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Antibody-Dependent Enhancement

I’ve had several questions about antibody-dependent enhancement, which has always been a worry as the coronavirus vaccines have been developed. I figured it might be worth a look at just what we know about it, why one might be worried, and why (on the other hand) one might be hopeful.

The simple definition of ADE is “raising antibodies that don’t protect, but actually make a viral infection even worse”. And obviously, that’s the opposite of what you want. Remember that there are “neutralizing” antibodies as opposed to non-neutralizing ones – a neutralizing antibody, as the name implies, binds to its target in a way that shuts its function down. That’s generally done by blocking the “business end” of a given protein target, smothering the binding surface that it would need to do its usual job. For the coronavirus, a straightforward example of a neutralizing antibody would be on that binds to the tip of the Spike protein, the receptor-binding domain (RBD) that is the part that recognizes and binds to the human ACE2 protein on a cell surface. Block that thoroughly enough, and it would seem that you have blocked the virus’s ability to infect your cells.

There are other ways, as this blog post earlier this year makes clear (or tries to!) You don’t have to just completely cap the end of the Spike protein to shut it down – as it turns out, you can bind an antibody further down the Spike and have it be neutralizing, just so long as it interferes with the structural changes that the Spike protein needs to undergo when it starts binding to a human cell membrane. There’s a whole subunit of the Spike (S2) that is involved in the membrane-fusion step, so throwing a wrench into that will work for you, too. Proteins make all sorts of adjustments as they fit to each other: this part has to shift down and over, that bond has to rotate, and some of those adjustments may be non-negotiable (and thus targets for blocking the whole process).

So there are plenty of ways to get neutralizing antibodies, with various ways of binding to the Spike protein and in binding to other coronavirus proteins as well. But there are also plenty of ways to get non-neutralizing antibodies, ones that stick to some part of the coronavirus particle without really inconveniencing it much. That’s obviously useless, and antibody-dependent enhancement takes things down another notch, from useless to outright harmful. With ADE, the binding of such an antibody actually assists the virus, by (for example) actually making it easier for the virus to get taken up through the outer membranes of human cells. Another possibility is that an antibody that would be neutralizing if present in sufficient amounts can actually enhance infection in lower dilutions, which has been seen with influenza antibodies and other viruses as well. This seems to be through aggregation of viral particles, although other factors might be at work.

You really don’t want ADE through any of these mechanisms – bad things happen. Dengue fever is a classic example, because it infects humans through four distinct serotypes. If you are infected with one of these and raise a successful immune response, you may well be at increased risk of serious infection with one of the other serotypes. The neutralizing antibodies for one of the types are often not neutralizing for the others, but instead allow that cell-antibody-receptor mechanism to kick in (easier infection of human monocytes), known as “extrinsic ADE”. There’s also an “intrinsic ADE” seen with dengue, which leads to greater viral replication inside infected monocyte cells before they burst and release their contents. The mechanisms for that are still being worked out, but seem to involve suppression of cytokine pathways.

ADE has been seen with HIV infection (where it may be mediated by one of the complement pathways, which kicks in after an antibody binds to its target), with Ebola (where a completely different complement-driven mechanism seems to be operating), with coxsackievirus (and other picornaviruses), and in many others. It should be noted that inappropriate complement activation can cause troubles of its own, which can contribute to the severity of ADE-driven disease – this is particularly noticeable in respiratory viruses (influenza and others) and their effects in the lungs.

Evolutionarily, you’d figure that developing such things would be under positive selection pressure: higher organisms are constantly fighting off viral infections by raising antibodies to them, so something that causes this to backfire would probably be an advantage for any virus that hits on such a mechanism. So ADE is not some weirdo exception in viral infections, unfortunately – it’s pretty widespread.

And in the same way that viral infections can involve ADE, so can the antibody responses raised by vaccines. There was an inactivated-virus vaccine tried in the 1960s against RSV (respiratory syncitial virus) that in human trials actually caused infants to come down with worse cases of RSV. This effect has been duplicated with RSV in cell cultures and in primate models, and one hypothesis has been that (as with the extrinsic-ADE of dengue), the exposed regions of the antibodies bound to the viral particles bind in turn to receptors on human cell surfaces, and allow them to be taken into the cell more directly. A 1960s inactivated measles vaccine candidate showed similar effects.

Here’s a recent paper taking all this into the context of the current pandemic. And since this post up until now has been rather gloomy, you’ll be glad to hear that the news starts to improve at this point. For one thing, the current coronavirus does not seem to productively infect macrophages, which are by far the main target for that antibody-receptor-uptake ADE mechanism. The related MERS coronavirus was able to do this, but not SARS-CoV-2, fortunately. So the two mechanisms seen in (for example) dengue do not seem to be as much of a worry. The complement-driven stuff is still on the table, though, and indeed matches up well with the “cytokine storm” lung damage seen in severe patients.

But as that new paper says, thus far “No definitive role for ADE in human coronavirus diseases has been established.” That may be a bit surprising, if you’ve been seeing worried stories about antibody-dependent enhancement over the last few months. That doesn’t mean that ADE can’t be operating, of course, just that we don’t have the solid evidence that it is. Another surprise in that line: there’s been a lot of talk about a possible protective effect of prior infection with the other respiratory coronaviruses. Well, there’s a flip side: antibodies raised against those could potentially make SARS-CoV-2 infection worse through ADE, if they’re non-neutralizing.

Now, there have been worries about ADE with coronavirus vaccines as well. This is another case where having all the work done against the 2003 SARS epidemic has paid big dividends this year. Some of the earlier attempts at a SARS vaccine showed ADE effects in mouse models, and further work showed that this seemed to be linked not so much to the antibody response as to the T cell response. Specifically, a “Th2” heavy response (as opposed to more Th1 or a balance between the two), was linked to lung pathology. Those are subdivisions of the CD4+ T cells, based on which cytokines they produce, and these results alerted everyone to keep an eye out for that. Mouse immunogenicity studies with the current vaccine candidates did not show these effects.

