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Antibody-Dependent Enhancement and the Coronavirus Vaccines

I’m getting a lot of queries about antibody-dependent enhancement these days, and I can only assume that’s because there’s a lot of talk about this making the rounds of various social media platforms. Many of the people who are contacting me sound a lot more worried than I would have thought, so that prompts me to follow up on the post I did on the subject back in December.

What’s ADE, Again?

First, a quick recap. ADE is a problem that has shown up in several sorts of viral infection, although it also has to be said that there are other viruses in which it’s never really been seen at all. It happens when a previous infection or vaccination has generated antibodies that fit some specific criteria. First, these existing antibodies have to be non-neutralizing against the new viral infection: that is, they bind to the second virus, but not in a way that shuts down its activity. It’s important to realize, though, that *all* immune responses to a viral infection generate a mixture of neutralizing and non-neutralizing antibodies. That’s one of the things about the immune system – it revs up production of a wide variety of antibodies, selected from the untold billions of them circulating around in your bloodstream. Some of them bind to one part of the pathogen, and some to another. And they bind in different conformations, sticking to different parts of the surface of the invading virus from different directions.

Some of these are inevitably going to be more effective than others at stopping that virus’ activity – and remember as well that there are several ways that can happen, too. An antibody can bind to and cover some key part of a virus protein without which it can’t infect human cells (in the case of the current coronavirus, that could be the receptor-binding domain (RBD) out on the end of the Spike proteins that decorate its surface. Antibodies can also cause aggregation, sticking viral particles in clumps that can’t function as they would otherwise. And they can also signal various kinds of defensive cells to attack an antibody-bound viral particle directly and destroy it.

But if none of these work as hoped for, then you have a non-neutralizing antibody. The immune system is actually optimized for selecting and amplifying the neutralizing ones, though. So it’s usually not a problem having the non-neutralizing ones around at the same time, since the other more useful potent ones are out there taking care of business. But what if you don’t have any of those, just the non-neutralizing ones?

That’s what happens, for example, with Dengue fever. Dengue comes in four different varieties (which is probably the single hardest thing about trying to treat it or prevent it through vaccination). The antibodies you generate that can get you past one of the infections really don’t match up well enough with the others to be effectively neutralizing, and if you get one of those later on you can actually get a worse case of Dengue than you would have had otherwise. That’s the “enhancement” part of ADE. As mentioned in that December post, there are at least two different mechanisms that have been worked out for this. One of them (the most straightforward) seems to be that when some types of non-neutralizing antibody are stuck to the denguevirus particle, that it actually speeds up its entry into human monocyte cells. The monocyte membrane proteins treat the incoming antibody surface like an incompetent bar doorman letting people through with fake IDs: “Looks good to me, come on in”. Which is exactly what you don’t want.

That December post has links to times this has been seen with vaccinations, too: there has been one RSV vaccine candidate and one measles vaccine candidate that have certainly shown this problem (the antibodies they generated made the next exposure even worse). It’s not common, by any means, but it can most certainly happen. And you can believe that vaccine developers are aware of this. Which brings us to:

ADE and Coronaviruses

Now, when SARS appeared in the human population back in 2003, there was a lot of work done on it to try to make vaccines, should it erupt again. And (links in the earlier post) some of these candidate did show signs of ADE. When vaccinated animals were re-exposed to the same virus, some of them got even sicker than usual. (As an aside, this seems to have been through yet another different mechanism: an altered T-cell response, rather than a direct effect of binding antibodies on cell entry). Immunology being what it is, this certainly didn’t happen in every animal. Every mammal’s immune system is different, like a fingerprint, and it’s clear that with such a vaccine some people (through sheer bad luck, impossible to predict with current techniques) would be more vulnerable.

What you can do is see what the statistics are like – if you see any sign of ADE at all in an animal model experiment, that’s bad news, because the sample sizes for these are far, far smaller than the population that’s going to be getting vaccinated. And that would mean completely unacceptable risks in that human population. So animal studies (both rodents and primates) are specifically designed to look for such effects, and if ADE is seen, well, it’s back to the drawing board. You’ll also be watching your clinical trial data and (indeed) the eventual real-world rollout for any signs of this as well.

The SARS experience taught us a lot of extremely useful lessons, as it turned out. SARS-Cov-2 is rather closely related to the 2003 SARS coronavirus, and if you’re going to have a worldwide pandemic, you’re far better off with one that’s so much like something you’ve already poured R&D investments into! In this case, the two big take-homes were that coronavirus vaccines could indeed suffer from ADE, and that this seemed to depend on which protein you chose to base your vaccine around. Specifically, it was the vaccines that targeted the N (nucleoprotein) antigen of the coronavirus that had ADE problems, while the ones that targeted the S (Spike) protein did not. Update: this isn’t accurate. There was trouble after immunization with a nucleoprotein-directed vaccine, but ADE could also be seen with some of the Spike-directed vaccine candidates as well – see reviews here, here, and here. That experience was thoroughly taken to heart in the vaccine developments of the last year: no one, to the best of my knowledge, even bothered to target the SARS-Cov-2 N protein at all, for just this reason. If you look at the antibodies generated in people who’ve been infected by the virus, they most certainly did make N-targeting ones, along with Spike-targeting ones and antibodies directed against the various ORF proteins. But for vaccine work, everyone has stuck with the Spike.

The Current Vaccine Data: Any Sign of ADE?

So now the Moderna and Pfizer/BioNTech vaccines have been rolled out in many parts of the world, along with the AstraZeneca/Oxford, Gamaleya, and CanSino adenovirus vector vaccines. Those look to be joined soon by J&J’s adenovirus vector and Novavax’s recombinant protein subunit vaccines, and likely more after that. So here’s the key question: did any of these show ADE hints during their development? And are any of them showing signs of it now?

The short answers: they did not. And they are not. Antibody-dependent enhancement was specifically tested for in the animal models as these candidates were being developed (re-exposure of vaccinated animals to coronavirus to see how protective the vaccine was). And no cases of more severe disease were seen – I’ve gone back through the reported preclinical studies, and I don’t think I’ve missed one, and what I’m seeing is not one single case of ADE for any of them. Indeed, as mentioned above, if something like that had shown up, it would have immediately released a bucket of clin-dev and regulatory sand into the gears of the whole project.

How about the human clinical trials? Again, no signs of ADE were seen. This is a bit less definitive, since we did not run deliberate “Here, have another blast of virus” challenges on the human participants the way we did in the preclinical studies. But at the same time, these trial participants were out there in the real world being monitored for signs of infection. The dramatic plots of the data after even one dose of the vaccines speak for themselves: the trials did hardly saw people getting infected at all after vaccination, and most certainly not with even more severe disease. To the contrary: one of the big features of the vaccines is that across the board they seem to almost totally wipe out the appearance of severe coronavirus symptoms. We’re still collecting data on transmissibility after vaccination and so on (things are looking good, though), but what seems to be beyond doubt is that the vaccinated subjects, over and over, show up with no severe coronavirus cases and no hospitalizations.

That is the opposite of what you would expect if ADE were happening. Remember, the bad thing about antibody-dependent enhancement is that it leads to more severe disease when you’re exposed again to the pathogen (or when you’re exposed after being vaccinated for it). And we’re just not seeing that. At all. We are, and I am very, very happy to be able to say this, seeing exactly the reverse. Watching the real-world data will alert us to any of the potential mechanisms (antibodies, T-cell effects, etc.) and nothing is showing up.

What About the Variants?

That’s a really good question. The earlier trials were run against what I’ve been calling “coronavirus classic”, and now we have several variant strains to contend with. The worse case is that one or more of these spread out to be as different as (say) the four types of Dengue fever, and that the antibodies raised by vaccination are inadequate to deal with them. That would mean several bad things: that people who are vaccinated would still be at significant risk for a regular infection, and even worse, that they cold be at risk for an even worse one than if they’d never gotten vaccinated at all. That seems to be the fuel for the current brushfire of ADE worries.

The news about vaccine efficacy against these variants is actually not as bad as you might have thought, based on some news reports. The B.1.1.7 variant (the one that was first characterized in the UK) seems actually to be handled quite well by the various vaccines, with only a very small dropoff in efficacy (and definitely not enough to start worrying about ADE). The B.1.351 variant that was first characterized in South Africa is a bit tougher. There’s no doubt that the antibodies generated by the various vaccines have a harder time with this one, but it looks like the degree of dropoff varies. On one end, the AstraZeneca/Oxford vaccine appears to lose potency to a degree that the South African government stopped vaccinating with it entirely. Now, that may or may not have been a hasty decision – the vaccine, even in South Africa, is a hell of a lot better than nothing – but that’s another topic. Meanwhile the J&J and Novavax vaccines show less efficacy against B.1.351, although apparently not to the degree that the AZ/Oxford one showed, and word has come within the past few days that the Moderna and Pfizer/BioNTech vaccines may be holding up even better than that: a drop in potency in lab experiments, but maybe not enough to even show up much in the real world population at all.

And so far, I have been able to find no reports of more severe disease after vaccination in South Africa. Please correct me if I’m wrong, those of you following this closely, but this would mean that there is (so far) no evidence of antibody-dependent enhancement against even this variant. There are of course other variants, and we most certainly need to keep an eye on them. But variants are what viruses do. This isn’t something weird and sinister – it’s expected and we know what to look out for. I’m going to have another post on these strains up on Monday or Tuesday, but I’ll just say that I’m actually relieved that we’re weathering these as well as we are.

The Bottom Line

So here’s the short version: no sign of ADE during the preclinical animal studies. No sign during the human clinical trials. No sign during the initial vaccine rollouts into the population. And (so far) no sign of ADE even with the variant strains in different parts of the world. We have things to worry about in this pandemic, but as far as I can tell today, antibody-dependent enhancement does not seem to be one of them. I understand why people would worry about it, and want to avoid it. But if you’re coming across reports that say that it’s a real problem right now and that you should avoid getting vaccinated because of it, well, I just don’t see it. Some of that is well-intentioned caution, and some of it is probably flat-out anti-vaccine scaremongering. Anyone with different data or different impressions, well, that’s why the comments are open around here!

313 comments on “Antibody-Dependent Enhancement and the Coronavirus Vaccines”

  1. RAD says:

    In TWiV #717 [1] guests Paul Bieniasz and Theodora Hatziioannou indicated that the variants all seem to converge on antibody escaping mutations similar to what they see in the lab. They speculated that reinfection is responsible for the selection pressure necessary to generate these variants.

    Reinfection of recovered individuals with a variant seems like a better explanation of B.1.1.7 outcompeting the original strain in the U.K. than increased transmissibility or founder effects and also explains why it has not taken hold in places like L.A. with a weak first wave. A cohort of reinfected individuals who dismiss their mild upper respiratory reinfection symptoms, since they are “immune”, seem like ideal super-spreader candidates.

    Reinfection by antibody escaping variants seems important for vaccinated individuals too. If this reinfection hypothesis is correct, shouldn’t we be doubling down on a regiment of rapid antigen tests for everyone?

    [1] https://www.microbe.tv/twiv/twiv-717/

    1. Sharla Winters says:

      Great article. In my research, it seems that the animals tested were not very susceptible (if at all) to SARS-CoV-2. https://www.sciencemag.org/news/2020/04/mice-hamsters-ferrets-monkeys-which-lab-animals-can-help-defeat-new-coronavirus
      So it seems a challenge study in animals to look for ADE would not provide meaningful data. Can you speak to that?
      I was able to find some data on the vaccines being tested in monkeys; however, it looked like they were just looking at viral load in the nose and lungs (to see how well they cleared the virus) rather than how sick they got.
      Thank you!

      1. Sharla Winters says:

        I wish the preclinical data wasn’t so hard to find. I’ve asked to see the IDB for Moderna, Pfizer and J&J with no luck. I didn’t think they would share it, but I think they should in a situation such as this. I think the lack of transparency is a huge factor in vaccine hesitancy. And of course the unknowns. Thank you for your thoughtful articles.

      2. KateM says:

        Can someone please help me understand something about the Pfizer-BioNTech’s animal study? In Pfizer’s briefing document for the FDA they site only one animal study, on page 13. In the summary of the study done on Rhesus macaques it’s stated that “there was no evidence of vaccine-elicited disease enhancement”. It also states in the footnote that two BNT162b2 variants (V8 and V9) were evaluated in the repeat-dose toxicity studies with the “same amino acid sequence”. Correct me if I’m wrong, but wouldn’t we only see ADE’s in repeat-dose toxicity studies with differing amino acid sequences? The new variants we’re seeing now around the world have different amino acid sequences compared to the “classic”.

        In Derek’s blog article he states, “animal studies (both rodents and primates) are specifically designed to look for such effects, and if ADE is seen, well, it’s back to the drawing board.” Was the Pfizer animal study design adequate enough to look for these effects? Can someone please explain how Pfizer can rule out ADE involvement when the same amino acid sequence was used in the test product as well as the repeat-dose product?

        Here’s a link to Pfizer’s briefing document (page 13): https://www.fda.gov/media/144246/download

    2. Chandru R says:

      Is anyone looking into the trends in India with the current spike in cases? I am hearing about worrying cases from friends and relatives who say they took the first vaccine shot of the Covishield vaccine but are experiencing severe lung infections before they could get the second dose. I am aware of one death after getting first dose of vaccine. Is there any chance of ADE with the variants in India? Is anyone actively testing this hypothesis?

      1. Caroline Dale says:

        Although I have not tested this hypothesis directly, there is currently an overwhelming amount of evidence that is increasingly supporting the claims made by several clinicians whereby they expressed concerns regarding possible lung failure and hypoxia experienced by recipients of the vaccine in India. As there is not sufficient data regarding the risks of ADE following reinfection to the same pathogen or exposure to a similar pathogen (over time), we cannot rule out the risk of developing ADE after a certain amount of time following vaccination. The preclinical trials are inadequate as they relate to the analysis of potential adverse effects as a consequence of ADE.

        1. Derek Lowe says:

          No, there is not any kind of “overwhelming evidence” for that. India barely had 2% of its population vaccinated when it got hit by this latest terrible wave.

          1. Prarthanaa says:

            India has completed vaccination for over 10% of the population, plus even if it is around 2% like you mention, those numbers are really big considering the overall population of the country. Even I had a couple of people in my family die of severe pneumonia and lung issues after taking 2 doses of the vaccine. Unfortunately, these deaths do not make it to the mainstream media. And these deaths are not studied or investigated by pharma companies. Then how you can claim there is no overwhelming evidence?

        2. Dounia says:

          Not sure this is relevant as there are no RNA vaccines distributed in India, as far as I know…

  2. Marko says:

    I think this may be the main paper that set off the ADE social media frenzy. The fact that it came out on the same day as your previous post probably created a social media “perfect storm” :

    https://www.biorxiv.org/content/10.1101/2020.12.18.423358v1.full

    “…Here, we screened a series of anti-spike monoclonal antibodies from COVID-19 patients, and found that some of antibodies against the N-terminal domain (NTD) dramatically enhanced the binding capacity of the spike protein to ACE2, and thus increased SARS-CoV2 infectivity. Surprisingly, mutational analysis revealed that all the infectivity-enhancing antibodies recognized a specific site on the surface of the NTD. The antibodies against this infectivity-enhancing site were detected in all samples of hospitalized COVID-19 patients in the study. However, the ratio of infectivity-enhancing antibodies to neutralizing antibodies differed among patients. Furthermore, the antibodies against the infectivity-enhancing site were detected in 3 out of 48 uninfected donors, albeit at low levels. These findings suggest that the production of antibodies against SARS-CoV-2 infectivity-enhancing site could be considered as a possible exacerbating factors for COVID-19 and that a spike protein lacking such antibody epitopes may be required for safe vaccine development, especially for individuals with pre-existing enhancing antibodies.”

    1. Sarina Rivera says:

      Thanks for this information, and presenting in a way that an average person can understand. That ability is rare and takes an extra amount of knowledge.

    2. Patricia says:

      Hi Linda, I am not disputing who’s right or wrong about getting vaccinated or not regarding the long term consequences for entire populations, BUT the aim of mass vaccination is to protect the health systems around the world, already in collapse or in the verge of collapse. If you have a good natural immune response to SARS-CoV-2 but has had a car accident and need hospitalisation you might die for lack of a hospital bed in ICU. Simples.

  3. Marko says:

    If you want to dispel the fears about the variants causing ADE, either in the case of reinfections or among infected vaccinees, the best way to do it would be collect the data and then show it to us. What is the IFR for variant reinfections in S.Africa, the UK , or Brazil, for example, and how does that compare to the IFR for the “classic” strain? Is this really so hard to do?

    If, on the other hand, you want to further encourage the conspiracy types, don’t collect this data, or, if you do, keep it well-hidden. That’ll do the trick.

    1. Marko says:

      Should have said “CFR” not “IFR”. It would be difficult to determine the IFR this early , but the CFR should be pretty straightforward.

    2. Oudeis says:

      I’m all in favor of people doing the research, but the conspiracy nuts will never hear about it either way. The few who do won’t care.

    3. Doug H MD says:

      it is odd we see no good data about this.
      are researchers blind to the need for this?
      i think reinfection is still very low. on the order of less than 1%. It will go up almost certainly.
      But i think that this is much ado about nothing for now. Except that we should be thinking about which vaccine platforms are safest for the long haul: annual injections.

        1. Marko says:

          That’s exactly the kind of study we need, only on a nationwide basis. Using a first wave/second wave basis to distinguish reinfections is plenty good enough to tell us what we need to know. As long as the first and second cases are separated by 3 months or more, the contamination of the results by persistent PCR positives should be minimal. Those doing reinfection studies who are still holding to the standard of requiring genomic IDs of both cases are wasting their time, as the numbers they can assemble will remain tiny over any reasonable timeframe.

          They detect an apparent increased rate of reinfections starting in month 8 after the primary infection. That means that as the pandemic ages, more and more data should be available, and a large enough study should be able to tell us what the CFR for reinfections is, as well as the rates of severe disease, and how these compare to primary infections.

          I remain doubtful that we’ll see such large studies done in the US and UK any time soon, much less in countries like Brazil and S.Africa, where it’s even more critical that we are monitoring the situation. I have no doubt, however, that as soon as it becomes apparent that antibody levels from vaccination are waning, we’ll know about it, and we’ll be urged to get our booster jabs, whether we need them or not.

    4. Not-an-epidemiologist says:

      Well, I’m not sure it’s that easy — one problem is that good, prospective studies looking at reinfection are rare. Hopefully the SIREN study in the the UK will update their interim findings at some stage (the preprint only covers the period until November 9th, although that certainly overlaps with the start of B.1.1.7 spread).

      But I would think in all of this that no news is good news. If there was any hint at all that ADE was possible (i.e. a spate of probable re-infections with poorer health outcomes, let alone fatalities) that’d be a researcher’s ticket to the high impact journal of their choice right now. There’s such a strong academic incentive to find this that I’d suggest absence of evidence hints at evidence of absence.

      1. Marko says:

        “If there was any hint at all that ADE was possible (i.e. a spate of probable re-infections with poorer health outcomes, let alone fatalities) that’d be a researcher’s ticket to the high impact journal of their choice right now. ”

        Yes, consider these two scenarios: Scenario #1

        Doc chatter: “We’re seeing a fair number of reinfections since the variant became dominant, and they’re at least as severe, if not more so, than primary infections.”
        Academic response: ” Do the study! Publish! Tweet! YouTube! We’re gonna be famous!! ”

        Scenario #2

        Docs: “We’re seeing a fair number of reinfections since the variant became dominant, but they’re invariably mild cases. We give ’em a lollypop and send ’em home.”
        Academics: (cricket sounds)

        If this is in any way reflective of what’s going on, it’s a very sad state of affairs, because both scenarios are equally worthy of study, publication, and dissemination of the info to the public.

