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More on Vaccine Side Effects

Back last summer, I was writing blog posts about possible side effects of mass vaccination. For readers who’ve shown up more recently and might have me filed as Defender of Vaccines, that might seem surprising, but remember, I’ve been in drug discovery for a long time now. All drugs, all therapies have side effects. It’s just a question of the risks and severity of those versus the benefits, and looking at either of those alone is a serious mistake.

One of the things I wondered about was Guillain-Barre syndrome. That’s because it’s already a known sequel to viral infections in general, and has also shown up response to vaccination. It’s an autoimmune disorder, which means that it’s going to be scattered around in the huge diversity of immune function from person to person, and it also means that it will be extremely difficult to predict who might be at risk. G-B involves an attack on a person’s own myelin sheaths around the nerves, which sounds very serious – and indeed, sometimes it’s severe enough that people need to be hospitalized while they recover. But fortunately the vast majority of patients do make strong recoveries – the immune response goes back down, and the body’s own remyelinating cells fix up the damage.

And now the FDA has issued a warning that there have been a few cases with the J&J vaccine. To the best of my knowledge, this has not been seen with the other vaccines, and that’s another illustration of the variability in the long tail of autoimmune side effects. (Update: see the comments. There are reports of G-B after the AstraZeneca/Oxford vaccine, although it seems that the statistics aren’t quite there yet to say that there’s a connection). You see these with small-molecules drugs as well, often when they can form covalent adducts and produce modified proteins that (in a few people) will set off the immune response, and this low-level idiosyncratic toxicity is a matter for constant surveillance.

Readers will recall the rare blood clotting problems seen with the AstraZeneca/Oxford vaccine, mostly in younger female patients. We now have more details on that, and this new paper seems to be the explanation. The affected people developed antibodies that respond to a particular 8-amino-acid region on the surface of the platelet factor 4 protein, in the same region that heparin binds to it. That sets off the same platelet activation cascade as heparin binding does, and thus the thrombosis effects that are seen clinically. The antibodies can also bind to existing heparin/PF4 complexes, which explains why heparin treatment makes things worse. Now, why just these particular people develop these particular antibodies, and why this seems to happen with the AZ/Oxford vaccine and not the others (to anywhere near the same degree, at any rate) are things hidden further down in the mysteries of human immunology. Meanwhile, the low-incidence side effect with the mRNA vaccines seems to be myocarditis, which has been noted mainly in male patients up to about 30 years old, generally after the second injection. This too is almost always a transient condition, fortunately, and is also down in the few-per-million range.

I know that these reports have many people with existing autoimmune disease concerned – that’s a completely rational thing to want to look into. I can only add, though, that the evidence is that coronavirus severity also seem to be greatly enhanced in people who have larger amounts of existing autoantibodies. All the medical advice I have seen so far is for people with autoimmune disease to indeed get vaccinated, and I agree with that as well.

That CDC link will take you through the sort of risk/benefit calculations that have to be done in all such cases. And since all of these side effects are in the few-per-million range, and since they all can be watched for, and can almost always be treated (or resolve themselves), the comparisons with the effects of the coronavirus pandemic itself are clear. It’s true that most people who catch the actual virus recover, but there certainly are deaths, even in the younger patients, and even more importantly, there are long-term effects. Reports of “Long Covid” have been growing with time, and there are now reports that the Altmann group at Imperial College has detected specific autoantibodies that are correlated with these long-running symptoms. (I’ll go more into that work when it gets published as a paper or preprint). Overall, the mortality/morbidity numbers are far worse with the actual disease – it’s no contest.

So as the CDC link shows, the choice is clear: mass vaccination does indeed have rare side effects, but mass infection with the coronavirus (which is the only other choice) is absolutely worse. And to reiterate a point that’s been made many times, the faster we can vaccinate people, the lower the chances we have of encountering a new variant form that will make everything even worse. We have to get as many doses out to the world as we possibly can, as quickly as we can.

Perversely, the current Delta variant may have done us a favor (although to be sure, I would rather it not have emerged at all). An earlier variant (Beta, the “351” strain) was actually better at evading vaccine protection than any of the others – not really to breakthrough levels, but certainly more than the rest. But it is disappearing from the world thanks to Delta being much more transmissible, and Delta is handled better by the vaccine-raised immune response. There are indeed vaccinated people who have come down with Delta infections, but the vast majority of cases are among the unvaccinated, a statistic that is seen most dramatically in areas where unvaccinated people are a minority of the population but are nonetheless the ones showing up infected.

No one has any idea of what the potential is for variant forms that could truly evade vaccine protection. Nor can we be sure about the potential for variants that are even more transmissible than Delta. And what we really, really don’t want is anything the combines those two properties. It would be very reassuring to show that you can’t have both those in the same strain, but we absolutely can’t say that yet. There are too many possibilities. We have to stop the virus from trying them, constantly and in every corner of the globe, if we don’t want to find out the hard way. Get vaccinated.

Update: as mentioned here, good faith discussion of all kinds on these topics is welcome in the comments section. Deliberately inflammatory posts, trolling, and conspiracy theories, however, will be deleted swiftly.

142 comments on “More on Vaccine Side Effects”

  1. David says:

    Not to mention that there’s a risk of Guillain-Barre syndrome from coronavirus infection itself. A recent paper (Ann Neurol 2021 Mar;89(3):598-603) estimates that at 15/1000. Considering only GBS risk, the J&J vaccine still seems like a good bet.

  2. J Curwen says:

    I did not know that mentioning the amount of residual template DNA in the RNA vaccines and possible consequences thereof are a conspiracy theory. Vita brevis, ars longa.

    1. Patrick says:

      When you use it as an excuse to cast aspersions on them that unbelievably large amounts of clinical data show to be nonsense? These mRNA vaccines are already well on their way up the “most patients dosed ever with any individual drug” list, and none of these “possible issues” have shown up.

      Then, yes, yes it is.

      1. J Curwen says:

        If you say so. My statement was about a possible mechanism which might effect the next generations that has been shown many times in the lab. But I am happy that there exist screenshots and a wayback machine so no one can say we were unaware of that risk. At least I tried.

        1. Ray says:

          Are you trying to imply that the mRNA vaccine could cause germline mutations…?

        2. Miles says:

          Curwen dear chap! Have you considered becoming a sci-fi author pursuing the dystopian future our children face? We have set up plenty to worry about without worrying about germline mutations.

    2. Van ‘t Oever says:

      This is the reason why there is a DNase treatment after transcribing the RNA in the production process, followed by further purification.

  3. Isidore says:

    “Overall, the mortality/morbidity numbers are far worse with the actual disease – it’s no contest.”
    Let me start with the disclaimer that I have received the vaccine and have advised my family and other people who have asked me (because I work in biotech they believe that I know more than they do, the fools!) to be vaccinated as well. So, this is truly a good faith question regarding the above statement, which is, indeed, true in that for every 100,000 people, say, who get the vaccine there will be fewer adverse events, including death, which is arguably an adverse event, than for 100,000 people who come down with COVID-19.
    However, this statement does not take into account the probability of being infected with COVID-19, which, I assume, is decreasing every day as more and more people get vaccinated. In other words, taking again 100,000 people who get the vaccine and another 100,000 people who don’t, the first group will exhibit a certain number of adverse events, and we have a good handle on this number from the clinical trials and the subsequent large numbers of people who have received the various vaccines. But for the second group do we have any good numbers as to how many will come down with the disease and of those how many will develop severe symptoms or die from it? And whatever these numbers are, they will certainly be different from, say, a year ago when there were no vaccines, or even from a couple of months ago, when fewer people were vaccinated.

    1. Kamil says:

      Looking at the UK and Dutch numbers moderate levels of vaccination will still allow a high attack rate. I.e. it seems like many if not most people will eventually get COVID. Maybe once we get close to vaccination levels in Israel the free-rider problem will be more significant, because attack rates for the unvaccinated are conceivably below 50-100% over the next N years. At that stage it should be the government’s job to handle the perverse incentives to the individual. One *may* be excused for trying to game the system if one’s life is on the line, even if the benefits are only marginal. The only fair thing would be mandatory vaccination or some programme that encourages the free-riders to contribute to society.

      It would be really cool if someone had more concrete numbers, though.

      1. bertram says:

        Lot’s of infections in vaccinated populations are a real worry for the emergence of escape mutations? Such an event is much more probable with non-sterilising vaccines and transmission is very high e.g. 200k + cases in the UK in the last week, which is a very heavily vaccinated population by global standards. The selection pressure applied on the virus by vaccine antibodies theory seems very plausible that we are going to encounter this event relatively soon? Is anybody worried that vaccine protection might not hold up for much longer?

    2. zero says:

      The numbers you’re asking for would be useful for a broader analysis that includes the risks and consequences of a breakthrough infection causing global pandemic round two.

      They would not be so useful for a risk analysis focusing strictly on short term consequences of mass vaccination vs. doing nothing while hoping infection rates continue to drop and no new variants appear.

      1. DrOcto says:

        Ah, the old ‘if everybody else gets vaccinated, then I won’t need to’ logic. I hope you see why this is also an issue.

        1. Daren Austin says:

          When Dr COVID calls to say “the virus will see you now”, it will be important to go in with some pre-existing seropositivity. I am in no doubt that all will eventually be infected. Multiple times. As one who was seronegative prior to my infection (April 20), I can only wish I had had some on-board antibodies at the time: 15 months, still no smell (among other things)

          1. Albert says:

            I don’t believe that those exposed to the virus necessarily get infected. I know of two severe cases (hospitalised) where nobody else living in the same household got infected despite prolonged exposure times in close confines (one involved a several hour car journey). Spouses tell me that they were indeed sleeping together in both cases, one family had 4 kids the other 2. I also know of a family gathering Christmas dinner where both grandparents present avoided infection. Severity of adult and child disease varied in this case, many PCR tests were also negative. There’s still a lot we don’t know

    3. Patrick says:

      This data is available and has been heavily used – Have you just been ignoring it?

