccination session?

    1. Marko says:

      You’re just looking for a good excuse to get naked for your vaccination.

      Not gonna help you with that one. Sorry.

      1. Adam says:

        What about the intranasal route? Wouldn’t vaccination be more likely to prevent transmission?

  13. eub says:

    Boy, I hope all the critical facilities in the vaccine supply chain have high-grade security against car bombings and other violent threats. I suspect there are already some stories that we’re not going to hear about until later.

  14. Rob says:

    I’m sure these mRNA vaccines work great. Thanks for participating in phase-iv human trials with all rights waived for those taking the shot. After you. 🙂

  15. Jeff M says:

    Question from a non-scientist here:
    Please help me to understand so that I may educate others – The mRNA vaccine enters (mostly) muscle cells and induces them to make the viral spike.

    Does the muscle cell die and release the spikes, like it would if it were infected with a virus or do the spikes leak out through a natural process?

    If the muscle cell survives how long does it keep making spikes and why doesn’t it keep making spikes for the life of the cell?

    Does the vaccine effect any other functions of the cell, metabolism, reproduction, etc?

    Thanks in advance for the knowledge and help

    1. John Wayne says:

      Does the muscle cell die and release the spikes, like it would if it were infected with a virus or do the spikes leak out through a natural process?
      – Probably not. The mRNA enters the protein production area of the cell and it starts making spike. How this spike gets out of the cell is probably unknown, but it probably not dependent upon the cell dying. On the other hand, some of these muscle cells will probably die as a result of being lysed by the injection stress or being attacked by the immune system. The nice thing is that muscle cells die and are replaced all the time. We have been using IM vaccines for a long time. This is unlikely to be a problem.

      If the muscle cell survives how long does it keep making spikes and why doesn’t it keep making spikes for the life of the cell?
      – The instructions to make spike are encoded at the RNA level, not the DNA level. The RNA instructing it to make spike will eventually be recycled by the cell and it will stop making spike protein. If you don’t understand the DNA vs RNA statement go read the wikipedia entry about Protein Biosynthesis.

      Does the vaccine effect any other functions of the cell, metabolism, reproduction, etc?
      – The cell does have to use some of its finite supply to energy to make spike, so it obviously isn’t doing everything it was doing before. On the other hand, it almost certainly isn’t only making spike. I’m not sure if this is out there, but I would bet that a relatively small percentage (1 to 25%) of the ribosomes are making spike instead of what they would normally be making. This may be known in the literature.

      1. sgcox says:

        Spike gets to cell membrane where it is exposed and recognised by immune cells. Extracellular domain also get get shedded. Cells stay intact after getting vaccine mRNA in.

      2. stewart says:

        After a short resort to Google Scholar I estimate that muscle cells produce about 6,000 different proteins. A typical eukaryotic cell has of the order of 10,000,000 ribosomes, and I wouldn’t expect muscle cells to be atypical.

        What proportion of the ribosomes are hijacked by the vaccine mRNA depends on the number of vaccine mRNA strands that enter a cell (how many are in lipid-mRNA nanoparticle?), but my gut estimate is that your 1%-25% of protein production being spike is an overestimate.

        1. John Wayne says:

          You are probably right. It could easily be a tiny fraction of a cell’s protein output. There may even be a subpopulation of muscle cells whose membranes were mechanically disrupted by the injection that make most of the protein. Lots of heterogeneity even within a specific tissue type.

    2. a grad student says:

      I’ll try to answer your questions in order.

      First, no, production of the spike protein does not itself kill the muscle cell. Any protein made in almost any cell in the body will have copies presented on the cell surface by specialized proteins called major histocompatibility complexes, or MHCs. There is an entire transport system that diverts copies of proteins made in a cell to MHCs so they can be displayed outside the cell. Presentation on MHCs allows to immune system to interact with the protein.

      For your second question, there will be a lot of variability. At the longest, muscle cells will produce the protein for a couple of days. mRNA is not exceptionally stable and will degrade relatively quickly; in addition to this, there are enzymes within a cell designed to break down and recycle mRNA.

      Finally, for your last question, I will admit I’m slightly out of my depth. I don’t think cells will be impacted in any significant way. The only effects I know of would be extremely minimal due to the cell needing to divert some resources (amino acids, tRNAs, ribosomes) towards producing the spike, but the spike protein isn’t going to do anything inside the cell.

      I hope this helps.

      1. Yes, fragments (p) from self proteins, as well as fragments (p’) from foreign proteins that find their way into cells, are expressed at the cells surface as pMHC complexes. There will be an immune response to the foreign non-self protein fragments (p’), but not to the self fragments (p).

  16. Anon says:

    Derek…..A big thanks for a lovely summary!

  17. Buck Fiden says:

    So, just wondering if there is any advantage, other than speed of production to the traditional killed, fractured or ‘attenuated’ vaccines coming online with the J&J platform?

    1. Barry says:

      With an mRNA vaccine:
      1-the RNA is itself a potent adjuvant/TLR ligand activating innate immune response
      and
      2-the antigen is presented twice to our T-cells, first by the cell (myocyte?) that reads the injected mRNA (on MHC1) and then by professional Antigen Presenting Cells on (MHC2).
      With a traditional “killed” vaccine, the antigen is presented only on professional APCs, and the adjuvant has to be added.