        1. Not-an-epidemiologist says:

          I completely agree. But publication bias has always been a problem in public health — that’s why funnel plots exist 🙁

        2. Oudeis says:

          Scenario 1 kills people until you solve the problem. Scenario 2 doesn’t.

          I agree they’re both worthy of study, but why are they “equally” worthy of study?

          1. Marko says:

            By not doing study #2, and remaining ignorant of the facts that would have been revealed, you end up wasting scarce vaccine on seropositives who don’t need it. That kills people, too – among the seronegatives who would otherwise have received those vaccine doses.

          2. Doug H MD says:

            you are partially right. if scenario two means we dont need to use two doses in people infected it could save lives!

        3. Adrian says:

          “We’re seeing a fair number of reinfections since the variant became dominant, but they’re invariably mild cases.”

          What is the point of discussing such fake news scenarios?

          Reinfections can be worse than the initial infection, this had been established already before the current variants existed:
          https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30764-7/fulltext

          1. Marko says:

            Anecdotes are not useful data, as even the authors of your citation recognize :

            “…If our patient is a case of reinfection, it is crucial to note that the frequency of such an occurrence is not defined by one case study: this event could be rare. The absence of comprehensive genomic sequencing of positive cases in the USA and worldwide limits the advances in public health surveillance needed to find these cases. Certainly, limitations in screening and testing availability for SARS-CoV-2 exacerbate the poor surveillance efforts being undertaken not only to diagnose COVID-19 but also to obtain actionable genetic tracking of this agent.”

            The unanswered question remains : What is the level of protection afforded by previous infection to a subsequent infection, and then, once re-infected, what relative protection against severe disease and death does prior infection additionally confer? If the combined protection reduces the risk faced by seropositives by a factor of ten or more, it’s insane to vaccinate them in a time of vaccine scarcity. And it’s particularly important to determine the level of such protection offered against the variants in places like Brazil and S. Africa, where the availability of sufficient vaccine for their populations may be many months, if not a year or more, away.

            Right now, we don’t know squat about any of this, anecdotal case reports notwithstanding.

          2. Adrian says:

            One single counterexample is sufficient to prove that a claim “they’re invariably mild cases” is false.

            That’s logic 101.

          3. Marko says:

            Would it have helped if I’d said ” they’re ALMOST invariably mild cases ” ? No , it wouldn’t have, because then you’d have said ” The same is true for seronegatives! “, since you’re not really interested in the debate, you’re interested in being difficult.

          4. Adrian says:

            Yes, it would have helped if you would not have started arguing based on a fake news scenario that is provable wrong.

            Reality is difficult.

            We do not even have data for mixing shots of different vaccines yet.

            When a vaccine has a interval of between 21 and 42 days between shots, then giving only one shot of this vaccine more than 42 days after any shot or infection is clearly outside of what has been tested and approved.

          5. Adrian says:

            Even if the data would exist, it would still be a lot easier and also cheaper to just vaccinate everyone.

            Two shots are already an enormous logistical challenge, a third appointment just for collecting blood samples for antibody examinations in a laboratory prior to the first shot is simply not a realistic option.

        4. Chris WW says:

          bingo!!!!!

  4. lizzy says:

    Marko: What’s IFR? (google says it’s Instrument Flight Rules)

    1. Marko says:

      Sorry. IFR is Infection Fatality Ratio , as opposed to Case Fatality Ratio(CFR). IFR is more difficult to determine because it requires you to know the number of asymptomatic and mild infections where there was no PCR test done. For CFR you just need the number of PCR+ and associated deaths.

  5. Doug H MD says:

    ” but what seems to be beyond doubt is that the vaccinated subjects, over and over, show up with no severe coronavirus cases and no hospitalizations.”
    That is a bit of hyperbole isnt it? No as in none? Not true. The Israel data shows that 6% of the people in the hospital were more than a week out from 2 doses doesnt it? That in itself is excellent, but it is not no cases.

    1. DataWatcher says:

      Since I just got my second shot (Pfizer), this does bring up one uncertainty I have — what, exactly, is the window of safety in terms of how long after the second shot one needs to wait before its effects have reached full potency? I’ve heard everything from 10-12 days to a minimum of two weeks, but for some reason I’ve never seen a definitive answer.

      Meanwhile, I hope I’m just one of the lucky ones — although my second Shingrix shot brought about some relatively minor flu-like symptoms, neither of my COVID shots have had any side effect at all, except for very slight arm soreness after the first one. Just hoping that doesn’t mean my immune system somehow didn’t respond to it, and I’m still not going to be protected!

      1. sgcox says:

        “common side effects” are defined is one in 10, that means ~90% had none.
        So you not lucky – simply normal 🙂
        Had my Oxford/AZ shot recently. Very disappointing affair, not side effects at all. If it was a trial I would be convinced of placebo.

        1. DataWatcher says:

          Yeah — after all this time and anticipation, I was actually looking forward to a little drama! (Ten-plus months of not seeing anyone or doing anything can do that to you.)

          1. sgcox says:

            Regarding the time to full potency, I do not think anyone has any clear answer. The build up of cases in published Pfizer P3 trial (Derek had the picture in some earlier post) showed the marked brake after about two weeks after the first dose, at about time of the second shot. As no one followed the people who dropped after the first shot, we do not actually know how actually important is the booster. Pre-clinical studies which measured the level of antibodies demonstrated it has a definitive effect but we do not really know yet how it translates to clinic. I think the tentative answer might come from comparison of J&J trials of single and double shots.

        2. Richard West says:

          I’m suspicious that people that don’t have side effects didn’t get a good vaccine – as it wasn’t stored at the right temperature. The Oxford vaccine can be stored in a normal fridge, but still has to be kept cool. Some people are probably getting vaccines that got too warm, so maybe the vaccines are no longer effective. Just something to think about!

          1. Adrian says:

            That’s unlikely.

            “Common” side effects like a day of arm pain or sick leave due to flu-like symptoms happened in the studies only for a minority of people.

            Numbers differ depending on the exact vaccine and symptoms, ballpark figures are 25% of all people getting something like this after vaccination and 3 out of 4 people don’t.

            (It would be interesting to see a study whether the people who have no side effects after vaccination largely overlap the people who would have asymptomatic COVID-19 if infected without vaccination.)

          2. DataWatcher says:

            “(It would be interesting to see a study whether the people who have no side effects after vaccination largely overlap the people who would have asymptomatic COVID-19 if infected without vaccination.)”

            Interesting point, Adrian — I thought of this myself. Correct me if I’m wrong, but I don’t think we have much research concerning the variables — genetic, biological, etc. — that might put some people at higher risk for serious (or even symptomatic) disease than others, although I have heard that people with certain blood types may be at relatively lower risk. I realize it’s difficult to control for confounding variables (socioeconomic status, etc.) in this kind of research, but it seems to me that it would be a good avenue to pursue.

            That being said, though, my understanding is that older people (which would include me — I just turned 68), while at much higher risk for serious and potentially fatal COVD, also tend to have milder reactions to the vaccine, because their immune responses aren’t as robust as those of younger individuals. So maybe this isn’t an apples-to-apples comparison.

        3. JonathanN says:

          I was as sick as a dog with my AZ shot. 48 hours of hell, but it was worth it. I wonder what my reaction to the second shot will be?

          1. George Dorbell says:

            I had a milder reaction to the OXAZ vaccine. Joint and muscle discomfort, slight headache and temperature the same evening and following day.

            More of a reaction than for the last two barely noticeable flu jabs (offered routinely to my age group). Reassured that OXAZ working for me.

        4. debinski says:

          Actually, it’s closer to 90% did have an adverse event. For Moderna, 84-89% had a local event and 55-79% had a systemic reaction (the lower numbers are from after dose 1). Pfizer’s numbers were slightly lower. If they would have combined local with systemic to look at the % with ANY event, the %s would have been even higher. J&J and Astrazeneca have not yet reported their AEs (except for serious ones) for their phase 3 data but from looking at phase 1/2, the numbers appear similar. J&J will have a somewhat lower % because they are only using a single dose and AEs tend to be worse after the 2nd dose. Elderly have fewer AEs than younger groups. If I had no reaction at all (not even a sore arm) I would be a little concerned that either my immune system was not the greatest or there was a problem with the vaccine. Another possibility is that you had some mild effects that you didn’t notice as abnormal (fatigue, headache etc.). Arm soreness might be missed if you didn’t press on your arm and notice tenderness.

          1. DataWatcher says:

            ” If I had no reaction at all (not even a sore arm) I would be a little concerned that either my immune system was not the greatest or there was a problem with the vaccine. ”

            I had no reaction at all, nor did at least one other person I know (who took it at a different location). I don’t have any immune deficiencies that I’m aware of (unless hay fever and a couple of minor food allergies count); in fact, I rarely get sick, even during flu season. I’m 68, my friend is in her mid-50s; not sure if age might have anything to do with it.

          2. DataWatcher says:

            For what it’s worth, here’s what the CDC says:

            “Results from monitoring efforts are reassuring. Some people have no side effects. Many people have reported only mild side effects after COVID-19 vaccination.”

            https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/adverse-events.html

          3. debinski says:

            I’m not arguing that there aren’t “some” people who have no side effects, but most do have them, although they are mostly mild if you look at the clinical trials data. My problem was with the posts above that claim either 75% or 90% have no side effects. The AE %s are lower in older people than younger, but the theoretical reason for that is because they have less of an immunogenic response to the vaccines. But the vaccines were still effective in the older groups – so having fewer side effects doesn’t mean the vaccine is ineffective, even if the immune system is not responding as obviously. (Actually, that would make an interesting study to correlate AEs with immunogenic response). I should have kept my own thoughts to myself as far as being worried about not having side effects…there may be no reason to worry. I just tend to worry about everything! I’m about to find out myself (tomorrow) how my immune system reacts to the first Pfizer dose. I’m hoping it’s not as bad as Shingrix.

          4. DataWatcher says:

            If my experience is any indicator, Shingrix II is worse. Although to be honest, that one didn’t really lay me out too badly, either — a little bit of body ache, probably mild fever (didn’t check) — popped a couple of Ibuprofens and I was pretty much good to go.

          5. Marko says:

            My guess is that a lot of the people who have strong reactions to the first jab are seropositives, and don’t know it. After all, upwards of 30% of the US population is estimated to have been exposed, even though only a fraction of that number qualify as “official” cases.

            If you have a severe reaction to dose one and want to test that proposition, you could get antibody tests after ~3 wks. Your anti-N titer may or may not still be positive, but your anti-spike titer would likely be sky-high.

          6. debinski says:

            I had a bad reaction to Shingrix I, so much so that I never went back to get Shingrix II. Extreme chills (teeth chattering) all night long, followed by headache and extreme fatigue. I also had multiple red welts on a very sore arm. But I will go back to get the 2nd Pfizer dose no matter what. It’s well worth it.

          7. DataWatcher says:

            Looks as if our bodies/systems are very different. From what I recall, Shingrix I didn’t affect me at all. (If it matters, I’ve had both chicken pox [as a child] and shingles; the shingles was at least 35 years ago.)

          8. debinski says:

            Hmm, interesting that you had shingles 35 years ago (assuming you would have been relatively young at that time). Maybe your immune response to chicken pox was somewhat weaker than is typical so reaction to Shingrix would have been less also. I think I may have had a strong reaction to Shingrix due to having multiple natural “boosters” over the years. I had chicken pox as a young child, then would have been boosted when my younger siblings caught it, then boosted again when my own child caught it 30 years later. And possibly other “boosts” along the way that I am unaware of. Since I am sure I never had SARS-COV-2 (unless it was very recent and completely asymptomatic), I am hoping I won’t have much reaction to shot #1.

  6. Not-an-epidemiologist says:

    Hi Derek,

    A timely post, and I don’t think there’s any data to suggest otherwise. A quick typo spot, btw: N is for nucleocapsid, not nucleoprotein.

    I’m looking forward to the hinted forthcoming post on AZ performance against B.1.351. Although I trust that leaked data as little as the massive CIs suggest that we should, I keep wondering why the AZ vaccine is performing a little sub-par in general compared to all other vaccines. They’re all using the Spike protein as their antigen — but are they all using the same sequence for that protein? I think that they’re all locked into the original sequence from China (my understanding is that they do not even incorporate D614G?) — but now I’m wondering if this is in fact the case. (If anyone has dug down into this already — it’d be very interesting to know. Maybe a chimp adenovirus just doesn’t generate as good an immune response, but it’s a little odd.)

    1. Marko says:

      Safety and efficacy of the ChAdOx1 nCoV-19 (AZD1222) Covid-19 vaccine against the B.1.351
      variant in South Africa

      https://www.medrxiv.org/content/10.1101/2021.02.10.21251247v1.full.pdf

      As far as differences in spike, I think the major thing that might distinguish the Oxford/AZ vaccine from the others is that it doesn’t use the “2P” pre-fusion configuration technology.

      1. sgcox says:

        A bit disappointing for sure.
        It should be noticed this is the first real data from human subjects infected with B.1.351.
        Unless I am mistaken, all other vaccines reports are the studies of the effectiveness of the serum of vaccinated people on different virus variants in the lab settings. We need to see how actually effective different vaccines against B.1.351 in the real life, not laboratory, before coming to the conclusions.

        1. Chris Phillips says:

          I think the new variant represented the great majority of infections in the South African arms of the Novavax and Johnson and Johnson trials too.

          I was a bit puzzled previously by the fact that almost all the AZ infections were with the variant despite the fact that they started vaccinating in June. But looking at the time course of vaccinations and of the emergence of the variant in Figures S1 and S2 of the supplementary materials one can see why:
          https://www.medrxiv.org/content/medrxiv/early/2021/02/12/2021.02.10.21251247/DC1/embed/media-1.pdf

          If there’s a simple explanation for the inferior performance of AZ, particularly regarding variants, that can only be good news.

      2. Not-an-epidemiologist says:

        Many thanks for the preprint link.

        Thanks also for the info re. vaccine S sequence — that difference probably explains everything. I wonder why Oxford didn’t use the stabilised pre-fusion form, or at least trial a version that used it?

        1. Marko says:

          I’ve never seen any informed discussion of what led Oxford to go in a different direction on the spike modification. This article is a good review of the technology, but also leaves that question hanging :

          The tiny tweak behind COVID-19 vaccines

          https://cen.acs.org/pharmaceuticals/vaccines/tiny-tweak-behind-COVID-19/98/i38

          1. James Gordon says:

            Perhaps we should be primarily concerned about the AZ vaccine? Lower efficacy and lacking the 2 proline modification. Millions have had it in the UK and E484K containing variants are seeded. I guess we will find out when restrictions are lifted soon.

          2. Not-an-epidemiologist says:

            Thanks again! I do hope it wasn’t a fear of patents that led Oxford to ignore this. I guess they had already made a non-stabilised MERS vaccine that was looking promising, and decided to not fix what wasn’t broken. It’s just unfortunate that the vaccine that got the muscle of AZ manufacturing thrown behind it happened to be the relative runt of the litter.

            There is a statement in the original 2017 paper (https://www.pnas.org/content/114/35/E7348) describing the S-2P modification that is looking worryingly prescient right about now (my emphasis):

            “However, the S protein ectodomain from MERS-CoV is less stable and more difficult to produce than other S proteins, and soluble constructs of the RBD have been the main focus of structural studies, antibody isolation efforts, and subunit vaccine development. A drawback of this approach is that coronaviruses can readily generate antibody-escape mutations in the RBD.

            (Presumably some of the AZ spike protein will be in a pre-fusion config some of the time, and some stem epitopes will be common regardless (although not many, looking at the structures) so it’s not as bad as just using the RBD. But … it doesn’t seem ideal.)

            Oxford / AZ have been talking about generating a B.1.351-specific booster shot. I wonder if they’re going to use a prefusion-stabilised variant for this one? (Or, alternatively, that they’ve already tested the stabilisation solutions and found that they made no difference — there’s no guarantee that this is the reason that their vaccine has lower efficacy, even if it makes a lot of sense.)

          3. Cass says:

            I’m really curious about the HexaPro spike, mentioned in that link and published here: https://science.sciencemag.org/content/369/6510/1501. It was developed by the McLellan lab to have 4 additional prolines for 6 total; it has 10x expression over 2P, improved thermostability, and McLellan suggests 10x potency. Curious if HexaPro will end up in any 2nd generation vaccines, or if that will require new phase 3 trials and discourage its use.

          4. Cristina says:

            Native-like SARS-CoV-2 spike glycoprotein expressed by ChAdOx1 nCoV-19/AZD1222 vaccine
            https://www.biorxiv.org/content/10.1101/2021.01.15.426463v1.full

      3. Chris Phillips says:

        Following on from Marko’s comments, I tried to separate the vaccines according to the “2P or not 2P” criterion.

        Perhaps I am misunderstanding something, but judging from this preprint – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747004/ – the lists are as follows:

        2P:
        Moderna, BioNTech/Pfizer, Novavax, Janssen [Johnson and Johnson] [also according to another source Curevac]

        Not 2P:
        CanSino, AstraZeneca, Gamaleya, Inovio, Clover

        Is that correct?

        1. Marko says:

          It looks right to me. The only thing I would add is that the trimer tag used by Clover might function in a similar manner as the 2P substitution in stabilizing the spike protein.

        2. Not-an-epidemiologist says:

          That’s a great review article.

          It seems that Novavax and Janssen are additionally mutating protease target sites that contribute to a post-fusion confirmation. However, I can’t see any clear evidence that having this additional feature helps much (Novavax don’t provide any data; Janssen imply that having either this or the 2P mods are beneficial, but show nothing to suggest that the combination of both adds anything).

          What is very clear (as the review you linked to notes strongly) is that having some form of stabilising mutation leads to significantly increased antibody titres.

          1. Chris Phillips says:

            Thanks for those comments. The odd one out in terms of basic efficacy seems to be Gamaleya. Though I realise that concerns have been expressed about the published efficacy results. And that (as far as I’ve seen) it has not been tested against the variants. Still, it doesn’t quite seem to fit in with the straightforward “not 2P bad” hypothesis.

          2. Not-an-epidemiologist says:

            I think it’s more a “not 2P, less good” hypothesis — “bad” is going overboard.

            But yes, Gamaleya is the odd one out. As you say, there could be a difference between efficacy against “covid classic” vs. efficacy against the new variants. It may be that Gamaleya will see a larger drop in performance than Moderna and Pfizer when it finally gets a solid run at B.1.351.

            But there’s another difference between Gamaleya and AZ. I just went back and looked at their Phase I/II publication (https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31866-3/fulltext), and they’re getting much higher antibody (and neutralising) titres compared to both convalescent plasma with their two dose strategy (as you’d expect) than with a single dose of either vector. One of the odd things about the AZ vaccine was that they didn’t see a huge increase in titres with the (at that stage, day 28) boost and they didn’t see antibody or neutralising titres strikingly different to convalescent plasma. Combined with the fact that AZ’s now-reported long-term efficacy for a single dose is not statistically significant from the two-dose efficacy … and I dunno. I have a lot of questions about that vaccine, but it really looks as though it under-performs on the boost. (Although I hasten to add that I’ll still happily take it when I’m given the chance — and that can’t come soon enough AFAIC. It’s much better than no vaccine.)

            So, maybe the spike stabilisation isn’t the reason for the relatively poor AZ response. (It’s also possible that the chimp adenovirus AZ is using forms less stable spike trimers than the other ad26 / ad5 — seems unlikely, but I don’t think we can rule this out?) I hope Oxford / AZ have tested a spike-stabilised variant, though. (And if they have, I wish they’d let us know …)

          3. eub says:

            Naive question, are there live examples of adenovirus vector vaccines given as a dose plus a booster with the same Ad vector? Like, examples of how that game works?