In primate models, there were reports on the earlier SARS front like this one: four different peptides as vaccine candidates, three of which seemed to generate protective responses and one of which made things worse. But that also reminded everyone to watch carefully, and it has to be noted that the primate models for the current SARS-CoV-2 vaccines showed no signs of this, either. Not all the earlier SARS work in primates did, either: these two studies went well, with no ADE signs. But immunology being what it is, one has to watch carefully as you move into humans, and the clinical trials that we have been seeing read out have been alert to these possibilities. So far, so good.

This has been why we’ve seen so many vaccines taking care to put the Spike protein into its “prefusion” conformation. The worry has been that if antibodies are generated to it after it’s had a chance to bind to human cells, that gives you a better chance for nonneutralizing ones (and thus potentially a better chance for ADE). And you’ll have noticed the emphasis on neutralizing antibody titers along the way as well – that would have been there anyway, but a high proportion of outright neutralizing antibodies is also a safeguard against antibody-driven enhancement of disease.

At this point, I would say that the main worry for any ADE effects would be if the coronavirus mutates to the point that the antibodies generated by the current vaccines become non-neutralizing. And honestly, I don’t see that happening (it certainly doesn’t seem to have happened yet). Targeting the Spike protein is another big benefit that we got from the earlier SARS work; which suggested that (for example) targeting the Nucleocapsid (N) protein was riskier. With the Spike, you put the virus in an evolutionary tight spot: evading the antibodies while trying not to lose the ability to bind to the human ACE2 protein. So far, that looks like too narrow a path for the virus to stumble through.

79 comments on “Antibody-Dependent Enhancement”

  1. HA Lurker says:

    Your autocorrect, I assume, had fun with the unabbreviated form of RSV – you may want to fix that…

    1. Joe says:

      syntactical-syncytial….tuh-may-toe, tuh-mah-toe

      Great post Derek!

  2. ScientistSailor says:

    Could vaccination against CoV2 bring ADE for MERS or another coronavirus that does infect macrophages?

    1. Adrian says:

      Could vaccination against CoV2 bring ADE for the human coronaviruses that are among the viruses causing the common cold?

      One can make likely/unlikely answers to such questions, but the reality is that noone can give definite answers to such questions right now.

  3. Marko says:

    It seems to me that close study of reinfections, in particular those that result in more severe disease in the second infection, would be one way to try to stay ahead of the ADE problem. Genomic analysis might point to mutation patterns in the reinfecting variants that lead to immune escape and/or ADE. It’s discouraging that sequencing has been done so infrequently in the US since the outbreak began, given that a full sequence of Cov-2 can now be done for ~$10 at scale.

  4. Matthew says:

    Can you do a blog post on Th2 misfunction next?

  5. pete says:

    Derek, great post — I learned.

  6. Don’t they teach says:

    To classify non-neutralizing antibodies as “useless“ doesn’t sit well. The exposed end of a non-neutralizing antibody is still a handle for fc receptors and the complement system. These are key elimination mechanism for virus and microbe particles.

    1. Immunophile says:

      Came here to say this, thank you! Very educational post but non-neutralizing antibodies are not “obviously useless” and seem to be pretty important for recent HIV vaccines.

  7. Moran says:

    Very interesting post. However, it does not seem to discuss the worry that the vaccine infuced neutralizing antibodies might induce ADE when their titre goes down over time (i.e., after a few months or years). I wonder whether there is any evidence regarding the possibilty of such a scenario.

  8. Calvin says:

    Derek, great post. In all of this ADE of some flavor is the one thing that still worries me a little.

    A couple of points about Dengue. We have no idea how long it takes each individual to develop antibodies such that they will have ADE. It is generally believed that it takes months to years, so the effect is not immediate unlike other viruses like RSV or Ebola. But break-bone fever (the second infection) is almost certainly caused by ADE.

    This was graphically demonstrated by Sanofi’s vaccine where it took around 18-24 months for the ADE to show up (it was completely absent preclinically). The hypothesis is that there is some B cell maturation process that goes on and so the effect take some time. The Sanofi vaccine primed the immune system and they saw ADE on subsequent infection. The interesting part is that it does not show such effects for those who were seropositive at immunization. So a prior infection does not lead to ADE when you are immunized.

    The effect in Dengue is extremely well lived. Those that were infected in Cuba in the 70s had severe Dengue when Dengue re-emerged a few years back. So it is a lasting effect.

    And just to add to this, dengue antibodies are definitely cross reactive to zika (and so presumably Chikungunya also) so you can see, preclinical at least, ADE between different viral infections of the same overall family. A real hornets nest.

    I think we’ll just have to cross our fingers a bit that we don’t see this with the COVID-19 vaccines. It would be a bit of a disaster…..

    1. Jennifer says:

      If we see this in relation to the covid vaccine in the future would we also see it in those who were naturally infected?

    2. Pablo says:

      “It would be a bit of a disaster…..”

      wouldn’t repeated boosters be the solution?

    3. Barbara Fortune says:

      If I had haemorrhagic dengue fever, (bone breakers disease) in the past, am I at increased risk of getting more severe symptoms with COVID-19? Also if I have the Pfizer vaccine am I then at higher risk of ADE if I come across a variant of COVID 19?
      Or are they completely unrelated?

      1. Derek Lowe says:

        They are indeed unrelated – completely different virus families, fortunately.

  9. CL says:

    Very informative post on ADE, thanks.

    Does anyone know why the developers of the Astrazeneca/Oxford vaccine chose not to use the prefusion conformation of Spike (the 2P variant)?