      1. Twelve says:

        If the mRNA in the vaccine is damaged could it produce proteins which may cause damage.

  18. Piero says:

    Excellent article

    “she’s enthusiastic about being able to watch a green glow coming from under her skin to know that the vaccine is doing its job, but freely admits that this would probably set off a lot of lunatic conspiracy theories as well.”

    No doubt

  19. Marko says:

    “…What is a mRNA vaccine? Here’s how the CDC describes them:

    …COVID-19 mRNA vaccines are given in the upper arm muscle. Once the instructions (mRNA) are inside the muscle cells, the cells use them to make the protein piece. After the protein piece is made, the cell breaks down the instructions and gets rid of them.”

    https://www.nationalreview.com/2020/12/you-can-trust-the-coronavirus-vaccines/

    Now the same CDC page says “inside the immune cells”. Why the switch? Maybe they were worried about how the Lucifer Lunatics would run with the earlier statement. Or maybe the CDC just made a mistake. One thing’s for sure, we’ll never know.

  20. Ralph Heckmann says:

    I wonder if the following question is amenable to a ready answer. Is there a good explanation as to why there seem to be so many functionally significant mutations occurring right now in this virus? (The 501Y.V2, B.1.1.7, etc.) Is the mutation rate consistent with expectations from evolutionary biology?
    It seems that it took roughly an entire year for a mutation to emerge that affects the actual structure of the surface proteins. Is this due to widespread rollout of the vaccines (in the UK for example)? Or is there a different explanation?

  21. Kip Rode says:

    Is it better to get the second shot in the same shoulder as the first shot or does it not make a difference? Is it better get the shot in the shoulder that is on the same side as the spleen or does it not make a difference?

  22. Kelsey says:

    There are people that get the vaccine and have a sore arm and then there are people that have fevers, chills, rigors for two to three days. Initially, I would think the intense response would portend a good immunologic response and thus efficacy. However, after reading your great review, I am wondering if the balance was missed. Are the intense responders having too strong of an innate response and thus not getting the durable adaptive response needed. Any thoughts?

    1. Susan says:

      I am a Pfizer trial participant. We had a daily symptom daily for 14 days followed by weekly entries on a phone app. It will be simple to compare response to the vaccine and antibody levels. I have my antibodies drawn first week of February and every 6 months for 2 years.

      1. Kelsey says:

        Susan,
        Thank you for being a trial volunteer! Yes, we should be able to discern the answer to my question from that information. They have not released that information though, correct? At least not in the symptom to serum level relationship.

  23. Adam Rubinstein MD says:

    Nice synopsis. It would be interesting to have more data from humans so we can better understand the process. Looking at all of the “lab rat” humans around me who have been inoculated the manifestations have been highly variable from minimal to no symptoms (sore arm, tiredness) to full blown reactions including lumps, adenopathy, headaches, chills, fevers, etc. Why are the vaccine responses so variable and what does this represent?

  24. stephen says:

    MORNING STAR: Rev. 22:16″ I, Jesus, have sent my angel to testify to you about these things for the churches. I am the root and descendant of David, the bright morning star.”

  25. Melanie says:

    I have seen pictures circulating of people who have received their covid-19 vaccine subcutaneously instead of intramuscular (administrator error). What, if any, effectiveness might the Pfizer and Moderna vaccines have if given subcutaneously?

    1. Rhea Cooper says:

      I asked same question. I think no one is exactly sure. There was great article about routes of administration in rodents that concluded there was not much difference in absorption between IM, SC and ID (intradermal). They also advised that rodents had different anatomy compared to lymphatic drainage in humans and rates of absorption between dermal layers and muscle layers. So I think we will not get an answer as there isn’t one.

  26. Rich Rostrom says:

    “lucifer” for a match was mid-1800s American usage too. Mark Twain mentions a troublesome baby’s fondness for eating “German lucifers”. However, it was about twice as common in Britain. It pretty much faded out in both countries by 1920.

  27. Rhea Cooper says:

    I have the same question as the person above. Many pictures of arms being squeezed during injection with subcutaneous administration probable. also many one inch needles on obese people. Would this make the vaccine ineffective as would miss the muscle for spike protein?

  28. Bob Marlee says:

    xkcd also has a good synopsis (see username link) for the layman.

  29. Gilly says:

    In previous trials with both the SARS and MERS Coronavirus vaccines (see below links), the subjects in the trials all developed pulmonary immunopathology when challenged with other common coronaviruses. Has anyone come across any studies that would indicate how researchers have overcome this hurdle?
    https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0035421
    https://www.tandfonline.com/doi/full/10.1080/21645515.2016.1177688
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318931/

  30. Bobby M says:

    What would you recommend to a “Hairy Cell Leukemia” patient in remission, 2 years after Rituximab? It is a lymphoma disease of mature B-cells with post-GC origin..
    Are the mRNA vaccines safe for such people?