      The mRNA vaccines haven’t been shown to cause death/harm at any rate worth considering epidemiologically (seriously, it’s just above the noise, and the risk benefit calculations are all benfits), but in comparison, the AstraZenaca vaccine has a meaningful risk of the clotting events in younger populations.

      The British medical regulator produced a pile of data showing that for younger populations, given their risk of catching COVID and having a severe case of it, the AZ vaccine risk/benefit was *marginal* vs COVID. Under certain assumptions of youth, good health, and low exposure, it could be *riskier* to get the AZ jab than not.

      And so they immediately stopped recommending it for younger populations.

      For reasons I don’t understand, the rate of those events is much lower from the J&J vaccine, so it’s still pretty much all green lights on the risk-benefit calculation even though it *can* cause those same clotting events.

      So… This is being considered, actively. You’re not hearing about it for the mRNA vaccines because there’s nothing to talk about. And if haven’t heard it about the AZ vaccine, then you haven’t been reading the right stuff.

      1. Jonathan B says:

        That’s right, there was a careful analysis in the UK of the relative risks – but interestingly those were based on a UK case rate only about a tenth of what it is now with the Delta variant resurgent. They haven’t re-run the calculation.

        Current UK vaccination rates seem to have dropped, and it is unclear whether this is hesitancy , other causes, or the limited supplies of the Pfizer vaccine (wheras previously the supplies could be used exclusively on first doses since older age groups mainly had AstraZeneca, they now have to be divided between first and second doses). With a daughter age 20 I can say that anecdotally that most of those young adults known to us are keen on vaccination but so many of them are currently infected or isolating due to contact with a case that this may delay their availability to take up appointments. And even when they have had their first dose, a single vaccination protects relatively poorly against Delta.

        More on the main topic, it is difficult to align the reported side effects with the biology. The J&J and AZ vaccines essentially use versions of a relatively benign cold virus – would natural adenovirus infection cause similar low rates of (say) Guillain-Barre syndrome if anyone was able to quantitate it? It also underlines how incredibly lucky the world is that the mRNA vaccines – about which so little was known before – have turned out to be not only effective but without serious side effects.

    4. eub says:

      The super-crude epidemiological model is that 1) we should not expect current vaccination levels to control Delta — and indeed, as noted, the U.K. is having it blow up. And 2) with Delta’s transmissibility, in the long run some 75-80% of the population is going to end up immune, one way or the other. (Threshold from: if each person would transmit to 5 others, but 4 are immune and dead ends, there’s no exponential growth.)

      So if 60% are vaccinated, the super-crude calculation is that if you’re unvaccinated, it’s a coin flip whether you’re one of those who gets it in the course of the convergence up to 80%. As the chance gets lower, it also gets more uncertain and more subject to the limitations of this super-crude model. tl,dr unless you have reason to expect real 85%+ herd immunity, you can apply a small free-ride factor, not very large.

      1. Nile says:

        Acquiring immunity ‘one way or another’ isn’t a good bet with Coronavirus in general, nor with Covid-19 in particular.

        The essential component of the virus – the spike protein – is not often targeted by the natural immune responses of a patient exposed to the virus: mostly, we see antibodies binding to capsid proteins elsewhere on the virus, which are highly variable in all Coronavirus strains.

        No surprises here, in evolutionary terms, that natural selection has resulted in the essential (and highly conserved) protein being a poor target for natural immune responses; and it is equally unsurprising that the components of the virus which most often elicit a natural immune response are highly variable.

        The designed immune response elicited by our vaccines is another matter: we know that this spike protein is essential for the virus, and any mutations that change it are far, far more likely to cripple the virus than free it from the effects of a vaccinated immune response.

        We were also able to perform extensive safety testing on our designed immune response: no such thing is possible for natural immune responses and ‘Long Covid’ is, in part, a complex of autoimmune pathologies.

        The safety testing we performed worked well on the tens of thousands of people we tested, and the numbers are holding-up very well in the hundreds of millions of people we’ve vaccinated.


        The dark side of that is that hundreds of millions of unvaccinated people are a natural laboratory for the virus, when we allow it to be so widespread.

        That means billions of mutations, every day, and ‘Far, far more likely to cripple the virus’ is an assumption that needs watching, when hundreds of millions of unvaccinated people are spreading the virus, every day, and coming into contact with tens of millions of vaccinated people.

        It is extremely unlikely that any mutation in the spike would result in a transmissible virus at all, and even less likely that this would ‘escape’ the vaccine: but extremely unlikely events are going to happen when we have hundreds of millions of infected people coming into daily contact with vaccinated people who would be perfect targets, if only that tricky mutation in a finicky-but-essential protein turns out in exactly the right way.

        Hundreds of millions of infected *and re-infected* people.

        When unvaccinated people encounter the virus, and clear it with an immune response that targeted a variable capsid protein, they are vulnerable to reinfection when that variable protein is absent in their second encounter; and their third, and their fourth.

        There is no guarantee – at best, a low-to-moderate expectation – that any naturally-elicited immune respone to any coronavirus strain will confer a lasting protection against repeated infections.

        There is no expectation of ‘herd immunity’ in an unvaccinated population.

        So there’s only ‘one way’ – vaccination and reducing the spread; your ‘another’ is a gamble that we’re going to lose and the only question is ‘How badly?’

    5. Philip says:

      Herd or community immunity formula: 1.0 – 1.0 / R0
      R0 for the delta variant (from The Lancet published July 12, 2021): 7
      That works out to 86% of people being immune enough to SARS-CoV-2 to not spread the virus if infected for herd immunity to be reached.
      That is not going to happen. The best vaccines we have are only 88% effective at preventing disease from the delta variant (Nature 6/22/2021). Keep in mind that is preventing disease, not infection. That is a subtle, but important difference. The vaccines are better at providing protection than surviving the disease. With vaccines only reducing transmission by about 50% (NEJM 6/23/2021) you can see there is no way we are going to reach herd immunity.

      Bottom line, over time almost everybody will come in contact with SARS-CoV-2.

      1. stewart says:

        It was claimed that Iquitos hit 93% seropositivity last year. I’ve looked, unsuccessfully, for data on the subsequent progress of the pandemic in that locality.

        A variety of factors worry me – overshoot of herd immunity, heterogeneity in vaccination coverage, and high variability in the number of infections per case.

        If the disease spreads slowly and the case rate remains low, then when the herd immunity threshold is reached there will be few infected people capable of infecting the remaining susceptible population. But if herd immunity is reached with a high rate of infection a lot more people will be infected before the pandemic subsides.

        Heterogeneity in vaccination coverage between subpopulations means that the people in the herd immune subpopulation can catch the disease from other subpopulations; even if the disease no longer spreads among care home residents and staff they can still catch it from other people. now has geographic vaccination coverage data; when I looked a few days back some (student-heavy) districts in some cities had vaccination rates in the 20% range, and some cities as a whole vaccination rates under 50%, which allows the pandemic to spread in those cities, and bleed into the better vaccinated suburbs.

    6. David says:

      Isidore: “the probability of being infected with COVID-19, which, I assume, is decreasing every day as more and more people get vaccinated.”

      Ah, the ethical problem of the freerider. Let others take the vaccine.

  4. Link in the handle to an account of what it is like to have Guillain-Barré from a doctor. “…something better not to get”.

    1. Simona says:

      COVID is also something that’s better not to get.

  5. Harry Nyquist says:

    Thomas Pueyo was explaining last year that, due to SARS-Cov-2 having a fairly long asymptomatic period, it has plenty of room to improve in both transmissibility and deadliness, by merely reproducing faster.

    Does that seem consistent with what we know, to this comment section?
    Could this be confirmed by comparing, say, how long patients with new variants stay asymptomatic?

  6. luysii says:

    Welcome to the world of the physician where the risks and rewards of absolutely everything we do must be balanced. The University of Pennsylvania Medical School class of 1966 (which includes a Nobel laureate) had a virtual reunion in May. We were all voluntarily vaccinated. This wasn’t good enough for our contractor who remains unvaccinated. You can try feeding the skeptics the following, but I doubt that it will help —

  7. Michael says:

    With regards to delta suppressing beta: the problem is that once the population reaches herd immunity, the only strains left in circulation will be those that can evade this immunity. As such, increased vaccination of the young is perhaps only bringing the moment of vaccine obsolescence that much sooner.

    It is surely only a matter of time before a variant with a high degree of immune-escape emerges, and if combined with high transmissibility there is no way the vaccine manufacturers are going to be able to react quickly enough. My personal mutation nightmare is of a reduction to the age-based variability in mortality. Is this all empty worry, or may our current situation – of total triumph over this virus – come to resemble the close of the first wave of Spanish Flu?

    1. Patrick says:

      “With regards to delta suppressing beta: the problem is that once the population reaches herd immunity, the only strains left in circulation will be those that can evade this immunity. As such, increased vaccination of the young is perhaps only bringing the moment of vaccine obsolescence that much sooner.”

      This statement makes absolutely zero sense, FYI. It’s just … nonsense. Immune escape variants have so far arisen in non-vaccinated populations, and is *less* likely in vaccinated ones, because the existing immunity suppresses the levels of virus, etc, etc.

      So, no. That’s not how this works.

      1. J Curwen says:

        Ravi Gupta showed how you really get escape mutants:
        The first evidence of in vivo SARS-CoV-2 escape from antibodies: emergent Spike deletion H69/V70 and D796H mutation in a convalescent plasma (CP) treated patient.
        Kemp, S.A., Collier, D.A., Datir, R.P. et al. SARS-CoV-2 evolution during treatment of chronic infection. Nature 592, 277–282 (2021).

      2. Michael says:

        It would be nice were that the case. Unfortunately, you simply haven’t understood. Mutations occur every time someone is infected with the virus, most of these are harmless, but rarely some are not. The result of these is the emergence of variants over time with features that are more problematic to us, their potential hosts. Variants will almost always emerge in unvaccinated populations for the simple reason that in the absence of transmission no mutation can occur.