    1. Marko says:

      It may relate to patent issues , and an unwillingness to purchase a license for the prefusion spike technology from NIH :

      https://www.citizen.org/article/the-nih-vaccine/

    2. Roland says:

      Maybe a timing issue too. Remember the Oxford team were ahead early, and about half their development time took place before McLellan Lab published details on the 2P stabilisation. It’d be really interesting to know how much stabilisation contributes to the 70% vs 95% ‘effectiveness’ difference.

  10. The Emergency Use Authorization for the Pfizer vaccine, and its briefing document for the review meeting, states there is an unknown risk of future vaccine enhanced disease (which includes other potential enhancement modes and not just antibody enhancement) after the initial immunity fades:

    https://www.fda.gov/media/144416/download
    “The Sponsor identified vaccine-associated enhanced disease including vaccine-associated enhanced respiratory disease as an important potential risk [….] risk of vaccine-enhanced disease over time, potentially associated with waning immunity, remains unknown and needs to be evaluated further in ongoing clinical trials and in observational studies that could be conducted following authorization and/or licensure.”

    I saw almost the same text in the briefing document for Moderna’s FDA review.

    i.e. the study simply hasn’t gone on long enough to see if people have sterilizing immunity producing the initial good results that fades, and then when people do actually get infections: the immune response they learned from the vaccine might lead to a worse case of covid-19. Hopefully not: but the trials just haven’t run long enough to demonstrate that.

    Yet the FDA isn’t telling patients about this risk, nor is the media. The FDA’s fact sheet for recipients of the Pfizer vaccine for covid-19 is here and there isn’t a peep about it:

    https://www.fda.gov/media/144414/download

    Nor is there in its doc for healthcare providers, nor is it in the UK’s NHS or Canadian equivalents.

    An International Journal of Clinical Practice article on

    https://onlinelibrary.wiley.com/doi/10.1111/ijcp.13795
    “Informed consent disclosure to vaccine trial subjects of risk of COVID‐19 vaccines worsening clinical disease”

    explains that the vaccine trials didn’t meet medical ethics standards regarding fully informed consent since the issue of vaccine enhanced disease wasn’t explained in a way they’d comprehend. The FDA’s information doesn’t even mention it, let alone explain it in the way people comprehend, which seems an obviously major violation of medical ethics. Its also doesn’t make sense: since enough people will likely risk it anyway, but they should get that choice because even some experts wouldn’t yet.

    If they don’t correct this soon, and chalk it up to an oversight in the rush to get this out the door: it risks a backlash in a few months if the public becomes generally aware of it, akin to the backlash after the Tuskegee study where participants weren’t fully informed. They’ll wonder: “If you didn’t tell us about this risk, what else aren’t you telling us, why should we trust it?”. People can understand that trials are still ongoing: they won’t understand not informing them of risks since it looks like a coverup, even if in theory they could have hunted through the FDA’s more technical documents to find it.

    Experts apparently don’t agree on the magnitude of the risk: which is why its particularly important for it to be disclosed for public debate.

    Media in countries hit hard by COVID-19 haven’t called attention to the issue to date. In contrast a Japanese paper quoted the director of the Japanese Society of Clinical Virology: “Concerns over ADE still remain. I am an elderly person myself, but if I were asked, I would say I don’t want to get a shot.” Elsewhere he explained: “In the past, a dengue vaccine proved effective in tests and was widely used, but then it worsened symptoms for people who were still getting infected.”. A leading professor of Immunology testified to Japan’s House of Representatives: “There’s no doubt that their effectiveness is quite high, but their safety is not guaranteed at all”.

    Its also the case that many studies *do* see concerns over potential vaccine enhanced disease in this case. Severe covid isn’t due to a lack of immune response: but a dysfunctional immune response. One study termed it an “uncoordinated” response. Will the response that occurs after the vaccine fades be a functional one, or an “uncoordinated” one? That paper suggests there is a risk that vaccines that only target the spike may be at risk of vaccine enhanced disease. Regardless, since they don’t understand fully the broken response with severe covid-19, its unclear how they can yet be certain what the odds are the vaccine will be more or less likely to trigger a broken immune response that leads to severe illness. Hopefully not: the tests just haven’t gone on long enough to demonstrate it.

    The links to the various studies I mentioned are on BuildVaccineTrust.com where I put together information out of frustration that I didn’t see it being addressed. Its focused on government and academic journal links and expert references for people to evaluate themselves.

    1. sPh says:

      Seems that without a vaccine pretty much 100% of the human population will be exposed to SAR-COV-2 by 2022 and thus vulnerable to immune-enhanced response the same x years later, if such a phenomenon exists, no? In other words given the prolific spread of this virus the risks are the same for both the vaccine and do nothing paths.

      1. Jennifer says:

        Yes, this is what I want to know that I can’t find an answer to – if the vaccine were to lead to ADE or more risk of severe disease later, would the same thing happen with those naturally infected or no?

        1. eub says:

          It does occur for natural infection with one dengue strain followed by another.

          I think the question is: is there reason to expect that the suite of antibodies raised against the whole virus might maintain good neutralizing ability, if the Spike protein escapes? Or to turn it around, are there useful non-Spike neutralizing antibodies in the whole-virus response?

          I certainly am not someone who can give a real answer to that, but as Derek said we don’t see neutralizing antibodies against the N(ucleocapsid) protein, and from that it seems hard to imagine that binding to the virion’s surface structural proteins would help either. And that’s all the exposed proteins the critter’s got.

          1. re: “Or to turn it around, are there useful non-Spike neutralizing antibodies in the whole-virus response?”