  31. Tom Kwan says:

    Why don’t they try to use radioactive isotopes or fluorescent tracers to follow the mRNA after vaccination to find out what cells of the body are used as entry points? Wouldn’t that answer the questions about potential s adverse side effects including long term side effects?

  32. Ari says:

    I’m sure there’s something I’m not completely understanding about the mechanism, but if the muscle cells are producing the spike protein (which ends up on the surface of the cell), is there a chance that immune cells may learn to attack healthy muscle cells elsewhere in the body, leading to some kind of autoimmune condition?

    1. Tim Mackey MS MD says:

      A fair portion is taken up by myocytes around site of injection. The LNP/mRNA like any foreign body that finds its way inside us is shuttled to the lymphoid system which is composed of dendritic cells and a few others which present the spike protein to T cells and B cells through an intermediary CD4 T cell (this is a VERY simplistic draft of what happens). From various prior animal models a small percent of (LNP/molecule of choice) after IM injection make there way into the systemic circulation with uptake primarily in liver and spleen, other tissues can be involved at a lesser extent. On the initial shots there is not enough immune response developed yet to target other non immune cells exhibiting the spike protein. There is theoretical possibility that after boosters, when the body has cytotoxic memory T cells primed and waiting for spike protein to be exhibited, the booster vaccine that escapes to say a liver cell could possibly lead to those cells destruction. There are mitigating factors in the immune system which could modify this response so it might be inconsequential or it might not. I have been actively perusing all the relevant literature and have not found any useful data at this time. I came to this board hoping a bright immunobiologist might shed some light on this topic.

      1. Marko says:

        ” On the initial shots there is not enough immune response developed yet to target other non immune cells exhibiting the spike protein.”

        Most of the complications are developing a week or more after the first dose. That’s enough time for a de novo Ab response to begin, if that is indeed the causative factor.

        It may be that a direct interaction of the vector with platelets and/or vascular endothelia is what sets off the aberrant immune response. This might be unexpected in the majority of vaccinations that properly target the muscle tissue, but could be a problem in the rare few that mistakenly get delivered IV, even if only partially.

        1. Marko says:

          Sorry, I may have butted in here. I’m talking about the recent clotting/thrombocytopenia issue.

        2. Jeremy says:

          The spike, whether part of the live virus or alone (as you would find post vaccination), (or the S1 subunit following), binds to ACE2 leading to downregulation of ACE2 which leads to leads to endothelial dysfunction–> thromobsis, hypercoagulability, platelet aggragation, complement activation. The spike crosses the BBB, and can do the same there.

          That is the mechanism

  33. Cassandra says:

    Utterly clueless as to reasons for adverse reactions? Not surprising really. Let’s move onto a measurable metric, that of vaccine efficacy. We can do this now, it’s looking pretty poor. Vaccine passports, green cards, bonuses and the other BS can wait. Let’s see if this really is a safe and effective medicine before we “jab” another few hundred million real people with the needle loaded with god knows what and what the consequences are.

  34. CG says:

    thanks for a great summary!
    While iv application of mrna in mice show that most of it goes straight to the liver, i wonder about concerns if it gets injected into artery by mistake?
    I got my sec shot of the pfizer vacc two days ago (it was injected without aspirating first) and it hit me hard, all the described side affects like fever chills nausea and arm pain but in addition aweful lower backpain. i recovered fast and this morning all that was left is a bright red line starting at the injection site going both ways (not painful, no swelling) and weird enough a very painful left heel.
    this left me to wonder if the mrna got carried to weird sites because it went into the blood stream instead of muscle tissue. keen to get your thoughts on this

  35. Curious me says:

    It’s been proven the the COVID virus spike proteins cause the virus to enter the brain, affecting our neurological function, and this is a long term effect of the virus. Couldn’t the vaccine provoke similar and even worse side effect having those spike proteins expressed in our own neurons? Is that possible? Does that occur?

    1. Some idiot says:

      Do you have references/data to back up these statements?

      1. Albert says:

        Not direct evidence but Bell’s palsy seems pretty common also the rarely and perhaps not associated transverse myelitis case are more likely auto-immune in nature?

    2. Jeremy says:

      The evidence is mixed over whether the live virus enters the CNS. The spike alone having been shed during cytolytic destruction of infected cells, or through ectodomain shedding does cross the BBB and end up in the parenchyma. (magro et al. 2021)

  36. Di Di says:

    Hi, would love to read any papers which demonstrate where in the body, when and for how long the host spike antigens are produced post vaccination. Have not found much on literature search for either human or animal models. Ta.

  37. Erik says:

    Does anyone have any idea as to whether sleep loss (5-6 hrs with multiple waking periods) in the nights surrounding vaccination (in my case, the night before and the night after), would be likely to affect the development of immunity? I know this has been shown previously with innactivated virus vaccines, but might there be some difference in the way the mRNA vaccines are handled by the immune system that could lead to a more favorable response despite the sleep deprivation? I received the pfizer vaccine.
    Thanks!

  38. Erik says:

    clarification: I slept 5-6 hours, with multiple waking periods. This was dose one.

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