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Good News on the Human Immune Response to the Coronavirus

One of the big (and so far unanswered) questions about the coronavirus epidemic is what kind of immunity people have after becoming infected. This is important for the idea of “re-infection” (is it even possible?) and of course for vaccine development. We’re getting more and more information in this area, though, and this new paper is a good example. A team from the La Jolla Institute for Immunology, UNC, UCSD, and Mt. Sinai (NY) reports details about the T cells of people who have recovered from the virus. To get into this, a quick explainer seems appropriate, so the next bit will be on the background of T cells and adaptive immunity – then we’ll get into these latest results.

So everyone’s heard of the broad category of white blood cells. One group of those are the lymphocytes (literally “lymph cells”, where they’re most easily found), and the lymphocytes include T cells, B cells, and NK cells. You’re looking at three big branches of the immune system right there. The NK (“natural killer”) cells are part of the innate immunity, the nonspecific kind, and they’re in the cell-mediated cytotoxic wing of that. The other side of the immune system is adaptive immunity. The B cells feature in my antibody background posts, because as part of the adaptive system they’re the ones that produce more of some specific antibody once one of the zillions of them present in the body turns out to fit onto a new antigen. The T cells are in the adaptive side as well, but they’re in the cell-mediated part of that army.

T cells come from the thymus (thus the “T”), so if you’ve been wondering what your thymus has done for you lately, that’s one good answer. They all have a particular surface protein, the T cell receptor. Similar to the way that the immune system generates a huge number of antibodies by shuffling and mixing protein expression, there are a huge number of different T cell receptors waiting to recognize what antigens may come along. The precursors of T cells come from the bone marrow and migrate to the thymus, where they branch out into different lines (and that branching out continues even once they leave the thymus and begin circulating in the lymph and in the blood).

The most direct of those are the cytotoxic T cells, also known as CD8+ T cells and by several other names. CD8 is another particular cell-surface protein that distinguishes this type. These cells aren’t going after viral particles; they’re going after the body’s own virus-infected cells and killing them off before they can break open and spread more viral particles. They’ll kill off bacterial cells in the same way. These are also the ones that the CAR-T therapies are trying to mobilize so that they’ll recognize cancer cells and do the same thing to them. How do they accomplish the deed? They’re thorough; there are several deadly mechanisms that kick in. One general one is to secrete cytokines, especially TNF-alpha and interferon-gamma, that alert other cellular systems to the fact that they’ve detected targets to attack. (The monoclonal antibody drugs for arthritis are actually aimed to shut down that TNF-alpha pathway, because in RA the T cells are – very inappropriately – attacking the body’s own joint tissue). A second CD8+ action is to release “cytotoxic granules”. These are payloads of destruction aimed at the target cell once the T cell is closely connected to it (the “immune synapse”). You need that proximity because cytotoxic granules are bad news – they contain proteins that open up pores in the target cell, and blunderbuss serine protease enzymes that slide in through them, whereupon they start vigorously cleaving intracellular proteins and causing general chaos (and eventually cell death). And the third killing mode is via another cell-surface protein the CD8+ cells have called FasL – it binds to a common protein on the target cells called Fas, and that sets off a signaling cascade inside the target cells that also leads to cell death. (Interestingly, the CD8+ cells use this system after an infection has subsided to kill each other off and get their levels back down to normal!)

And then there’s another crowd, the CD4+ T cells, also known as T-helper cells and by other names. They work with another class of immune cells, the antigen-presenting cells, which go around taking in all sorts of foreign proteins and presenting them on their cell surfaces. A CD4+ cell, when it encounters one of those, goes through a two-stage activation process kicks in (the second stage is sort of a verification check to make sure that it’s really a foreign antigen and not something already present in the body). If that’s successful, they start to proliferate. And you’re going to hate me for saying this, but that’s where things get complicated. Immunology! The helper T cells have a list of immune functions as long as your leg, interacting with many other cell types. Among other things, they help set off proliferation of the CD8+ cells just detailed, they activate B cells to start producing specific antibodies, and they’re involved with secretion of more cytokine signaling molecules than I can even stand to list here. These are in fact the cells targeted by HIV, and it’s the loss of such crucial players in the immune response that makes that disease so devastating.

OK, there’s some background for this new paper. What it’s looking at in detail are the virus-specific CD8+ and CD4+ cells that have been raised up in response to the infection in recovering patients. As you’ve seen, both of these subtypes are adaptive; they’re recognizing particular antigens and responding to those – so how robust was this response, and what coronavirus antigens set things off? You can see how important these details are – depending on what happens, you could have an infection that doesn’t set off enough of a response to leave behind B and T cells that will remember what happened, leaving people vulnerable to re-infection. Or you could set off too huge a response – all those cytokines in the “cytokine storm” that you hear about? CD4+ cells are right in the middle of that, and I’ve already mentioned the TNF-alpha problems that are a sign of misaligned CD8+ response. The current coronavirus is pretty good at evading the innate immune system, unfortunately, so the adaptive immune system is under more pressure to deliver. And one reason (among many) that the disease is more severe in elderly patients is that the number of those antigen-presenting cells decline with age, so one of the key early steps of that response gets muted. That can lead to a too-late too-heavy T cell response when things finally do get going, which is your cytokine storm, etc. In between the extremes is what you want: a robust response that clears the virus, remembers what happened for later, and doesn’t go on to attack the body’s own tissues in the process.