            The issue again is what happens *after* the initial fully sterilizing immunity level of antibodies fades and the other components of the immune system are involved since an infection actually occurs, e.g. T-cells and various other aspects of it kick in (including of course generating more antibodies). As some of the studies I link notes: there isn’t a shortage of antibodies in patients with severe covid: in fact the titers may be higher. One describes the immune reaction as “uncoordinated” and suggests that a vaccine targeted only to the spike protein might be more likely to inspire an uncoordinated response.

            Here is one article about that study in Science:

            https://www.sciencemag.org/news/2020/09/uncoordinated-immune-response-may-explain-why-covid-19-strikes-some-hard-particularly
            “And training an immune system to make strong T cell responses against SARS-CoV-2 ultimately may require using more parts of the virus in a vaccine than the spike protein alone.”

            and a Cell journal article on the study:
            https://www.cell.com/action/showPdf?pii=S0092-8674%2820%2931235-6
            “” Thus, fatal COVID-19 case C92 represented an uncoordinated adaptive immune response, with neutralizing antibodies but a largely undetectable SARS-CoV-2-specific CD4+ T cell and CD8+ T cell response….A vaccine does not have to directly mimic protective immunity observed in natural infection, but should be informed by protective immunity observed in natural infection. Resolving an ongoing infection is more challenging than prophylaxis. The data presented here suggest that neutralizing antibodies play a role in resolving acute COVID-19, but statistical associations found less of a role for antibodies than SARS-CoV-2-specific CD4+ or CD8+ T cells”

      2. Adrian says:

        “Seems that without a vaccine pretty much 100% of the human population will be exposed to SAR-COV-2 by 2022”

        This is not true.

        Many countries in East/Southeast-Asia and Oceania have chosen to take a strict suppression strategy from the beginning instead of hoping for a vaccine.

        China/Australia/New Zealand/Thailand/Vietnam/… – more than 20% of the human population are protected from SAR-COV-2 by their governments even without a vaccine.

        1. sPh says:

          Unfortunately the now-globalized supply chain can’t operate that way forever. A lot can be done via Zoom but my clients have several projects that are proceeding at a crawl because in-person visits to several of the locations you mentioned cannot be made. Eventually either restrictions have to be relaxed or we all have to prepare for a decade-long Great Depression 3.

          1. Adrian says:

            The way of China is to get through a tight lockdown in the affected area(s) once early and then live a normal life.

            In late January the Chinese government correctly determined that the economically cheapest way is strict suppression.

            China had a very tight lockdown in the 2 months February+March in the affected region.
            4% of the population of China were under lockdown, 96% were not.

            Since then they are living a normal life by continuing strict suppression whenever an imported case slips through.
            They do routine screenings, and when there is a single case in a city with 10 millions residents they test all 10 million people within 2 days to contain the outbreak.

            Economically the strategy in Europe/US of hoping for a vaccine and trying to somehow live with the virus until then never made sense.

          2. Adrian says:

            It is beyond imagination that countries like China or Australia would sacrifice the lives of their citizens by letting potentially infected people into their country. Who pays the bill if they have to put 10 million people under lockdown because you reintroduced a deadly virus into their country?

            The funny thing is that even today a 2-3 month strict lockdown to get rid of the virus might still be faster and cheaper than the ongoing vaccine rollout.

          3. Bill says:

            I don’t think so. Lockdowns don’t work in a sustained sense. They bring peaks down but inevitably the numbers spring back up. If you live in a benign region, hold your breath. Because probably your time is coming.

            Whereas the Vaccine rollout ought to end the Whack-a-Mole effect.

          4. sPh says:

            @Adrian,
            Australia and New Zealand are self-sufficient at a median 1920s level of food and luxury. That’s not a bad place to be historically if shared equally across the population, but neither can stay isolated forever at a 2010 level. Post-1990 and the great globalization no one can.

          5. 이웅견 says:

            @adrian
            >> It is beyond imagination that countries like China or Australia would sacrifice the lives of their citizens by letting potentially infected people into their country. Who pays the bill if they have to put 10 million people under lockdown because you reintroduced a deadly virus into their country?

            Of course they wouldn’t. You will “pay” by undergoing testing+quarantine on entry.
            This imposed what economists would call “friction”, the effect would be that for the time being, some kinds of endeavor won’t be worth going through that type of trouble.
            Your company might send you there for a few months, so you can have face2face with your partner companies over there and zoom with your HQ. Business procedures will adapt.

          6. 이웅견 says:

            @adrian:
            One more, sorry for splitting by topic.
            I will have another look at China in March, for various reasons I’m having my doubts about their successes’ long-term sustainability.
            How far will they be able to reduce the huge population movement for the New Year Festival this time?
            This will be early mid-February in 2021.
            Another worrisome point is their use of forced labor, e.g. the Uygurs in cotton production.
            If other countries with migrant/forced labor are any indication, their living quarters might be just a little bit virus-friendly. Remember what happened a few weeks ago in Malaysia where 60% of the world’s latex gloves are made?

            Another country in the area that had been performing very well so far is South Korea.
            But now they’re seriously thinking about going into (their first) lockdown.
            Over the last few days, some patients have died while waiting for hospital/ICU beds to become available. They’re expanding capabilities at the highest possible speed, but there are limits. Especially medical personnel doesn’t grow on trees.

          7. Adrian says:

            The British government has just announced that 25% of the population in the United Kingdom will not be allowed to meet other people unless necessary, even allowing your children who live nearby into your house on Christmas is illegal.

            I have no doubt the Chinese government would implement similar restrictions for Chinese New Year if they consider it necessary, but with the current situation in China it is unlikely they will need any strict restrictions except perhaps on long-distance travel.