            It seems like a situation the likes of AZ would not rush into without data to direct their tread, so I figure it must exist.

    2. jbosch says:

      As far as I recall both mRNA vaccines use a slightly modified sequence from the Corona classic variant, that stabilizes the spiker trimer in an open conformation (the one that then binds to ACE2). One of them I think Moderna has also some N-terminal extension while the Pfizer one does not.
      I don’t recall if the Astra/Zeneca one introduced those amino acid changes as well or not. But if not that may explain the difference in effectiveness.

  7. Lane Simonian says:

    I am going to broaden this out into a separate but still related category: immune responses that you do not want. More may surface, but the emerging problem in the mRNA vaccines is a condition called acute immune thrombocytopenia where the immune system attacks platelets. The New York Times recently and without sensationalism looked at this problem in possible relationship to the vaccine.

    The story may be behind a paywall so here are some highlights:

    “It is not known whether this blood disorder is related to the Covid vaccines. More than 31 million people in the United States have received at least one dose, and 36 similar cases had been reported to the government’s Vaccine Adverse Event Reporting System, VAERS, by the end of January. The cases involved either the Pfizer-BioNTech or Moderna vaccine, the only two authorized so far for emergency use in the United States…

    Hematologists with expertise in treating immune thrombocytopenia said they suspected that the vaccine did play a role. But they said that cases after vaccination were likely to be exceedingly rare, possibly the result of an unknown predisposition in some people to react to the vaccine by developing an immune response that destroys their platelets. The disorder has occurred, rarely, in people who received other inoculations, particularly the measles-mumps-rubella one.”

    There is a difference between irrational fears of vaccines and fears based on very rare but potentially life threatening side effects.

    1. Ndp4949 says:

      But here’s the thing, if you come across this virus in sufficient amount with no vaccine protection in you almost certainly will get the virus, to varying degrees of severity. If you get this vaccine, you almost certainly won’t get those things you describe.

      1. Ola Paz says:

        There is also almost certainty that if you are under 65 and do not suffer from any underlying conditions, COVID will be no more that a cold for you. So, given the side effects of vaccines, known and unknown, the decision to get the vaccine or not, for healthy young people that are not frontline workers, is not so easy.

  8. C says:

    Very helpful post. Since you mentioned ADE was seen in some N-targeting SARS vaccines, I’m curious if there’s any evidence of ADE from previous or current inactivated vaccines that don’t solely target N but do include the N protein in the vaccine and presumably induce anti-N antibodies?

    1. Mandark says:

      There was no ADE in preclinical studies of inactivated whole-virus vaccines for SARS-CoV-2. As for clinical studies, two of them completed phase 3 trials and are being rolled out in several countries: CoronaVac from Sinovac and BBIBP-CorV from Sinopharm. Neither of them has published results so far but I assume cases of disease enhancement were not observed.

  9. Richard West says:

    I’m going to get my shot at a hospital that seems to have plenty of vaccine. If I get a choice between the Moderna and Pfizer/BioNTech vaccines, which one should I ask for?

    1. Adrian says:

      Personally I would take Pfizer/BioNTech, but I could not even give a good reason against the Moderna one.

      Both vaccines are pretty similar, be grateful if these are your choices and you are spared from the inferior Oxford misdesign.

  10. O.K. says:

    I think this part is inaccurate: “word has come within the past few days that the Moderna and Pfizer/BioNTech vaccines may be holding up even better”

    Depending on which preprint you look at, the neutralizing titers from Moderna and Pfizer/BioNTech show a 6~8.5x drop-off when all the mutations in B.1.351 are included. It’s hard to scale titers to vaccine efficacy of course, and immunity depends on many factors other than just titer counts (such as T-cells), but this takes them from being several times above the neutralizing titer counts of recovered patients to around half the titer counts from prior infections. Given circumstantial evidence from various other vaccine trials, I think our default guess should be that this only confers immunity at a level fairly comparable to Novavax’s.

    1. Roland says:

      Yup. I think it’s really alarming Pfizer & Moderna have been able to say “Yea there’s a big drop we think that’s fine” and everyone nods along while the vaccines which have actually had trials against significant amounts of E484K variants get downgraded.

      Some Pfizer comments last week indicated they weren’t even trying to run a trial because “we’ve already done trials in South Africa and Brazil”. And the lab study where they tested vaccination-derived antibodies against each point mutation individually from the variants and announced loudly that they were all okay was as disgraceful as it was meaningless.

      If I had to guess they will probably handle the variants a bit better because they raised higher antibody tilters to begin with, but really how much is a bit? It’d be nice not to have to guess.

      1. jbosch says:

        Well, there’s at least an N=14 for the Pfizer/BioNtech being effective against B1.1.7 in real live.

        I’m referring to an outbreak in an elderly home facility in Osnabrück, Germany where all residents had received the Pfizer/BioNtech second dose by January 25th. Turns out a couple days later February 10th(?) 14 residents tested positive for the B1.1.7 variant but had no symptoms. To me this means two things, first the vaccine did work and protected these people from getting really sick and secondly at least people in the older range who get vaccinated may still be able to potentially transmit as they may not raise a sufficiency high response to completely block viral replication.

        1. DataWatcher says:

          (Sorry, I mistakenly posted this at the bottom of the thread, where it doesn’t make any sense.)

          It’s conceivable they contracted it from a caregiver (or caregivers) working closely with them, not from one another. But you’re right — it does, suggest that vaccination protects against serious disease, even among the high-risk elderly.

        2. Adrian says:

          Noone is seriously claiming that the current first generation vaccines are offering protection against infection or transmission for any age group – the data says otherwise starting with the initial monkey studies. The current vaccines offer good protection only against severe disease.

          It is an open question whether the current vaccines at least reduce infections and transmissions, the initial data seems to support that but much less than the 95% reduction for severe disease.

          1. Chris Phillips says:

            “It is an open question whether the current vaccines at least reduce infections and transmissions, the initial data seems to support that but much less than the 95% reduction for severe disease.”

            We discussed this before, when you claimed that the vaccines didn’t have any effect on the number of infections, but just made infections milder.

            In fact, the AstraZeneca Phase III data indicated a decrease of around 50% in the total number of infections. And in terms of overall data, AstraZeneca is the least effective of the vaccines currently being administered.

            It might help if people could admit they were wrong sometimes.

          2. Adrian says:

            “when you claimed that the vaccines didn’t have any effect on the number of infections, but just made infections milder”

            It would help if people like Chris Phillips would not spread lies about what I said.

            What I did actually say was that we did not have the data for that.

            Initial data for that available now seems to be more in the 50% ballpark than 95% like symptomatic infections.

            This is better than nothing, but also a clear sign that first generation vaccines alone cannot provide herd immunity no matter how many people get vaccinated even against COVID-19 classic.

            If we assume 50% reduction in infections, this would be partially offset by the higher transmissibility of the improved COVID-19 variants compared to COVID-19 classic.

            If reduction of infections is lower against the improved variants of COVID-19, the reduction of infections by vaccines might struggle to keep up with the increase of infections by the improved COVID-19 variants.

          3. Chris Phillips says:

            Adrian

            “It would help if people like Chris Phillips would not spread lies about what I said.
            What I did actually say was that we did not have the data for that.”

            I apologise – it was someone called “GM” who said that.

            However, we do have the data, and we have had since early December, so it’s not “an open question whether the current vaccines at least reduce infections and transmissions”, as you suggested.

          4. DataWatcher says:

            @Chris Phillips — Do we have actual data (i.e., numbers) on the extent to which the vaccines might prevent infection / transmission? Aside from that kerfuffle over AZ’s confusing press releases a few weeks ago, I haven’t seen anything specific.

            (Although I’m becoming increasingly concerned that it may not matter much anymore, because everything we thought we knew about vaccine efficacy, and probably most of what we thought we knew about reinfection, will be obsolete within a few weeks as B.1.1.7 and B.1351 [just for starters — B.1.525 has now joined the club] become increasingly dominant, and p.1 is out there, too]. I’m seriously starting to wonder if 2021 is going to be 2020 “Groundhog Day” Redux.)

          5. Chris Phillips says:

            DataWatcher

            The figure of around 50% reduction in overall infections (including asymptomatic infections) comes from the paper on the AstraZeneca trials published in the Lancet in early December.

            For reasons already discussed (including reduced viral load and reduced duration of positive testing) the effect on transmission would be expected to be greater than that, though how much greater remains to be seen.

            Given AstraZeneca’s relatively mediocre performance in reducing symptomatic cases, I think it would be surprising if it were as effective as the mRNA vaccines in reducing overall infections.

          6. DataWatcher says:

            Judging from what’s happening in Israel, it would appear as if Pfizer (and, by association, most likely Moderna, as well) is highly effective against B.1.1.7 — or at least the “original” B.1.1.7, which has since mutated further and more ominously. We’ll have to see how well it works against B.1.351, p.1, and others yet to come . . .

        3. Roland says:

          “Well, there’s at least an N=14 for the Pfizer/BioNtech being effective against B1.1.7 in real live.”

          Right, but I was talking about the E484K variants. The original B.1.1.7 isn’t a concern antibody wise, and I think we’d easily see herd immunity to it in many countries once 80+% are vaccinated, not just based on the AstraZeneca results but because there’re decent levels of naturally-acquired immunity already suppressing transmission among the demographics most likely to catch it.

          Sadly we probably won’t know whether we get there since we’ll still have NPIs to deal with the other variants.

  11. James Gordon says:

    Very good article. Much appreciated. There is this albeit small study from Brazil that shows some evidence of enhanced severity after previous infection(different from vaccination I know) upon exposure to PI variant in health care workers. I will get any vaccine when offered but still think there are many unknowns and more data is needed. https://www.sciencedirect.com/science/article/pii/S0163445321000438

    1. James Gordon says:

      Doesn’t specifically say PI variant but ‘distinct viral sequences’ presume the PI variant.

  12. asd says:

    Anyone seen this letter from the UK Medical Freedom Alliance re vaccine-related deaths in the elderly and care homes (link below)? I have also seen other similar evidence from credible sources. What do you think?

    https://uploads-ssl.webflow.com/5fa5866942937a4d73918723/601ffc3e56a64132caa3f42f_Open_Letter_from_the_UKMFA_Vaccine_Deaths_Care%20Homes.pdf

    I fear that what is currently happening may do serious long-term damage to confidence in vaccination.

    1. Adrian says:

      The first question would be what “the UK Medical Freedom Alliance” is.

      Their website was registered in November, this is not look like an organization that already existed half a year ago.

      1. Chris Phillips says:

        According to their website, they are two “Integrative Doctors”, two GPs, one retired doctor, one dentist, one osteopath, one lawyer and one “Cognitive Scientist and Therapist” – who runs a spa using “complementary medicine and ancient wisdom traditions”.

        1. Richard West says:

          Epidemic exposed a lot of good and bad in the medical profession. One of the bad things is that it turns out a few physicians are total nut jobs!

          1. Meddediah Chem says:

            @Adrian, Chris Phillips, Richard West

            https://blogs.sciencemag.org/pipeline/archives/2021/02/10/does-prior-exposure-to-coronaviruses-protect-you#comment-338630

            …Loh! Doubly blessed. Ruling Clinical Thought hath spoken too. Thrice. Glory to the Lord. Glory Be. And welcome to the party (Dr) West. New worshippers always welcome at the Consecrated Church of Ruling Clinical Thought.

            Homeopathy and holistics aside, am inclined to think the Medical Freedom Alliance has put together a well written and researched summary of reports of vaccination outcomes in care homes. Maybe as Ruling Clinical Thought implies, the Medical Freedom Alliance is anti-vaccination per se. Care home vaccination outcomes still a matter for the relevant clinical experts to consider and respond to.

            As for the homeopathic, for a fungal mouth infection am inclined to favour the wonders of the still-miraculous-after-all-these-years macrolide NYstatin over the dubious pleasures of any formulation of the surgical bisbiguanide disinfectant hibitaine. Intriguingly junior and senior general practitioner clergy have on occasion prescribed a form of either option for the aforementioned affliction. I’m with the junior clergy on this one.

            LIkewise junior over senior for betamethasone over fusidic acid. Ditto a dentist of any denomination who offers local anesthesis for a filling over a dentist who doesn’t, on the basis that the pain’s all in the mind, laddie, and by the way, laddie, I come from a neck of the woods where we’ve always put a premium on economy, frugality and painless tooth extraction without anesthesis.

            Interesting story, NYstatin. First isolated in 1950 from soil sample taken from a farmyard in New York state. Hence the name. A cattle yard, if I recall right. NYstatin proof that good truly can come out of ordure. Chemical and antifungal characterisation carried out in New York State Department of Health laboratories by a highly experienced microbiologist in her sixties and a just as highly experienced chemist in her fifties.

            Seems back then Public Health took on more than surveillance, detection and prevention. Subsequent fermentation scale up, formulation, commercialisation and distribution led by ER Squibb and Co. NYstatin approved by the FDA in 1954.

            As for holistic heresy, am still inclined to think state of mind may on occasion have bearing on physical illness (but rarely, if at all, in dentistry). If only those clever Imperialist College mathematicians and an ex-physicist could come up with that Mindreader algorithm…

            …Ask patient to plug self into device in comfort of patient’s own home and bingo, observe state of patient’s mind on own device in comfort of own vicarage using special Mindreader GP app. Prescribe accordingly, ranging from NYstatin to Pull Yourself Together Man delivered via WhatsApp. That endless stream of face to face consultations done with once and for all. Next!

            *****

            Quote for the day: “I decided that my main business was with the imponderables, the things that work secretly and have to be apprehended mentally.”

            Said by a physicist (1851-1940). Son of North Midland hilltop parish. Self-taught disciple of James Clerk Maxwell and the School of Electromagnetic Radiation. Father figure of wireless transmission. Inventor of a commercialised spark plug. Inaugural Prof of Physics and Maths at a Northern red brick university.

            Man of His Time. Father of twelve. Member of the Fabian Society. Described as a Christian Spiritualist. Researcher into psychic phenomena, fashionable in some quarters at the time. Believer in primacy of the aether, until aether well past sell by date and superseded by more plausible theory conceived by a lone genius, who in 1901 wrote, “Unthinking respect for authority is the greatest enemy of truth.”

            Era of War of the Worlds, Intolerance and The Machine Stops, written in 1909, dramatised in under ten minutes over a hundred years later, and set in the future…

            https://www.youtube.com/watch?v=SWiBicmWuNg

    2. asd says:

      It’s the *data* that bothers me

      Search out @RealJoelSmalley on Twitter and judge for yourself

      1. asd says:

        Also see this whistleblower report from Germany. I can’t vouch for the veracity of it, but it would seem an odd thing to invent…?
        https://2020news.de/en/whistleblower-from-berlin-nursing-home-the-terrible-dying-after-vaccination/

        1. Chris Phillips says:

          Can you give us any reason to think you’re not just posting any nonsensical anti-vaccine stuff you can find?

    3. Alexis Lieberman says:

      Was there an official response to this letter?

  13. Gmac says:

    ADE with anti-S might be less of a problem than VAH when antibody responses to vaccines wane to sub-neutralising levels and new variants/future mutations have the potential to exacerbate this. In my opinion this scenario will definitely play out in the future and at a grand scale. Initial efficacy could potentially still backfire and there is no current evidence available that provides me with any comfort that this will not happen, as vaccination is irreversible I’ll happily take the much better known risks of natural infection. Interested to hear thoughts on this!

    1. Richard West says:

      I would say it depends on your age. If you are younger than 40, it seems you can skip the shot and take the risk of Covid. Apparently, after 40 the risks of infection are too great to take a chance, as you might not recover!

      1. fajensen says:

        You will likely regret that decision, once you get COVID-19. It is really not “the flu”.

        “The flu” for me is where we get a 4-finger whiskey and some blankets to vegetate on the sofa while watching brain dead action and sci-fi for a week.

        COVID-19 is not sleeping for 6 days because of trouble breathing combined with a certain feeling of, “make one mistake (like whiskey), and it’s intubation time”. I measured an SpO2 around 90% for 2 weeks. Was given grams of paracetamol and ibuprofen, stacked, to calm the inflammation (doctors orders)

        And, This is what my doctors called a “mild” case. Not “mild”, means going into hospital.

        A month on, my lungs are still excreting goop and my trail running, what I actually like to do, is of course totally screwed up..

        Relying on “natural infection” means up to half the population cutting out 4-6 weeks of every year with “COVID-19 downtime” – for years until one of the variants makes them a statistic and it’s not their personal problem anymore.

        I will definitely recommend the vaccination over COVID-19!

        1. Moran says:

          At least in my experience, “the flu” is a week of lying down in bed; almost unable even to get to the kitchen on my own to get something to eat. And I am still quite young (35), I guess for older people the flu is even worse. Underestimating the flu is not a good idea, regardless of your opinion about COVID-19.

          1. confused says:

            While COVID is clearly significantly worse than flu (except *possibly* in the very youngest age groups) I agree many people tend to underestimate how bad flu can be. I think this may partially be because people at least in the US tend to call all sorts of non-influenza illnesses “flu”, eg “a stomach flu”.

            OTOH, there is a ton of individual variation. The last time I had flu was the 2009 pandemic H1N1 “swine flu”, and I really do not remember it being that bad – I threw up a couple times, felt sick and woozy for two or three days, then was back to normal.

            (There is a lot of individual variation for COVID too…)

    2. wst says:

      “I’ll happily take the much better known risks of natural infection. ”

      If you are in UK, the very well known risk of natural infection is that one of 34 tested positive die (4M/117k). You may refine this figure with your age group’s statistics.
      This is CFR, lets say that we prefer IFR estimation as x 10 CFR, now it’s 1:340 .

      1. Gmac says:

        I’d look at the numbers very differently. In fact, most cases of ‘flu are asymptomatic, I’d also believe this to be the case for COVID even if proper data is lacking. PCR confirmed cases of COVID are likely the ‘tip of the iceberg’ and are currently running at 0.4% serious/critical – less than 1 in 200, even if you are unlucky enough to be infected or have no symptoms and somehow get tested as a close contact. 1 in 34 is way off the mark even though the UK test a lot compared to other countries – recent asymptomatic testing/screening in small pockets of the UK population will not make the virus any more or less deadly!
        Vaccines designed and tested against original virus that don’t stop infections or transmission are inevitably going to accelerate the emergence of escape mutations and vaccination is just too clunky to hit a moving target. Vaccines are also not going to be equitably distributed or administered on a global level. Do we stop international travel indefinitely? Unchecked we know this virus can sweep the world in months.
        As per my original post the initial efficacy data appears great and but there are many reasons to believe that it will not last (even with current circulating variants) and might even make things worse in the long run. Biology bites and this vaccination experiment is not very well designed or thought out.
        Enough of the problems – a solution would involve properly focusing on a treatment to reduce mortality in the tiny minority of those infected that actually need a treatment? The problem in my opinion is no the virus but the unfortunate aberrant immune response elicited by
        a VAST minority of people.

        1. Meddediah Chem says:

          Very well put, Gmac. Meanwhile among the VAST majority of the remaining 67 million people here in the UK…

          VAST majority of 9M kids have been home schooled by VAST majority of 12M parents for all bar 12 of the last 48 weeks, 400K UK citizens in rent arrears and number reportedly set to triple in next year, 395K redundancies in 3 months to November 2020, £5000K per head added to national debt, etc, etc, etc.

          Similar picture across Western World. Take a bow, Experts And World Leaders. Well intentioned, but wrong all along.

          All head together in direction of nearest village stocks for a well earned plaudit of rotten tomatoes.