Comparing infected patients with those who have not been exposed to the coronavirus, this team went through the list of 25 viral proteins that it produces. In the CD4+ cells, the Spike protein, the M protein, and the N protein stood out: 100% of the exposed patients had CD4+ cells that responded to all three of these. There were also significant CD4+ responses to other viral proteins: nsp3, nsp4, ORF3s, ORF7a, nsp12 and ORF8. The conclusion is that a vaccine that uses Spike protein epitopes should be sufficient for a good immune response, but that there are other possibilities as well – specifically, adding in M and N protein epitopes might do an even more thorough job of making a vaccine mimic a real coronavirus infection to train the immune system.

As for the CD8+ cells, the situation looked a bit different. The M protein and the Spike protein were both strong, with the N protein and two others (nsp6 and ORF3a) behind it. Those last three, though, were still about 50% of the response, when put together, so there was no one single dominant protein response. So if you’re looking for a good CD8+ response, adding in epitopes from one or more of those other proteins to the Spike epitope looks like a good plan – otherwise the response might be a bit narrow.

And here’s something to think about: in the unexposed patients, 40 to 60% had CD4+ cells that already respond to the new coronavirus. This doesn’t mean that people have already been exposed to it per se, of course – immune crossreactivity is very much a thing, and it would appear that many people have already raised a response to other antigens that could be partially protective against this new virus. What antigens those are, how protective this response is, and whether it helps to account for the different severity of the disease in various patients (and populations) are important questions that a lot of effort will be spent answering. As the paper notes, such cross-reactivity seems to have been a big factor in making the H1N1 flu epidemic less severe than had been initially feared – the population already had more of an immunological head start than thought.

So overall, this paper makes the prospects for a vaccine look good: there is indeed a robust response by the adaptive immune system, to several coronavirus proteins. And vaccine developers will want to think about adding in some of the other antigens mentioned in this paper, in addition to the Spike antigens that have been the focus thus far. It seems fair to say, though, that the first wave of vaccines will likely be Spike-o-centric, and later vaccines might have these other antigens included in the mix. But it also seems that Spike-protein-targeted vaccines should be pretty effective, so that’s good. The other good news is that this team looked for the signs of an antibody-dependent-enhancement response, which would be bad news, and did not find evidence of it in the recovering patients (I didn’t go into these details, but wanted to mention that finding, which is quite reassuring). And it also looks like the prospects for (reasonably) lasting immunity after infection (or after vaccination) are good. This, from what I can see, is just the sort of response that you’d want to see for that to be the case. Clinical data will be the real decider on that, but there’s no reason so far to think that a person won’t have such immunity if they fit this profile.

Onward from here, then – there will be more studies like this coming, but this is a good, solid look into the human immunology of this outbreak. And so far, so good.

95 comments on “Good News on the Human Immune Response to the Coronavirus”

  1. David Young MD says:

    If anyone want an entertaining primer on our blood cells and immune system, watch the Japanese Anime “Hataraku Saibou” (Cells at work).!

    You can watch it on or other anime sites. There are fragments of the show on Youtube.

    Sort of zany but they pretty much get their immunology and hematology right.

    1. UVCatastrophe says:

      How does it compare with Osmosis Jones?

    2. aairfccha says:

      Also there is the much more widely available “Once Upon a Time… Man” series (original title “Il était une fois… l’homme”)

      1. aairfccha says:

        correction, I meant “Once Upon a Time… Life”/”Il était une fois… la vie”

  2. psoun says:

    Derek – great post, learning a lot.

    Excuse my ignorance as this is not at all my area but you note “And here’s something to think about: in the unexposed patients, 40 to 60% had CD4+ cells that already respond to the new coronavirus.” Would such patients, if exposed to Covid later, prospectively be more likely to be asymptomatic?

    1. Patrick says:

      Basically, that’s a strong possibility but we don’t know – that’s what the next few sentences of Derek’s post talk about.

      Here in particular:
      “What antigens those are, how protective this response is, and whether it helps to account for the different severity of the disease in various patients (and populations) are important questions that a lot of effort will be spent answering.”

    2. Dr AV says:

      I keep wondering, if a skin test, similar to the Mantoux was for TB, could test the availability of a T cell response (type IV cellular response). Even if just a cross reaction for COVID-19. I think the antibody response may be weak or even wane over time, but the T cell response measured by the skin test may remain, with a longer memory. Even an aspecifically strengthened T cell response may have caused by a remote BCG mitigated the spread of COVID infection in certain countries where BCG is still mandatory.