      3. re: “Seems that without a vaccine pretty much 100% of the human population will be exposed to SAR-COV-2 by 2022 and thus vulnerable to immune-enhanced response the same x years later, if such a phenomenon exists, no? ”

        No since the immune responses aren’t necessary the same, which is the whole problem. An immune response trained *only* on the spike protein is different from one for the whole virus, and some studies explicitly comment on that leading to greater risk of vaccine enhanced disease. Again: severe covid-19 isn’t due to a lack of immune response: its due to a dysfunctional immune response, one termed “uncoordinated” by one paper, and others view it as an *overreaction*. Its not clear how anyone can be certain in advance that the risk of severe covid won’t be *higher* in those who are vaccinated, after the initial immunity fades. Hopefully not: but its not clear that anyone knows enough to accurately predict that. Hopefully its great: but there is some chance it could make things worse. Or perhaps a booster will help it and solve the issue, its not known.

        The major issue is that the public needs to be aware of the fact that there are risks with a vaccine that hasn’t been studied long enough: otherwise its experimenting on millions of people without their fully informed consent and risks a backlash. Even when hopefully the vaccines do prove safe: people may have reason not to trust they are told everything.

  11. Nate says:

    Perhaps you can answer this one for me…
    Pfizer and Moderna reported seroconversion of around 95 percent prior to a booster.
    Currently 94 of the non-placebo Pfizer trial participants have contracted covid. And currently the exposure probability on a crowded airplane is between 14 and 59 per 100,000.
    By my math, of the 44,000 partipants (if they travelled on a crowded airplane for each of the 30 or so days). 200 would be expected to have been exposed.
    Why are we celebrating that only 94 of an expected 200 or so have contracted covid.
    Seems to me that 95 percent seroconversion of actually effective antibodies (even absent the booster) would have led to a number far less than 94.

    1. Roland says:

      By the same math the entire US population should immediately get on a crowded air-plane to protect them from Covid since roughly 67 per 100,000 are being diagnosed every day, and the true infections will be several times that. The ‘exposure probability’ (whatever that precisely means) in any crowded space is not anywhere near as low as 59 in 100,000. There have been some very dodgy airline-funded studies which might be misleading you.

    2. WST says:

      Pfizer phase 3 results announcement:
      “Among participants with and without evidence of prior SARS CoV-2 infection, there were 9 cases of COVID-19 among vaccine recipients and 169 among placebo recipients, corresponding to 94.6% vaccine efficacy (95% CI [89.9, 97.3]).”

      1. Ace says:

        This seems like nothing BUT a play to cause ADE vaccine injury in world populations. These results you just quoted, seem highly dishonest as the individual efficacy is not calculated. I’ve seen a great breakdown of this:

        “Based on the 94 cases in a trial that has enrolled about 40,000 subjects: 8 cases in a vaccine group of 20,000 and 86 cases in a placebo group of 20,000. This yields a Covid-19 attack rate of 0.0004 in the vaccine group and 0.0043 in the placebo group. Relative risk (RR) for vaccination = 0.093, which translates into a “vaccine effectiveness” of 90.7% [100(1-0.093)]. This sounds impressive, but the absolute risk reduction for an individual is only about 0.4% (0.0043-0.0004=0.0039). The Number Needed To Vaccinate (NNTV) = 256 (1/0.0039), which means that to prevent just 1 Covid-19 case 256 individuals must get the vaccine; the other 255 individuals derive no benefit, but are subject to vaccine adverse effects”

        Now we KNOW that one of the main factors in the set up of an ADE response is an ineffective vaccine:

        “one risk with any vaccine that winds up ineffective is that they could actually enhance disease.

        The process is called antibody-dependent enhancement (ADE), where a vaccine generates antibodies and binds the virus but does not neutralize it. These antibodies could then enhance viral entry into the cells and increase viral replication, said Sanjay Mishra, PhD, project manager of the COVID-19 and Cancer Consortium in Nashville, Tennessee.”

        “Poor-quality antibodies that bind a virus without neutralizing are one reason why the vaccine candidates often fail,” Mishra told MedPage Today in an email. “Any ineffective vaccine, in theory, could cause ADE.”

        https://www.medpagetoday.com/infectiousdisease/covid19/87933

        So here we are with a vaccine that is highly ineffective. (A subject being lied about.)

        And to make matters worse, as my US government sees a very, very reluctant medical community unwilling to be the Guinea pigs, they are chomping at the bit to squirt any of this into our bodies, now messaging to the population through our very compromised media that we should delay the second shot and just give everyone a single shot. Without any knowledge of how this effects efficacy, with no tests whatsoever to back up this adventure. Logically we should assume that this lowers an already ineffective vaccine, or treatment modality as it isn’t at all designed to stop the virus just lower some severity.

        In sum: ineffective vaccines of this type can cause ADE, and that’s what we have. Probably in all the vaccines, unless you really are so gullible to believe these claims of efficacy.

        For me, it’s a no go. I will not take this ineffective garbage.

    3. Ace says:

      We should not be celebrating this lie of efficacy, as the individual efficacy paints a different picture entirely –

      Using Pfizer results:

      “Based on the 94 cases in a trial that has enrolled about 40,000 subjects: 8 cases in a vaccine group of 20,000 and 86 cases in a placebo group of 20,000. This yields a Covid-19 attack rate of 0.0004 in the vaccine group and 0.0043 in the placebo group. Relative risk (RR) for vaccination = 0.093, which translates into a “vaccine effectiveness” of 90.7% [100(1-0.093)]. This sounds impressive, but the absolute risk reduction for an individual is only about 0.4% (0.0043-0.0004=0.0039). The Number Needed To Vaccinate (NNTV) = 256 (1/0.0039), which means that to prevent just 1 Covid-19 case 256 individuals must get the vaccine; the other 255 individuals derive no benefit, but are subject to vaccine adverse effects”

      Now we KNOW that one of the main factors in the set up of an ADE response is an ineffective vaccine.. Which is what we seem to have. Now my country is getting even stupider, and suggesting that we completely deviate from the vaccine distribution protocol and just take one shot- a desperate play to put an entire population at risk of ADE before we realize that this is the wrong way to go.

