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What mRNA is Good For, And What It Maybe Isn’t

The huge success of the mRNA vaccination platform during the pandemic has set a lot of people to thinking about what comes next. Moderna and BioNTech, of course, have been thinking this way for quite some time. But Sanofi now says that they’ll be investing large amounts into the technology, and this previously hadn’t been a big priority for them. There are others as well. So let’s step back a little and look at what mRNA can do and what it can’t.

Therapeutic mRNAs

The first distinction is between vaccines and therapeutics. It’s hard to remember now, but Moderna did not really start out as a vaccine company – they were going to make mRNA-based therapeutics, and there are some key differences. It’s an exciting idea to reach into the body and tell particular cells to start making particular proteins (of your choice) by sending mRNA messages into them. You can think of a lot of possibilities, but there are a lot of difficulties along the way to realizing that.

For one, you’re not taking advantage of the memory that the immune system brings, which is what lets you vaccinate for a brief period and then have months, years, maybe even decades of protective effects. This sort of mRNA work isn’t immune-driven at all, in theory, and if you need your target cells to keep producing your desired protein, you’re going to have to keep telling them that by sending them more mRNA. Once a day? Once a week? Who knows? That’ll need to be worked out by experiment.

A second problem is that “not immune driven” part. If you go back to the earliest attempts to treat cells with external mRNA constructs, the people running these experiments weren’t trying to set off an immune response – they were trying to do that “make me a protein” trick. But foreign mRNA can be very immunogenic indeed – the innate immune system is constantly watching for various foreign nucleic acid species as a sign of infection. In fact, one thing that had to be worked out for the vaccines over the years was how to turn down that immediate immune response so that the more long-lasting adaptive immune one had a chance to kick in. (As mentioned in this post, that may well have been what sank the CureVac mRNA vaccine, which will continue to stand as a demonstration that mRNA technology is not the Magic Road to Efficacy. Nothing is the Magic Road to Efficacy). So if you’re going to give patients an mRNA injection and you don’t want to set off alarm bells in the innate immune system, you’re going to have to carefully engineer your sequences at the very least.

But remember, you’re doing all this to force the cells to make some protein that they weren’t making before. That’s the point of all mRNA work. What if that protein is sufficiently foreign-looking that it sets off an immune response of its own? Well, whether you felt like it or not, you have now vaccinated people against it, so if you wanted it to be produced undisturbed to do its work, that’s a problem. There’s going to be a window you can work in: an all-human protein sequence should be fine, but the more modifications you make after that, the greater the chance you might trip one of the alarm systems, at least in a few patients. The immune response is hugely variable from person to person, and the response to a foreign protein can range from nearly silent changes in circulating antibody profiles (at one end) through skin rashes and other allergy symptoms, then into things like the myocarditis and clotting effects seen with the current coronavirus vaccines in small numbers of patients, up to sudden anaphylactic shock and potentially death (think of people who are hugely sensitive to penicillins, peanut antigen proteins, or bee stings). Animal studies can  alert you to some of the alarming outcomes, but the only way to really establish the levels of these sorts of things is with human clinical trials. And maybe not even then: as the vaccine work illustrates, no clinical trials are large enough to pick up the truly very-rare-but-serious things, which makes development rather fraught.

A third problem is targeting. As has been mentioned in previous posts, the lipid-nanoparticle mRNA vehicles tend to pile up in the liver above all other organs. That’s no particular distinction; most things we dose people with in this industry either pile up in the liver or get shredded to some degree each time they pass through it. But we have no good ways to inject someone with mRNA constructs and send them to some particular tissue without dosing every other tissue in the body. As with antisense, CRISPR, RNAi, and other exotic nucleic-acid-based technologies, the two ways that people have slid past that problem have traditionally been (1) pick a disease of the retina, because you can inject into the eye and things tend to stay there or (2) decide that you wanted to treat a liver disease anyway and just roll with the fact that that’s where your stuff is going to go. The recent human CRISPR results take that second route, which is exactly the route that the first RNA interference-based therapy took as well.