  3. Immunologist says:

    This virus is matching textbook anti-viral immunity pretty well – which is a very good thing. There’s a reasonably clear viral entry pathway, anti-viral interferons are being induced in infected cells, there’s development of protective neutralizing IgM and IgG responses, and T cell responses develop to multiple viral antigens (that may be cross-reactive to other viral antigens). It’s everything classic immunology would teach us to expect. All of this together continues to bode very well for both public health control (this virus behaves like we expect respiratory viruses to behave) and monoclonal antibody / vaccine development (this virus is blocked by the immune system in the way we generally expect viruses to be blocked).

    It’s the pathology of the disease that seems more complex and requiring lots more study – perhaps a longer asymptomatic period than related viruses, more complex tissue infectivity leading to the effects like loss of smell, GI tropism, etc. How much does initial infectious dose affect the likelihood of productive infection? At what point in the disease progression is blocking viral replication enough to stop disease? Maybe the virus encodes an interferon antagonist, or maybe it has other ways of avoiding intracellular anti-viral restriction or suppressing NK cells or other innate responders – who knows what all those mystery ORFs are doing? How is viral sepsis, if your immune system *doesn’t* manage to control things, causing severe COVID and mortality, and what are the therapeutically accessible points once a patient is on that path? But all these are downstream from preventing infection with a vaccine or cutting it off quickly with a good monoclonal (which could even be used prophylactically in high-risk individuals), which seems to be as realistic a possibility as we could have hoped for.

    1. J N says:

      I’m concerned that people associate “recovery” or “subclinical case” with “all done.”

      Viral infection sequelae are common and often worse than the initial infection, which may be subclinical. Given the panoply of symptoms seen in sick patients and at least one child sequela (MIS-C), I hope that healthy, young people will restrain the urge to “go out and get it” as there is every reason to worry that there might be an Act 2 in this play.

      As far as I know, human CoV falls into two types: Innocuous (cold) and deadly (SARS/MERS). Sequelae observed in SARS were pulmonary damage, sometimes permanent, and osteonecrosis (from high dose steroid treatment). MERS is infrequent and deadly enough that I don’t know whether this has been studied.

      I don’t know whether other CoV has been found circulating in humans.

      I don’t know if any studies of aftereffects of human cold CoV have been done. One might wonder if cold CoV could be responsible for immune response to SARS-CoV-2, or if there are other benign SARS-like CoV out there in the population.

    2. In8 immunity says:

      “Maybe the virus encodes an interferon antagonist, or maybe it has other ways of avoiding intracellular anti-viral restriction or suppressing NK cells or other innate responders – who knows what all those mystery ORFs are doing?”

      Some of these viral proteins are definitely involved in evasion of immunity. SARS-CoV2 (and other coronaviruses) encodes two highly conserved RNA methyltransferases, Nsp14 and Nsp16. These enzymes form part of the viral replicase complex, and their role is to generate a 5′ cap on the RNA genome, both helping to stabilise it, and importantly to evade recognition by the innate immune sensing machinery (RIG-I and MDA5). RIG-I and MDA5 recognise double stranded RNA structures and initiate a type 1 interferon response, which constitutes a major early response to viral infection in all cells – not just the immune cells themselves. Mutation of nsp14 or nsp16 of other coronaviruses reduces their infectivity and demonstrates the importance of this mechanism to evade another important part of our (complicated) immune system. Targeting RNA modifying enzymes could be another interesting way of treating COVID19 (or other viruses).

  4. loupgarous says:

    “And here’s something to think about: in the unexposed patients, 40 to 60% had CD4+ cells that already respond to the new coronavirus.”

    Ok, I freely admit I know less about virology or immunology than Derek or most other responders to this blog. So, I stipulate this may be a stupid question, but… what role might Antibody-Dependent Enhancement play in SARS_CoV2-naïve people whose CD4+ cells cross-react to the new virus? Hopefully none at all, but I just wondered.

    1. loupgarous says:

      A pre-print in The Lancet specifically discusses vaccine risks for ADE, but doesn’t get into cross-reactivity-caused ADE. Is there a reason we don’t need to worry about that?

    1. The Science Mechanic says:

      That article is about viral tests (for current infection), which are not the same thing as antibody tests (for prior exposure, which *may* indicate immunity). Viral test results have nothing to do with “immunity passports”.

  5. luysii says:

    There is much better news than this.

    Some 10% of ASYMPTOMATIC Bostonians have antibodies to the virus and another 3% have a positive culture for the virus. Some 750 people were tested. This means for most people, the pandemic coronavirus doesn’t make you very sick.

    Of course the worst possible spin was put on the news by the Mayor and those interested in continuing the lockdown, namely that 90% of the population is at risk for infection (catch the lead). But so what, if it doesn’t make you sick (if you’re young and healthy). In Massachusetts some 15% of those with a positive viral culture are over 80, but they account for 63% of the deaths. These are the people who must protect themselves (and be protected).