        However: once a variant has arisen that can evade pre-existing immunity, this can infect immunised individuals and spread across vaccinated populations. The fact that these populations are (at least partially) immune to other forms now gives the immune-escape variant a transmission advantage, as they no longer have to compete for hosts with other variants on an equal basis.

        Over the long-term, increasing immunisation reduces the rate at which variants emerge. However, as long as there are billions of people worldwide remaining unvaccinated, marginally increasing the proportion of our own populations that are vaccinated will not solve this problem.

        1. biologist says:

          The vaccines have non-sterilising immunity, breakthrough infections in Israel occur in a reported 50% of cases. The acceleration of escape mutations does indeed and unfortunately appear to be very imminent.

          1. Michael says:

            Interesting, thank you. The UK’s figures from PHE seem substantially better. Perhaps this is due to the longer 8-12 week interval between doses than in Israel, which uses the standard 3 weeks? If so, this is something that other countries might want to copy, especially as future variants take over.

          2. David says:

            I don’t think that you need an ‘escape mutations’ to get to this 50%, just the law of big numbers (more people are vaccinated) and relative risk (most of the vaccinated are those more at risk). The risk of a 70-year-old is 32-fold that of a 35-year-old, so even a >90% reduction from vacation wouldn’t overcome this difference, leaving the 70-year-old with twice the risk of the 35-year-old. This seems to fit with the PHE data (63% of fatalities had at least one shot).

            Does this mean that future ‘escape mutations’ are not a problem? No, just that the data is not all that unexpected

          3. biologist says:

            It’s very early to tell both countries only recently lifted restrictions and it’s not yet the season to really find out. Transmissions are massive in the UK, virus is getting an opportunity and will take same. Nothing personal, just nature (even if semi-synthetic on release).

          4. David says:

            Maybe, but as rates of vaccinations go up, so too should the % of positives in vaccinated people.
            I still haven’t seen any real seasonality, for that we will have to go back to ‘normal’.

            What do you mean by ‘semi-synthetic on release’?

  8. Lane Simonian says:

    Johnson and Johnson and AztraZeneca executives announced an important initiative today:

    “J&J and AstraZeneca are conducting early research into whether potential modifications of their Covid-19 vaccines could reduce or eliminate the risk of rare, but serious, blood clots associated with the shots.”

    Moderna and Pfizer executives were give the opportunity to join in this endeavor, but refused to do so for fear that it would tarnish the reputation of their vaccines.

    The cases of vaccine-induced thrombosis are about one in 75.000 for the Johnson and Johnson and AztraZeneca vaccines (the numbers may be slightly better for the Moderna and Pfizer vaccines). The death rate for vaccine-induced thrombosis is about 20 percent. Developing less lethal or non-lethal vaccines would go a long ways to reducing vaccine hesitancy.

    1. Mariner says:

      I’d sort of hope that this is just PR fluff because I’d expect that both J&J and AZ should have been working hard to try and discover WTF was going on to cause the clotting from the first moment it became apparent that there was an issue. Of course, it may be that they couldn’t work out why there was an issue. There was a German paper claiming to know the cause a couple of months back (and they said they thought it was something which could be fixed in the vaccines) but I’m not sure if that group had similar findings to the paper mentioned by Derek.

      I know AZ are testing a modified vaccine targeted at the Beta variant so probably too late for that one, but future Delta (plus?) vaccines which could remove or massively reduce the risks of thrombosis would be helpful, to say the least.

      1. anonymous says:

        It’s not PR fluff. I’m an AZ R&D employee, and we have studies on-going to try to understand better the clotting issue. Not clear if that will lead to a vaccine version without the problem down the road, but at least we’re looking.

        1. Mariner says:

          My point was that the announcement itself must surely have been PR fluff. It seems pretty obvious that AZ would be investigating the reasons for the issues at the first opportunity so this should have been underway for several months.

  9. Arogya says:

    Serious vaccine side effects are thankfully uncommon, but as they are becoming more well known, public health bodies should reconsider their recommendations to vaccinate individuals with evidence of prior infection. With no clear real world benefit in vaccinating these individuals, why expose them to unnecessary risks even if uncommon?

    1. Mariner says:

      One or two papers are out which indicate that the vaccines provide stronger and broader protection than prior infection. Whether or not prior infection provides enough protection against future serious illness after reinfection with one of the newer variants remains to be seen, I suppose. A single dose of vaccine ought to be enough to give a hefty boost to anybody with prior infection. Anecdotal evidence that vaccination can improve the outcomes of those with ‘Long Covid’ which would be helpful if it could be proven to be correct.

      Especially here in the UK where our government is going GBD in all but name so we’re likely to see another few hundred thousand people suffering long term problems following millions more cases by the end of the summer.

      1. Madge Hirsch says:

        Here in France that is the policy. Those who have had Covid only get one dose of vaccine and they have to wait at least 3 months after recovering.

        1. Jen F says:

          If they’d offered one shot here for recovered people I probably would’ve done that – but sadly, it isn’t an option for us.

    2. JenF says:

      Exactly – I was infected w a very bad bout in Mach 2020- I STILL have high levels of antibodies 15 o this later. I also have autoimmune – which makes me wary of this vaccine just for that reason. I have long Covid issues. All this taken into account- I don’t want to take the vaccine now (maybe Novavax is better for me?). In Feb ppl were commenting about durable unity in the recovered – but not now? Even a month ago natural immunity was being taken seriously and now nothing. Now I’m destroying society because I don’t want to worsen my autoimmune or long Covid. Why is natural immunity (again 15 months later and I have high amount of antibodies) totally off the table? I’ve endured so much and to risk revving up an immune system that’s trying to recover with threats of not being allowed to work etc also seems wrong. I wear a mask at all times and quite frankly I’m still trying to heal. Will recovered cases never count? All papers I’ve read indicate no reason to throw another monkey wrench in so to speak.

      1. Derek Lowe says:

        Every study I’ve seen points toward natural immunity being weaker than that achieved by vaccination.

        1. steve says:

          It’s not just studies. The city of Manaus had over 70% of its population infected with the original SARS-CoV-2 strain and then the P1 variant hit. The “natural” immunity did nothing to prevent wholesale meltdown of their health system due to overwhelming infection. Meanwhile, the Pfizer and Moderna vaccines are >90% effective at preventing infection by P1. Natural immunity just is not as good as the vaccines.

          1. David says:

            Why do we have to chose when most of the first world can have both (

          2. steve says:

            Because the last thing you want is to risk infection just for the dubious
            “honor” of having “natural” immunity.

      2. Charles H says:

        I’ve seen one report that the vaccine reduced or eliminated long COVID symptoms. I don’t remember the source, but it was either in Science News or New Scientist. So your argument is dubious.

        OTOH, one reported study isn’t THAT impressive. If you don’t trust that, it’s probably reasonable. But I haven’t seen ANY studies that indicate it makes things worse.

      3. Michael says:

        That seems fair enough to me. Ultimately it’s a decision for each person to make for himself. Also, one thing to consider: following infection, a single dose of a vaccine produces a boost to antibody levels similar to that seen following two doses in the uninfected. Perhaps something to discuss with your doctor?

        A hopeful thought, for people with auto-immune conditions, is that there are vaccines in early development (from Inovio, Clover, Vaxxinity) that claim much milder side-effects than seen in the first-generation vaccines. Whether they achieve success in phase three trials, receive regulatory approval, and are ever made available in any particular country is completely up in the air. Just something to look optimistically towards for the future.

        1. Jennifer F says:

          Thank you! I had asked my GP about Novavax ( sorry, can’t look up the spelling at the moment but you probably know the vaccine I’m referencing ) – but she didn’t know what type of vaccine it is. It is concerning that autoimmune was left out of trials and the primer on mRNA vaccines in Nature from April of (I think ) 2018 had serious concerns about people with autoimmune taking the vaccines ( concerns about development of other autoimmune issues, inflammation etc). I realize the author of the blog says natural immunity isn’t good enough- but I have read several papers on enduring immunity in the comments section of other posts on this blog. I had a month long battle with Covid, and lost the majority of my hair, have some joint issues and swelling in both feet that is painful and won’t go away, swollen glands every few weeks. I can’t do any more inflammation. I wear two masks everywhere. I’ll be wearing them for a long time.

      4. gcarr says:

        I know that my account is anecdotal, but both my wife and 15 year old son had COVID in February 2021, with a lasting loss of taste and smell. Both of them recovered their taste and smell after receiving their vaccination. It could certainly be coincidence, but there have been others who have said some of their long COVID symptoms resolved after receiving the vaccine. You may want to look into that.

  10. steve says:

    Oy. So much theory and so little practice. In the real world, the vaccines work and the side effects are minuscule and rare. In most US States now, virtually every person who dies from COVID is unvaccinated. The risk/benefit ratio is better than almost any drug we have and all this theorizing does nothing to those real world results.

  11. Kaleberg says:

    One quick way to compare vaccine and virus risks is to consider that roughly 50% of the US has been vaccinated. The vast majority of the COVID cases and almost all of the deaths are among the unvaccinated. There have been very few vaccine related deaths or serious side effects requiring hospitalization. You can move the window back and forth in time to more or less than 50% or try to compensate for the fact that older people are both more likely to have been vaccinated and more likely to have serious or deadly cases of COVID.

    Over a hundred Americans die from COVID every day. How many days go by between vaccine related deaths? You can quibble about the exact relative risk and slice and dice it demographically, but unless vaccination was killing close to a hundred every day, it’s safer to get vaccinated.

  12. Adrian says:

    “the faster we can vaccinate people, the lower the chances we have of encountering a new variant form that will make everything even worse.”

    I am worried the opposite might happen.

    Vaccines are very good at preventing serious infections, but while they are good they are not as strong in preventing all infections and transmissions. If we vaccinate everyone and go back living as if it was 2019, Delta or other (future) variants might still have R >1.

    Politicians in most first world countries currently aim at vaccinating everyone (at least all adults) and go back living as if it was 2019.