Now to the big overarching fourth issue: you need to identify diseases that can be treated by causing some particular protein to be expressed in the first place. There are quite a few possibilities, but there are also plenty of diseases where we have no handholds of this sort at all. One of the most obvious ideas is to pick a genetic disease where a less competent (or downright nonfunctional) protein gets produced, and alleviating that by making cells produce the right one instead. If you do that via mRNA, though, you will presumably be making the good stuff on top of still making the original bad stuff, whereas if you do it by CRISPR or some other genetic engineering technique, you will switch over (permanently?) to making the good stuff only. So the genetic approach has that big advantage, with the warning that you’d better be really sure that you’re making the change you want to make. For something like sickle cell or PKU that’s pretty clear, but as you get out of the list of molecular diseases it can become less so. As alluded to above, you can also imagine getting cells to make some enhanced or altered protein instead for some other function entirely, but things get tricky here very quickly. We do this sort of thing all the time in a research setting, but using these things as therapeutics is a big step, and there are far fewer immediately actionable stories in this category.

To get an idea of the complications, stop thinking about sickle cell and start thinking about (say) Alzheimer’s. What protein would you want neurons in the hippocampus to start expressing in order to alleviate Alzheimer’s disease? The only honest answer is “We have no real idea”, because we’re still arguing about what causes Alzheimer’s in the first place, which necessarily means that we’re also arguing about what to do about it. How about Type II diabetes, then? We know a lot more about the mechanisms involved in that one, although there are still some key mysteries. But what particular protein would you want expressed in order to alleviate it? Here at least you can think of a list of ideas, but it’s safe to say that they’re all going to be steps into the unknown when you try them out in patients. You’re also going to be up against some pretty well-characterized small molecule therapies, and in an area with significant safety standards on the regulatory end – so it’s no wonder that people are trying other things first for that disease.

But that still leaves you a lot of room to work in. What other diseases do we treat by administering some external protein? How about all the monoclonal antibodies out there? You could imagine getting your own cells to make those instead, and that’s being looked into. In these cases you already have a lot of clinical validation thanks to the existing antibody drugs; you just have to work out if your endogenous route is effective and what advantages it might have. That’s plenty of risk for anyone, but at least the targets are solid.

mRNA Vaccines

Vaccines are of course aimed at producing a durable immune response – you have a short series of injections to achieve this, and then the memory functions of the immune system take over for lasting protection. Immunizing against some sort of foreign protein found in a dangerous virus or bacterium is the most obvious way to work this – it’s absolutely the most straightforward use for mRNA vaccination, and that’s exactly what Sanofi looks to be targeting. As we can see from CureVac there are ways for it to go wrong, and as we can see from malaria or dengue there are pathogens that are very difficult to find effective antigens to use as the basis for immunization. But overall this is still the most solid bet, by a huge margin.

The therapeutic opportunities for siccing the immune system on targets inside the human body are limited, to say the least. Years ago I saw a presentation from someone who was trying that with adipocytes for weight loss, and my eyebrows nearly escaped my head – even now, I have to remind myself that this was not some weird dream. No, what you want is (somehow) a source of foreign (or foreign-ish) proteins inside the human body. Hmm.

How about targeting some sort of protein found on the surface of particular cancer cells, and turning the immune system against those instead? That’s not a new idea. It’s been tried quite a few times over the years, but rarely with much success, immunology being what it is and oncology being what it is, too. It’s true that immuno-oncology has been a very hot topic for some years now, but that’s partly because successful approaches were found that did not depend on trying to find a way to directly immunize against cancer cells.

The closest thing we have is CAR-T, chimeric antigen receptor T-cell therapy. As you can tell from the name, that’s not an antibody-driven approach at all, but rather uses T cells on the attack, and instead of a vaccination to rouse them (which hasn’t really worked), it’s a much more laborious procedure that engineers a patient’s own T cells to deliberately recognize some particular surface antigen on the targeted cancer cells. It works for some kinds of leukemia (and not always then), and the successes are due partly to leukemia cells being individually accessible out in the bloodstream, and very much because some key antigens have been identified that lets these cells be specifically attacked. Even then, your leukemia cure likely comes at the cost of permanently impairing the population of the leucocytes involved. That’s a real concern, but if you’re to the point of doing CAR-T your alternative is basically death within months, so it’s a worthwhile trade. Naturally, people are working on other specific ways to mobilize T cells as well.