          VAST majority please draw own conclusions if so inclined…

        2. stewart says:

          1 in 34 seems a pretty good match for the UK official figures. The CFR is currently running at just shy of 3% on PCR confirmed cases (I’m wondering what is the cause of the high CFR in the UK; I doubt that we’re worse at detecting cases than the rest of Europe), and that’s an underestimate of deaths. The fact that we’re still getting cases in quantity implies a limit on how large the proportion of undetected cases can be – at 15:1 we’d be in herd immunity territory by now; at 10:1 we shouldn’t need a stringent lock down to bring R below 1.

        3. Chris Phillips says:

          “PCR confirmed cases of COVID are likely the ‘tip of the iceberg’ and are currently running at 0.4% serious/critical – less than 1 in 200, even if you are unlucky enough to be infected or have no symptoms and somehow get tested as a close contact.”

          That’s absolute rubbish.

          In the UK in the second wave (since 1 August) there have been 3.75m positive tests and officially 76.9k deaths. That’s a fatality rate of 2%.

          And I thought the “tip of the iceberg” stuff had long gone.

          Look at the UK figures from the placebo arm in the AstraZeneca trial. Primary symptomatic COVID-19 was 2.0% of participants, and asymptomatic or symptoms unknown was 1.3%. Probably the infection rates are lower than for the population as a whole, but there’s no reason to think the percentage of asymptomatic cases (about 40%) should be an underestimate.

          1. Gmac says:

            Asymptomatic is one thing, another is people who are exposed and not susceptible to picking up infection. Have you used the same supermarket and noticed familiar faces on the tills? Not sick or dying and must have immunity, employers have thousands of these on the payroll and don’t report cases significantly above background infection rates. Cases of a family member having PCR confirmed virus and their spouse and children not getting infected – how big is this problem? Have any proper studies been carried out? I wish we knew and earlier serological studies are flawed. Has anyone an informed idea of when this might end?
            Take stock of the long term economic and health related damage due to disruption to essential standard medical care. Spanish flu ended without a vaccine. Swine flu also but the lasting damage caused by Pandemrix should have been an eye opener (narcolepsy and cataplexy cases still being defended by governments). The long term unknown consequences of variant challenge and imperfect antibodies primed by vaccination (and lack of informed consent for patients as regards the risks involved) are now something that we will only find out in time. If the ship hits the iceberg it was predictable.

          2. Chris Phillips says:

            Gmac

            If you can point to data backing up the claims you make, I’m sure everyone will be interested to see it. Otherwise, you probably aren’t going to convince anyone.

            And in fact, when lives are at stake, I’m sure you wouldn’t wish people to accept claims – whatever they are – unless there’s evidence behind them.

          3. Med Chem says:

            @Chris Phillips re, “That’s absolute rubbish. In the UK in the second wave (since 1 August) there have been 3.75m positive tests and officially 76.9k deaths. That’s a fatality rate of 2%.”

            Tut, tut – quick to berate, Prof/Dr/Mr Phillips, yet “fatality rate of 2%” dashed off without making clear that’s the CFR. As for the IFR, even Imperial College Report 34 goes no higher than 1%, while Oxford CEBM make case for IFR as low as 0.3%.

            So the 1 in 340 figure cited by “WST” and the “1 in 200” cited by Gmac (albeit phrased a little loosely), ain’t necessarily right, but ain’t necessarily rubbish either.

  14. DataWatcher says:

    “We’re going to be doing this for years. We’re still going to be doing this 10 years down the line, in my view.” (Professor Sharon Peacock, director of the COVID-19 Genomics U.K. Consortium)

    https://bestlifeonline.com/news-uk-strain-covid/

    1. Chris Phillips says:

      Hmm. The BBC report explains that her team works on sequencing variants of the virus, and that that’s what she thinks will continue for years. Hardly surprising.

      And then it spells it out:
      She explained this was not because she thought the pandemic would go on for 10 years, but she believed they would be sequencing new variants for that length of time.

      https://www.bbc.co.uk/news/uk-56019995

      But perhaps that wasn’t “chilling” enough for the writer of that US report.

      1. DataWatcher says:

        Okay, thanks for the clarification. I try to stay immune (if you’ll pardon the expression) to out-of-context “click-bait” sensationalism, but I guess “they” got me that time. I guess I owe an apology (as do the editors of “Bestflife”).

  15. Richard West says:

    Why do people say they are sicker after the second shot?

    That doesn’t make a lot of sense … one would think they should be sicker after the first shot when they have no immunity … no?

    1. sgcox says:

      Inoculation is not infection, immune system is not at the real war with the replicating invader. It simply reacts to been exposed to a new antigen and slowly (thankfully, or we would all die because of cytokine storm) build up the response. By the time of second exposure , jab or real virus, it is ready and go full monty.

      1. guneapig says:

        In laymans terms, it was explained to me like this–

        after the first shot: “Hey, who are you and why are you in my house?”
        after the second shot “INTRUDER ALERT! INTRUDER ALERT! REPEL BOARDERS!”

  16. Nick says:

    Isn’t ADE also about replication in the infected monocytes? FCoV for example is a mild disease in cats but sometimes the coronavirus persists in the gastrointestinal tract (GI) mutates and is able to infect macrophages AND replicates in them and eventually causes the deadly FIP.

    As far as I know SARS-CoV-2 is able to at least infect macrophages to some extend and escpecially in alveolar macrophages causes mayhem in some kind of endless cytokine cycle – but the infection is abortive.

    Thus, as long the virus isn’t able to replicate in monocytes, I wouldn’t be concerned too much about ADE. If there is a variant that can also replicate in monocytes I would be much more concerned, especially because some papers suggest that like FCoV the virus can persist in the GI of humans as well.

  17. lizzy says:

    JBosch:
    Is it true that Moderna used an N terminal extension? If so, do you know why? I thought that the S glycoprotein NTD developed mutations through deletions specifically in the RDR’s (recurrent deletion regions), thus morphing its shape.
    The only reason I can think of for this elongation would be further stabilization of the spike in its prefusion configuration.
    https://science.sciencemag.org/content/early/2021/02/02/science.abf6950

    Thanks Marko, Jbosch and others. I just couldn’t figure out why the Astra Zeneca results were so dismal. Blaming the viral vector didn’t make sense. But I didn’t realize that they hadn’t stabilized the spike.

  18. AQR says:

    Could ADE have something to do with why convalescent plasma is not as effective as either the Lilly or Regeneron monoclonal antibodies in treating Covid during the early stages of infection? Presumably, the convalescent plasma contains antibodies directed against both the spike protein and the nucleocapsid protein while the Lilly and Regeneron monoclonals are directed against just the spike protein. If neucleocapsid-directed antibodies are present in convalescent plasma, I would think that someone who received a blood transfusion from someone who had recovered from Covid would actually be primed for ADE for as long as those antibodies were present in their system.
    Along a similar vein, I notice that both Lilly and Regeneron are testing their monoclonals as a prophylactic treatment for Covid (kind of like a vaccine) in nursing home residents who are particularly susceptible to infection and have weakened immune systems. I would expect that this would be effective, although the duration of protection will depend on the antibody half-life rather than the body’s immune system response to infection. Any thoughts?

    1. Sc says:

      Convalescent plasma is likely to contain interferon-targeting autoantibodies which are counterproductive, as outlined in an older post here.

  19. Simon Auclair the Great and Terrible says:

    Hear of these? https://theprint.in/health/israeli-hospital-claims-it-has-developed-a-covid-cure-drug-trial-shows-96-positive-result/599512/

    Not heard alot on non vaccine drugs lately…

    1. Adrian says:

      This is not the first substance that has promising initial results against cytokine storms, and I wouldn’t put too much weight on claims that are not based on placebo-controlled studies.

    2. Alexis Lieberman says:

      Look at ivermectin stuff on trialsite news.com and fluvoxamine stuff on treatearly.net or com??)

  20. Guy Gadboit says:

    These macaques got vaccine-enhanced disease from an MVA vector vaccine encoding just the SARS1 spike:

    https://insight.jci.org/articles/view/123158

    I think pretty much everything that was tried enhanced for SARS1, but didn’t for SARS2, even inactivated whole virus vaccines like Coronavac appear to be fine.

    Interestingly inactivated SARS1 enhanced even for a chimeric vaccine with a different spike (but a SARS1 backbone) https://www.nature.com/articles/nm.3985

    I think the current vaccines are safe against the current variants but I feel like we never got to the bottom of this issue.

    This is great news but I would much

  21. Masher says:

    Some of you experts might like to look at this article about a proposed approach targeting the nucleocapsid protein.

    https://www.independent.co.uk/news/health/covid-vaccine-variant-universal-nottingham-scancell-b1801966.html

    Are they playing with fire?

  22. Melon says:

    Has anyone looked at ADE in infections with MERS or another coronavirus in people vaccinated against SARS2? The virus will accumulate hundreds of mutations over the next few years so maybe those other coronaviruses are the best model for testing if there will be any ADE in the future.

    1. confused says:

      Aren’t MERS infections really, really rare? Do we even know if there has been a MERS infection in someone vaccinated for COVID? I am *sure* there have not been enough to have an useful sample size (especially as MERS is really deadly already…)

      OTOH, as it’s winter in the Northern Hemisphere where most COVID vaccine doses have been given, I would think significantly enhanced disease with “common cold” coronaviruses ought to have shown up by now…

      1. Adrian says:

        Yes it is rare, WHO says 2 (two) new cases of MERS in January 2021:
        http://www.emro.who.int/health-topics/mers-cov/mers-outbreaks.html

  23. Wormholio says:

    There is another aspect of ADE in all this — does previous exposure to one of the other more common human coronaviruses cause more severe symptoms due to ADE? While it’s not stated here, it seems to be implied by Derek’s previous post, “Does Prior Exposure to Coronaviruses Protect You?” More specifically, “There’s no difference in the infection/hospitalization rates of the people who had cross-reactive coronavirus serum antibodies ready to go versus those who didn’t. They’re basically useless.” That’s disappointing, but it also shows is that those antibodies are not causing harm, which is good news. Or had that already been established previously?

      1. Tracy B says:

        “The antibody in Williams’ blood was the natural infection, not from the vaccine.”

        Exactly, how is this determined?

        1. Marko says:

          The anti-spike antibodies in his blood could have come from the natural infection or the vaccine, or both. Anti-nucleocapsid antibodies could only have arisen from natural infection.

          All they can rightfully say based on antibody tests is that he’d had previous infection. They can’t say that he didn’t have antibodies from the vaccine, unless the anti-spike test was completely negative, which is doubtful.

  24. Marko says:

    SARS-CoV-2 re-infection risk in Austria

    https://www.medrxiv.org/content/10.1101/2021.02.08.21251362v1

    This is the kind of simple, first-pass type of study that could be used to inform vaccination strategy for those previously infected, and is especially important to do in areas affected by the troublesome variants.

    Multiple such studies have now shown that previous infection provides a similar level of protection as the vaccines, which shouldn’t be too surprising. An infection IS a vaccination for those who recover, in effect. We’re about to approve the J&J vaccine, a single dose , so there’s not even a compelling reason to think that the previously-infected need a “booster”, at least not until we see the impact of waning immunity showing up as measurably higher re-infection and disease rates in that group. Vaccinating them at this time with TWO doses would be utter madness.

    1. Marko says:

      “The opinion of Professor Iwasaki, a leading expert in immunology (Yale University, USA) on the single dose for those who have already had covid . France is the first to make a useful decision to effectively vaccinate as many people as possible, as quickly as possible.

      https://twitter.com/RemiSalomon/status/1361021694777958406

      France is only giving one dose to those with a history of previous infection, and is recommending a wait of at least 3 months, and preferably 6 months, from the time of that infection to the vaccination. Somehow they feel that they can overcome the seemingly insurmountable logistical problems that we in the US fear we’d face if we instituted such a commonsense policy.

    2. Marko says:

      “Antibody titers of those vaccinated with pre-existing immunity are not only 10-20 times higher than those not infected at same time points (pthan 10-fold.”

      https://twitter.com/MonicaGandhi9/status/1361053015361261568

      1. Marko says:

        The full quote:

        “Antibody titers of those vaccinated with pre-existing immunity are not only 10-20 times higher than those not infected at same time points (pthan 10-fold.”

        1. Marko says:

          I give up. Read the tweet.

        2. sgcox says:

          Necessity is the mother of invention.
          France is in a dire straits with vaccination program so no wonder.

          1. Marko says:

            I predict that other countries will follow suit in fairly short order, and the US will resist, or wait so long that it won’t matter anymore.

  25. Richard West says:

    Someone told me if you get the first shot in your left arm, you should get the second one in your right arm. Does that make sense … or it doesn’t make any difference?

  26. Marko says:

    “4 people in Oregon have tested positive for the coronavirus after receiving both doses of the Covid-19 vaccine, health officials said.”

    https://twitter.com/NBCNews/status/1360993235141877762

    Not one, not two, but FOUR anecdotal examples!

    That’s it. Shut it down. Clearly the vaccines do nothing at all. The numbers out of Israel must be completely fake.

    1. Marko says:

      Israeli study finds 94% drop in symptomatic COVID-19 cases with Pfizer vaccine

      https://www.reuters.com/article/us-health-coronavirus-israel-vaccine-idUKKBN2AE0Q2

      1. Chris Phillips says:

        Perhaps even more significant than the efficacy for symptomatic disease is a 92% reduction in the rate of severe illness. As the study looked at 600,000 people there is much more statistical power than in the Phase 3 trials (assuming the matching with the comparison group worked adequately), so probably more confidence can be placed in the high efficacy for severe illness than was the case with the trials (in which the numbers for severe illness were small).

        Other reports say the study found equal effectiveness in all age groups.

        1. Marko says:

          It is impressive. I’m assuming the numbers would compound to an overall risk reduction against severe disease of >99%.

          1. DataWatcher says:

            It’ll be interesting when/if we can compare actual data in terms of severity of disease in vaccinated people who’ve become infected vs. non-vaccinated people who’ve been “reinfected.” Even more interesting (and important, I think) will be the data on severity in people (from either group) who’ve been “reinfected” by B.351, P.1, or any mutant yet to come . . .

          2. Chris Phillips says:

            I read those reports as saying severe disease goes down in almost the same proportion as symptomatic disease. But I take that as good news.

          3. Marko says:

            You might be right, and either way it’s good news. My thinking was that most of the models of vaccine efficacy have been suggesting that it would be lower for asymptomatic disease than for symptomatic, which would then be lower than for severe. I thought they might have compared severe disease rates between vaccinated infected vs unvaccinated infected to come up with the 92% rate reduction figure.

    2. confused says:

      This seems completely irresponsible to report. 95% protection isn’t 100%, so this seems entirely expected… The only thing that makes it “newsworthy” is the *false* implication that it shows a problem with the vaccine.

      1. Adrian says:

        A much bigger problem is that people even here miss what these numbers are and what they are NOT.

        These headline 95% reduction numbers are for symptomatic infections only.

        95% reduction in infections (and transmission) was never claimed, and based on the little available data sounds unlikely.

  27. Marko says:

    Some optimism from Gilbert and Pollard of the Oxford Vaccine Centre :

    “…As to the kind of future that vaccines will give us, both Gilbert and Pollard are optimistic. “We might be able to live with Covid-19 as we do with other coronaviruses that infect us in childhood,” said Pollard. “I would be quite happy if I just get a cold with this virus in future – as long as we stop people dying from it. And the vaccines we have may be enough to achieve that. However, if the disease turns out to be more like flu, we may have to regularly update vaccines to maintain immunity in the population.

    “That will be a huge problem if we have to do it for all age groups every year. However, I think there’s a reasonable chance that won’t be necessary and only the most vulnerable will need the vaccine every year, one that could be combined with flu vaccine in the future.”

    https://www.theguardian.com/world/2021/feb/14/life-savers-story-oxford-astrazeneca-coronavirus-vaccine-scientists

    1. DataWatcher says:

      I know it’s a too-frequently-asked question, but does the growing proliferation of mutant variants, many more contagious, some probably more virulent, and some possibly with enhanced immune escape capability, throw a wrench into this optimism? When even Fauci starts talking about “nightmare scenarios,” it would seem to be time to worry . . .

      1. confused says:

        I would think it would only significantly change the picture if “immune escape” means severe disease at comparable levels to immunologically-naive (or close enough to be a major public health issue), not just reinfection.

        And I remain skeptical that there will just be endless new variants. We don’t get hit by endless variant-waves of the other four human coronaviruses, even though at least some of these might have entered the human population in events like this (1890 “Russian flu”?)

        1. DataWatcher says:

          I guess my primary concern, which I think I share with quite a few others, is, how many deaths and how much more suffering must we endure in order to reach a point where few enough people are immunologically naive that we no longer have to be terribly concerned? Even if, as many postulate, upwards of 30% of all Americans have been exposed, and even if vaccine distribution and uptake continue to improve, that still leaves a lot of time, a lot of immunologically naive people, and hence and a lot of opportunity for more spread, probably more mutations, and much, much more suffering and death.

          (And, for that matter, what evidence do we have that the rate of mutation is slowing down, or will in the near future? If anything, it seems to be picking up. If there’s a “turning point,” what is it? Remember — this particular virus does not kill most of its hosts; it doesn’t even make most of them terribly sick. So it has a big “cushion,” so to speak, to work with in terms of becoming more contagious and more virulent, before it begins to threaten its own survival. )

          1. confused says:

            >>I guess my primary concern, which I think I share with quite a few others, is, how many deaths and how much more suffering must we endure in order to reach a point where few enough people are immunologically naive that we no longer have to be terribly concerned?

            Well, that depends primarily on the vaccination rate — which is why IMO too much discussion of vaccine escape is actually counterproductive. The message needs to be that vaccines will genuinely allow a return to normal.

            >>So it has a big “cushion,” so to speak, to work with in terms of becoming more contagious and more virulent, before it begins to threaten its own survival.

            Yeah … but I don’t really think that can be the only thing involved. I’m no virologist, of course, but… you could say the same thing about the four “common cold” coronaviruses, or RSV, or parainfluenza, or …

            Yet these don’t continuously mutate to be worse and worse… or if they do our immune systems keep up.

            In fact pandemics seem almost always, if not always (cholera maybe an exception?) to be animal -> human spillovers, not mutation of a virus within human population. (Even influenza pandemics are new strains from birds, swine, etc.)

            So *something* is a limiting factor even if we don’t know exactly what.

  28. Meddediah Chem says:

    Over the last year, this limey scientist contends more good science, good sense, evidence based medicine and functioning vaccine has come out of Cowley than Imperialist or Fenland.

  29. lizzy says:

    On vaccinating Covid 19 survivors:
    In a pinch, I do think they should just get one dose. The second dose won’t harm them but trial evidence of even higher antibody titers, or even better T cell response to this third exposure to the Covid 19 spike is lacking. At least I haven’t seen it. In addition, I’ve never heard of a real world third infection, although second infections with variants are relatively common.
    On Israeli data:
    Medscape gives us a little more data: https://www.medscape.com/viewarticle/945700?src=mkm_covid_update_210211_MSCPEDIT&uac=130465ER&impID=3186318&faf=1
    Eran Segal seems to be the one to follow on twitter:
    https://twitter.com/segal_eran/status/1359558268994150408

    1. Adrian says:

      Second infections are quite common, it is just hard to prove in many individual cases that they are distinct infection.

      Based on experience with common cold coronaviruses and expectations for vaccines, few people are expecting lifetime protection after vaccination with two shots.

      The UK Health Secretary said it is possible that people might need a fresh vaccination every 6 months. This is the most pessimistic scenario that cannot be ruled out.