    Results like this will determine the results of the coming presidential election — for details —

    1. J N says:

      Some back of the envelope math relating to that study puts the floor of IFR at 0.8%, although there are several reasons it should be somewhat higher.

      I have trouble finding the good news part of that.

      1. intercostal says:

        Well, IFRs are going to vary from place to place based on what demographics get infected.

        Massachusetts seems to have had a ton of infections in long-term care facilities – about 60% of COVID deaths in Massachusetts are from LTCFs.

        So that’s probably a comparatively high IFR (at least for a population with an US-style age distribution; Italy for example is older) and would likely be lower in a place where LTCFs haven’t been so badly impacted.

        (And a suburb near Boston (Chelsea) supposedly had over 30% seropositive…)

        1. David Chase says:

          Regarding 30% of Chelsea showing exposure, that was a sample of “people on the street”, i.e., not random, and oversampling people who don’t stay put. You’d expect it to be higher than the true rate.

    2. Academologist says:

      I’m worried that the 10% of asymptomatic Bostonians with antibodies to the virus might contain a large portion of people with cross-reactivity based on infection with a previous coronavirus. What test were they using for this study and how well was it validated?

      1. Thomas says:

        In the Netherlands, a baseline test was done of blood donated previous year. This gave 7% reactivity, post-Covid this was 10%.

  6. nobody says:

    Given the potential for crossreactivity between other coronaviruses and SARS2, it would be a prudent idea test if deliberately infecting people with (multiple?) common-cold level coronaviruses conveys any protective effect.

    Of course, the medical ethics crowd would froth at the mouth that such trials are unethical. However, with tens of thousands of people dying from COVID-19 every day, the onus ought to be on the mouth-frothers to justify why risking a few hundred people to get results that could save hundreds of thousands, or millions, is unacceptable.

      1. Ah kids with runny noses…. I guess their parents and teachers are getting constant exposure

        1. RA says:

          Wonder if some good epidemiological research could help explore this hypothesis. If it is correct, I would think you would see lower rates of severe disease among those who have regular contact with kids and their runny noses – parents, day care workers, teachers, pediatric health care providers, etc- compared to those who don’t…controlling for other risk factors, of course!

          1. Doug Benbow says:

            My wife has worked with K-5 (mostly K) for years and gets “snotted on” all the time. She never gets a cold, never gets the flu and has never had a flu shot. She’s still teaching at 69, eats healthy, is lean and lifts weights.

    1. loupgarous says:

      Deliberately infecting people showing cross-reactivity between SARS2 and other coronaviruses with SARS_CoV2 may cause worse COVID-19 cases than infection acquired in the wild.

      Immunization for Dengue Fever viruses caused worse disease than the researchers were inoculating for, when antibody-dependent enhancement caused patients receiving a vaccine for one of the four strains of dengue virus to suffer a higher degree of infection with another strain of dengue virus than happened without that vaccination..

      It’s prudent, before we embark on a campaign of purposefully infecting SARS_CoV2-naïve with a potentially deadly virus, to examine the potential for ADE in SARS_CoV2 viremia, given the large number of mutant strains of the novel coronavirus.

      1. Tony says:

        You can pretty quickly test whether common coronavirus antibodies cause ADE. Cast a wide enough net and you will find a small number of donors with common coronavirus antibodies. You can test whether these antibodies enhance uptake of SARS2 into various human cells in vitro.

        For what it’s worth we have a lot of experience delivering viral particles via nasal spray (common colds, influenza). So, it’s highly unlikely delivering common cold coronaviruses will be lethal. I would suggest that people could be primed with common cold coronaviruses. Then people can be boosted with SARS2 – obviously this would need to be dose response (start with 100 particles, then 1000, then 10,000 etc etc).

        Of course, the issue here is that to do a proper experiment you need to give one group common cold then SARS2, you really need a control group of placebo + SARS2. Therein lies the danger, but if you used a cohort of 20 year olds, the risk would be very, very tiny.

    2. Barry says:

      In the usual way these things unfold, the virus will mutate and a mutant that is less virulent will dominate*, will spread widely through the populace and the immune response to this less virulent version will afford (more or less) protection against the earlier more virulent version. That’s a lot like widespread administration of an attenuated virus vaccine–but without the testing, without the FDA, without the profit motive.

      *especially when the sick stay home but the asymptomatic are out there in society spreading disease.

      1. Immunologist says:

        This is not necessarily the case. The coronaviruses mutate slowly – there is no reason to expect a less virulent version to emerge in a short time frame. Many viral infections do not become so “less virulent” that they aren’t concerning – polio, measles, smallpox, are still quite virulent despite long-term circulation through humanity (until we eliminated / heavily suppressed them with vaccines). Also, in general, a less virulent version doesn’t necessarily spread faster – so most people are still more likely to be infected by the original virulent version. So, while this technically could happen, it’s a very small chance (meaning something like 0.000001%, not 5%) that it happens rapidly and broadly enough to be protective before a large percentage of the population is infected and likely millions die worldwide.