Finding markers that are even that useful for solid tumors has been difficult, though – there’s nothing to say that it’s impossible, but it’s definitely hard. So a first problem has been finding good antigen candidates in the first place, and mRNA tech in this case is just a neat way to get that antigen delivered. A second problem is the selectivity of any of these candidates in the real world. This is the other side of the sword when you’re letting the immune system do your work: if you turn it loose against the wrong things, the consequences can be catastrophic. And the aforementioned variability of the human immune response will always have you tiptoeing around in the clinic. What if the occasional patient mounts a vigorous immune attack on their own islets of Langerhans , or their own hepatocytes, or their own peripheral motor neurons? There’s only one real way to be sure, unfortunately.

And those issues, among others, are what has kept the cancer vaccine field from taking off, mRNA-powered or not. Pre-pandemic, Moderna was working on these, and no doubt they still are. But whereas we could go from “new pathogen” to “new vaccine” in about a year (an amazing feat, to be sure), developing any similarly effective cancer vaccine is already in the “decades and counting” category. There’s a huge amount of promise in this area, but don’t expect it to zip along like a viral vaccine might be able to.

Perspective

So mRNA-based techniques have a lot of power and a lot of promise. But there’s definitely a low-hanging-fruit area here, and that’s infectious disease vaccines. Beyond that the promise holds up, big-time, but the difficulties mount up as well. It’s going to be a long story with a lot of plot twists, but I’m glad we’re telling it.

51 comments on “What mRNA is Good For, And What It Maybe Isn’t”

  1. MrXYZ says:

    Nice post. I know you may have discussed this in a post on the COVID vaccines, but what is the (current) cost for making mRNA therapeutics (which naturally includes the Lipid nano-particle production costs)? Is it cheaper than COGS for biologics?

    Also, to be a bit nit-picky, CAR-T is in many ways an antibody-based therapy in that the modified T cell is (generally) targeted by an antibody (albeit in an scFv rather than an IgG format) fused to a T cell signaling domain of some sort. All (most) CAR therapies begin with an antibody either against a blood cell surface marker (e.g. CD19 on B cells) or a tumor-associated antigen.

  2. Mantis Toboggan says:

    Derek, you write in regards to mRNA vaccines that,

    “Immunizing against some sort of foreign protein found in a dangerous virus or bacterium is the most obvious way to work this.”

    I’m no immunologist, but I wanted to push back a little bit on the targeting dangerous bacterial proteins, or at least discuss it. It seems to me (from my naive perspective), that bacterial vaccines are more likely to take the form of things that can’t be encoded by mRNA such as capsule polysaccharides (i.e. prevnar 13, Pneumovax 23). Have bacterial proteins made for good vaccines previously?

    1. Erwin says:

      Diphtheria. Tetanus. Also I believe a much more recent protein vaccine for Neisseria meningitidis type B.

    2. Martin says:

      Meningococcal group B vaccines are protein based. Suitable protein targets for other bacterial pathogenes could perhaps be found but it’s difficult and therefore polysaccharides are prefered.

    3. Derek Lowe says:

      Good point, but there are definitely some if you include the bounce-shot immunize-against-the-toxin ones. . .

    4. Immunologist says:

      The Lyme vaccine was protein-based, and safe and effective (pulled for economic reasons / bad press: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2870557/)

      1. Isidore says:

        I hope I am not running afoul of Derek’s new comment policy here, but I must say that the bad press was, to a significant degree, deserved. There were quite a few cases of people who suffered serious side effects from the SKB vaccine, I happen to have known two of them personally. Perhaps the Lyme disease vaccines should have been directed not towards the general population but towards those most at risk, e.g. avid hikers, hunters, park rangers, etc. in high risk areas, but then it would not have been commercially viable. Let us not take the opposite approach of the anti-vaccine people and try to sweep under the rug the serious problems that some vaccines present for some people. And I speak as someone who has not missed a single recommended vaccine for myself and my children.