    It is possible that the virus will be permitted to run freely through vaccinated populations, with billions of opportunities to find a way to mutate to weaken vaccine protection.

    1. steve says:

      This shows an unfortunate lack of knowledge. Look at every other vaccine we have, with the exception of flu which just is not a good vaccine. The rate of transmission drops dramatically and you don’t generate escape variants. So far SARS-CoV-2 has shown a limited bag of tricks and the vaccines work against all of them. Again, lots of theory while ignoring the facts on the ground.

      1. Adrian says:

        “So far SARS-CoV-2 has shown a limited bag of tricks and the vaccines work against all of them.”

        This is not true.

        The performance of the AstraZeneca vaccine against the Beta variant is so poor that 4 months ago South Africa decided not to use 1 million doses they had when this variant was dominant there.

        1. steve says:

          Obviously I’m referring to Pfizer/Moderna vaccines, not the other wannabes. Novavax is the only other vaccine worth consideration in this context. AZ and the others will need boosters from one of the others that are truly effective.

          1. Adrian says:

            “Obviously I’m referring to Pfizer/Moderna vaccines”

            You were attacking me, and I was not talking about any specific vaccines.

            Are you man enough to apologize for throwing unsupported insults like “This shows an unfortunate lack of knowledge.” and “Again, lots of theory while ignoring the facts on the ground.” at me when it is you who is making broad claims not supported by facts, or are you one of these culture warrior morons who can never admit when they are wrong?

            Even for the Pfizer vaccine, the numbers for protection against infection after two doses against infection with the Beta or Delta variants are somewhere around 75-80%. It is not obvious whether or not 100% vaccination rate with the Pfizer vaccine would be sufficient to stop the Delta variant if we start living as if it was 2019.

            “AZ and the others will need boosters from one of the others that are truly effective.”

            Even assuming your trust in the Pfizer/Moderna vaccines would be correct, it does not matter much for my point what happens with you only 5% of the population of this planet living in the US.

            Delta is from India, the Beta and Gamma variants that are good at evading vaccines emerged in South Africa and Brazil and have traveled around the world from there. There is already a “Delta Plus” variant from India that combines the improved transmissibility of the Delta variant with the E484K mutation that is suspected to be one reason why the Beta and Gamma variants manage to reduce protection by vaccines like the Pfizer vaccine. Sooner or later such new variants bread abroad will also reach you in the US.

          2. steve says:

            Sorry, wrong again. There is simply no data whatsoever to suggest that vaccination with an effective vaccine causes emergence of the variants you’re describing. None. These kinds of arguments only give succor to the anti-vax crowd and are based on faulty understanding of the immunology.

          3. Adrian says:

            Steve, do you have anything to contribute apart from culture warring and insults?

            Whatever your hypothetical effective vaccine would do has little relevance, in practice it is not clear whether any of the current vaccines could be sufficient for herd immunity against current and future variants. Pfizer is developing a version of their vaccine specifically against the Delta variant because they are not sure their current vaccine is good enough against a current variant.

            It is you who brought up just a few comments above the Manaus example where a variant evaded immunity created by natural infection. You are throwing insults like “These kinds of arguments only give succor to the anti-vax crowd and are based on faulty understanding of the immunology.” at me when saying that the same might happen with the current vaccines. If you actually want to be constructive, stop your insults and explain in detail why you think I would have a “faulty understanding of the immunology” and why this is 100% impossible.

            Derek made a claim in this post, and I am worried the opposite of it might be true.
            If my worry is completely unfounded, I would appreciate if someone could give a proper explanation why it is actually impossible.

          4. steve says:

            You’re again confusing things. Herd immunity has nothing to do with your original claim that somehow vaccines contribute to the formation of variants. It’s just wrong. Viruses mutate all the time. Your hypothesis that “it is possible that the virus will be permitted to run freely through vaccinated populations, with billions of opportunities to find a way to mutate to weaken vaccine protection” is just poppycock. Sorry if that offends you but it’s true.

          5. Adrian says:

            Steve, it would help if you would try to understand what I am describing, instead of only inventing new insults.

            If vaccinations bring hospitalizations and deaths down to a flu-like level, it will not be politically feasible to close down high-risk places like restaurants for something that is then literally “just a flu”. This is unfortunately currently happening.

            It is not clear whether vaccines alone are enough for herd immunity (even with your favoured Pfizer vaccine the math is not clear), and the above implies that if they aren’t the virus might be let run through the whole population being largely ignored like the flu (which usually kills around 30k people in the US every year).

            The result would be that the virus causes more infections than ever before during this pandemic, and every infection in an infected person is an opportunity to try random mutations in a vaccinated person for an escape mutation that brings enormous benefits to the virus.

            lack of herd immunity -> many infections in vaccinated people -> many opportunities for the virus to test ways how to escape vaccine protection -> more variants that escape vaccine protection

            It’s just that simple, everyone with a brain should be able to understand that this is not poppycock.

            And so far I haven’t seen any convincing argument that any part of my scenario would be unlikely to happen.

  13. Paul A says:

    The ensemble of vaccine side effects seems reminiscent of the story of the blind men and the elephant, who missed the big picture when focusing on individual details.
    The elephant in the room is that these side effects (thrombosis, myocarditis, capillary leak syndrome, Guillain-Barre) generally seem similar to, though milder or rarer than, the spectrum of systemic problems caused by the virus.

    Of course what all the vaccines, and the virus, have in common is the spike protein, which is suspected as a major player in the damage caused by infection.

    Arguments can be made about why the vaccine spikes should not cause problems, but the gaps in our knowledge about the underlying mechanisms in both infections and vaccinations should inspire humility, and the need for empirical tests.

    Are any experts taking this issue seriously, and conducting proactive physiological investigations rather than just relying on noisy signals to emerge from VAERS?

    For example, cardiac MRIs were done of athletes post-infection, and it was found that reported cases of myocarditis were just the tip of the iceberg of detectable cases.
    Why not do the same for a sample of un-infected people, pre- and post-vaccination?

    One could imagine also testing for other known infection effects such as neuroinflammation and long-COVID.
    Could there be such a thing as long-vaccine (or vaccine-induced chronic autoantibody syndrome)?
    Personally I’ve had post-Pfizer problems continuing for almost 3 months now, and I wonder how many other people are in the same boat.

    1. steve says:

      The blind man here is those who focus on rare side effects and miss the elephant of side effects from COVID. The cardiovascular, neurologic, renal and other long-term sequelae from COVID (not to mention death) far outstrip the rare side effects you refer to.

    2. MP says:

      I think the Covid-19 related heart issues have been mostly debunked or at least significantly knocked down a peg. It could be worth trying to gather a really strong dataset with pre and post infection cardiac MRIs, but the athlete data wasn’t convincing.

      Unfortunately, the vaccine-related myocarditis (especially in younger males) does seem to be a real signal in a population where the risks of Covid-19 are low (admittedly, long Covid isn’t totally understood). I’m glad to see mRNA vaccines being tested in children with lower doses, and I think it’s reasonable to consider either increasing time between doses or even only using one dose to reduce risk (most myocarditis is following second dose).

      1. Paul A says:

        @steve, right, as I said, the vaccine side effects are milder and rarer than the virus effects (broadly averaged).
        However, this is a separate question from what I presented. It does not nullify the idea of investigating vaccine side effects more systematically.

        Regarding the comparison between vaccine and virus effects, it is also not such a simple question since there are dependencies on subpopulations and circumstances, which is why there are benefit/harm analyses like the CDC does. For example, serious complications from the virus are rare in teenagers, and even then, perhaps they largely occur in the presence of identifiable risk factors. I do also wonder about the vaccine “harms” rates in the CDCs being underestimated by large factors because of the reliance on VAERS reporting, although even then, most of the harms would not be not equivalent in nature to hospitalizations and ICU admissions from the virus.

        @MP, references to the heart issues being debunked are appreciated.

        1. steve says:

          It’s incorrect to say that serious effects are not common in teenagers; that’s an old view no longer supported by the data. A friend of my daughter’s is in his early 20’s – an athlete – and has had long-term cardiac arrhythmia and neurological sequelae from COVID. His girlfriend had her leg amputated and later died of it. Aside from that anecdotal evidence, the fact is that COVID hospitalizations are now skewed towards younger populations. The demographics of those requiring ICU care skewing younger and younger as the older population is increasingly immunized.

          1. Adrian says:

            “A friend of my daughter’s is in his early 20’s – an athlete – and has had long-term cardiac arrhythmia and neurological sequelae from COVID. His girlfriend had her leg amputated and later died of it.”

            I am wondering if Steve is is just making things up on a crusade to scare people into getting vaccinated.

            Amputations in people in their 20s due to COVID-19 would be very rare, likely related to a serious preexisting condition.
            The CDC data says during the whole pandemic so far (until July 10th) there were 398 women in the age group 15-24 in the US who died of COVID-19.
            And then her boyfriend is claimed to be an athlete in the early 20s who has had long-term cardiac arrhythmia and neurological sequelae from COVID.

            It is questionable whether a couple with such unlikely combinations existed at all in the US, and someone from Steve’s family knowing such a couple is against all odds.

        2. Adrian says:

          Both the risks and benefits of COVID-19 vaccinations of healthy teenagers for the teenagers themselves seem to be so marginal that it might be hard to justify them getting vaccinated only for their own benefit.

          If I read the CDC data correctly, 213 children age 5-17 have died in the US of COVID-19 during the whole pandemic so far. People who are telling scary stories about the odd case of a teenager who died of COVID-19 are not better than people who are telling scary stories about the odd case of a teenager who had a serious side effect after vaccination.

          Like in some population groups with other vaccines, the best case for vaccinating teenagers is that they help protecting others by reducing the risk that they get infected and transmit the disease to other people.

          1. Not-an-epidemiologist says:

            Given that I’d guess only ~10% (as per current overall US covid stats) of 5-17yos have so far been infected to yield >200 deaths so far, and that you’d expect far fewer deaths, if any, to arise from immunisation (if using the mRNA vaccines, you’d expect zero deaths on current showings) … it seems a pretty obvious thing to do from my perspective.