        1. Barry says:

          You’re right, of course. If I in any way implied that this would happen quickly, I apologize. Darwin’s timeframe is not ours.

        2. J N says:

          The “pathogen naturally becoming less virulent” model only works well when transmission depends on the health of the host.

          This really isn’t the case with COVID-19 due to the apparently high frequency of asymptomatic/presymptomatic spread.

          We could get lucky and a mutation could emerge that greatly increases transmissibility while reducing virulence, which would tend to replace the existing virus in the population. But greatly increased transmissibility and greater virulence would do the same, just leaving fewer people around afterward.

          1. J N says:

            I should mention that there is some speculation, along with (last I heard) enough evidence to make it a reasonable suspicion, that the “European” virus developed a spike protein mutation that is causing it to spread preferentially. Derek discussed this:


            Along with that, there is curiosity whether this strain might have increased virulence that might in turn have been responsible for the large death tolls in Europe and the East Coast, but there doesn’t seem to be evidence of that.

          2. intercostal says:

            Yeah, you would expect Europe and the Northeast US (the Southeast is generally doing better) to be hit worse because of urban density / mass transit / movement patterns, and (at least in Europe) an older population. Virus differences aren’t needed to explain that, IMO.

          3. Reziac says:

            One word: rabies.

        3. Riah says:

          bear in mind that in the developed world, perpetuation of measles has been facilatated by two things:1. shedding of live vaccine strain virus from vaccinated persons – meaning from the vaccine itself. 2. new breast fed babies used to be protected via maternal antibodies but this no longer happens with vaccinated mothers who do not pass on protective antibodies leaving young babies with no protection from measles. Measles declined very rapidly in UK to almost nothing before vaccines were introduced in early 60’s- just look at the oficial statistics- who knows if like scarlett fever, sweating disease, smallpox and many others, it would have disappeared completely in the UK and elsewhere if it had not been for this vaccine facilitated perpetuation.

  7. Damien G says:

    Doesn’t this imply an important role for cellular (Vs. humoral) immunity and thus reduce probability of success for those vaccine types which weight towards more humoral response?

  8. Zee B says:

    since all the patients had CD4+ cells that responded to all 3 proteins (SPIKE, M and N), how do we get to Spike alone being sufficient?

    1. gcc says:

      I was wondering this as well. It seems to me the broad immune responses seen in this study are probably good news for immunity in people exposed to the virus, but not necessarily for the likelihood of success of the first vaccines being tested, which all seem to use just the spike protein from SARS-CoV2. It would be interesting to see what epitopes are targeted in people whose immune responses aren’t able to clear the virus (those with severe COVID-19 who don’t recover and end up dying).

  9. loupgarous says:

    from wikipedia. Antibody-dependent enhancement:

    “The neutralization ability of an antibody on a virion is dependent on concentration and the strength of interaction between antibody and antigen. High-affinity antibodies can cause virus neutralization by recognizing specific viral epitopes. However, pathogen-specific antibodies can promote a phenomenon known as antibody-dependent enhancement (ADE), which can be induced when the strength of antibody-antigen interaction is below the certain threshold.[13][14] There are multiple examples of ADE triggered by betacoronaviruses.[13][14] Non-human primates vaccinated with modified vaccinia Ankara virus encoding full-length SARS-CoV spike glycoprotein and challenged with the SARS-CoV virus had lower viral loads but suffered from acute lung injury due to ADE.[15] ADE has been observed in both severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) animal models allowing the respective viruses to enter cells expressing Fc𝛾R including myeloid lineage cells.[16] It was shown that the SARS-CoV-1 virus (SARS-CoV) can enter macrophages via a antibody-mediated pathway and it can replicate in these cells. [17] ADE of acute lung injury has been documented in animal models of both SARS and MERS. Rabbits intranasally infected with MERS-CoV developed a pulmonary infection characterized by viremia and perivascular inflammation of the lung, and an antibody response that lacked neutralizing antibodies.[18] The rabbits developed more severe lung disease on re-exposure to MERS-CoV, and developed neutralizing antibodies after reinfection.[18] In SARS, mice vaccinated with four types of vaccines against SARS-CoV, as well as those infected with SARS-CoV itself, developed neutralizing antibodies.[19] Mice were then challenged with live SARS-CoV, upon which all developed immunopathologic-type lung disease, although none had detectable virus two days after challenge and were protected compared to control.[19] The development of immunopathology upon exposure has been a major challenge for coronavirus vaccine development[19] and may similarly impact SARS-CoV-2 vaccine research. ADE in coronavirus infection can be caused by high mutation rate of the gene that encodes spike (S) protein. A thorough analysis of amino acid variability in SARS-CoV-2 virus proteins, that included the S-protein, revealed that least conservative amino acids are in most exposed fragments of S-protein including receptor binding domain (RBD). Therefore, antigenic drift is a most likely cause of amino-acids variability in this protein [14][20] and ADE. This drift can occur in a form of changes of both types of antigenic epitopes, including conformational and linear. The pathophysiology of SARS and COVID-19 diseases may be associated with ADE. The authors of the study[14] believe that ADE is a key step in the progression of disease from its mild to severe form. Onset of ADE, due to antigenic drift, can explain the observed sudden immune dysregulation, including apoptosis of immune cells, which promotes the development of T-cell lymphopenia and an inflammatory cascade with the lung accumulation of macrophages and neutrophils, as well as a cytokine storm. ADE goes along with reduction of Th1 cytokines IL2, TNF-α and IFN-γ and increase of Th2 cytokines IL-10, IL-6, PGE-2 and INF-α, as well as with inhibition of STAT pathway.[21]”