        1. Immunologist says:

          I won’t pretend that “safe” means “no side effects”, and certainly am all for being realistic about the imperfect safety profiles of vaccines, but all the aggregate data I’ve seen suggests that Lymerix is/was “reasonable enough”, and that bad press (warranted or not) contributed to it being economically unviable more than there being no population in which it was worth using. It certainly doesn’t seem like it’s the best vaccine ever developed from either safety or efficacy (I’d like better than 80% protection after three doses!), but it is a protein-based vaccine that “works”.

          On the original topic, though, it is interesting to note that the Lyme vaccine is something that’s not 100% clear could be readily mimicked with an mRNA vaccine, as the antigen in that case is a bacterial lipoprotein and therefore wouldn’t be made identically in host cells. I would suspect you could lop off the lipoprotein signal sequence and still get immunogenicity that would be protective, but that’s not a surefire prospect. It does point out that more broadly, bacterial proteins are going to be tougher because of different post-translational modifications. Whether it would be necessary/sufficient to, say, mutate out all N-linked glycosylation sites from any sequence for a bacterial immunogen, would be interesting to see. I’m also curious how that will go even for viruses with high tissue tropism – can you make a vaccine against an enteric virus, where the glycosylation pattern based on normal (i.e. during infection) production in intestinal epithelial cells may be quite different from what you get with intramuscular vaccine administration?

    5. Mantis Toboggan says:

      Thanks Erwin, Martin, Derek, and Immunologist for your responses/discussion. I appreciate hearing your perspectives and learning about the examples you each mentioned. It does look like most bacterial protein vaccines are as Derek said, ‘immunize against the toxin’ situations.’

      I’d wonder a bit about the safety of toxin expressing mRNA, but maybe it could be done. I didn’t mean to be overly critical about the idea that mRNA vaccines could be useful for bacterial vaccines, was just interested in a discussion.

      1. patrick says:

        Perhaps truncating the toxin gene could preserve the immunogenicity without the toxicity?

        1. LdaQuirm says:

          Or you could spend a few years building up an immunity to iocane powder your bacterial toxin.

    6. FoodScientist says:

      Most pathogenic bacteria that actively attack, use proteins. Pneumonia normally infects sick-ish people and isn’t transmissible between healthy people. I wouldn’t be surprised if the pneumonia polysaccharide was still bound to the protein that anchors it In the capsule.

      Pathogenic Ecoli strains normally have cellular invasion proteins or secrete proteins that shred cell walls.

      C. botulinum toxins are proteins the bacteria use to paralyze nerves; so it can grow in the intestines for a week. ~40lbs could kill everyone.

      Staph aureus causes food poisoning. It secretes a protein that acts as a “super antigen”. Apparently it takes less than a minute after injecting a rhesus monkey with a couple nano-grams for it to start projectile vomiting and projectile defecating.

  3. Joseph says:

    https://www.cell.com/molecular-therapy-family/nucleic-acids/fulltext/S2162-2531(20)30106-2#secsectitle0110
    Not sure if others are familiar with this one but here is an interesting use of mRNA in a mouse model to produce factor VIII.

    1. metaphysician says:

      That was one of my first thoughts, too. Hemophilia seems a good candidate here, since you don’t need a huge amount of functional protein for clinical benefit. Granted, its anybody’s guess whether mrna generated Factor would be less susceptible to autoimmunity…

  4. Koss says:

    “What if the occasional patient mounts a vigorous immune attack on their own islets of Langerhans”
    Actually I have heard about this happening to someone in their teens, due to an influenza virus infection knocking their immune system off kilter. Patient survived the incident with permanent, insulin-dependent Type I diabetes.

  5. ccm says:

    Nice post. I was a little surprised there was no mention of BioNTech’s work on EAE with mRNA. If that approach is effective and can be generalised it could be very valuable for treating autoimmune diseases.

  6. Bion says:

    Don’t forget ribozymes, riboswitches, CRISPR, molecular programming, and of course, origami…

    1. Bion says:

      Oh, and I’m missing a bunch too — shame on me for missing RNAi.

      Reverse transcriptase is a can of worms. These woods are lovely, dark, and deep!