            And those numbers are not even considering those children who do not die but are incapacitated from serious illness and/or post-infection syndromes, and it’s not considering the deaths that result from infected children passing on the infection to susceptible adults …

          2. Adrian says:

            I would suspect most of the deaths in the age group 5-17 were children with known pre-existing conditions, the known benefits of vaccination for healthy children are so marginal that it is not obvious that the benefits outweigh the risks. Arguing that a tiny benefit outweighs tiny risks is a risky strategy.

            Vaccinations reduce (but do not eliminate!) the risk of getting infected and transmitting this infection, this is really the strong point of vaccinating children.

  14. Joe Psycho says:

    I am a 20 year old male with poorly controlled asthma and other respiratory issues as well as autoimmune issues(very high risk). I received the moderna vaccine and only had a sore arm with inflammation at the injection site. It seems that the mRNA based vaccines are superior in terms of safety and efficacy as of now.

  15. Mark L says:

    “To the best of my knowledge, this [Guillain-Barre syndrome] has not been seen with the other vaccines”

    There have been reports of GBS after the AstraZeneca vaccine:

    Case of Guillain-Barré syndrome following COVID-19 vaccine

    Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 3-6 May 2021

    Guillain–Barré Syndrome Variant Occurring after SARS‐CoV‐2 Vaccination

    Guillain‐Barré Syndrome following ChAdOx1‐S/nCoV‐19 Vaccine

    1. David says:

      These are such complicated cases:
      – 100 CBS cases in the US/VAERS, following 12.5M J&J vaccinations = 1/125,000
      – 3,000-6,000 cases in the US a year, usually linked to bacterial and viral infections = 1/100,000.
      – CBS has been documented as a side effect of Covid-19 (maybe 0.4% of hospitalized cases in Italy)
      In addition, in the J&J clinical trial, there was 1 case in the vaccinated group – and a similar event in the placebo group.
      What does this mean? I don’t know, only that it’s very rare (with a very small increase in cases, if at all) and maybe not that surprising.

      There may be a link with a Shingles vaccine and the flu vaccine, but also at a level lower than the rate of GBS among these diseases.

  16. TallDave says:

    a few facts about vaccination seem under-emphasized generally:

    1) excess deaths almost everywhere seems to fall to normal or near-normal levels when the at-risk populations are immunized, which is exactly what we should expect from the ratio of at-risk deaths to deaths among the young and healthy

    2) an unknown but probably significant of number of people see almost no benefit from vaccination because they’ve already recovered from COVID

    3) at this point, due to 1 and 2, not vaccinating is a personal decision that makes little difference to anyone who is vaccinated

    but my biggest gripe with this whole process is that mRNA vaccines were not made available to informed volunteers in summer 2020 after Phase 2 results showed they were safe — millions of deaths might have been prevented

    1. TallDave says:

      on the last point, to put this into perspective, in the US around 3/4 of the excess deaths came after the point at which we knew at least one mRNA vaccine was safe

      and, crucially, we also knew who was most at risk

      not immunizing at-risk volunteers was an historic miscalculation of relative risks and I hope it will be re-examined if this happens again

    2. Charles H says:

      People tend to focus on death because it’s emotionally important, and also easy to research and report on. I, however, tend to be more concerned about long term disability. I include things like irrecoverable brain damage. And long COVID it therefore extremely worrying to me. It’s also a lot more common than deaths when proper treatment is available. The good thing is that most cases seem to recover within about 6 months according to the reports that I’ve read. The bad thing is that’s only “most” and the reports I’ve seen didn’t say what that meant, or how they determined that recovery happened. Sometimes “recovery” means that other parts of the body have adapted to cover for the damaged ones, at the cost of doing their proper job less effectively. And I’ve read reports that kidney damage cannot be recovered from, exactly, it’s just that the normal healthy body has sufficient overcapacity that partial damage is tolerable. But as you age kidney damage tends to accumulate until you no longer have any overcapacity, and under capacity is quite harmful. (See dialysis.)

      So one possible result of this is in a couple of decades a much larger part of the population ends up on dialysis. Another part has more dementia (possibly due to blood clots having killed parts of the brain). Other parts have other major problems. And, of course, these parts of the population have large overlaps, which have more than one problem.

      I strongly encourage everyone to get vaccinated AND to avoid contagious activities. I don’t think the real risks are properly calculated. Everyone’s going to die eventually, but ending up needing full time care is a much higher cost. (My brother has a disease that is destroying his family.)

      1. TallDave says:

        true, but excess hospitalizations are strongly correlated to excess deaths

        i.e. at-populations at risk of death are also far more likely to be hospitalized with COVID

        really a shame so much of both could have been prevented, although obviously no one could have known just how effective the early mRNA vaccines would turn out to be (recall scoffing here at the notion of a 90% effective vaccine)

        1. bertram says:

          Israel have revised down real world efficacy to 64%, so you were right to scoff. Guess it will rise back up again?

    3. David says:

      TallDave: “at this point, due to 1 and 2, not vaccinating is a personal decision that makes little difference to anyone who is vaccinated”

      except …

      except for 2 things, both important. First, I care about the fates of people who cannot be protected by vaccination (patients with immunosuppression, maybe patients with cancer, and children too young for the vaccine). Healthcare systems are societal efforts to help everybody, not just personal decisions. Second, the potential emergence of variants means that people who refuse vaccination now are putting everybody at risk in the future. We don’t allow drunk driving, and for the same reason we shouldn’t allow non-vaccination.

      1. TallDave says:

        agree vast majority of people should vaccinate, but certainly not that the reluctant should be forced, particularly if they’ve already been infected

        we license people to drive, but not to live

        at any rate, according to the CDC excess deaths graph, in the US the at-risk immunizations clearly carried at least 90% of the marginal benefit, and immunizing the young , healthy people who already had COVID and didn’t immunize yet has a benefit too small to measure

        seems safe to say excess deaths among the immunocompromised will not be measurably increased by the failure of those young, healthy, already infected people to vaccinate, as COVID is far from their only vulnerability

        1. Jen F says:

          agree vast majority of people should vaccinate, but certainly not that the reluctant should be forced, particularly if they’ve already been infected

          I agree wholeheartedly. I’m not as knowledgeable as most here on immune science (just a basic understanding of cell structure and epigenetic from college courses on human nutrition and sports medicine) but I do know psychology and I’m telling you that I see people who are in no way anti- science or conspiracy nuts getting very anxious of the encouragement of shaming others – and blaming of the pandemic on the “unvaccinated.” I’m absolutely aware of the science and dangers but all this route is going to accomplish is a divided fighting public while we lose the Covid battle. If that’s the goal this stance is the correct one. Even if every person was compliant there are many other hinderances to vaccinating everyone – supply in every country, longer testing for kids, logistics of getting vaccines to some counties – etc.

          I’ve am still suffering every day with long Covid – have high antibody levels 16 months out, and autoimmune. Taking just one shot is not acceptable for recovered people in the US- and just who are the people who can’t be vaccinated that we are protecting because to my knowledge there is no criteria for being exempt. Believe me I take precautions like crazy because I know what this thing felt like. But I’m still trying to heal and people are quick to angrily say – “you don’t deserve to be in society.” They have no clue what someone else has been through. If you force people, shame, and show zero empathy you are not only stressing the heck out of some of us trying to recover- but even those who reluctantly get vaccinated will be more resistant the next time. That I can guarantee unfortunately.

    4. Adrian says:

      “but my biggest gripe with this whole process is that mRNA vaccines were not made available to informed volunteers in summer 2020 after Phase 2 results showed they were safe ”

      It is not a good idea to approve a vaccine before you know it actually works.

      Without the benefit of hindsight, how would you have picked the mRNA vaccines in summer 2020?
      In summer 2020 the mRNA vaccines were “no human vaccine of that type has ever been approved”, and the Chinese inactivated virus vaccines would have been a less risky choice since they were based on proven technology.
      Among Western vaccines, AstraZeneca completed Phase 2 in summer 2020 but Moderna did not.

      Phase 3 also assesses safety, especially in groups like elderly who had a most urgent need for these vaccines.
      AstraZeneca had so little safety data on elderly people in early 2021 that many countries used it only for people under 65 at that point, would you have administered it to millions of elderly people in summer 2020 without any safety data?

      “millions of deaths might have been prevented”

      There were less than a million COVID-19 deaths worldwide between summer 2020 and the end of 2020.

      Two thirds of all COVID-19 deaths so far have been in 2021, after several vaccines had been approved.

      1. B1C2 says:

        Two thirds of 4.1 million COVID deaths are in 2021? That does not sound right at all. Have any data to back this up?

  17. Ed says:

    “An earlier variant (Beta, the “351” strain) was actually better at evading vaccine protection than any of the others”. Could it be that beta variant may become dominant again due to the vaccine?

  18. Vicki says:

    Thanks. I have MS, and my doctor looked at that and said “you’re fragile, we’re going to try to put you on a list of people who will be vaccinated early.” I got a call at the end of February inviting me to come get the vaccine because they were “squeezing out a few extra doses.”

    I said yes, thank you, even though autoimmune disorders weren’t on any of the official list of risk factors, and then spent some time going back and forth between “should they have called me” and “everyone says that if they offer you a vaccine, take it, even if it’s because you happen to be stuck in the right traffic jam.”

    But I’m still glad to know that my doctor was onto something, medically, about MS and Covid.

  19. Calvin says:

    Would be grateful for a link from PHE to back up the statement that it’s the vaccinated that are being infected. Based on the science that would be astounding.

    1. Albert says:

      I posted this and it was removed. I was polite and pointed to reliable data. This is no longer a scientific forum. There was no abuse or ill intent. PHE data – 257 deaths, only 92 of these in unvaccinated. Pg 17 of PHE report. I will post the link separately (maybe link cause removal of the data you requested? to give moderation and free speech the benefit of doubt)

      1. Ravenous bugblatter says:

        When reading these PHE reports it’s important to read them carefully, otherwise you’ll end up with the wrong conclusion, Albert.