      For a blueprint of what I believe to be a plan in action, I examine the Vaccine-Derived Polio Virus (VDPV) outbreaks inflicted on mainly African countries. According to the CDC they are on their 4th polio vaccine aimed to solve the outbreaks specifically caused by the vaccines. In the context of The Great Reset, which proposes to keep the world’s population “home”, we cannot ignore the risks of a plot to make world populations completely vulnerable to COVID-19, which would both kill many, and frighten the world into a stay at home lifestyle as we continually search for vaccines to cure problems created by vaccines.

      Natural herd immunity sounds better than this track, every day of the week.

  12. Adrian says:

    Derek, your posts unfortunately tend to make the same mistake as most of the media by ignoring the vaccines developed outside the US and Europe.

    The Sinovac vaccine now has Phase 3 trials in Brazil finished, and submitting the data based on 170 cases of COVID-19 is expected to be done before Christmas.

    This might end up being the most widely used vaccine in the world, the 3 biggest countries committed to using this vaccine alone have a population of 2 billion people.

    The Sinovac vaccine is based on an inactivated whole virus, my expectation would be that ADE caused by that vaccine would be more similar to ADE after natural infection than ADE caused by the vaccines currently approved in the US.

  13. Dominik says:

    An infectivity-enhancing site on the SARS-CoV-2 spike protein is targeted by COVID-19 patient antibodies

    “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.”

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

    So ADE seems to be a thing, at least with antibodies targeting the NTD. The question is: are vaccine makers aware of that? Has the NTD been excluded / edited out from the vaccines? Are those antibodies found after vaccination and what happens when a variant with a mutation in the NTD hits someone who has been vaccinated?

  14. Qn says:

    Hi Derek,

    There’s some distrust about long term effects of rna vaccines, even from my doctor friends. They know that rna is immunogenic and while they see the steps taken to ameliorate it, they aren’t convinced that there are no long term inflammatory effects. And I don’t blame them. Is there any data about inflammatory markers and cytokines pre and post vaccination from pfizer and moderna which can put his to rest?

    1. PV=nRT says:

      It’s a good thing to have immunogenic material in your vaccine. We routinely inject adjuvants alongside the antigens in our vaccines — stuff like saponin, LPS (from bacterial cell walls) etc — it stimulates the immune system and makes the vaccine work better. The RNA in this case is acting as its own adjuvant.

  15. wkw says:

    ADE is a real concern and I too Q why FDA/CDC haven’t been more forthright like a prior poster has rightly called attention to (BuildVaccineTrust)
    ADE issue may come back to haunt us… also have to keep eye on prevalence of allergic reactions
    Antibody-dependent enhancement of coronavirus
    https://www.sciencedirect.com/science/article/pii/S1201971220307311

  16. DHMD says:

    Derek: no mention of VAH ?
    “VAH was first described in humans in the early 1960s, after formalin-inactivated measles vaccines were introduced in the United States and Europe. Within months, large numbers of vaccinated children developed a severe breakthrough disease, called atypical measles [6]. A similar outcome, vaccine-associated enhanced respiratory disease (VAERD), was observed in infants aged 4–12 months who were given formalin-inactivated respiratory syncytial virus (RSV) and a few months later infected by RSV [7].”
    https://academic.oup.com/jid/article/222/12/1946/5891764

  17. idiotraptor says:

    FYI

    Non-neutralizing monoclonal antibodies can prevent lethal alphavirus encephalitis
    A L Schmaljohn, E D Johnson, J M Dalrymple, G A Cole
    PMID: 6280072 DOI: 10.1038/297070a0

  18. LRB says:

    I am beginning a medical program in the Spring so I am very much a layperson. My question is, do we know if any of the vaccine trials have included people with existing autoimmune disease? Take for example an individual with SLE. They already have a high ANA, anti-dsDNA, APL, Anti-Sm, IgG and elevated CRP (to name just a few). Could it be argued that the vaccine may have a devastating impact on those whose bodies are already attacking itself and whose inflammatory markers are already high?

  19. Martha Careful says:

    Check this out:

    Viral targets for vaccines against COVID-19

    Published: 18 December 2020
    Learning from the previous experience with these CoVs, the S-2P design is now being used in several vaccine strategies against COVID-19. SARS-CoV-2 S-2P (comprising proline substitutions at residues K986 and V987) is used as the target antigen in three gene-based vaccine candidates (mRNA vaccines by Moderna/National Institute of Allergy and Infectious Diseases (NIAID) and BioNTech/Pfizer and a recombinant Ad26 vaccine by Janssen Pharmaceutical Companies) and a protein-based candidate (by Novavax)4,86,87,88,89,90,91,92,93,94,95,96 (Table 1).

    https://www.nature.com/articles/s41577-020-00480-0

    1. Martha Careful says:

      Also see:

      immunization programmes require further exploration. For instance, almost all vaccine candidates in clinical trials are delivered via intramuscular or intradermal routes. It is unclear whether nAbs in the sera reach the respiratory system, especially the lungs, to function. It is possible that mucosal vaccination via the respiratory system would be beneficial to induce immune responses at the mucosa and protect against SARS-CoV-2 transmission in situ through the respiratory tract. Accordingly, a recent report describes an intranasal ChAd vaccine that provides mostly sterilizing immunity to SARS-CoV-2 infection in a mouse model149. In general, as COVID-19 vaccines will be the first such efforts for a human CoV control strategy, more challenges remain.