  7. George says:

    Has there been any longterm research on potential for autoimmune conditions to present? I’m mostly curious if some people’s immune systems would code, not only on the foreign protein produced by their cell, but potentially on other parts of their cell that made it.

  8. steve says:

    With all the hype about mRNA vaccines it’s good to keep in mind that Novavax’ baculovirus produced, protein-based VLP vaccine was more effective than either Pfizer’s or Moderna’s and was so in the face of newer variants. The immune system attacks repeated epitopes and you can’t get closer to mimicking a virus than a VLP. One wonders if mRNA can really compete on a cost-basis with a VLP.

    1. steve says:

      Sorry – shouldn’t have said “more effective”; it’s top line numbers were similar to Pfizer/Moderna but again the key differentiator was that it was started later, after the variants had taken hold. Be interesting to see a direct head to head.

  9. J Curwen says:

    Why is it not possible to synthesize mRNA via synthesizer as we do with DNA?
    As long as we produce the RNA via in vitro transcription, we will always have the problem of contaminating DNA in the LNPs and therefore a small risk for integration.

    1. Gareth says:

      The issues are length and scale. Making long RNA molecules is difficult synthetically. But so is making long DNA. You typically paste together synthetic DNA fragments and have bacteria amplify it. Double stranded DNA makes this much more tractable than it would be for ssRNA. Polymerases are needed for anything more than nanogram scale because they’re so much more efficient than synthesis.

    2. Mantis Toboggan says:

      Piggybacking onto the previous comment. As I understand it, RNA is a bit more difficult to synthesize than DNA because it has the 2′ OH that needs to be protected. These protecting groups cause steric hinderance at the 3′ Phosphoramidite that needs to couple to the cpg resin, so RNA is more difficult to chemically synthesize than DNA.

      The bigger issue I think, expanding on Gareth’s comment, is that long polymer synthesis in general is difficult (peptides, DNA, RNA, etc.) because of the way that yields work out in multistep processes. If you had 95% reaction yield per base (combining deprotection and coupling steps) and wanted to synthesize a 30 mer, your yield would be 0.95^30 = 21%. It only gets worse as you get bigger with a 60 mer around 5%. So to make long DNA molecules, shorter overlapping sequences are made and then molecular biology (PCR) is used to stitch them all together and amplify the DNA. You can’t easily do those same tricks with RNA, so it’s easier to make the DNA, then transcribe it to RNA. There was a good explanation of the mRNA vaccine development process shared in the comments of this blog (or even a main blog past long ago), but I don’t know where it is.

      1. Mantis Toboggan says:

        Found the link to twitter thread. I misstated above, looks like fragments are ligated together instead of PCR amplified together.

        https://twitter.com/pallithordarson/status/1326339931078225920?lang=en

  10. Gareth says:

    Personalized cancer vaccines against unique, tumor-specific neoantigens are potentially a good fit for an mRNA platform. It’s not currently possible to design, optimize and manufacture a traditional vaccine against an arbitrary target quickly enough to immunize someone whose just had their cancer sequenced. Small scale mRNA/LNP production could remove one bottleneck. Do Illumina or Foundation Health have a stake in BioNTech?

  11. TallDave says:

    all great points

    provoking the immune response by spamming it with a protein is a bit of an ideal case, practically a “hey look guys we got an zettaflop processor with a trillion lines of operating code to write HELLO WORLD! a million times” scenario in terms of what artificially-coded proteins generated by our cells might eventually be capable of

    really the main achievement there was just inserting a tiny snippet of messenger code in an operating cell, seems not much of this excitement would be happening without that pseudouridine breakthrough a decade ago

    of course one really fun thing about proteins is they can self-assemble 🙂

    with another decade or two of advances in understanding of how proteins interact (and how immune systems respond) and associated advances in application, it’s conceivable we might eventually build self-assembling protein-based bio-machines of boundless utility

    or the immune system might keep breaking pieces much faster than we can make them 🙁

  12. Nile says:

    Good summary!

    I think the short term future of mRNA will be Pfizer and AstraZeneca releasing tweaked booster shots of their COVID-19 vaccines, modified for recent strains of the virus which show a partial ‘vaccine escape’, now and next year.