  30. Marko says:

    This looks like someone to follow if you want to watch for early signals of vaccine efficacy in the UK :

    https://twitter.com/VictimOfMaths/status/1361372645380526087

    1. Marko says:

      As far as the US goes :

      “I think it’s too early to attribute falling cases to #COVID19 #vaccine with only 12% of US having received a dose & 4% fully vaccinated. I put my money on peak so high from holiday travel that everything after looks good + health depts focused more on vaccine than testing.”

      https://twitter.com/tmprowell/status/1361372948926500872

      I put my money on the reason for falling case rates in the Northern Hemisphere on only one thing: February. February is just an all-around, sucko month. Everyone is curled up in the fetal position in bed all day, trying to stay warm. How could anyone get infected?

      In the summer, August is similarly sucko. If you can’t travel for vacation, you lock yourself indoors and crank up the AC. Again, few infections. Same patterns in the Southern Hemisphere, only hot becomes cold and cold becomes hot.

      In March we’ll start breathing on each other again and it’ll be a different story.

      1. Richard West says:

        Marko wrote: “My guess is that a lot of the people who have strong reactions to the first jab are seropositives, and don’t know it.”

        I believe that’s true. My first Pfizer shot made me pretty sick. Does not mean I won’t get so sick after the second one?

        1. Marko says:

          My guess would be that the second jab would be less severe, but it’s just that, a guess. I hope you’ll let us know.

          If you were a seropositive, you won’t get a comparable additional antibody boost with the second jab coming so soon after the first, that I’m fairly certain about. If I was a seropositive and wanted to get the vaccine, I’d wait 6 months or so for my second jab, or just wait for the new “variant booster”.

  31. DataWatcher says:

    It’s conceivable that they contracted it from a caregiver (or caregivers) working closely with them, not from one another It does, however, suggest that the vaccination protects against serious disease, even among the high-risk elderly.

  32. stephanie says:

    Where did my comment go?

  33. Stephanie says:

    I keep trying to post this but it disappears or won’t post for some reason.

    I first learned about VAE from a podcast interview of Dr. Paul Offit by Dr. Peter Attia. I had never heard of it before, and I’m a pharmacist. I feel like I should have known more about this, but I suppose we’re all constantly learning. I’ve been reading what I can.
    I find this column to be reassuring.
    I’ve also read that the fact that convalescent plasma doesn’t seem to lead to enhancement is a source of reassurance. There is further reassurance here:
    https://www.ema.europa.eu/en/documents/rmp-summary/comirnaty-epar-risk-management-plan_en.pdf
    Much to my disdain, I understand that this issue is being politicized by antivaxxers of the right-wing persuasion here, as I do not want to be painted with this brush. I very much WANT the vaccine, but I want to feel like the risk of VAE has been put to rest. I’ve also had concerns about autoimmunity, which seems to be rare, as well as questions about whether the vaccine will reduce transmission and mild infection, or will it instead lead to a false sense of security and a breeding ground, thus, for escape mutations that are associated with greater M&M?

    While my choice would be no vaccine AND no infection, I’m not sure I can for sure avoid the latter. And given the choice of being infected–and developing a grab-bag of polyclonal antibodies, which seemingly would INCREASE the risk of ADE and autoimmunity, I’m inclined to choose the vaccine. Not there totally, and part of me is being a weenie about the impending fever/chills/HA that’s in store.

    But these folks who say they’d rather be exposed to the full virus instead of the smallest effective piece of the virus? On what basis do you make that preference? It seems particularly foolish to me.

  34. Blaine White, M.D. says:

    As with ADE, there’s been a lot of hyperventilation about C19 variants and reduced antibody neutralization titers. That ignores cellular immunity, and in fact the breadth of T-cell responses to SARS-CoV-2 infection mitigates against clinically serious reinfections. Tarke et al (https://doi.org/10.1101/2020.12.08.416750) studied 99 convalescent patients and noted-
    “Based on our results, we expect that each donor would be able to recognize about 19 CD4 + T-cell epitopes, on average. Likewise, for CD8 + T-cells, we expect at least 17 epitopes per donor to be recognized. Overall, T cell responses in SARS-CoV-2 are estimated to recognize even more epitopes per donor than seen in the context of other RNA viruses, such as dengue, where 11 and 7 CD4 + and CD8 + T-cell epitopes, respectively, were recognized on average. This analysis should allay concerns over the potential for SARS-CoV-2 to escape T-cell recognition by mutation of a few key viral epitopes.”

    With respect to Spike, they found CD4+ “Responses to S… were focused on discrete regions of the protein involving the N-terminal domain, the C-terminal, and the neighboring fusion protein (FP) region; only a few responses were focused on the RBD.” In contrast, “CD8 + T-cell reactivity did not reveal any particular immunodominant region in S, with epitopes and non-epitopes roughly equally distributed along the sequence.”

    Because the Pfizer and Moderna mRNA vaccines are using our ribosomes to synthesize foreign Spike – as with the virus, some of it will also be recognized as a DRIP (defective ribosomal protein) and proteolysed for MHC presentation for T-cells. As found above, that will result in T-cell recognition epitopes all over the Spike protein. The current viral variants are unlikely to escape that, and I expect (as suggested by the Israel study) we’re going to see a rate of post-vaccine variant infection that is too low to support propagation of the disease. I’m fully vaxed and booking a cruise while they are still cheap.

    1. DataWatcher says:

      Blaine, I have been asking myself whether it’s a ridiculously misguided layman’s question to wonder why there’s been virtually no mention of T-Cells or memory B-Cells in most of this reporting we’re seeing about diminished antibodies, fears of limited duration of immunity, etc. — and even in a lot of the “immune escape” reporting we’ve seen. Are the reporters (and not just mainstream journalists, but a lot of science reporters as well) simply missing the point? Or is some important testing and follow-up research simply not being done?

      1. confused says:

        Wasn’t it discussed earlier on here that antibody responses are way easier to measure, thus they tend to get disproportionate focus relative to B/T cells?

      2. Blaine White, M.D. says:

        Datawatcher, I think that, unlike Dr. Lowe here, many of the folks reporting and their editors have very limited understanding of immunology or molecular biology. They have a fuzzy concept of an antibody and no idea of the signalling complexities on the Fc end. And Memory B-cells, T-cells (let alone CD4, CD8, and T-regs), and specifics of antigenic epitopes give them vertical nystagmus. Moreover, the molecular pathophysiology and the connection of the immunology to macrophage hyperinflamation, endothelial cells, hypercoagulopathy, and lethal hypoxia is completely opaque. They aren’t fluent in the language and don’t understand the ins and outs, and neither does most of their audience. So how do you journal and report from there? They recognize the initial reluctance to grasp the extent of the losses we could endure before we learned enough to get the CFR trending down and effective vaccines deployed. Now they fear another monster behind every bush, and there is lots of doubt that things are actually starting to improve. Of course, there could be another monster, and that fear helps motivate vaccination and social caution for a bit more time. But a pandemic escape from this pandemic seems unlikely and did not occur after 1918.

      3. Stephanie says:

        Then how do you explain reinfection?

        1. Marko says:

          There’s no need to explain reinfection if the contention is only that immunity, whether naturally-acquired or from vaccination, provides high levels of lasting protection against severe disease and death. That contention hasn’t been conclusively proven yet, but the evidence that is available is leaning strongly in that direction. The smart bet right now is that memory B- and T-cell activity to CoV2 will last years, if not decades.

          Reinfection will probably occur once antibodies decline sufficiently, but if the result of the overwhelming majority of those reinfections is something akin to a common cold, nobody will care. Similarly for primary infections that occur after vaccine-induced antibodies wane.

          What I find hard to explain about reinfections is the meager attention the subject receives from the Covid-19 research community. “Follow the money” would seem to be the obvious path to that explanation.

          1. Doug H MD says:

            it is deeply concerning that we dont see more data on this matter. Hopefully it will be forthcoming soon. no more important question exists in this area imo

          2. Adrian says:

            It is quite lunatic to demand data “conclusively proven” regarding “lasting protection”.

            It is known that reinfections happen in some cases and that they can be worse than first infections, including deaths.

            Instead of “Follow the money” conspiracy theories, the simple explanation is that long-term data simply does not exist for a disease that appeared only a year ago.

            For vaccines we are basically starting at zero, and they also destroy any long-term data on people who were infected during the first wave a year ago.

          3. Alex Beribisky says:

            The problem is (I think) that it can be quite difficult to set up such a study. I also lean towards the notion (not unlike a few people here) that reinfections are under-reported, however a plurality (if not the majority) of them are asymptomatic or mild. A study that looks at reinfections will intrinsically undersample such these kind of cases cases as people with little or no symptoms will naturally be less prone to getting tested.

          4. Blaine White, M.D. says:

            Actually, here are parts of the Abstract of a large (43,000 subjects) and carefully done study of reinfection in Qatar by a Cornell University team (https://doi.org/10.1101/2021.01.15.21249731) – Abu-Raddad et al.

            “All SARS-CoV-2 antibody-positive persons with a PCR-positive swab ≥14 days after the first-positive antibody test were individually investigated for evidence of reinfection. Viral genome sequencing was conducted for paired viral specimens to confirm reinfection.
            Results: Among 43,044 anti-SARS-CoV-2 positive persons who were followed for a median of 16.3 weeks (range: 0-34.6), 314 individuals (0.7%) had at least one PCR positive swab ≥14 days after the first-positive antibody test. Of these individuals, 129 (41.1%) had supporting epidemiological evidence for reinfection. Reinfection was next investigated using viral genome sequencing. Applying the viral-genome-sequencing confirmation rate, the risk of reinfection was estimated at 0.10% (95% CI: 0.08-0.11%). The incidence rate of reinfection was estimated at 0.66 per 10,000 person-weeks (95% CI: 0.56-0.78). Incidence rate of reinfection versus month of follow-up did not show any evidence of waning of immunity for over seven months of follow-up. Efficacy of natural infection against reinfection was estimated at >90%….
            Conclusions: Reinfection is rare. Natural infection appears to elicit strong protection against reinfection with an efficacy >90% for at least seven months.”

            This is very clear. Reinfection is rare, and post-infection immunity appears enduring – as was also found for SARS.

          5. DataWatcher says:

            On the other hand, escape mutations seem to proliferating at higher and higher rates . . .

            https://www.msn.com/en-us/health/medical/english-health-authority-says-38-cases-of-new-covid-variant-found/ar-BB1dJqmG?ocid=msedgdhp

          6. DataWatcher says:

            @DHMD — Encouraging, indeed. I’m still holding out, though, for research on transmissibility post-vaccination. Again, what we’ve seen anecdotally looks promising, but actual data would not only be welcome from an epidemiological perspective, but might start to loosen up some of the more dire predictions about post-vaccination life (see above) that we continue to hear.

        2. confused says:

          I’d be more worried if reinfections *weren’t* reported (since it would mean we were somehow failing to detect them) – nothing in biology is 100%.

          Even diseases classically thought to provide really good protection against reinfection aren’t truly absolute – when the chickenpox vaccine came out, my family was told that I didn’t need it since I’d just had the disease, and I caught it again shortly thereafter. (Presumably because my initial case was quite mild.)

          The existence of reinfections – and even the occasional severe case – doesn’t disprove the general picture that prior infection does provide immune protection (though the exact degree/duration is uncertain).

  35. Bill Laird says:

    ImmunityBio has a N+S vax in phase 1.

    https://finance.yahoo.com/news/immunitybio-nantkwest-announce-fda-authorization-231300411.html

    During period of elevated risk, I plan on adjunct ivermectin to S vax immune response .

  36. Marko says:

    Saliva Test May Predict Severity of COVID-19

    https://www.yalemedicine.org/news/saliva-test-covid-19-severity

    Widespread rollout and usage is expected shortly after the end of the pandemic, if all goes well.

  37. Chris Phillips says:

    Press reports based on early data suggest vaccination in the UK may be cutting illness by two third, and also cutting transmission:
    https://www.itv.com/news/2021-02-16/covid-early-data-on-vaccine-effect-on-transmission-encouraging-zahawi-says

    On the presumption that that predominantly reflects single doses among the elderly, partly of Pfizer and partly of AstraZeneca, it seems encouraging.

    1. DataWatcher says:

      When will we have more conclusive data on transmissibility post-vaccination? Indications are that there will, indeed, be some protection, probably to a significant extent, but it would be very beneficial to have actual data. This will also be important as policymakers try to forge new behavioral guidelines as more and more people become vaccinated. We’re already seeing a lot of queries along the lines of, “Can I get together with my vaccinated friends and socialize?” or “Can my vaccinated mother hug her grandchildren?” So far, the answers from the “experts” to such queries have been conflicting and confusing.

    1. Adrian says:

      When will the US follow the lead of the rest of the world and start using proper masks instead of pieces of cloth?

      In East Asia people started using surgical masks a year ago.

      In parts of Germany surgical masks are no longer considered sufficient, wearing at least FFP2 (similar to N95) is a legal requirement for entering shops or using public transport.

  38. DataWatcher says:

    Also, the news that limited supply will probably push the “mass vaccination” timeline in the U.S. back to mid-summer sometime does not bode well for our current “race against time” with the mutant variants. The longer it takes for the majority of people to get vaccinated, the more likely we are to get sabotaged by increasingly contagious, virulent, and resistant strains.

    1. Marko says:

      Osterholm is apparently again on the bandwagon for the US to adopt the UK rollout strategy, which I agree with, but not enough to listen to his hour-long banality- and metaphor-filled podcasts. For those with stronger stomachs :

      https://www.cidrap.umn.edu/covid-19/podcasts-webinars/episode-43

      1. Marko says:

        The transcript is also available at the link. You can usually get the gist by quickly scanning that, but even that exercise is like wading thru quicksand.

  39. Marko says:

    Germany plans to offer free rapid coronavirus tests from March 1

    https://www.reuters.com/article/us-health-coronavirus-germany-idUSKBN2AG0X2

    France is already doing this. The US might look into this eventually, if they can work out a way to maximize corporate profits, without the necessity of taxing the rich.

  40. K. Smith says:

    Newbie question. Having just come out of isolation following having covid together with rest of my house hold. With my company want me to get vaccinated as soon as I came back.This is puzzling me. We keep being told that were not protectected for 2 to 3 weeks after vaccination what is it that allowed me to battle and overcome the infection in 5 days and out of isolation in 10 days . If antibodies take a few weeks acquire.

    1. Marko says:

      You were “vaccinated” by the infection several days (~4-10 ) before you became symptomatic, so you had time for the immune response to clear the infection within the similar 2-3 wk period it takes for a vaccine to take effect.

      You should seek some medical guidance on when you should get vaccinated. I think it’s better to wait at least a few months after your recovery from infection. Your employer may have have a different idea, but it’s your body.

      1. K smith says:

        Thankyou for your insight. Much appreciated. Informed information allows me to function better. Having witnessed colleges most who had been infected over a three month period all get vaccinated on the same day .it was observed that those who where vaccinated shortly after their infection seemed to suffer far worse with reactions than those who had a few weeks between. This is why I deferred mine till they come round for second dose. My wife is currantly suffering long haul and has just been called up but i feel she needs to have rocovered first. However our dr say shouldn’t be a problem. (Not looking for a awnser to last comment just voicing)

  41. Marko says:

    ” The coronavirus is here to stay — here’s what that means : A Nature survey shows many scientists expect the virus that causes COVID-19 to become endemic, but it could pose less danger over time.”

    https://www.nature.com/articles/d41586-021-00396-2

    Most of the unanswered questions here could be resolved by studying reinfection outcomes, particularly in the areas where the variants predominate. This is too hard, apparently, so we continue to research the easy, irrelevant stuff.

    1. DataWatcher says:

      Interesting, though, that most of the estimates of the amount of uptake necessary for some kind of HIT to be approached are somewhat lower than the 70 – 85% we’ve been hearing.

      I will repeat a query I posed earlier, though, because I am honestly curious. Do we have actual data (i.e., numbers) on the extent to which the vaccines might prevent infection / transmission? Aside from that kerfuffle over AZ’s confusing press releases a few weeks ago, I haven’t seen anything specific.

      I must add, though, that I’m becoming increasingly concerned that it may not matter much anymore, because everything we thought we knew about vaccine efficacy, and probably most of what we thought we knew about reinfection, will be obsolete within a few weeks as B.1.1.7 and B. 351 (just for starters — B.1.525 has now joined the club, and p.1 is out there, too) become increasingly dominant. I’m seriously starting to wonder if 2021 is going to be 2020 “Groundhog Day” Redux.

      Too bad — I was really looking forward to being able to smile at strangers again, and maybe even go back to some of my favorite show lounges and juke joints to hear some live music.

      1. Marko says:

        I can’t be bothered with the HIT and transmission debates, because my only concern is that immunity reduces hospitalizations and deaths to such a level that we can get on with normal life. The “HIT” for hospitalization and death is thus the number I care about.

        I think you have to be crazy to think the vaccines won’t reduce transmission to at least some degree. Vaccines reduce the rate of PCR positives, i.e. symptomatics, and asymptomatic infections transmit less than symptomatic, so even if symptomatics are simply being converted to asymptomatics, you’ll see reduced transmission. If literally the entire world was infected asymptomatically, whether with variants or not, nobody would care as long as there was no severe disease and death.

        1. DataWatcher says:

          I agree with you that “reduc[ing] hospitalizations and deaths to such a level that we can get on with normal life” should be the goal, even though we don’t usually hear that talked about very much among most “mainstream” commentators and health/public policy operatives. Articles like the “Nature” article cited above hint at this, but (understandably, because we don’t have the data yet) they don’t provide very clear timeline estimates.

          Maybe a topic jump (and I DON’T want to sound as if I’m parroting the anti-masking/go-for-broke-and-open-everything-back-up-yesterday contingent, because I most assuredly am not), but I wonder whether one of the reasons we don’t see much discussion of a possible “normal” future with a steady (if much reduced) incidence of cases but very few serious cases/hospitalizations/deaths might be that the “experts” don’t want to spread a false sense of security among the population, many of whom are already resisting public health behaviors (e.g., those Super Bowl superspreaders). Or maybe, as some have postulated, it’s because the traumatic events of the past year have made the very word COVID a kind of trigger for a PTSD-type reaction that makes discussions like that seem risky, if not downright frightening, to a lot of people.

          1. confused says:

            If B.1.1.7 is going to make a dramatic difference, we should know very soon.

            Perhaps I am being overoptimistic, but I think seasonality now looks to be a much larger factor than I would have believed in the summer (at least north of the subtropical/desert band of latitudes – still not sure about the summer/winter peaks in TX FL AZ – but Europe and the northern US look like pretty classical respiratory seasonality).

            If so, this might help — in the UK B.1.1.7 hit in fall while seasonality was already making things worse, whereas the couple months delay in the US means it’s only becoming common now in late winter while seasonality is pushing the opposite way…

            @DataWatcher: I think you are right about the reluctance to say optimistic things – but I think it has the opposite of the desired effect; the people who already aren’t taking it seriously are *more* likely to dismiss what they hear if it seems unrealistically pessimistic.

            If we hadn’t been told that TX and FL were going to be “the next NYC” two or three weeks after Spring Break, people might have taken it a bit more seriously in May and June rather than dismissing it quite so much as a Northeast-specific problem…

            (I think many public health people missed how deep the cultural divide is, too; NYC experience is not much more relevant to most Texans than Italy or Britain, IMO.)

    2. Blaine White, M.D. says:

      Marko and K Smith: We have in these posts discussed T-cell and Memory B-cell immunity and the study of 43,000 convalescent C19 patients showing reinfection to be very rare. So – SHAZAM – today a preprint from NIH & Hopkins appears showing even the C19 variants just are not escaping CD8 (T-killers or cytotoxic T-lymphocyte) antigen targeting (https://doi.org/10.1101/2021.02.11.21251585). I’ve seen several immunologists comment that post-infection immunity is always more effective than that obtained by vaccination. I find no basis for encouraging anyone who is post-C19 infection to be further vaccinated at this time. Post-infection antibodies and T-cell immunity have been studied and are far more diverse than the response to any of the vaccines using just the Spike antigen. Furthermore, the evidence so far is that immunity is enduring. I would expect an infectious disease specialist to readily inform an employer of that.