        1. The data in this table starts with confirmed delta variant cases (infections). Therefore it says nothing about the vast majority of vaccinated people who haven’t been infected.

        2. The data for infections from the same table (row 1) shows that out of 123600 infections, <11k had received both vaccine doses. Less than 10%, not the majority.

        3. Taking your figures for deaths, you haven't accounted for the fact that in the UK the vaccinated and unvaccinated populations are completely different. The vaccinated are older and/or clinically vulnerable, whereas the unvaccinated are younger. If you look at the age range in the table, 90% of delta cases were in under 50s.

        4. Now take the death figures at the end of the table. Nearly all of these are in over-50s, the same population that has been vaccinated (but only half of them had had 2 doses). A cursory look at these figures suggests that vaccination makes you more likely to die of Covid but that is to ignore the age biases in the two sets. What you'd have to do is to compare the risk of a vaccinated over-50 to an unvaccinated over-50, taking account of the fact that most of the over-50s have been vaccinated, and if you do that the death stats revert to what you'd expect, a lower death rate in the vaccinated, even neglecting the fact that vaccinated people are less likely to have been infected in the first place.

        1. johnnyboy says:

          Albert’s main initial contention was that “most deaths are in the fully vaccinated”. Looking at the numbers, that is actually true in absolute numbers, but it ignores other factors and basic statistical considerations, that you point out well. Some more details, for those without time to go through the document: deaths in 2x vaccinated (all ages) = 118, in unvaccinated = 92 (I’m not including the 1 vaccine patients). So yes, a few more in the 2 vaccine group, but it’s 56% vs 44% of all deaths, fairly close proportions that are not reflected when one states “most deaths are in the fully vaccinated”. But the main issue with the comparison, which you point out well, is that the “fully vaccinated” population is very different from the “unvaccinated”, since vaccination in the UK was prioritised by vulnerability and age. So the fully vaccinated at the time of this report were either the vulnerable, or roughly the over 45y, which are most likely to die from Covid (and we are now well aware that the rate of protection from death from the AZ vaccine (by far the most used in the UK) is not 100%, since vulnerable/immunocompromised patients would be expected to have a higher rate of vaccine failure). By contrast the unvaccinated would be mostly in the 0-30 year range, a population much less likely to die from the disease.
          But just focusing on deaths for this disease is very reductionist, as the death rate is quite low, and much more significant is the hospitalisation rate, as this will be associated with more long-term sequelae for the affected, as well as the strain on the health care system, causing severe restrictions on care for all other diseases, which will might in the end turn out to have even greater consequences than Covid itself. Looking at the hospitalisation rate in the fully vaccinated vs the unvaccinated (again, two very different populations by age and vulnerability, but let’s have a go anyway) we have about 11K hospitalisations out of about 33M fully vaccinated adults (about 0.03%), compared to 72K hospitalisations out of 19.6M unvaccinated adults (about 0.37%), so a roughly 10x greater rate of hospitalisation in the unvaccinated, even though that population is much younger and healthier. Any way you look at it, broad vaccination, even with an imperfect vaccine like the AZ, is immensely preferable at the level of the whole population.

          1. Albert says:

            My point of contention was that Fauci constantly rolls out that 99.5% of deaths are in unvaccinated and Derek used similar language in the article, the PHE data proves that wrong. The delta variant is dominant in UK now – accounting for way over 90% of all infections, that will change with time also, used to be the Alpha variant. Delta plus or Lambda next or another new mutation, who knows? Assume vulnerability to others where exposure has been very limited to date. Real world data is not in the real world where restrictions exist, we already know that seasonality in summer 2020 appeared to play a massive role in supressing the virus.

        2. Albert says:

          I’d like to get your read on this latest data from Israel please. The analysis of the figures could be wrong? Appears the vaccines have lost efficacy in the real world. Might also help to explain Curevac’s recent clinical trial failure? Appears timing was of the essence in that case.

      2. Tony M says:

        Using data from that Table and comparing it with vaccinated population as at 30 June you get the following Table:

        Delta Infection Rate

        Est. Population………Vaccination Status…………….Cases………….Est. Infection Rate ( 1 in )

        Under 50:
        22,027,705…………….Unvaccinated…………………..70,664………………………. 312

        8,036,244…………. – 2 Doses…………………………….5,600……………………….1,435
        5,916,332…………. – >=21 days Dose 1…………….13,391………………………….442
        3,147,243…………. – =21 days Dose 1………………..4,542……………………….145
        …. 60,318……………..- < 21 Days Dose 1……………………109 ……………………….553

        ………………………………- Unknown……………………………..1,252

        21,297,965………………Total Over 50…………………………12,404…………………….1,717


        Unvaccinated vs Fully Vaccinated:

        Category Risk of Infection

        Under 50 – Unvaccinated…………………312
        Under 50 – Vaccinated 2 Doses……..1,435 (vaccintion reduces risk of Infection by 78%)
        Over 50 – Unvaccinated…………………..764
        Over 50 – Vaccinated 2 Doses………..3,747 (vaccination reduces risk of Infection by 80%)

        Using same categories and comparing deaths to estimated population:

        Category……………………………………………Deaths……………Est Pop/Death

        Under 50 – Unvaccinated………………………21………………….1,048,938
        Under 50 – Vaccinated 2 Doses ……………..2…………………..4,018,122 (reduced risk of 74%)
        Over 50 – Unvaccinated…………………………71………………………13,638
        Over 50 – Vaccinated 2 Doses………………116……………………169,068 (reduced risk of 92%)

        Biggest Risk group is the Unvaccinated Over 50. However, they only account for 1.6% of the population. Consequently, the next biggest risk group Vaccinated Over 50, which accounts for 32.5% of the population, dominates the recorded deaths.

        1. Tony M says:

          Sorry, part of the first table disappeared into the either. Will see if this works leaving out the greater than signs:

          Delta Infection Rate

          Est. Population………Vaccination Status…………….Cases………….Est. Infection Rate ( 1 in )

          Under 50:
          22,027,705…………….Unvaccinated…………………..70,664………………………. 312

          8,036,244…………. – 2 Doses………………………………5,600……………………….1,435
          5,916,332…………. – Gr=21 days Dose 1…………….13,391………………………….442
          3,147,243…………. – Ls= 21 Days Dose 1………….. 8,453……………………………372

          ……………………………. – Unknown…………………………12,900

          39,127,524……………Total Under 50………………….111,008………………………..352

          Over 50:

          19,611,831……………..- 2 Doses…………………………………5,234…………………….3,747
          ….657,533……………..- Gr=21 days Dose 1…………………4,542……………………….145
          …. 60,318……………..- Ls=21 Days Dose 1……………………109……………………….553

          ………………………………- Unknown……………………………..1,252

          21,297,965………………Total Over 50…………………………12,404…………………….1,717


          1. Albert says:

            Hi Tony, the Israeli current data is truly alarming, if true, could this be a hoax?

          2. Calvin says:

            Thank you Tony M and Johnnyboy. I think that clears that up. Data always has to be interpreted carefully and the data does indeed show that the virus is going after the unvaccinated as you would anticipate. Nice breakdown. Thanks

        2. Albert says:

          Looks pretty good in isolation, however, the situation on July 1st last year in the UK looked like this – 2020 – 0% partially/fully vaccinated, 63 daily cases, no deaths. 2021- 66% one jab, 49% two jabs and 27,989 daily cases. Deaths yesterday hit 50 in a single day. So it’s 100 % clear that the vaccines are working, right?

          1. I think a statement like “100% clear” is possibly both over-stated and potentially misleading. Is there data available on whether those most unfortunate deaths happened amongst those who had been vaccinated or those who were not vaccinated. If there was a portion of the deaths were amongst vaccinated people, could their death be in any way attributable to:
            a)the Antibody Dependant Enhancement phenomenon (that caused catasprohic failure of most of the pre-2020 corona virus trials)
            b) The risks of mass vaccination in the middle of a pandemic incl the capability of viruses to out-do the vaccine grow in strength/virulence and the VERY strong potential for the original virus mutating into a ‘super bug’ as more variants emege as doubtless they will. Would this explain how the Delta variant seems to be virulent than previous variants that seemed to be much closer to ‘covid classic’.
            c) Will it be a case whereby, because of the dominance of each new variant and their potentially increasing virulence, it will become pointless to vaccinate against ‘covid classic’.
            d) Will this situation evolve like the annual flu vaccine programs that are continuously trying to keep pace with the current and emerging influenza mutations?

      3. Not-an-epidemiologist says:

        The very simple explanation for what’s troubling you:

        Age >50, UK deaths from Delta: 116 fully vaccinated, 71 unvaccinated
        Age >50, proportion of the UK population fully vaccinated: >>90% (as of 1st July, source: NHS)

        A very, very crude (hey, I’m not an epidemiologist, after all) and conservative estimation of vaccine efficacy against death, assuming 90% of the 50+ population fully vaccinated, is thus:

        ((116/0.1n)-(71/0.9n)) / (116/0.1n) = 81.8%

        (where n is the population aged > 50, but cancels out in the equation and does not need to be considered further)

        The calculation is very sensitive to the rate of vaccination. If we assume that an average of 95% of people 50+ were fully vaccinated over the period of infection (not unreasonable given the numbers) then we get a best-guess of 91% vaccine efficacy against death for the over-50s. (And I would imagine that this will improve further as more numbers come in …)

        Does that make sense?

        1. Albert says:

 Seems like the situation in Israel is somewhat worse than the UK for infections and hospitalisations. Deaths not so much of an issue thankfully.

          1. Albert says:

            I guess the data from Israel is so damning it cannot be met with a reply?