    Antibody-dependent enhancement is well documented in betacoronaviruses like SARS and MERS to cause worse illness than infection in those who’ve never been exposed. Why aren’t we worrying about it when we talk about infecting SARS_CoV2-naïve people who cross-react to SARS_CoV2?

    1. luysii says:

      Points well taken, but 15 – 30% of common colds are said to be due to coronavirus (presumably this statement was made using antibodies to them — I’ve tried to contact the author Dr. Landry of Yale with no luck). As far as I’m aware, antibody dependent enhancement hasn’t been seen with the cold coronaviruses.

    2. Toni says:

      I do not know but I find the explanations (e.g. the wikipedia article) of the mechanism of ADE more than unsatisfactory.
      Still, Fc-mediated uptake of pathogens into cells is one of the keys to innate immunity.
      Usually, only aggregated Fc is taken up or certain Fc-receptors, such as CD64, are ramped up after (in)appropriate inflammatory stimuli.
      In the first case, it might not be the “sub-neutralizing” effect for an uptake, but the type of binding valence of the antibodies that would be responsible. In the case of CD64, it could be an unbalanced immune response that makes things worse.

      It is also strange that according to current models, viruses that enter the cell (e.g. a macrophage) via ADE can replicate within the cell, whereas uptake via neutralizing Antibodies leads to the elimination of the virus.

    3. Immunologist says:

      There is no good evidence of ADE for coronaviruses in humans, including in all the serological studies so far with COVID-19. Presence of antibodies so far has not been linked with increased disease, viral burden, or risk of re-infection. Multiple animal models (mouse and monkey) have shown protection from re-infection and no ADE with vaccination strategies that induced potent neutralizing antibody titers (, The likely risk of ADE from a good vaccine is next to nothing and far outweighed by the potential protective benefits.

      In the citations to the wikipedia article you linked, many of the animal models showed that antibody responses were protective in reducing viral infection, even in the models where vaccinated animals showed increased inflammation – so the antibodies protected from the virus. In the rabbit model of MERS, presence of non-neutralizing antibodies increased inflammation without protection, but presence of neutralizing antibodies was protective. It’s also worth noting that in many of those animal studies, the disease course was not lethal – animals weren’t dying of the coronavirus infections, while we know that MERS and SARS are. highly lethal in humans. This makes a comparison of the risk-benefit difficult. So, as long as a vaccine induces high-potency neutralizing antibodies, we would expect from all available evidence that there would be no ADE, and in fact protection from infection.

      One more general note about ADE studies, and some of the original work that supported the reviews cited in the wikipedia article – in vitro ADE is very different from actual enhancement of infection in an animal (or human). Often, in vitro ADE is shown by methods that don’t reflect a valid in vivo infection pathway. For example, Fc receptors might be overexpressed on HEK293T cells and then enable enhancement of viral uptake. Fortunately, humans don’t have HEK293T cells overexpressing Fc receptors anywhere in their bodies. Macrophages and other immune cells with Fc receptors are very different from HEK293Ts, including having a suite of extra anti-viral immune sensors and effectors, because they have evolved to take up viruses coated in antibodies. Other common in vitro ADE experiments, including with macrophages, use pseudoviruses – these are often attenuated viruses that can replicate in cells, but not form infectious viral particles, so we can use them safely in the lab for infection studies. Many pseudoviruses are even formed from a different backbone (for example, VZV) that has a single protein from the virus of interest placed in – so, a MERS study might use VZV pseudoviruses expressing just the MERS spike protein. MERS and VZV replicate differently, might not be able to survive in the same cell types, and have vastly different pathways for infection – so all the pseudovirus can really tell us is now the MERS spike protein impacts uptake of the viral particle (which is useful information, but limited to just that). We specifically used pseudoviruses that we can study in the lab because they replicate in cell types we study – so ability to promote pseudovirus uptake (which some studies use to show “ADE”) doesn’t tell us anything about actual infection. All this means that productive uptake in a cell culture dish (which is often the readout of “ADE” studies) doesn’t mean there will be effective infection of macrophages through ADE in vivo. Even if there is, that is still not enough to indicate a risk of ADE in the human – are the macrophages producing virus at meaningful levels to contribute to infection? Will they be exposed at levels sufficient to infect through ADE (which is often weaker than natural infection)? If a macrophage gets infected in the lung and moves to the liver later on, does that matter if the virus can’t replicate in other cells in the liver?