      1. DataWatcher says:

        . . . meaning that a combination of widespread vaccination along with already-existing natural immunity could result in more positive outlook than some of the futurists in the “Nature” article proposed? That’s certainly encouraging, if it’s possible. I still wonder, though: If the new strains, which we already know are more contagious, are in fact also more virulent to the degree that is now being suggested, how much more suffering and death will we have to endure to get to that point?

      2. Marko says:

        I agree. I’ve been pounding the drum here for quite a while to stop vaccinating seropositives. That we’re wasting TWO doses of scarce vaccine on each of them at the moment is lunacy, IMO.

        Months from now, when all the seronegatives have been vaccinated, and perhaps we have more information on reinfection incidence and outcomes, we can decide whether vaccinating seropositives, as well as endlessly boosting everyone else, is going to be necessary or not.

  42. K. Smith says:

    @Blaine white m.d. thankyou for the insight . Good food for thought .will follow this thread with interest.

  43. Marko says:

    It looks like Jon Cohen may have been reading this blog’s comments. He touches all the bases :

    How soon will COVID-19 vaccines return life to normal?

    https://www.sciencemag.org/news/2021/02/how-soon-will-covid-19-vaccines-return-life-normal

  44. Marko says:

    The smart bet on transmission reduction from vaccines :

    https://twitter.com/mlipsitch/status/1361877159686635522

    Find an anti-vaxxer or denialist and propose a wager. Easy money.

    1. A Nonny Mouse says:

      I received the AZ one yesterday.

      I was speaking to one of the other people on this site who said that his aunt and 6 others in the care home who had had their first AZ dose tested positive for Covid, but none of them experience any symptoms at all.

      Surely this is the objective of any vaccine….

      1. DataWatcher says:

        Yes, it should be. Once again, though, the wild card is the ongoing evolution of mutants, incl. potential escape mutants, in the asymptomatic people who still carry the virus. That’s the primary reason why so many formerly optimistic authorities (even including Fauci, if you read between the lines of his recent statements) are now predicting a much longer, more difficult, and bleaker road ahead. It’s also the main reason why transmissibility data, while encouraging so far, need to be studied further.

  45. Chris Phillips says:

    A report of comments by Clive Dix, “interim chair of the Vaccines Taskforce” (apparently the successor of Kate Bingham), gives an interesting insight into the likely UK strategy regarding approval of vaccines modified in response to new variants.
    https://news.sky.com/story/covid-19-every-uk-adult-could-receive-both-jabs-by-august-says-head-of-coronavirus-vaccine-taskforce-12220149

    Some of his comments seem a bit strange to me, but his idea seems to be that approval would be on the six-week timescale. He also says he sees no problems with delivery of existing vaccines and thinks the whole adult population may have received two doses by August or September. If anything, that probably implies an acceleration of the current rate of vaccination.

  46. gabriel says:

    please tell me the so-called pfaizer vaccine is it a vaccine or a prolonged-release drug with a short lymphocyte memory, or a full-fledged vaccine ??
    second question if permission is given as an extraordinary one, the vaccinated must not sign the Helsinki protocol and the vaccination agreement ??
    the third question is whether tests were carried out to determine cellular immunity in all subjects after vaccination? I have a suspicion that at a young age, mainly cellular immunity is needed and lymphocytic, to put it mildly, is not very important, it seems to me that due to the tension of two immune systems, vaccinated young people may have disproportionate immune responses .. I think that the only tcell immunity test that determines the need for vaccination is why ?? in my opinion, far from n110 million have been ill, but I think at least 10 times more .. I also have a suspicion that the disease is associated with the onset of puberty and more severe after menopause in women and a drop in testosterone in men

  47. gabriel says:

    advanced inactivated Covid-19 vaccines seems to me the best solution, but the fact that they only have 70 percent of the production of lymphocytic antibodies is better for young people, since they will develop full-fledged cellular immunity for several years, and pfaizer is like a drug that must always be added after the fall of antibodies, something like a carolic wedding

  48. DataWatcher says:

    There seems to be growing resistance in Europe and UK concerning the AZ vaccine, but not the others as much. Will this derail the vaccination effort?

    https://www.msn.com/en-us/money/markets/astrazeneca-s-vaccines-go-unused-in-eu-as-mutants-spread/ar-BB1dLkkT?ocid=msedgdhp

    1. Mariner says:

      My brother in law (mid-50s, pre-existing heath issues so he’s at home shielding at present) had flu-like symptoms for a day or two after his first dose of the AZ vaccine but has been fine since then. Is this what people are complaining about in the msn link? Ridiculous, if so.

      Sounds like too many people have listened too much to the politicians politicking rather than the scientists saying, “Nope, nothing to see here”. Better not give those kids their MMR jabs just in case they develop a fever for 24 hours or so afterwards, eh? It’s a similar argument.

      1. A Nonny Mouse says:

        I had mine a few days ago and nothing really to report. My son had the Pfizer jab (already antibody +ve) and did get hit fairly hard.

        1. Mariner says:

          I should have mentioned that my brother in law potentially had Covid back in March 2020. He was unwell for a week, perhaps 10 days, with some of the symptoms. No chance of getting a test here in the UK back then. The rest of the household were unwell for a day or two with a fever but nothing else to report. His pre-existing health issue (which required an autologous stem cell transplant about 7 years ago), means that he does tend to have more serious reaction to common illnesses in the rest of his family so we’re not sure if he did have Covid in the past or not. Quite possible that it was one of the other coronaviruses or cold bugs in circulation which he hasn’t caught since before his transplant.

          I suspect I’ll be getting the AZ vaccine during the next couple of months due to my mild asthma so it will be interesting to see if I suffer any side effects.

  49. DataWatcher says:

    . . . and things are looking increasingly grim for 2021 and beyond:

    https://bestlifeonline.com/news-covid-wave-winter-2021/

    1. Doug H MD says:

      we cant even predict next week let alone a year out

      1. DataWatcher says:

        True, but with the vaccine roll-out apparently even slower than we’d thought (wide availability in the U.S. now looks as if it won’t occur until June, at least), and with the mutant variants accelerating, it does look increasingly as if that much ballyhoo’d “race against time” between the vaccines and the virus is favoring the opposition more every day. I don’t want to believe we’re facing an indefinite masked/faceless/hugless future, either, but I do want to be realistic and not fall prey to false optimism. “Good news” isn’t the same thing as “good science.”

        1. Doug H MD says:

          IHME gets a C- on their predictions

        2. confused says:

          I’ve certainly been overoptimistic before about this (especially in late summer/early fall) but vaccination likely isn’t the only thing working in our favor – there is natural immunity and probably seasonality too.

          Now the variants are working against that, sure, but there may be a huge difference between B117 becoming an issue when cases are already rapidly rising (as in the UK) vs. when they are already rapidly falling.

          If seasonality *is* important, even a fairly slow rollout ought to be good enough to preempt next fall/winter.

          1. DataWatcher says:

            That still leaves us with B.1.351, p.1, and the newly “enhanced” B117 to contend with, as well as anything else likely to come along in the interim. . .

          2. confused says:

            Sure, I know the other variants exist, but isn’t B117 the primary one in the US?

            Anyway, I think there is a big difference between a more-transmissible variant becoming an issue when cases are already rising, vs. when they are sharply falling.

            Again, I’ve been overoptimistic in the past – but I think we will know soon. Isn’t B117 really common in places like Florida now?

  50. Marko says:

    ” Up to 90 volunteers in UK to take part in pioneering Covid infection trial – Human challenge trial will monitor healthy 18- to 30-year-olds given virus to aid vaccine and therapy research”

    https://www.theguardian.com/world/2021/feb/17/uk-to-begin-worlds-first-covid-human-challenge-study-within-weeks

    When you consider such things as genomics surveillance, the RECOVERY trials, reinfection studies like SIREN, and now this, the UK has represented itself quite well in Covid-19 research, relatively speaking.

    On the other hand, the US Covid-19 experts absolutely dominate in the social media space.So there’s that….

  51. Marko says:

    Delayed Second Dose versus Standard Regimen for Covid-19 Vaccination

    https://www.nejm.org/doi/full/10.1056/NEJMclde2101987?query=featured_home

    The US is inching towards making the right decision on this, and that decision will come just in time for it not to make a speck of difference.

  52. Marko says:

    Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies

    https://www.biorxiv.org/content/10.1101/2021.02.12.430472v1

    “Nasal swabs from vaccine recipients were not neutralizing, except in individuals who were diagnosed COVID-19+ before vaccination.”

    Why haven’t we seen more data like this on mucosal antibodies/neutralization, both from natural infection and vaccination? Is Institut Pasteur the only lab capable of doing this?

    1. confused says:

      I am sorry, but is this a distinction between mucosal antibodies (this preprint) and antibodies circulating in the blood (most other studies)?

      Is one more important than another for COVID?

      1. Marko says:

        Well, given that infection starts in the nasal passages, you’d think there would be more curiosity about what’s going on with regards to mucosal immunity. If you really want to stop transmission, a strong mucosal response is probably what you want to promote. The simple answer is that yes, for any viral respiratory illness, you want to know what’s happening with mucosal immunity.

        I just don’t understand why I’ve seen scores of papers investigating neutralization in sera, and only this single paper that looked at nasal swabs. Maybe they’re out there and I’ve just missed them.

        I suspect that one factor may be that it requires a very sensitive neutralization assay to detect the activity, and maybe Pasteur is one of the rare labs that can do it. The positive titers they got from the nasal swab samples were only ~1:10 or less. That’s not to say that they wouldn’t have seen higher titers in swabs from recently-recovered patients, however.

  53. Gmac says:

    https://www.nbcnews.com/news/us-news/pfizer-says-south-african-variant-could-significantly-reduce-vaccine-protection-n1258198
    Now we urgently need to find out if the reduced efficacy carries any increased risk. Vaccines rendered pretty much useless unless this strain is contained (impossible and we know from lab experiments that it will mutate to this spike conformation regardless of geography). The results if this is actually dangerous via imperfect antibody/antigen pairing are potentially catastrophic – tens to hundreds of millions of shots later.
    Maybe now NIH, WHO, Gates etc. will properly fund treatments that have a decent chance of working. All the eggs went into the vaccine basket save for ‘hail mary’s’ on repurposed drugs with CGT and advanced therapeutic approaches out of scope. Back to square one now and lots of time wasted

    1. Chris Phillips says:

      “Gmac”

      The work referred to in that article was published three weeks ago, and what’s actually said in that article is very far from “Vaccines rendered pretty much useless”, as you claim.

      I really wonder what people like you think you are doing. Are you just an “anti-Vaxxer” spreading whatever disinformation you can find, perhaps? If so, you’re beneath contempt.

      1. Gmac says:

        Dear Chris. Legitimate scientifically founded concerns and fears are not anti-vax, especially when there has been an unprecedented roll out of vaccines and preclinical data from closely related coronaviruses provided a clear and largely ignored warning signal. The experiment continues.

        1. Chris Phillips says:

          “GMac”

          “Legitimate scientifically founded concerns and fears are not anti-vax …”

          Of course scientifically founded comment is valid.

          But – as I think you know full well – what I was saying was that outright misrepresentation, like your comment “Vaccines rendered pretty much useless”, is the stock-in-trade of “anti-vaxers”. Just stop misrepresenting the facts.

          1. Gmac says:

            Sorry you reiterated why ‘people like me’ have doubts about vaccine safety. I have proposed a mechanism of action for a recent risk caused by variant challenge that has been seen in vivo with other experimental coronavirus vaccines. Dengvaxia showed initial efficacy too, look what happened there. You or anyone else cannot predict that VAH or ADE will not occur in the future and previous data is of no comfort. So I’m genuinely concerned as regards long term safety. Everyone is free to make their own decisions and I don’t think my debate here on this forum is where an antivax propagandist would choose to operate. Let’s hope that these fears don’t materialise and the still valid theoretical risk should be clearly stated in the vaccine PILs. Don’t hide it.

          2. Chris Phillips says:

            “Gmac”

            Please just read what I am saying.

            I don’t care whether you’re against vaccines. That’s up to you. What I object to is lies like “Vaccines rendered pretty much useless” when the article you linked to said something quite different.

            If you’re against vaccines, then argue honestly against them. Don’t lie and mislead people.

          3. Gmac says:

            Lying and misleading people like an accidental half dose regime of a certain vaccine gives 90% efficacy to keep up with the Jonses over at Moderna and Pfizer. Now where did I hear that one?
            Omitting risks from laypeople while having full governmental indemnification of any harms that may be caused is beyond reprehensible.

          4. Chris Phillips says:

            “Lying and misleading people like an accidental half dose regime of a certain vaccine gives 90% efficacy to keep up with the Jonses over at Moderna and Pfizer.”

            If you’re saying you feel justified in lying and misleading people because you think that finding was accidental, that tells us all we need to know about you.

      2. Gmac says:

        Now that you are slinging mud let’s look back at selective use of data ………. get off your moral high horse you are just starting to look bad now…
        https://www.bmj.com/content/360/bmj.j5845/rapid-responses

        1. Chris Phillips says:

          Gmac

          You are absolutely unbelievable (in more senses than one!).

          You blatantly misrepresent an article as implying vaccines are “rendered pretty much useless” by variants, when it doesn’t say that at all. And when it’s pointed out, all you can do is repeatedly point the finger at other people, as though that justifies your own dishonesty.

          And now you accuse me of “slinging mud” for setting the record straight. It is quite beyond belief.

          I just wish you would answer the one interesting question about this. What motivates people like you to act in this way? Why do you do it?

          1. Gmac says:

            If vaccines can’t address new variants then it’s back to justify my original statement that raised your ire, yes they are pretty much useless. This is the case with AZ as clinically proven with the SA variant (and I’d be surprised if not the case with P1 also). Other spike targeted vaccines are so similar that I’d reasonably and logically expect them to fail also. I find the notion absurd that a failure to prevent moderate disease will somehow prevent severe disease? How by magic? In any event selection pressure in mass vaccinated populations will cause these and other escape variants to appear. So it looks like a futile exercise to me, expending great energy for what exactly? To start all over again with new variant targeted vaccines? Nice business model but that’s my unbelievable thinking explained.

        2. Chris Phillips says:

          And _still_ you go on with this completely unevidenced anti-vaccine propaganda! Unbelievable.

          Your evidence? Originally – an article that essentially said the opposite of what you claimed.

          And now you claim it’s “clinically proven” that AstraZeneca is “pretty much useless” against the South African variant – on the basis of a sample that is statistically too small to prove anything whatsoever!

          And not content with that, you can’t think of anything that would differentiate any other vaccines from AstraZeneca (apart from the fact that they are so much more efficacious, presumably), so you’d “reasonably and logically expect them to fail also”.

          Are you attempting some kind of reductio ad absurdem of the whole anti-vaccine case?

          I can only say again – please tell us why you are doing this. That would be so much more enlightening that anything you are posting now.

          1. Gmac says:

            I’m clearly delusional. Can you please explain to me why these companies are all developing vaccines targeting variants?

    2. Alex Beribisky says:

      First, there were strong indications during all the vaccine trials that when it comes to cellular (T-cell) response, it is strongly skewed toward a non-VAH/ADE pathway (Th1 vs. Th2, Derek explains it really well in his reviews of the early phases of the trials). Consistent with this data, there were no reports of VAH/ADE so far.

      Second, what is no less (and in my opinion even more) important – every vaccine we have will, with a very high degree of likelihood, protect you from severe disease and death. It is becoming more and more clear that whether you get seriously ill or not is contingent less so on neutralizing antibody activity, but much rather on your T-cell response. Since all vaccines elicit a robust cellular response which we know is longer lived and is less sensitive to viral mutations due to the presence of many more T-cell than antibody binding sites on SARS-CoV-2’s Spike protein, it is safe to say that getting vaccinated will keep people out of the hospital or worse, a key of getting out of this pandemic.

      1. Gmac says:

        And old people have weakened or robust T-cell responses? There are no real clinical data from vaccine vs. variants, except for AZ in a questionable study cohort. Safety is paramount for the industry so these studies should be mandated as part of emergency authorisations.

        1. Alex Beribisky says:

          The T-cell response is robust across all age populations. Check the publication data of any vaccine. As for vaccine performance vs. variant, there is solid Phase 3 J&J data in South Africa. While efficacy against symptomatic Covid is against the South African variant is indeed diminished, protection from severe disease remains the same – very high independent of age, only increasing with time after vaccine administration.

          “The vaccine candidate was 85 percent effective in preventing severe disease across all regions studied, 28 days after vaccination in all adults 18 years and older. Efficacy against severe disease increased over time with no cases in vaccinated participants reported after day 49.”

          https://www.jnj.com/johnson-johnson-announces-single-shot-janssen-covid-19-vaccine-candidate-met-primary-endpoints-in-interim-analysis-of-its-phase-3-ensemble-trial

          1. Gmac says:

            The dangers of press release data! Less than a week ago Moderna and Pfizer were releasing that their vaccines should be effective against SA variant. The Brazilian variant is also already on the scene and can vaccines genuinely be expected to keep up with emerging variants? Short term data looking are looking just fine and I’m not disputing that.

          2. Chris Phillips says:

            “Gmac”

            “The dangers of press release data!”

            I’d rate the dangers of anti-vaxers posting misleading information in online comments rather higher.

            I asked before why people like you do this kind of thing, given the likely cost in human life of anti-vaccine propaganda. You didn’t answer. If only you could explain that, it would be a hundred times more valuable than the rubbish you’re posting.

          3. DataWatcher says:

            @Gmac — I tend to lean strongly toward pessimism, but I agree with @Chris Phillips: Hard-eyed realism is one thing, fear-mongering is another. Right now, it definitely appears as if the vaccines do have some efficacy against mild disease, and very strong efficacy against severe disease and death, for both B.117 and B.1.351 (I’m not familiar with the efficacy data concerning p.1). If you’re advising people to still be careful and maintain public health measures in most public settings even after getting vaccinated, I agree with you. But if you’re suggesting, as you seem to be, that there’s really no reason to even bother getting vaccinated now that the variants are on the march, or even that getting vaccinated might be riskier than not doing so, I think that’s irresponsible in the extreme. Can the vaccines “keep up” with the ongoing evolution of variants? Good question, and I admit I’m deeply concerned about it. For now, though, they definitely seem to be protective, and we should utilize them to the fullest extent possible.

          4. Alex Beribisky says:

            @GMAC Antibodies elicited by the Moderna and Pfizer vaccines ARE effective in neutralizing SARS-CoV-2, albeit at a lower dilution, hence not as efficiently. Again, read the manuscripts, it is all there.

            As for the J&J data, I doubt that what we will see in the publication, would be too different from the press release. This was the case with all the other vaccines.

          5. gabriel says:

            Summary of age-related changes in T cells.

            CD4 T cells
            Reduced TCR signaling intensity
            Reduced expansion in response to TCR stimulation
            Reduced Th1 and Th2 effector differentiation
            Reduced cognate helper function
            Retain the ability to differentiate to Th17

            CD8 T cells
            Reduced TCR repertoire diversity
            Development of clonal expansions
            Reduced antitumor responses

            Regulatory T cells
            Increased numbers
            Retain/gain function with age
            Downregulate antitumor responses
            May contribute to Th17 skewing

  54. Gmac says:

    I thought it sounded very fishy when AZ failure was supposedly addressable by mRNA making essentially the same antigen (differences were discussed here).

  55. gabriel says:

    dear Alex Beribisky -he T-cell response is robust across all age populations???