    The medium term future is that we find out how many times we can inject one of these vaccines – or this class of vaccine – before the patient’s immune system renders it impractical.

    Hopefully, that ‘many’ is a very large number.

    Medium to long term, I think you’ve covered all the bases.

    1. Charles H says:

      Well, when you get into the distant medium term or longer there’s at least one other possibility.

      Cultured T-cells programmed with an mRNA that’s too dangerous to let loose in the body. This would be one way to attack several diseases that can’t be handled in any simpler way. (But which ones are those?)

      Longer term would be custom modified cell cultures that were grown into new organs. mRNA would only be one of the tools used in that process. You’ve got to set the epigenetic programming correctly, for most organs you need lots of varieties of cells arranged in just the right order. Etc. To me (a non-medical professional) that looks generally 20 years away. Labs keep reporting progress, but anything beyond the very simple things doesn’t look at all close. And just what’s “very simple” isn’t usually clear.

  13. Sili says:

    I’m sure someone has already found a way to use mRNA to dope bikers in time for this year’s Tour.

  14. anonymous pharma says:

    Gareth,

    BioNTech (and some other companies, see Neon, Gritstone) were previously in the business of making personalized cancer vaccines using a LNP based mRNA platform, until COVID happened. These have unfortunately not been of high efficacy, at least as evidenced by the results from early trials by Neon and BioNTech. In fact the treatment against covid is not the first time this technology was tried in humans, the studies in cancer vaccines preceded this by a few years.

  15. Carl Pham says:

    Maybe synthetic mRNA would find some additional near-future use as an adjunct to in vitro cell engineering. Exempli gratia, maybe some aspect of CAR-T or related approaches could be sped up/made more efficient/taken in new directions by the use of mRNAs delivered in vitro.

  16. Gus says:

    Agggh another layman’s question and please correct me if I’m wrong which I hope I am again.
    Inn the uk there is high levels of vaccine and virus doesn’t this mean the perfect breeding ground for a vaccine resistant variant? The tories are about to “open” indoor public venues, pubs etc because even though cases are soaring deaths aren’t (because its young people) making it even more likely?

    1. Longtime medicinal chemist, first time poster says:

      Having a vaccinated population means lower overall levels of virus in the community which in turn means fewer opportunities for variants to develop. The problem is that we have problems getting everyone vaccinated either due to lack of available vaccine or antivax sentiments in the population. Those people continue to provide fertile grounds for the development of new strains, and it is possible that against some of those strains the vaccines will be less effective. It. Is. NOT. the vaccinated population which leads to the development of resistant strains. Evolution works because the genetic variation is there PRIOR to it being exposed to the selection criteria. It is not an intelligent response to trying to evade a problem.

      1. biologist says:

        The transmission rates are very high in vaccinated populations, there is very good reason to believe that their antibodies will cause and accelerate the emergence of vaccine escape mutations. This can bring us back to square one very quickly. It would make no sense to me if the strategy to exit this situation is a new escape variant based vaccination campaign. The modelled and witnessed number of delta infections in heavily vaccinated populations runs into the tens of millions. The probability of complete vaccine escape is 100%, most likely this year.

  17. chemist says:

    “The huge success of the mRNA vaccination platform during the pandemic ”
    According to whom? Seems like a disaster to me! They don’t confer superior immunity compared to the virus itself, and have been causing injuries in healthy people. A family member is suffering from Bell’s Palsy. Another friend had his hands paralyzed for days. Only a fool would inject this non-FDA approved experimental drug into their body, for a vaccine with such high survival rates.

    1. chemist says:

      *for a virus

      1. RobZ says:

        If you don’t get vaccinated, you need to stay masked up and stay socially isolated.

        Otherwise, you are gonna get it almost without a doubt.

        The virus will then run an uncontrolled experiment in your body resulting in the creation and release of all sorts of non-FDA approved chemicals. Possibly, you will be one of the unlucky hosts in which the virus mutates to an even worse version.

        I got vaccinated. Hurt for a day or two.