      ADE is an interesting and worthwhile phenomenon to be aware of. It’s a real concern with dengue virus. Dengue virus is immunologically very interesting, very challenging, and far different from the coronaviruses. It’s also the only really solid example of ADE in humans. 999 times out of 1000, ADE will not happen for a virus. The bar to say we should be genuinely concerned about ADE is high, and it has not been met by any study with SARS-CoV2 in animals or humans. Even much of the other coronavirus ADE literature is shaky, at best. Everything points to the fact that potent neutralizing antibodies are protective, with no risk of ADE, and a vaccine that elicits those will likely have protective effects. It’s critical to make sure that any vaccine does induce those potent neutralizing antibodies, in a smaller Phase 1 trial, before mass vaccination happens, but if that bar is passed, all the good evidence says we should plan on mass vaccination to prevent potentially millions of infections and deaths.

      1. Derek Lowe says:

        Dengue is truly a beast, and as you say, we should be very glad that the coronavirus doesn’t share its immunological properties!

        1. NL says:

          But just to correct a fine point in Derek’s excellent post: The Sette paper does not actually address ADE. The relevant quote is: “There have been concerns regarding vaccine enhancement of disease by certain candidate COVID-19 vaccine approaches, via antibody-dependent enhancement (ADE) or development of a TH2 responses (Peeples, 2020). Herein, we saw predominant TH1 responses in convalescing COVID-19 cases, with little to no TH2 cytokines.”

          1. loupgarous says:

            Thanks to everyone for your thoughtful answers.

      2. Riah says:

        Do you think ADE may be the reason we are seeing Kawasaki like cases with SARS-CoV-2? So prior priming in some unknown way of the the immune system by certain childhood vaccines (some more than others) which then cause an abnormal reaction when the child then comes into contact with particular viruses? Kawasaki cases started in the 60’s.

  10. Derek Lowe, in this text (, you told us

    And then you have some answers to the previous immune puzzles: the body is able to recognize so many antigens because we constantly carry a ridiculously huge variety of antibodies in our B cells, much more than will ever be activated in the life of any individual. And we “increase” the response to these antigens, selecting those that target and with their carrier cells multiply and produce a large number of these specific antibodies. And finally, some of these cells are specifically designed to stay behind, surviving for decades, as a repository of things that worked back then, just in case that specific pathogen appears again. ”

    In this way, therefore,
    T cells recognize the combination of MHC molecules and the antigenic fragment and are activated to multiply rapidly in an army of specialized T cells.

    A member of that army is the cytotoxic T cell. Cytotoxic T cells recognize and destroy cells and tissues that do not belong to the body or cells infected by viruses. Another T cell is the memory cytotoxic T lymphocyte, which remains latent in the body. If, at some point in the future, these T cells encounter this specific antigen, they will quickly differentiate into cytotoxic T cells, forming a fast and effective defense.

    Helper T cells coordinate specific and nonspecific defenses, largely by releasing chemicals that stimulate the growth and differentiation of T and B cells.

    Suppressor T cells inhibit the immune response so that it stops when the infection is cleared. Although the number of helper T cells increases almost immediately, the number of suppressor T cells increases slowly, allowing time for an effective first response.


  11. S says:

    This work is much needed but suffers from very less sample size (n=20 for unexposed and n=20 for exposed individuals) and therefore, this is not a reliable statistics. One cannot know if these findings can be extrapolated at large population level, thus.

  12. Athaic says:

    Immunology, complicated? Perish the though!

    And you’re going to hate me for saying this, but that’s where things get complicated. Immunology!

    Eh, when I tried to describe to an antivaxer the basics of B-cell and T-cell behavior, he accused me of spinning and making things up.
    Granted, I was not as articulate as Derek here.
    (note to self – save the link for further reference).

  13. Calvin says:

    I am not of the view that the lack of ADE observed has much value. It’s good that there is no immediate ADE but that still doesn’t give much comfort. Don’t forget that the Sanofi Dengue vaccine saw no ADE during development. It was only after they got through Phase 3 they started seeing it. It takes about two years after immunization for it to show up. Why 2 years? Who knows. B-cell maturation? Anyway Sanofi had no real idea it was there and even when it appeared they didn’t really believe it.

    So as ever we’ll just have to do the experiments and sorta cross our fingers here. We still don’t know the long term effects of this virus so we just have to do the science

    1. Oudeis says:

      “Do the science.” Amen, brother.

      Do I know whether antibodies can make SARS-CoV-2 worse? No.

      Does anyone? No.

      Are smart people paying attention to the problem while they develop vaccines? Yep.

      So it’s good to see signs that it isn’t happening, but as with nearly everything in this pandemic, there’s no sense setting opinions in stone right now. Wait and see, and in the meantime, be careful.