      4. Duane Schulthess says:

        There were 3,546 confirmed cases of Delta in the fully vaccinated over 50 population in the Public Health England report since February 1st. Of that population, 50 died after receiving two vaccine injections. That’s a CFR of 1.4%. There were 976 unvaccinated cases in the over 50, with 38 deaths. This is a CFR of 3.8%. Obviously, there are a lot more fully vaccinated in the over 50 population than unvaccinated, thus the low number of unvaccinated cases.

        Vaccination reduces your risk of infection by 64%, according to Israeli data, so the adjusted IFR if you’re over 50 and fully vaccinated is .52%, roughly 750% lower than the unvaccinated CFR.

        Israel also claims that being fully vaccinated reduces your risk of hospitalization by 93% (I’m making an assumption that this risk is equally distributed over all >50 that have been vaccinated for simplicity). Backing out that number, the UK population of fully vaccinated over 50 years of age with a hospital emergency room visit or hospital admission gives us 602 subjects. A 93% reduction in hospitalization then give us a total N of 602/.07=8,600. Dividing that number by the 50 deaths gives us an alternative IFR of .58%, which checks out very nicely against our previous IFR of .52%.

        Again, to reiterate, the unvaccinated Delta CFR >50 is roughly 4%, the vaccinated IFR, assuming the Israeli and Singaporean percentages are correct, is roughly .5%. A big difference.

        However, of the 53,822 cases in the total unvaccinated population, there have been 44 total deaths, a CFR of just .08%! The vast majority of the known unvaccinated cases are in those under 50 (98%) , and even if you’re unvaccinated, your risk of actually dying from Delta if you’re under 50 is extremely low.

        In fact, according to page 8 of the report, including all data since February 1st for the entire population and all ages, Alpha has an overall CFR of 1.9% and Delta has a CFR of just .3%!

        These data are from the 25th of June report, but I don’t anticipate any of the ratios being radically changed in the July update which I’ve not had a chance to dig into.

        Fear mongering around Delta is highly counter productive, and not supported by the data. It appears to be less deadly than Alpha, with vaccination highly effective against both infection and hospitalization.

        1. WST says:

          Israeli characterisation of the 152 “breakthrough” cases :
          152 patients were included, accounting for half of hospitalized fully-vaccinated patients in Israel. Poor outcome was noted in 38 patients and mortality rate reached 22% (34/152). Notable, the cohort was characterized by a high rate of comorbidities predisposing to severe COVID-19, including hypertension (108, 71%), diabetes (73, 48%), CHF (41, 27%), chronic kidney and lung diseases (37, 24% each), dementia (29, 19%), and cancer (36, 24%), and only 6 (%) had no comorbidities. Sixty (40%) of the patients were immunocompromised. Higher SARS-CoV-2 viral-load was associated with a significant risk for poor outcome. Risk also appeared higher in patients receiving anti-CD20 treatment and in patients with low titers of anti-spike IgG, but these differences did not reach statistical significance.”

          As the vaccinations progress, there will be less and less infection in unvaccinated cohorts and … the CFR in these group will be falling or just random, while the “breakthrough” cases will be happening mostly with the subjects with serious health conditions with high risk of fatal outcome. The direct CFR comparison between these two groups with be less and less meaningful.

          1. Immunology 101 says:

            Unless of course we see the dooms day scenario unfold: Transmissions are now known to be common in vaccinated people, and positive selection pressure applied by their Abs will cause escape mutations to evolve. I say will as this is a certainty with non-sterilising vaccines and massively high infection rates. This will occur (probably within the next 6 months) and under these conditions ADE is most likely to become apparent (non-neutralising Wuhan Abs vs. the evolved escape mutation). Leaky vaccines could make big trouble out of the little problem that originated in China.

          2. David says:

            Why do you think that ADE suddenly appear? What do you think the mechanism would be? Furthermore, I would expect a milder infection, leading to improved immunity

          3. Immunology 101 says:

            ADE occurs in the scenario of non-neutralising antibodies. An escape variant by very definition will not be neutralised by vaccine induced antibodies. So yes I believe that the emergence of an escape mutation will likely be accompanied by ADE (and suddenly). I would imagine this scenario is far more lethal than in the case of waning vaccine antibody titre and challenge by the Wuhan strain (but this strain is long gone from circulation).

          4. Immunology 101 says:

            The more exact MOA would most likely be immune complex/viral particle formation or conformational change of virus mediated by non neutralising Abs. Enhancement of disease could occur via viral particle-Ab FcR/C3/C1Q/ mediated uptake, vaccine Ab NTD binding to enhance infectivity.

  20. J says:

    For those who are interested this is a link to the guidance made available to us in the UK.

    I’m grateful that we have all the major types of vaccines available to us.

  21. Carl says:

    Got a COVID19 vaccine question i’m hoping someone here can answer. I have a relative with a heart arrhythmia and they’ve apparently been told there’s somthing in all the vaccines that would interfere wit their meds. so they can’t have it. Anyone got a clue what that might be and explain it for me. t’s honestly left me scratching my head a bit.

    1. Derek Lowe says:

      I’m baffled by that one, too. I can’t think of anything off the top of my head that would fit that description – and what’s more, there’s hardly any ingredient in common between “all the vaccines” as well. That’s a very strange thing to be told, for sure.

      1. Carl says:

        Well glad it’s not just me and thank you for answering.

  22. Project Osprey says:

    Regarding the blood clotting issue. Is there any possibility that the lipids used to make the nanoparticles can being confused with platelet-activating factor? The structures do seem similar.

    1. Derek Lowe says:

      Ah, but the blood clotting issues are showing up mostly with the adenovirus vector vaccines (particularly AZ/Oxford), which don’t have a lipid nanoparticle formulation.

      1. Project Osprey says:

        That is a good point. Although, as the vaccines are all very different – they may cause clots by more than more mechanism (I expect the lips are so obvious that they’ve been looked at, I’m just playing devils advocate here)

        How do they made the adenovirus vector vaccines anyway? They’re supposed to be non-replicating, so how do you culture enough of them?

        1. Mammalian scale-up person says:

          The cell line they are grown in supplies one of the critical replication proteins. Which can be a problem with, say, new processes rushed into production: the cell lines’ stability in expressing this protein to a given functional quality, may not have had a long-term many-generations (e.g. >>100 generations stability) evaluation or there may not have been time to do a lot of clone selection for it.

    2. Van t Oever says:

      The VITT is examined in more detail here
      The relevant immunogenic factor causing this (or something else completely) in the vaccines is not clear yet. One possible explanation is the host cell proteins remaining in the vaccine (40-60% purity for AZ (HEK293 modified line (human) and J&J has 81 HCP’s in the product (Per.C6, human)), we do not have data on Sputnik or CanSino adeno-based vaccines. The Russians claim to have a more pure product and no VITT, but the side-effect reporting is severely limited, so we cannot proof/disproof.

  23. A Nonny Mouse says:

    Today’s REACT-2 study results on COVID-19 antibody prevalence shows that the antibodies are rapidly lost in the older population after the AZ vaccine, but not with the P-B vaccine. Clearly, this has been the most widely used in the older population and the infections with vaccinated older people may be as a result of this. Clearly, there are other methods of protection with T-cells, etc, but this was not examined.

    1. Jack Komisar says:

      Can you post a link to this study? All I can find is this paper. and it says nothing about loss of antibodies in the older population.

    2. Adrian says:

      “AZ vaccine, but not with the P-B vaccine. Clearly, this has been the most widely used in the older population and the infections with vaccinated older people may be as a result of this.”

      Your “clearly” underestimates how huge the differences in vaccination policies between countries are.

      Take the UK and Germany in Q1 2021 as an example:

      Due to the cold storage requirements of the Pfizer vaccine, in the UK at that point vaccinations of (young) healthcare personal in hospitals was done mostly with the Pfizer vaccine, and old people in retirement homes usually got the AZ vaccine.

      During the trials of their vaccine the University of Oxford and AstraZeneca displayed an epic amount of incompetence. One effect of the resulting mess was that the data of their vaccine in elderly people was pretty small at the time of emergency approval. As a result, before March their vaccine was not to be used for people over the age of 65 in Germany and elderly people got only the Pfizer (or the Moderna) vaccine.

  24. Bill says:

    Have there been any recent comprehensive seroprevalence surveys in the US that would tell us what the at-risk population number is? You obviously can’t just add vaccinated to infected for two reasons. We don’t know the total infected…only the number of positive tests. And we don’t know the overlap of those who fit both categories.

    Earlier in these comments there was discussion of herd immunity, and it seems to me you can’t even discuss the status of herd immunity without knowing how many at-risk remain in the US. CDC used to publish an Estimated Disease Burden report periodically, but they seem to have given that up.

    1. Adrian says:

      You are assuming natural infection or vaccines would remove (not only reduce) the risk of getting infected with COVID-19. This is not true.

      In a detailed picture you would also have to factor in different levels of protection – vaccines provide better protection than natural infection, and any protection from an infection in March 2020 might already have waned or provide little protection against the improved variants of COVID-19 going around today.

      When it comes to herd immunity, the first question is whether it is possible at all with the current vaccines alone against the current variants.
      Mathematically, the protection against infection by the current vaccines against the Delta variant might be too low for achieving herd immunity even if 100% of the population are vaccinated.
      Israel has the highest vaccination rate with the best vaccine (Pfizer). The Delta variant is currently starting to fill the ICUs in Israel again.

    2. healthpolicywonk says:

      Bill – Here is my back of the envelope “progress toward herd immunity” calculation:

      1) As of today, the NYT covid tracking page reports the total number of positive tests to date in the US at 10.253 per 100K.

      2) As you correctly point out, this is only the number of people who tested positive – we don’t know what percent that represents of the total infected to date. But over the last year, experts have typically been using a multiplier ranging from 3 – 5. So, I will take the midpoint of that and use a multiper of 4, which gives a total of about 41% of the US population previously infected.

      3) The NYT also reports today that 48% of the US population has been fully vaccinated. This is likely to increase soon as 56% have already gotten at least one dose, so I will use 52% as the fully vaccinated number (this conservatively assumes that at least 50% will choose to get their second dose).