        1. chemist says:

          I already had coronavirus over a year ago. Fever, fatigue, low appetite that lasted for less than a week.
          You don’t need a vaccine for this stuff unless you are extremely old or have serious pre-existing conditions. I even have asthma and I experienced no respiratory symptoms. Can we just stop pretending that this virus is like the Black Plague?

          1. RobZ says:

            Your idea to just let nature take its course is extraordinarily reckless. Each viral replication is an instance where it might mutate into an even worse variant and following your advice would maximize the number of replications.

            There’s already evidence that the Delta variant is causing considerable damage among the young.

  18. biologist says:

    Fauci reports 99% of Covid deaths are in unvaccinated folk. This is at huge odds with the situation reported in the UK where the majority of Covid deaths are now recorded in vaccinated folks – both partially and fully vaccinated (Public Health England). The system in America apparently does not test for Covid in many instances where the patient has been vaccinated and has a breakthrough infection. I’ve seen anecdotal reports of this where vaccinated sick are systematically being denied PCR tests. Is this what’s happening to account for the distortion in figures between US and UK? Could it be that breakthrough vaccine deaths are instead being recorded as ‘pneumonia’? Is there a reluctance to test sick and vaccinated people? I’ve seen this thread on Twitter and it looks genuine: https://twitter.com/nicolestoutpt/status/1409959585566412810

    1. 이웅견 says:

      This seems to be… debatable.
      Please check out https://www.bbc.com/news/health-57610998 which seems to relate to the PHE report you might be alluding to.
      Also yes to one point: in Israel, the delta variant seems to have reduced the efficiency of the Pfizer vaccine relating to avoiding hospitalization only slightly , but very significantly reduced the protection against getting infected, from 94% to 64%. So maybe a little bit early to burn that mask and forego social distancing.

      1. Tony M says:

        The data discussed in your link comes from Table 4 of the report “SARS-CoV-2 variants of concern and variants under investigation in England Technical briefing 17 25 June 2021” Source: (https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/997418/Variants_of_Concern_VOC_Technical_Briefing_17.pdf)

        Page 16 of that report states that “Delta variant accounted for approximately 95% of sequenced and 92% genotyped cases from 7 to 21 June 2021. (Page 16)”;

        Table 4 details “Attendance to emergency care and deaths by vaccination status among Delta confirmed cases” A summary of the deaths in that table may be useful l:

        Cases ….% of Total…..Status……………….Deaths………Mortality Rate ( 1 in )

        Under 50:
        52,846….57.4%…..Unvaccinated……………….6…………..(1 in 8,808)
        19,693….21.4%…..Vac (Full/Part)……………..2 ………….( 1 in 9,847)
        9,892……10.7%…..Unlinked………………………0 ………………..n/a

        Over 50:
        976………1.1%…….Unvaccinated……………..38 ……………( 1 in 26)
        7,499……8.1%…….Vac(Full/Part)…………….68 …………….( 1 in 110)
        1,123……1.2%…….Unlinked………………………3 …………….(1 in 374)

        92,029…..100.0%…..Total…………………….117………………( 1 in 787)
        Points to Note and ignoring the “Unlink”:
        – The highest rate of death category was the Over 50 Unvaccinated with a 1 in 26 dying;
        – These odds reduced to 1 in 110 if they were fully or partially vaccinated;
        – The largest group in the table was the Under 50 Unvaccinated accounting for 57.4% of total infections and only 6 deaths or rate of death 1 in 8,808. This was slightly higher than the Fully and Partial Vaccinated group of Under 50s which had only 2 deaths or 1 in 9,847;
        – The interesting point to note is that in the Over 50s while vaccination reduced your rate of death by a factor of 4.3 from 1 in 26 to 1 in 110, the rate of death in this vaccinated group was still 79.9 higher than the rate of death in the Unvaccinated under 50s group ( ie. 1 in 8,808 compared to 1 in 110);
        Regards

        1. Tony M says:

          It should also be noted that the Over 50s accounted for 10.4% of total delta cases in the above table but make up about 34.4% of the population based on 2011 population census.