    1. Alex Beribisky says:

      The T-cell response seems to be independent of participant age, at least with the Moderna vaccine when the higher (the currently used) dosage is administered:

      https://www.nejm.org/doi/full/10.1056/NEJMoa2028436

      Figure 3: In response to S-specific peptide pools, the vaccine elicited a strong CD4 cytokine response involving type 1 helper T (Th1) cells among participants in the two age subgroups who received the 100-μg dose and among participants between the ages of 56 and 70 years who received the 25-μg dose; the tumor necrosis factor α responses were greater than the interleukin-2 responses, which in turn were greater than the interferon-γ responses (Figure 3 and Fig. S13). In the subgroup of participants who received the 25-μg dose, the cytokine response was lower among those who were 71 years of age or older than among those in the other subgroup.

  56. gabriel says:

    https://www.nature.com/articles/s41598-018-28111-8
    Age-related differences in humoral and cellular immune responses after primary immunisation: indications for stratified vaccination schedules

    1. Gmac says:

      Yeah, measured when? Easy to engineer results. How long lasting? What long term effect on reduction in mortality? If we used the metric of dying WITH the ‘flu or common cold (or looked for it) and suffered covid hysteria we’d all have been hiding under rocks decades ago. Can you show me any data supporting a significant reduction in mortality from ‘flu vaccination campaigns? … these have been running for a long time and crunching the numbers doesn’t look all that great. So the basic question is – Are vaccines the answer? In my honest opinion more lives could be saved or prolonged with an effective treatment i.e. that really reduces mortality to an acceptable level – we could then dump the masks, hand washing, quarantines and travels bans (all apparently working exceptionally well?). Many misdirected billions went into vaccines (how are numbers 10-130 going to recruit for trials?). Such a treatment would also be likely to prepare us infinitely better for a more dangerous pandemic, ‘the big one’ as Mike Ryan called it. Assuming that this will be a respiratory virus of course. Could the aberrant immunological response have been unravelled with the money diverted to vaccines? I bet it could have.

  57. Bernd says:

    The Bottom Line
    maybe next time put it up not at the end

  58. Barbara says:

    https://www.timesofisrael.com/study-israeli-anti-covid-nasal-spray-reduced-infection-risk-at-mass-gathering/

    i – just a normal newspaperreader – read all of your enriching and informative comments – thanx so much for your varied discussion

  59. Rob McMillin says:

    Thank you, Derek, for this fabulous material. I am immensely grateful for it.

  60. Med Chem says:

    Dedicated to commenters and repliers primed to “call out” any questioning of perceived mainstream scientific opinion as, “rubbish,” “witless, malicious nonsense,” “beneath contempt,” “denialism,” etcetera, ad hominem ad nauseam…

    …You are a retired, evidence-based medicinal chemist living in the United Kingdom. A few days into a serious viral respiratory epidemic, you begin to suspect The Science and the “scientific evidence,” said by the country’s government to be “driving government policy,” may not be all it’s cracked up to be.

    A year later, to help crystallise thoughts, and by now a recently vaccinated, retired medicinal chemist, you compile an evidence-based questionnaire looking back over the events of the previous twelve months…

    EPIDEMICAL QUESTIONNAIRE

    1) The idea that the four common cold coronaviruses began in the distant past as “flu epidemics” is:

    a) Plausible
    b) Potentially relevant
    c) Rubbish

    https://www.theguardian.com/world/2020/may/31/did-a-coronavirus-cause-the-pandemic-that-killed-queen-victorias-heir

    2) The idea of “prior immunity” is:

    a) Plausible
    b) Potentially relevant
    c) Rubbish

    https://www.bmj.com/content/370/bmj.m3563
    https://www.sciencedirect.com/science/article/pii/S2211124721000413

    3) In response to the preceding linked BMJ article, a British professor of public health wrote on 21 September 2020, “A long series of trials inoculating individuals with a range of viruses, including coronaviruses, and investigating who developed symptoms and became ill, consistently showed increased risk for those who were stressed.[1]”:

    a) Plausible
    b) Potentially relevant
    c) Rubbish

    https://www.bmj.com/content/370/bmj.m3563/rapid-responses

    4) Ref [1] in the preceding linked comment (“The Pittsburgh Common Cold Studies”) is:

    a) Based on extensive investigational data
    b) Potentially relevant
    c) Rubbish

    https://link.springer.com/article/10.1207/s15327558ijbm1203_1

    5) The idea that disease severity broadly correlates with amount and physiological locale of initial viral load is:

    a) Plausible
    b) Potentially relevant
    c) Rubbish

    https://www.nature.com/articles/s41467-020-19057-5

    6) The idea of asymptomatic spread is:

    a) Under-stated
    b) Over-stated
    c) Rubbish

    https://www.nature.com/articles/d41586-020-03141-3

    7) A role for Vitamin D in the human immune response is:

    a) Plausible
    b) Potentially relevant
    c) Unsupported by conclusive evidence

    https://www.thelancet.com/action/showPdf?pii=S2213-8587%2821%2900003-6

    8) A study published in Nature Communications by China- and Western-based academics and public health officials on the Wuhan epidemic of Jan-Apr 2020, reporting, out of a city of ten million, around five thousand deaths and under two hundred thousand cases, is:

    a) Plausible
    b) Implausible
    c) Debatably propaganda

    https://www.nature.com/articles/s41467-020-19802-w
    https://www.medrxiv.org/content/10.1101/2020.05.28.20116012v2.full.pdf

    9) The specificity of SARS-CoV-2 reverse transcriptase polymerase chain reaction testing (“RT-PCR”) is:

    a) Invariably greater than 99% in all laboratories around the world
    b) Illustratively greater than 95.6%, as stated on the Cepheid Xpert Xpress test kit package insert, as per link below (page 11, Table 3)
    c) Conceivably variable from rubbish to over 99%, depending on setting and assay operating characteristics

    https://www.cepheid.com/Package%20Insert%20Files/Xpert%20Xpress%20SARS-CoV-2%20Assay%20ENGLISH%20Package%20Insert%20302-3787%20Rev.%20B.pdf

    10) Plugging 500K swab samples, 50K expected positives, 96% specificity and 82% sensitivity (published value from a study in a community and small hospital setting in the Chicago suburbs) into a RT-PCR testing calculator, published in the BMJ, predicts for:

    a) 40K True positives
    b) 20K False positives
    c) 10K False negatives
    d) 430K True negatives

    https://www.bmj.com/content/369/bmj.m1808/rapid-responses
    https://academic.oup.com/ofid/article/7/8/ofaa315/5876007

    11) The number of amplification cycles (Ct) in SARS-CoV-2 RT-PCR testing that gives a 70% correlation with viral growth in cell culture is reported as:

    a) 25
    b) 35-40
    c) >40

    https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1491/5912603
    https://www.medrxiv.org/content/10.1101/2020.08.04.20167932v4.full.pdf

    12) The maximum number of DNA amplification cycles (Ct) recognised in criminal evidence in a UK court of law is:

    a) 28
    b) 36
    c) Informative or uninformative context for discussing the merits of of mass RT-PCR testing

    https://www.cps.gov.uk/legal-guidance/high-sensitivity-dna-analysis#:~:text=Routinely%2C%2028%20amplification%20cycles%20are,that%20have%20only%20been%20handled

    13) The operational a) specificity, b) Ct cut off value, c) false positive rate, and d) number of replicate determinations for SARS-CoV-2 RT-PCR mass testing across the various UK “community testing pillars” are:

    a) Undisclosed and undisclosable
    b) Undisclosed and undisclosable
    c) Undisclosed and undisclosable
    d) n = 1

    https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/926410/Understanding_Cycle_Threshold__Ct__in_SARS-CoV-2_RT-PCR_.pdf
    https://www.whatdotheyknow.com/request/704591/response/1677888/attach/2/1873%20FOI%20Information%20on%20RT%20PCR%20assays%20used%20by%20PHE%20labs.pdf?cookie_passthrough=1

    14) The percentage of “first wave” deaths in the UK attributable to infection acquired in a hospital or care home is reported to be:

    a) Less than 20%
    b) 20-30%
    c) More than 30%

    https://www.telegraph.co.uk/news/2021/02/12/40-per-cent-first-wave-covid-cases-could-have-caught-hospitals/

    15) Major influences on the course of the UK’s viral respiratory epidemic, that started in earnest in March 2020, may include:

    a) Massive and irrevocable viral seeding by numerous index cases entering the UK from late January 2020 to mid March 2020, before introduction of any restrictive measures
    b) Viral spread in hospitals and care homes, and by hospital and care home staff
    c) Adherence to social distancing restrictions, guidelines and laws
    d) Any number of inadequately understood local and national variables

    https://www.bbc.co.uk/news/health-54976192

    16) In front of a House of Commons standing committee on 17 March 2020, the number of deaths anticipated to constitute a “good outcome… but still horrible” by the UK government’s Chief Scientific Advisor, was by stated as:

    a) Less than 20,000
    b) 20,000
    c) More than 20,000

    https://www.youtube.com/watch?v=jGOuvXHsboE

    17) As of 17 February 2021, the number of deaths recorded in the UK within 28 days of a positive test for the SARS-CoV-2 virus is:

    a) Less than 118,933
    b) 118,933
    c) More than 118,933

    https://coronavirus.data.gov.uk/details/deaths

    18) The UK Department of Health and Social Security’s “Coronavirus Action Plan,” published on 3 March 2020, was broadly followed for:

    a) The duration of the viral respiratory epidemic
    b) The next 3 months
    c) Two weeks up to 16 March 2020

    https://www.gov.uk/government/publications/coronavirus-action-plan/coronavirus-action-plan-a-guide-to-what-you-can-expect-across-the-uk

    19) The preceding linked Coronavirus Action Plan informed the British public that:

    a) “The UK is well prepared for disease outbreaks… having undertaken significant preparedness work for an influenza pandemic for well over one decade”
    b) “System-wide response plans for pandemic influenza, focused on the continuity of public and critical services and the stability of the economy, have been adapted for COVID-19…”
    c) “Once a case has been detected, our public health agencies use tried and tested procedures for rapid tracing, monitoring and isolation of close contacts, with the aim of preventing further spread”

    20) The seminal internally peer reviewed publication, released on 16 March 2020, and originating from the Imperial College COVID-19 Response Team, part of the WHO Collaborating Centre for Infectious Disease Modelling, the MRC Centre for Global Infectious Disease Analysis, and the Abdul Latif Jameel Institute for Disease and Emergency Analytics…

    …that forecast up to 500,000 deaths in the UK, includes in the main body of the publication the word “assume” (or derivative thereof):

    a) Less than 10 times
    b) 10-40 times
    c) More than 40 times

    https://www.imperial.ac.uk/media/imperial-college/medicine/sph/ide/gida-fellowships/Imperial-College-COVID19-NPI-modelling-16-03-2020.pdf

    21) The preceding internally peer reviewed publication specifically assumed:

    a) An immunologically naïve population with no “prior immunity” whatsoever
    b) “Approximately one third of transmission occurs in the household, one third in schools and workplaces and the remaining third in the community” (yet made no assumptions about transmission in hospitals and care homes)
    c) “The impact of five different non-pharmaceutical interventions… using plausible and largely conservative (i.e. pessimistic) assumptions…”
    d) “Social distancing (plus school and university closure, if used) need to be in force for the majority of the 2 years of the simulation…”

    22) The decision to divert from a pre-existing, thought through action plan, in favour of an off the cuff plan involving unprecedented, untested and unproven restrictive measures, that included school, leisure and extensive workplace closures, was:

    a) Correct
    b) Debatable
    c) Unwise
    d) Arguably betrayal of an unspoken “Hippocratic Oath of Government” to act in the best interests of as many of the country’s 67 million residents as humanly possible

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482690/

    23) The consequences of restrictive measures have been:

    a) Economically negative
    b) Educationally negative
    c) Socially negative
    d) Sportingly negative
    e) Summed up as, “A pantomime of scientists against business”

    https://www.bbc.co.uk/news/uk-56137815

    24) The UK Conservative government has responded to a request made in the House of Commons on 2 November 2020 by the Chairman of the Conservative Party 1922 Committee to, “Publish a full impact assessment, setting out the cost of the lockdown in terms of the jobs that will be lost, the businesses that will fail, the enormous toll on people’s mental health and other aspects of their health…” by:

    a) Compiling a “balance sheet”
    b) Not compiling a balance sheet
    c) The current democratically elected UK government will never compile a balance sheet

    https://www.theyworkforyou.com/debates/?id=2020-11-02c.24.0&s=graham+brady#g35.1

    25) Police officers wearing face masks dispersing British citizens sledging outdoors down snow-covered hillsides in North East England on 11 February 2021 was:

    a) Necessary to safeguard police officers and the general public
    b) A political statement
    c) State sponsored killjoying

    https://www.bbc.co.uk/news/uk-england-56039285

    26) The Prime Minister’s remark to the House of Commons on 2 July 2020 that a cricket ball is a “natural vector of disease,” and that the start of the 2020 English club cricket season should therefore be further delayed for the first time in two centuries, a feat never managed by Weather, Act of God, Kaiser, Fuhrer or Foot & Mouth, was:

    a) Correct
    b) Later disproven by a scientific study
    c) Emblematic of a wider state-sponsored vandalism of youth and grassroots sport by a government devoid of sportspersons, good sports and sporting instincts

    @1 m 15 secs: https://www.youtube.com/watch?v=44dyvfrknEs
    https://www.medrxiv.org/content/10.1101/2021.02.04.21251127v1

    27) The UK government slogan, “Stay Home, Save Lives, Protect the NHS” is, along with, “Control the Virus”:

    a) Fundamentally sound
    b) A sound bite
    c) State sponsored non-sequituring

    https://www.bmj.com/content/369/bmj.m1917/rr

    28) Police arresting British citizens protesting, predominantly peacefully, against UK coronavirus laws, for violating coronavirus laws, is:

    a) Justified in the interest of public health and safety
    b) Applying the letter of the law
    c) State sponsored Catch 22

    https://www.bbc.co.uk/news/uk-england-london-55116470

    29) In a Good Morning Britain interview on 22 October 2020, Barnsley pensioner and former local parish councillor Maureen Eames said, “I’m not going to stay at home… I didn’t vote for scientists… The young people are going to have to pay for this.”

    While husband Michael said, “People think this is something new. Look, I’ve gone through six pandemics, and the only difference between this and the others is government interference…”

    a) Agree
    b) Disagree
    c) Anecdotal rubbish

    @ 2 m 50 secs & 3 m 35 secs:
    https://www.youtube.com/watch?v=aEC1YOJSyng

    30) Forward looking and innovative science is better served by an open and questioning society, in which scientific truth is sought independently of excessive government and vested-interest intervention:

    a) Agree
    b) Disagree
    c) Idealistic rubbish

    https://www.bmj.com/content/371/bmj.m4425

    31) The early 2020s vaguely resemble historical accounts of 1650s England, an era of superstition, heresy, cancellation of Christmas, and an era that preceded the forthcoming eras of the satirists Defoe, Swift and the age of reason:

    a) Agree
    b) Disagree
    c) Historical and literary rubbish

    https://www.nationalarchives.gov.uk/education/resources/christmas-is-cancelled/

    32) Reduction in CO2 emissions due to drastic reductions in aviation and other travel during the pandemic provides a model for targeted governmental intervention directed at the issue of energy consumption and climate change:

    a) Agree
    b) Disagree
    c) Eco-politics rubbish

    https://www.nature.com/articles/s41558-020-0797-x.pdf

    33) The version of the musical item linked below is:

    a) Born in the USA and played in the UK
    b) A piece of music loosely derived from a song written in 1852, said to be prescient of the American Civil War
    c) Musical rubbish

    https://www.youtube.com/watch?v=Fw-b0OeI3QY

    (but don’t assign much credence if a visarge bloke comes on strong in the ad afterwards, or for that matter in an ad beforehand, or indeed in any ad anywhere…)

    34) Doing nothing can, on occasion, be preferable to DOING SOMETHING

    a) Agree
    b) Disagree
    c) Blarney rubbish

    http://www.irisheconomy.ie/index.php/2010/03/01/the-economics-of-something-must-be-done/

    35) Unthinking respect for authority is the greatest enemy of truth

    a) Agree
    b) Disagree
    c) Philosophical rubbish

    …Cheer up! Soon be another cricket season, plus or minus natural vector of disease:

    There’s a breathless hush in the Close to-night —
    Ten to make and the match to win —
    A bumping pitch and a blinding light,
    An hour to play and the last man in.
    And it’s not for the sake of a ribboned coat,
    Or the selfish hope of a season’s fame,
    But his Captain’s hand on his shoulder smote —
    ‘Play up! play up! and play the game!’

    1. Mark E Shulgasser says:

      Too bad you don’t make your points directly. No one is going to go through this rigamarole.

      1. Med Chem says:

        @ Mark E Shulgasser: Thank you for feedback. Loads of specific points posted (and emailed) elsewhere. Example included here, scrolling down to “I’M PUZZLED TOO…”

        https://blogs.sciencemag.org/pipeline/archives/2021/01/25/vaccine-roundup-merck-wipes-out-and-more#comment-337039

        …More rigamarole I’m afraid. Storming mysterious barricades never was forte of this old timer, nowadays long resident in scientific wilderness of own choosing.

        How to get a message across? Maybe try a different medium? Like medium of Edgar Darby, Billy Pilgrim and any number of other characters? Arguably tried that out for size already using this blog’s reply option?

        Perhaps ideas will somehow spread, akin to how a virus reputedly did from humble beginnings in a bat cave? Although I doubt it. If nothing else, reading, inwardly digesting and replying keeps an old timer’s mind active.

  61. Pablo Lopez says:

    I haven´t read all comments so sorry if I repeat this question:

    I don`t see in your article the reasons you get so many queries about ADE.
    I will tell you why I searched for it and ended up here:

    Since vaccination started in Spain (Pfizer) there have been many care homes for old age people which never had a single case of covid since the pandemic started and now they are seeing cases appear after vaccination, either asymptomatic positive PCR results, symptoms and even deaths. There is a twitter user who is monitoring these cases in local press and she has already found around 140 care homes so far where this is happening. The typical comment in these care homes is “its such a pity because we were doing so well”.

    So I wondered what was happening. The standard explanation is that it is just coincidence and “third wave” in action. But these care homes passed through the first and second waves with no cases. Thats probably because since the start of the pandemic they have become bunkers with super security. So when I heard about ADE I thought I found an explanation. But you say there’s no indication this is happening. And since there is already an explanation for it and no indication anywhere that a possible ADE effect is being investigated, people then naturally suspect. That is the reason, I believe, ADE is being talked about extensively in social media.

    So my question is, what do you think is the reason for this? The third wave?

    Thanks so much in advance

    1. Med Chem says:

      Only came across your query yesterday. An earlier commenter has posted a link to a letter dated 5 Feb 2021 to the UK’s Minister for Covid-19 Vaccine Deployment, Secretary of State for Health and Social Care, Medicines & Healthcare products Regulatory Agency (MHRA) and Joint Committee on Vaccination and Immunisation (JCVI). The UK’s Prime Minister is ccd on the letter. Link to letter here:

      https://blogs.sciencemag.org/pipeline/archives/2021/02/12/antibody-dependent-enhancement-and-the-coronavirus-vaccines#comment-338580

      The letter conveys to the UK government concerns around, “the impact of Covid-19 vaccines on the very elderly and those in care homes.” May have some bearing on your summary of recent observations in Spanish Care Homes.

      Minutes of the UK’s Joint Committee on Vaccination and Immunisation are available on the JCVI website. Last available minutes uploaded 10 Feb 2021 are from meeting held 29 Dec 2020.