  20. wkw says:

    Japan playing it a bit more cool re Vax, inc ADE risk
    link below

    read Walter Reed and labs in UK testing whether the new variant in UK is resistant to mRNA vax… let’s hope not… as we may be on path to immune escape, which may eventually be case given a world full of people for the virus to adapt to (ginormous pot of selective pressure)


    https://www.japantimes.co.jp/news/2020/11/25/national/science-health/japan-experts-coronavirus-vaccines-safety/

    Dr. Tetsuo Nakayama, a project professor at Kitasato Institute for Life Sciences and director of the Japanese Society of Clinical Virology, says although the vaccines under development by Pfizer and Moderna successfully created antibodies in trials, there are still doubts about whether those antibodies remain a year or two after vaccination.

    There are also underlying concerns about the vaccines’ safety over the long term. Judging from past precedents, their safety and effectiveness are not something that can be determined until at least a year after a massive number of vaccinations have been administered, experts say.

    In a worst-case scenario, antibodies could worsen the disease by essentially helping the infection of cells — a phenomenon called antibody dependent enhancement (ADE) — rather than fighting the virus pathogens.

    For example, a dengue fever vaccine made by Sanofi, based on a yellow fever vaccine embedded with a part of the dengue virus genome, at first appeared to be effective. But it caused the deaths of children who had been given the vaccination due to the ADE phenomenon.

    “Concerns over ADE still remain. I am an elderly person myself, but if I were asked, I would say I don’t want to get a shot,” Nakayama said. “Not all of the 120 million people (in Japan) should get the vaccinations. Children, for example, would not need it because there’s scarcely any risk of severe cases.”

    1. Also from Japan:

      https://mainichi.jp/english/articles/20201120/p2a/00m/0na/008000c
      “Should you rush to get a COVID-19 vaccination? One specialist in Japan says he won’t
      … But Masayuki Miyasaka, a leading immunologist at Osaka University, told the Mainichi Shimbun in a recent interview that even after these vaccines become available, he does not plan to receive them for the time being.

      At a meeting of the Committee on Health, Labor and Welfare of Japan’s House of Representatives on Nov. 17, Miyasaka stated, “There’s no doubt that their effectiveness is quite high, but their safety is not guaranteed at all,” sounding a word of caution about expectations for the vaccines. …
      Looking back on the history of the development of vaccines, only about 4% make it all the way from pre-clinical trials (on animals) to approval. So if there are 100 candidate vaccines, 96 of them will fall by the wayside. But this is not because they were unable to produce antibodies. Even if they are effective in triggering an immune response, the reality is that most of them are rejected due to side effects. …
      But during phase 3 trials, you can’t examine the possibility of ADE — that can only be done after it goes on sale. “

  21. MrXYZ says:

    I think some of the concern about ADE for SARS-CoV-2 has come from the veterinary medicine community. Feline Infectious Peritonitis (FIP) is a pretty nasty cat disease and it is a coronavirus. My understanding is that development of a vaccine against FIP was hampered by ADE – vaccination was making infection worse for some animals so the vaccine was abandoned. Anyone have more information on that?

    1. cynical1 says:

      Just that it was through infection of macrophages by FIP. As Derek pointed out, SARS-CoV-2 does not seem to infect macrophages which is a good thing.

      1. Rz says:

        Wrong.its infect macrphages very well

        1. cynical1 says:

          Reference?

          1. Aaron says:

            Here’s one from a couple of days ago: https://www.nature.com/articles/s41586-020-03148-w
            “Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia”

        2. Eva Smagacz says:

          Rz, plenty of data that macrophages found in Covid-19 patient’s lungs have plentiful expression of ACE2, giving Sars-Cov-2 opportunity to enter cells, but it is activation of myeloid population that causes damage in severely sick patients. Oxford scientists opined that the cytokine storm was predominantly driven by monocytes and neutrophils, and was different from MAS ( = macrophage activation syndrome (paper not yet reviewed). On the other hand, paper from Shanghai, where they actually do autopsies and look at the tissues, rather than try to divine what happens from path lab data, indicate that lung damage was looking like diffuse alveolar damage (DAD) and alveolar cavities were filled predominantly with large numbers of macrophages and occasional lymphocytes and neutrophils.

          Vanderbeke, L. et al (2020). Monocyte-Driven Atypical Cytokine Storm and Aberrant Neutrophil Activation as Key Mediators of COVID19 Disease Severity. SSRN Electronic Journal. https://doi.org/10.2139/ssrn.3646561
          Wang, C., et al (2020). Alveolar macrophage dysfunction and cytokine storm in the pathogenesis of two severe COVID-19 patients. EBioMedicine, 57, 102833. https://doi.org/10.1016/j.ebiom.2020.102833
          Martinez, F. O et.al (2020). Monocyte activation in systemic Covid-19 infection: Assay and rationale. In EBioMedicine (Vol. 59). Elsevier B.V. https://doi.org/10.1016/j.ebiom.2020.102964
          Mann, E. et.al (2020). Longitudinal immune profiling reveals key myeloid signatures associated with COVID-19. In Sci. Immunol (Vol. 5). http://immunology.sciencemag.org/

      2. Eva Smagacz says:

        Kittens died…

        Vennema, H., De Groot,’, R. J., Harbour, D. A., Dalderup, M., Gruffydd-Jones, T., Horzinek, M. C., & Spaanl, W. J. M. (1990). Early Death after Feline Infectious Peritonitis Virus Challenge due to Recombinant Vaccinia Virus Immunization. In JOURNAL OF VIROLOGY. http://jvi.asm.org/

  22. Murat Farmer says:

    Thank you for amazing analysis.

    Do concerns persist that COVID-19 vaccines could cause antibody-dependent enhancement, which can potentiate viral entry into host cells and worsen disease?If yes , how long does it take to appear ADE after vaccination?Is it understandable if it is ADE or Re-Infection?