      4) As you also correctly point out, we also don’t know how much overlap there is between the two populations. I think a conservative estimate of the percentage of the vaccinated population that was previously infected is 25%. This is due in large part to the age and other demographics breakdowns of the two groups (for example, people are 65 were arguably significantly less likely to have been previously infected, and almost 90% of them have been vaccinated).

      5) So, this leaves us with an unduplicated percentage of 41% previously infected plus an additional 39% vaccinated who were not previously infected, for a total of 80% of the US with some level of immunity.

      Obviously one could make different assumptions, and there is no way to be certain how accurate this is. But the fact that cases began declining even before large numbers were vaccinated, and until recently continued a steep decline, suggested that some level of herd immunity is in play.

      I think the very recent increase in cases (infections) have to do with two factors: 1) herd immunity levels (both natural and vaccine-driven) are uneven throughout the country; and 2) as discussed above, neither factor completely prevents infection.

      I would welcome any thoughts on my assumptions and methodology above.

      1. healthpolicywonk says:

        Correctly typos in #4 above… the last sentence of #4 should read:

        This is due in large part to the age and other demographic breakdowns of the two groups (for example, people 65 and over were arguably significantly less likely to have been previously infected, and almost 90% of them have been vaccinated).

        1. healthpolicywonk says:

          Darn, just found another typo… it’s easy to make mistakes typing in this little box. #1 should read:

          1) As of today, the NYT covid tracking page reports the total number of positive tests to date in the US at 10,253 per 100K (10.253%).

          Hopefully that was obvious, but just in case!

      2. Bill says:

        I understand and don’t disagree with your methodology. But you’ve had to guess at so many unknowns that I think the bottom line is greatly in doubt. I don’t think the at-risk population is subject to calculation (and expect any accuracy).

        Since we’re well over half immune, it would be an easier job to determine who remains at risk, not who’s no longer at risk. And I gather the tool for that is seroprevalence surveys. Done deal if it were conducted on a national level, but I guess such is not in the cards. Next best is a sampling of various community profiles and attempt to extrapolate to the full population. I can’t believe that no one in the government would be doing that. It seems like a basic required metric for public health policy.

      3. TallDave says:

        fair points but “herd immunity” is a bit of pre-Bayesian shibboleth as no level of group immunity protects the group from all levels of exposure

        best group immunity can do is minimize outbreaks at given levels of exposure, which is highly contingent and often totally unpredictable

        proper measure of group immunity is whether the group suffers excess deaths

        by this measure the US reached sufficient group immunity in March

        next significant milestone is the total eradication of all extant variants in humans

        that still looks achievable (probably) but at least another year off

        if it turns that’s not achievable in a reasonably short time frame many of the less relevant metrics still governing policy (case counts, raw deaths) will need to be thrown out of the equation

  25. J says:

    There is mention of Israel study above. Below is a link to actual report.

    Hope useful. Thank you Derek and various people who make measured and well presented comments backed up with references.

  26. Lane Simonian says:

    It is beginning to appear that the U.S. strategy to rely on vaccines to reach herd immunity has been a miscalculation. The vaccines are not safe enough nor effective enough to achieve that goal. The reliance on the spike protein approach has led to very rare adverse side effects that can be deadly. The argument that the coronavirus itself is much more deadly misses the calculation that some people make: I can take precautions against the coronavirus but I cannot take precautions against potentially deadly side effects from the vaccines. It is the same reason some people are much more afraid of dying in a plane crash than in a car crash, even though the latter is much more likely to happen.

    The efficacy of the vaccines is the second problem. As of the end of April, the CDC reported 10,262 breakthrough infections, with 995 patients hospitalized, and 160 patients who died (28 of whom were asymptomatic and who died from other causes). In the grand scheme of things, these are good numbers. But the larger problem is how many people who have received the vaccine are still spreading the virus (as well as those who have had the coronavirus but did not receive the vaccine). Outside of the unvaccinated who are not wearing masks, who is spreading the virus more, vaccinated people not wearing masks, unvaccinated people who have had the coronavirus and who are not wearing masks, or unvaccinated people who are wearing masks?

    Los Angeles county where approximately 70 percent of the population has been vaccinated but cases are nevertheless surging has wisely reinstituted mask requirements for everyone in indoor locations. It is becoming clear that asymptomatic spread of the virus is not limited to unvaccinated people. The more transmissible delta virus is partially responsible for the current increase in cases, but so too were large gatherings during the Fourth of July (where people symbolically declared independence from a virus they were not yet independent of) and the continuous non-use of masks by both vaccinated and unvaccinated individuals.

    The vaccines are not a chimera but they are not a cure-all either. Relying entirely on the vaccines to try to get us out of this pandemic is a mistake.

    1. Paul A says:

      Is there an alternative to the spike protein approach?

      1. Lane Simonian says:

        Non-spike protein or largely non-spike protein based vaccines seem to be quite a long ways off.

        The nearest next vaccine likely to be approved-Novavax-may be among the best. It contains saponin as an adjuvant (as an immune system “promoter”) so less of the spike protein needs to be present. This not only reduces the chances of serious clotting events, but saponins themselves can dampen inflammatory responses. I hope it works as well in practice, as it has in trials and as it should work in theory.

  27. pete says:

    Derek said; “No one has any idea of what the potential is for variant forms….”


    The vesicular stomatitis virus (VSV) mainly infects animals, but can produce a flu-like illness in humans. VSV has become a favorite for vaccine development as its genome is relatively simple, well understood, and easy to manipulate. Vaccines based on VSV are being developed for influenza, HIV, SARS, MERS, Ebola, Marburg, and Lassa fever. The Ebola vaccine, Ervebo, has been trialled and approved for humans. [32-39]

    More stuff on VSV….

    Spike swapping in VSV has long been used to study viral spike proteins. It has become routine and in the paper “A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells,” [23] they produce six spike swapped viruses all of which could have become vaccine candidates.

    In this paper the researchers create four mutant SARS-CoV-2 spike proteins. They are;
    1) SARS-2-S(RaTG) which has the SARS-CoV-2 S1/S2 cleavage site replaced by the bat RaTG13 S1/S2 cleavage site;
    2) SARS-2-S(SARS) which has the SARS-CoV-2 S1/S2 cleavage site replaced by the SARS-CoV S1/S2 cleavage site;
    3) SARS-2-S(delta) has all the basic amino acids in the S1/S2 cleavage site removed or replaced; and
    4) SARS-2-S(opt) which has extra basic amino acids (arginine and lysine) to make the cleavage site super-basic.

    They also create two mutant SARS-CoV spike proteins. They are;
    1) SARS-S(RaTG) which has the SARS-CoV S1/S2 cleavage site replaced by the bat RaTG13 S1/S2 cleavage site; and
    2) SARS-S(SARS-2) which has the SARS-CoV S1/S2 cleavage site replaced by the SARS-CoV-2 S1/S2 cleavage site.

    They then incorporate each of these foreign spike proteins into a VSV backbone, creating six different vaccine candidates/viruses. They also introduce the three wild-type spike proteins of SARS-CoV, SARS-CoV-2, and MERS, into a VSV backbone, creating three more vaccine candidates/viruses. Finally they simply produce spikeless VSV particles (i.e., the spike protein G is deleted with no replacement). They do this to investigate the pathology of the nine different spike proteins once expressed in your cells. The spikeless VSV particles (empty vector) serve as a control. Having created these hybrid viruses they then infect cells with them and record the results.

    The researchers chose Vero E6 cells (ATCC Cat# CRL-1586) a cell line from monkeys that expresses ACE2 and is commonly used to model human cells. Generally, ACE2 expression in human cells is low.[28][29] They prepared;

    1) Vero E6 cells without any added protease/enzymes,
    2) Vero E6 cells with extra-cellular trypsin, and
    3) Vero E6 cells expressing TMPRSS2.

    Each of the nine VSV hybrids, as well as the spikeless particles, were used to infect each of the three cell cultures. This gave thirty cultures to report on. The results are shown as a matrix of small photos (shown below) of the cultures 48 hours after infection. These photos show the results of having the various spike proteins expressed on the surface of the Vero E6 cells. They indicate the level of damage done by the various spike proteins to the ACE2 expressing cells in your body.

    More stuff….

    The SARS-2-S(opt) hybrid virus looks amazingly dangerous. The relevant photos are (1,1) (1,2) and (1,3). Here, syncytia formation is extreme. Here the cleavage motif at the S1/S2 cleavage site has been destabilized by adding extra arginine (R) and lysine (K) units. In other coronaviruses this causes the spike proteins to be so unstable that they are able to fuse neighboring cells without the need of any receptor.

    Fortunately, such heavily multibasic motifs can never establish themselves naturally….

  28. peter says:

    The above commentary on the article “A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells” is copied from: does not link to this page.

    Too much truth for google.

  29. Louigi says:

    I’m confused by the statement that Beta is “disappearing from the world thanks to Delta being much more transmissible”.

    Surely the Delta variant doesn’t actually *suppress* the transmission of The Beta variant; wouldn’t that be sort of like saying that Hep C was disappearing from the world thanks to influenza being much more transmissible?

    Put another way, it seems to me that the fact that in absolute terms Delta is massively more widespread than Beta, doesn’t actually make Beta’s increased ability to evade vaccine protection any less worrying. Or am I misunderstanding something?

    1. Derek Lowe says:

      Ah, but influenze and Hep C are not competing for the same receptors on the same cells. . .

      1. Louigi says:

        You wrote “ Ah, but influenze and Hep C are not competing for the same receptors on the same cells”. True; but that mechanism only leads to Delta suppressing Beta in patients who actually get infected by Delta. So far, that’s a very small percentage of the overall population, and presumably the goal is to keep it that way.

    2. John says:

      You’re confused by the statement that Beta is “disappearing from the world thanks to Delta being much more transmissible”.

      That is because the statement is incorrect.

      In the real world Beta and Delta never compete. They would both go their independent ways and both flourish.

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