      Vaccination widely considered UK success story, which it is thanks to Oxford University, AstraZeneca and government funding and commitment. Call me cynical, but ministerial recipients vested interest in advising MHRA and JCVI to sit on this one until Official Governmental Epidemical Exit Strategy fully executed.

      In the meantime, any binary thinkers adding one and one might conceivably want to make one and zero, subject to cognitive bias and/or inclination.

      1. Chris Phillips says:

        “Link to letter here”

        No bit of anti-vaccine propaganda is too crazy to give another push to, apparently.

        1. Med Chem says:

          True to form, C Phillips can always be relied upon to lead from the front, mount the flak plate himself in person and fire off the anti-anti aircraft gun. Yes, My Leader.

          Instead of the pre-judgemental, let’s leave Sr Lopez who posed the question (and the JCVI whose job it is) to take a look at the evidence for himself and reach his own conclusion.

          Maybe my memory’s playing tricks. That brief comment a few weeks ago, those throw away lines about turning down the flu jab and avoiding humanity so as not to catch covid. Perhaps that was a different commenter? Must track down comment when time permits.

          Meanwhile, at least I’ve had the decency to have my annual flu jab, and my first covid jab too. Very appreciative of the local surgery both times. Thank you to all concerned for doing the business with spectacular efficiency in difficult circumstances. Ditto the Oxford Group, AstraZeneca, GOV.UK and the Civil Service. Makes me proud to be British.

  62. Eric says:

    I spent quite few years working on dengue ADE. I tried to build a dengue mouse model using wild-type mouse by mixing anti-dengue antibody with virus particles before infecting mice. In my hand, I could only observe ADE with lower concentration of antibody. Too much antibody then I can not see ADE.
    For people with less experience in ADE, it’s easy to think when you don’t see ADE NOW, you won’t see ADE in the FUTURE. Philippine actually realized there is ADE from dengue vaccine after 3 years.
    For COVID vaccine, I’d suggest setting up an animal study with serial diluted vaccines and longer observation time to observe whether weaker immune response or waned antibody would elicit ADE.

    1. NewsView says:

      @Eric

      I think you make an absolutely key point about the nature of ADE. It’s one thing to vaccinate for immunity that may be life long (many childhood vaccinations for example). It’s another thing to vaccinate on a seasonal basis for temporary immunity to respiratory illnesses, which also introduces the possibility of “virus interference” (increased susceptibility to other illnesses):

      https://pubmed.ncbi.nlm.nih.gov/31607599/

    2. Doug H MD says:

      “For COVID vaccine, I’d suggest setting up an animal study with serial diluted vaccines and longer observation time to observe whether weaker immune response or waned antibody would elicit ADE”
      Can anyone say if this has been done or not? I could not find the studies…

  63. Jill-bean says:

    Please forgive me if you have covered this previously. You mentioned in your article: “Antibody-dependent enhancement was specifically tested for in the animal models as these candidates were being developed (re-exposure of vaccinated animals to coronavirus to see how protective the vaccine was). And no cases of more severe disease were seen – I’ve gone back through the reported preclinical studies, and I don’t think I’ve missed one, and what I’m seeing is not one single case of ADE for any of them.” That is good news, but I wondered if you would be able to demonstrate this with some (lay-person friendly) details/data/results?
    Thank you for your time.

    1. Derek Lowe says:

      Here’s the key part, now that we have millions of people vaccinated. Remember, what you want is that if a person is vaccinated and then gets re-exposed to the virus, they’re either protected completely (to where they don’t get any disease at all) or partially (where they just have much milder symptoms). If ADE is happening, though, then re-infection leads to *more severe disease* than ever, which is of course the opposite of what you want to see.

      So, in the statistics from the countries with the most vaccinations so far (Israel, the UK, and the US), are we seeing this? Severe infections in people who’ve been vaccinated? No – we’re seeing the exact opposite. Cases as a whole dive in the vaccinated cohorts, and severity of disease dives, too, among the increasingly smaller fraction that show any disease at all. In particular, severe disease, hospitalization, and death from the coronavirus go down tremendously. I’ll be glad to talk about the preclinical studies and the earlier trials if you’d like, but I think that this real-world data makes the most convincing case of all. Antibody-dependent enhancement simply does not appear to be happening.

      1. Adam says:

        The key here, though, is time. ADE only appears once antibodies have dropped below a certain level. In the case of the covid vaccines, we know antibodies remain neutralizing for at least 6 months. Only the people in the first clinical trials have had the vaccine for more than 6 months. Most people have been vaccinated within the past 4 months. It could take 2 years before antibodies fall to a level where ADE could be observed. There is also the matter of future strains of this virus evolving to use antibodies to its favor. I think the most prudent statement we can make about covid and ADE is that there simply hasn’t been enough time to know anything for certain.

  64. M Zend says:

    To see ADE, you need the neutralizing Ab levels to have dropped to a certain ratio below the total Ab, and there has not been sufficient time yet for the window in which this would be observed, since we know this ratio for Moderna and Pfizer is at least to six months for phase 1 bleed data. We are not a year out even from the first Phase 1 groups for any vaccine, and its possible that you need at least 2 years or longer- whatever the rate of neutralizing Ab decline is in a person. There has not been time, for bulk of immunized folks on the ADE question, but, interestingly, cases of those dying after dose 1 of vaccines, before ability to get dose 2, have been reported in different countries, including Israel. I think it is way too early to claim ADE isn’t an issue with this virus. Even the animal study re-challenges did not wait for a sufficient reduction in neutralizing antibody. We need to start measuring neutralizing and total Ab titers post vaccination, so we can be ready, in case we find a shift in deaths in vaccinated folks around this time next year and beyond.

  65. Jill-bean says:

    Thank you both of you for your helpful replies!

    Mr. Lowe, that is great to hear that there does not appear to be any ADE happening in post-vaccination people so far!
    I do appreciate your offer to address my original question about the preclinical studies and earlier trials. If you wouldn’t mind, any details/data/results (or just links to pertinent web pages) from them that you could share with me would be valued.

    MZend, you raise a good point about how long we need to wait to reach a level of confidence that the Covid vaccines will not generate ADE. I have been struggling with that. You seem to know quite a bit on this topic also. If there is any further information or sources you can provide regarding your statement about having to wait at least six months-two years to confirm this, could you please provide this?

    Thank you! 🙂

  66. gabriel says:

    I agree with us you suspiciously that in Israel the health insurance funds have limited the ability to measure the value of antibodies, but they propose to make additional doses to everyone vaccinated after 6 months .. in other words, apparently the pgfiser knowing about the drop in antibodies, is trying to prevent the appearance of hell by raising antibodies at the expense of an additional dose, it means that the vaccinated must receive a new dose all the time, does it not say that the MRnI vaccine does not give cellular tissue immunity ??… it turns out that those who have been ill naturally will have natural immunity and maintain it due to cellular immunity, and those who were vaccinated with unnecessary lymphocytic ??that is, pfizer is not a vaccine but a kind of drug imposing its use and creating a vital necessity for its use??(otherwise the minimum lack of cellular immunity is the maximum wade ??)I think that up to 70 years old, lymphocytic immunity is not needed at all Who got sick
    and what that got vaccinated? (otherwise, at least the lack of cellular immunity – maksimum vade ??) I do not understand why give pfaise to young, healthy people ?? why children ?? I think pfaizer was needed only after 70 years or at most risk groups before the invention of the present vaccine that gives full-fledged tissue immunity .. fed on making a t cell immunity test – it is impossible no one does

  67. gabriel says:

    thanks for the article, but there is a discrepancy .. the article was published on September 30, 2020, the beginning of research in modernity and pfaizer on July 28, so in 2 months the company had answers about vade and long-term cellular response ?? is this an anecdote ??

    1. stewart says:

      Your date for the start of research is incorrect. The results of the Pfizer/BioNTech phase I/II trials were published on August 12th. There was a press release about them on July 1st, when they had been in progress for at least 28 days. It looks as if research in human subjects started sometime in May.

  68. gabriel says:

    On May 18, Moderna issued a press release trumpeting “positive interim clinical data.” The firm said its vaccine had generated neutralizing antibodies in the first eight volunteers in the early-phase study, a tiny sample.
    Moderna was the first drug maker to deliver a potential vaccine for clinical trials. Soon, its vaccine became the first to undergo testing on humans, in a small early-stage trial. And on July 28, it became the first to start getting tested in a late-stage trial in a scene that reflected the firm’s receptiveness to press coverage.

  69. Swedina says:

    I do not understand why so much emphasis is being placed on a vaccine we have very little long-term data on, when we could all easily wear N95 surgical masks, distance, and isolate to get rid of the virus in a short period of time. That’s what Asian countries did effectively with previous virus epidemics. Why aren’t we learning from their experiences?

    1. Chris Phillips says:

      You mean like we easily got rid of it in a short time last year?

      1. John Titor says:

        You mean 2020 when anti-mask protests were taking place all over the world and the US President was holding super-spreader rallies?

  70. Swedina says:

    In my comment above, I am referring to the emergency use of vaccines whereby minimal testing is done prior to vaccine administration. Of course, vaccines are important but we need to test long-term efficacy and safety prior to administering them to the worldwide population. By rushing, we could easily be creating an entirely new future global health crisis, possibly a permanent one.

    1. matt says:

      Tens of thousands of people have had both doses for more than six months by now. As time goes on, the likelihood of some widespread horrible side effect decreases dramatically–in fact, the vaccine just becomes an immune system memory within a few months. After 85 million people have had doses with very few extreme adverse events in the short term, the likelihood of longer term harm is greatly diminished. And, in this case, especially because this is an RNA virus, that unlike other viruses does not appear to infect and hide in immune system cells like HIV or even chicken pox /shingles.

      It’s always possible some not-yet-seen danger lurks, but in the meantime, a very real and fatal danger is seen all around us. Delaying an intervention that will save tens of thousands or hundreds of thousands of lives, on the shadowy fear that some unknown thing might possibly happen, is not supported by sound reasoning.

      On the other hand, if this fear is paralyzing you, you can wait and be one of the last to get a vaccine. You could read very carefully the prior coverage here and pick one of the vaccines that has a long history of usage for other diseases, like the attenuated or inactivated virus vaccines. Or wait for the Novavax vaccine, using protein, which is widely used for other medicines. Or travel to some other country that is slow to roll out the vaccine, and give yourself a few more months.

      Is there some date at which you think your fears will be invalidated, or do you think you will continually want at least six months to a year more, just to be extra extra sure it’s okay? Would you feel more comfortable taking a vaccine if you knew the timeline since early trials was about the same as past vaccines like polio or measles? Meaning, if it took them a year to go from first-in-humans to widespread rollout, would you be comfortable taking this vaccine at the one-year mark, reasoning it had as much testing as those vaccines? Or would you still be uncomfortable?

  71. kontoller says:

    But all the same, apart from good wishes, what is the belief in the absence of ade based on, after all, 6 months have not passed after the mass vaccinations and no one has checked what happens after the fall in the amount of antibodies, is it really an unfounded come on, or is someone interested so as not to focus attention? ?

  72. kontoller says:

    in Israel, vaccination began in December, about 4,000,000 were fully vaccinated, all the time they want to give one more vaccination after 6 months sounds so that someone does not want it to be seen what happens after a drop in the amount of antibodies, in general, the testing of antibodies after vaccination has been limited… all vaccination data are closed for 30 years, why ?? who are tens of thousands??

  73. Jill-bean says:

    This is a re-post from March 12th.
    Would dearly love to hear back from both DEREK LOWE AND M ZEND!
    _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

    Thank you both of you for your helpful replies!

    Mr. Lowe, that is great to hear that there does not appear to be any ADE happening in post-vaccination people so far!
    I do appreciate your offer to address my original question about the preclinical studies and earlier trials. If you wouldn’t mind, any details/data/results (or just links to pertinent web pages) from them that you could share with me would be valued.

    MZend, you raise a good point about how long we need to wait to reach a level of confidence that the Covid vaccines will not generate ADE. I have been struggling with that. You seem to know quite a bit on this topic also. If there is any further information or sources you can provide regarding your statement about having to wait at least six months-two years to confirm this, could you please provide this?

    Thank you! 🙂

  74. Peter Olins says:

    There have been a few examples suggesting increased disease severity after re-infection (or possibly relapse):

    https://www.cdc.gov/mmwr/volumes/70/wr/mm7008a3.htm
    https://www.sciencedirect.com/science/article/pii/S0163445321000438
    http://www.rimed.org/rimedicaljournal/2020/12/2020-12-24-extra-case-selvaraj.pdf
    https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30764-7/fulltext

    However, it’s not clear to me if these are simply examples of the natural variation in levels of symptoms seen with covid-19 (i.e. not specifically related to reinfection): the vast majority of reinfection events may have been mild, and therefore not recorded.

    Conversely, it also seems conceivable that some cases of severe covid-19 may actually be examples of re-infection, with the first infection being undiagnosed.

    (As always, Derek, an excellent article. Thanks.)

  75. Jill-bean says:

    Thank you, Kontoller for these links!

  76. lightning detector says:

    Is there any reason to think that mRNA vaccines are more or less likely to provoke ADE than other types, such as AstraZenica?

  77. lightning detector says:

    I am a 75 year old resident of Ontario, Canada. It is expected that within a couple of weeks, by early April, I will have a vaccine, probably Pfizer, available to me. I will have a decision to make: Should I take it? Until recently I did not realize that this issue was so controversial, and created so much negative comment.

    I think Derek Lowe is right that there is no indication yet of ADE in COVID-19 vaccines, that vaccines reduce the disease, and that a prudent person might accept a vaccine for himself.

    There is real world evidence for this. I will refer to two situations: 1) Israel, and 2) nursing homes in Ontario. Both of these had severe outbreaks in January but are much improved now in March after mass vaccinations. Israel has both old and young people while the nursing homes host old and vulnerable people. Both have trouble enforcing precautions (distancing, etc.). Both used mainly mRNA vaccines. The severe outbreaks mean that there must have been many exposures of vaccinated people to infected people, which would reveal any ADE threat.

    In Israel there were 100,000 cases and 770 deaths in a population of 9.2 million for the 2 week period ending January 28. This has decreased by about 3/4, to 27,000 cases and 200 deaths, for the 2 weeks ending March 20, and continues to decrease. Comments from Israel suggest that it is rare for a person who has 2 vaccine doses to become seriously ill. (Source: Wikipedia “COVID-19 pandemic in Israel”)

    In the Ontario Long Term Care (nursing) homes (about 77,000 residents) there were about 1350 cases and 400 deaths of residents during the 2 weeks ending January 30. For the 2 weeks ending March 19 this is down to about 30 cases and 14 deaths. News reports here in Ontario suggest that there is no serious vaccine problem except for impatience for more doses. (Source: Ontario Government website: COVID-19 update – data and details – archived daily epidemiologic summaries)

  78. kontoller says:

    the impression is that no one has read that the drop in the level of antibodies and the beginning of a possible vade 6 months after the second injection, as declare the conclusion when in Israel 3 months have passed since the beginning of vaccinations !! the impression that some are traveling in time or wishful thinking, the only group that at this stage can fearlessly vaccinate over 70 years due to a significant decrease in cellular immunity

  79. kontroller says:

    the Israeli Ministry of Health insists on extending the validity of green passports for at least 3 months, and is also going to conduct a large-scale serological study in order to find out the level of immunity in citizens after vaccination.
    This will allow us to find out if and when the third COVID-19 vaccination will be needed.
    what is such a statement for ??
    Has anyone, AFTER INFLUENZA VACCINATION, TRIED AN ANTIBODY CHECK TO GET AN ADDITIONAL VACCINATION?
    Does this not say that this Jacobi vaccine works only at the lymphocytic level and not at the cellular level ??
    does it say that they are afraid of the appearance of vade after the fall of antibodies ??
    Besides
    Representatives of the Ministry of Health appealed to the government with a request to allocate an additional 7 billion shekels for the purchase of additional batches of vaccines from COVID-19.
    It is noted that an urgent meeting on this issue was supposed to take place today, but it was postponed to Monday in connection with the demand of the head of the Ministry of Defense Benny Gantz to explain the need to allocate such a large amount in conditions when more than half of the population has already been vaccinated against COVID-19, and the available stocks of vaccines enough. Reported by The Times Of Israel.
    At the same time, the Ministry of Health demanded that members of the government sign under the obligation not to publicly disclose the allocation of this amount.
    your thoughts gentlemen scientists

  80. Patricia says:

    The thing is, nobody knows what happens inside a human body when it comes to immune reactions because each person has a unique immune system. All scientists can do is work with high numbers and average responses. The ADE phenomenon can and probably is happening in someone somewhere but this means nothing when we’re dealing with a pandemic infection. Biology is not an exact science as much as people want it to be, it doesn’t work like that. Evolution is the branch of Biology that can almost be regarded as an exact science because it deals with large numbers of individuals and time. One of the key features of the immune system is to be highly variable so some of the individuals will always escape from an specific infection and guarantee the survival of the species. Vaccines mimic the natural process of infection (with artificial enhancement) but the immune response is still subjected to Nature’s Laws.

    1. Peter says:

      Exact! The only working antivirus concept is the human immune system.

  81. Tim says:

    The only thing that can be concluded from this article is that although there are currently no problems, we do not know what problems might occur in the mid, or long term.

    1. Caroline Dale says:

      I have reached the same conclusion. Based on the data I have been able to obtain and verify, along with the inadequacy of the preclinical trials regarding the potential risk of ADE, I do not feel confident that certain concerns have been adequately reviewed. The lack of data regarding the reinfection of the same pathogen or exposure to a similar pathogen, is particularly concerning, as it means we have no accurate data focusing on the risks of ADE over a period of time. To summarize, we cannot be confident that the immune system will respond in the desired way when later exposed to the strains of the virus that are associated with the original virus of which the vaccines were developed.

  82. Justin Ward says:

    There is some anecdotal evidence of second infections being worse than the first in South Africa. My initial feeling was that this is impossible but now maybe not?

  83. Bob says:

    “The short answers: they did not. ”

    That links goes to the 2006 report of SARS-Cov-1 you fucking shill

  84. kontoller says:

    Could it be that the virus itself produces antibodies at the cell level in those who have been ill, which recognize not only the spike, but also other landmarks on the virus and then give the order to attack, and after receiving the vaccine we will attack in an inadequate measure everything that has spike on the TB cellular level ?? and cause a severe prophylactic response to other non-pathogenic corona viruses in normal life ?? even the usual flu ?? it will be a disaster, it is known that if one dominant population (virus, bacterium) leaves, another comes in its place

  85. kontoller says:

    Could it be that the virus itself produces antibodies at the cell level in those who have been ill, which recognize not only the spike, but also other landmarks on the virus and then give the order to attack, and after receiving the vaccine we will attack in an inadequate measure everything that has spike on the T,B cellular level ?? and cause a severe anaphylactic response to other non-pathogenic corona viruses in normal life ?? even the usual flu ?? it will be a disaster, it is known that if one dominant population (virus, bacterium) leaves, another comes in its place..the answer will probably be a vaccine based on an inactivated virus, if it can be made with 70 percent effectiveness … 95 percent efficiency and a higher bluff vaccinated about 30 percent of those who were ill

    1. Derek Lowe says:

      The flu isn’t a coronavirus. Note that prior infection with common-cold coronaviruses doesn’t seem to provide much (if any) protection from SARS-CoV-2, so vaccination against it is very unlikely to have consequences with later exposure to them. I believe your worries are unfounded.

  86. jeff says:

    Funny how we make canned statements like follow or trust the science. Yet, isn’t easy to ignore the science of purposefully making people sick with modern processed foods that make them the highest risk for ending up in the ICU. I don’t trust science and their research cause ya know, one thing you can count on is follow the money

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