  23. Marko says:

    The data suggests that the best preventative regimen against Covid-19 may be drinking vodka while in the sauna. Better than hydroxychloroquine , even :

    https://twitter.com/simongerman600/status/1341413280926101508/photo/1

    Thanks to Belarus for figuring this out. I’m off to give it a try……

  24. wkw says:

    and as to those (rare… at least so far) allergic reactions, a safety concern beyond ADEs (more attn/more awareness should be paid to this imho) — NIH going to test in a trial… first do no harm
    https://www.washingtonpost.com/health/covid-vaccine-allergic-reactions-study/2020/12/21/e01001d2-431a-11eb-b0e4-0f182923a025_story.html

    1. Wkw says:

      Def some legit concerns on reactions – safety
      X24 more reactions than what should be expected based on dosing so far

      https://www.sciencemag.org/news/2020/12/suspicions-grow-nanoparticles-pfizer-s-covid-19-vaccine-trigger-rare-allergic-reactions

      Anaphylactic reactions can occur with any vaccine, but are usually extremely rare—about one per 1 million doses. As of 19 December, the United States had seen six cases of anaphylaxis among 272,001 people who received the COVID-19 vaccine, according to a recent presentation by Thomas Clark of the U.S. Centers for Disease Control and Prevention (CDC); the United Kingdom has recorded two. Because the Pfizer and Moderna mRNA vaccines use a new platform, the reactions call for careful scrutiny, says Elizabeth Phillips, a drug hypersensitivity researcher at Vanderbilt University Medical Center who attended an NIAID meeting on 16 December. “This is new.”

  25. Ilya says:

    Does that mean that classic inactivated vaccines are worse than modern mRNA-or-adenovirus-anti-Spike ones?

  26. William Sculti says:

    How were the mouse immunogenicity studies conducted? Is there data available on that? Would love to see that experiment tried again on more recent variants.

    This is a big deal no, that should be verified periodically?

  27. ThatGuy says:

    I’m a first responder and currently have the vaccine available to me. I’ve been on the fence about receiving it since I learned that it was being made available to us this month. I had heard about ADE, but until this article couldn’t find anything that explained the ADE risk that was dumbed down enough for me to fully grasp.

    Just wanted to say thanks for the excellent explanation in the article and all the followup comments that shed extra light on the subject. I’m feeling much more confident in my decision to hold off on receiving the vaccine. I’m not anti-vax by any means, but don’t feel comfortable taking part in this experiment. I hope that all the concerns are unfounded and I’ll take the vaccine once the risks are fully known and understood.

    1. aCuriousSPT says:

      I am in the same boat as you as a grad student in the health sciences. I am beginning to do more direct patient care as a part of my course work have been offered the vaccine. Unfortunately, (and fortunately) I tested positive in the beginning of December but had very mild symptoms (barely a sore throat & no fever) and am nearing the end of my 90 day natural immunity period (as suggested by the CDC). I briefly read something about ADE (although not in that terminology) and began to do some of my own research.

      This article synthesized a lot of content from the various articles I was finding and the discussion has also supported my decision to hold off on the vaccine. I am grateful my science background has given me the tools to do such research. Still, I know that is majorly not the case for the general population, let alone access to scientific literature. I would like to see this information discussed on a larger, more widespread platform.

  28. Sam says:

    It will be interesting to see if the South African Covid variant will lead to ADE…….

    1. Katherine says:

      Exactly my question, too. Or the 1-dose or delayed regimens being argued for, though thankfully FDA is against anything that wasn’t explicitly tested.

      1. Sam says:

        Reported today was the death of a 56 OB-GYN in Miami 16 days after receiving his first dose on 18 December, healthy and no pre-existing conditions…….spots on the hands and feet and died of stroke…….could well be an ADE death

        1. debinski says:

          I heard about this case but it sounds like idiopathic thrombocytopenic purpura rather than ADE to me. Could have been caused by an autoimmune reaction caused by the vaccine. It has happened with other vaccines.

        2. Marko says:

          Was he PCR+?

          1. Marko says:

            No reports I’ve read suggests he was Cov-2 positive. If that’s the case, it’s not ADE.

  29. savageps says:

    Is there any possibility that the coronavirus will mutate so the curent neutralizing antibodies become non-neutralizing? I mean, of course there is a chance for that, but how big is this risk?

    1. Barry says:

      The (published) mAbs against SARSCoV2 are all against the RBD of the Spike protein. Any non-trivial change to that region would destroy the virus’ ability to dock to ACE2 and to infect a cell. So yes, mutations will occur that escape from mAb binding, but they’ll no longer be infectious.

  30. virshowcrux says:

    any opinion on 12th & 13rd january news?

    https://www.nature.com/articles/d41586-020-00502-w

  31. Covidnurse says:

    Im a nurse and was exposed taking care of covid+ and ultimately tested positive however got vaccinated (huge pressure from workplace). Sequence.

    January 10- exposed to suspected Covid+ patients
    January 12- vaccinated with Pfizer covid vaccine
    January 17- positive covid 19

    I dont have any symptoms at all so far. Will I take the 2nd dose of Covid vaccine? No, I’ll pass this time.

    1. Viking says:

      So you were exposed before you were vaccinated..and you’re positive. I doubt the hospital will allow you to pass…and why would you?

  32. SMK says:

    I have a question. What about breastfeeding and ADE? I’m currently breastfeeding a 1 year old & may be up for a vaccine in the coming months. Do I need to wean? Is there a risk of ADE if my child is exposed to the virus after receiving maternal antibodies? Does my child have an increased risk of response to a future vaccine herself? I’m seeing the vaccine being recommended to nursing moms, without talk of this anywhere. It concerns me.

  33. MM says:

    Thoughts about potential risk of ADE with the vaccines currently in phase 3 trials? Johnson and johnson, Novavax? Thanks

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