          1. 이웅견 says:

            Thank you very much for pointing us at the primary source!
            I’m sorry for not having managed to locate it, and my source for the Israel numbers is probably pretty useless for most readers here. I provided it as “website” for the fearless:)

        2. biologist says:

          Thanks for the great analysis. So the idea of a vaccine passport being required to dine indoors puts vaccinated over 50’s directly in the line of fire (prolonged mask free indoor time) and they have an 80 times greater risk of death compared to unvaccinated under 50’s. Who’s this vaccine passport meant to protect? No vaccine = eat outside or not at all. If the idea is for personal safety then over 50’s regardless of vaccination status should just stay at home.

          1. David says:

            That’s a weird way of putting it. It’s an issue of lowering risk, and every bit factors in(outdoor, mask, vaccination/recovery etc.)
            How about: ‘Don’t want to do your part to slow infections? Eat outside’

        3. Tony M says:

          The above table calculates the estimated mortality rate of the Vaccinated/Unvaccinated Under/Over 50s based on the data in Table 4 of the linked report for those who have caught the delta variant. After posting the table it begged the question, What is the relative risks of the groups actually catching it as opposed to dying from once you have caught it? Hence my comment about only 10.4% of the cases been over 50.

          I don’t want to mislead anyone by the above table as the risks of catching the Delta variant also varies between groups. While the Over 50s appear to have the highest risk of death if they catch the variant, in contrast they also appear to have a lower risk of catching it.

          Using data from the NHS report on vaccination status as at 31 May of the England population, I have done rough calculations to construct a table which shows the relative risk of actually catching the Delta variant:

          Est. Population………..%………….Vac Status……………Cases………% of Cases……..Est. Inf. Rate ( 1 in )
          Under 50:
          22,639,541…………40.2%…. Unvaccinated…………..52,846…….57.4%………………428
          12,603,757…………22.4%…..Vac(Full/Part)………….19,693……..21.4%……………..640
          ………………………………………Unlinked…………………..9,892…….10.7%

          Over 50:
          …..844,342…………..1.5%…..Unvaccinated……………..976………..1.1%……………….865
          20,243,514…………..35.9%…Vac(Full/Part)…………..7,499………..8.1%…………….2,699
          ………………………………………Unlinked………………….1,123………..1.2%

          56,331,154………….100.0%….Total……………………92,029……….100.0%……………..612

          Points to Note:
          – Est. Infection Rate in > 50 Unvaccinated was 3.1 times higher than in > 50 Vaccinated. This compounds the higher death rate of 4.3 for those who have caught the Delta Variant in this group. Relative risk of both catching and dying would be 13.3 (= 3.1 x 4.3);
          – Est Infection rate in those vaccinated > 50 was 6.3 times lower than the Est. Infection rate in those < 50 and still Unvaccinated. This lower risk of catching this variant would offset some of the higher death risk this group has if they caught it. The apparent relative combined risk of both catching and dying from it would be 12.7 higher (=79.9/6.3);

          The above is only rough calculations done to show how some of the higher risks of death if you have the Delta Variant appears, to some extent, to be offset by a lower risks of catching it;

          Regards

          1. Another Idiot says:

            A weakness in all of this is grouping partially and fully vaccinated in the same group. It seems pretty clear that there’s a much bigger difference in effectiveness between the two with the delta variant than other variants. It would be interesting to see what the numbers looked like if you grouped the partially vaccinated with the unvaccinated. Of course, it would be best to see three separate groups.

  19. Dan says:

    It is all laughable to believe that we are anywhere close to a solution when the experimentation is all we know!

    Having said that the future is a long way off!

  20. Jen F says:

    What about recovered people? I still have high levels of antibodies from a month long infection 15months ago. I have autoimmune issues and based on the concerns of effects of this kind of vaccine on people with autoimmune (a primer on the vaccine technology in Nature April 2018 had reservations about outcomes for people with autoimmune – and there were no people with autoimmune in the trials) so I’ve not chosen yet to be vaccinated- I still am having inflammation issues post-Covid and don’t want and more stimulation of my immune system at the moment. I use a mask everywhere – no eating in restaurants. Recovered people with high antibodies are still categorized horrible anti vaxers. If I’ve fought this off and 15 months later still have high antibodies, is over stimulating my immune system really gong to do much more for

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