      1. Immunologist says:

        Yes, it took time and frankly very unfortunate events to discover ADE for dengue. However, we’ve had a lot more time than that for lots of other vaccines, and lots of other viruses without vaccines, and still no compelling evidence of ADE in any other human viral infection. My explanation was more out of caution against over-emphasizing the risk of ADE – given that the evidence is pretty shaky at best for coronaviruses (and basically all non-dengue viruses) in general, and non-existent for SARS-CoV2 specifically, it’s probably not worth changing our plans based on that risk. Derek wasn’t advocating for this, but others have suggested slowing down vaccine trials (as one example) out of a concern for ADE. I think the risk of something like improper manufacturing control from rapid scale-up is bigger than the risk of ADE from rushing into a vaccine expansion (and that’s also hopefully quite low, as long as we’re aware going in!). Doing the science requires we aren’t paralyzed by fear, so let’s go at the fastest reasonable pace and hope for the best.

        1. Oudeis says:

          Thanks. The info is much appreciated.

          That’s interesting about Dengue. Is there anything you’d recommend reading about those unfortunate events, or why Dengue is so unusual in this way?

          1. Immunologist says:

            The possibility of ADE of Dengue goes back a very long time – at least back to the 70s ( for discussion and early in vitro experiments). Definitive proof in humans did have to wait a while – there was some suggestion in the initial Ph3 clinical trial results ( but it took a longer time to see the real effects ( One of the particular “unfortunate events” was a vaccination campaign in the Philippines that prompted severe backlash that may have had (negative) impact on overall vaccination rates in the country –, and a host of associated news articles from the time pointing blame in every possible direction.

            One explanation for why ADE is a real phenomenon in Dengue infection has been the circulation of multiple serotypes of the virus, such that it is relatively easy to have non-neutralizing antibodies from a previous infection with a different serotype. Dengue is also good at infecting and replicating in macrophages and similar cells and avoiding the extra cell-intrinsic immune responses present in those cells, which is not a path many viruses take. Not being a virologist, I don’t know the full state of how we understand Dengue pathogenesis aside from saying it’s considered “weird” – you get things like cytotoxic CD4 T cells ( and ADE, and the whole flavivirus family has some interesting features like a relative propensity for neurotropism and a potentially super polyfunctional NS1 protein (

            ADE popped up as a concern with the Zika outbreak, since both Dengue and Zika are flaviviruses and there is some level of cross-reactivity in antibody responses between the two. The idea was that pre-existing antibody responses to Dengue may enhance Zika infection. The short response is there’s no good evidence of that happening in humans. Here’s a pretty succinct review on Dengue / Zika cross-reactivity and ADE in humans – and the differences between ADE in vitro and ADE as an epidemiologically meaningful phenomenon: Again, it’s very difficult to prove a negative, but ADE really properly relies on epidemiological evidence as well as meaningful infection of myeloid cells that can take up antibody-coated virions (

  14. nathanbp says:

    Thanks very much for the detailed immune system explanation.

    1. Derek Lowe says:

      Thanks! But if you want detailed, you’d better sit down for a while and bring plenty of food and water. Every door you open in the study of immunology leads to another hallway full of doors. . .

      1. Glen L Weaver says:

        Detailed study of immunology is a never ending night alone in the Miskatonic University Library.

      2. Grumpy Old Professor says:

        So true, and still genuine surprises coming forward… it’s barely any time since the ILC system was discovered; a whole ‘new’ immune system protecting the interface between the outside of the body and the inside. I love it!


    2. loupgarous says:

      Thanks, again, for remedying my ignorance re: ADE in dengue virus vs. the other viruses.

  15. RA says:

    Hi, I was wondering if you have those reactive CD4+ cells (i.e. from prior infection with common cold coronaviruses) and they are protective, whether you would still generate covid-19 specific antibodies upon exposure?

    1. Derek Lowe says:

      One of the functions of the CD4+ cells is to assist B cells in making antibodies, so the response should be even better. There are several varieties of CD4+ cells, of course, some of which are involved in self/nonself immune recognition (among other things), but if things are working as planned the effect should be beneficial.

      1. RA says:

        Thank you! That makes sense…I am curious about how that fits with the finding that some with mild symptoms have weak antibody responses.

  16. dhdhdhhdhhddhhd says:

    This whole thing harkens back to the old debate about ” can we understand what we don’t see??”. A few years ago i would have said yes: we have the science departments at Harvard, MIT, Scripps, whatnot….that is their specialty right? Now, Im not so sure. EM might be a good way to go because its a new way to ‘see’, but I would frankly just trash all of the X-ray (watson/crick) field because that doesn’t amount to a way to meaningfully ‘see’ apparently. I mean, if they didnt find a way to stop a virus with x-rays after 100 or so years of work, whats the point? How long are we going to beat this horse?

      1. Dfroolkffggvv says:

        Ya you dont get it and never will…..maybe do another PhD??

  17. Erik Dienemann says:

    Is there any chance that some, most or even all of the 40-60% of unexposed individuals who had reactive CD4+ T cells, suggesting cross-reactivity, which might be partially protective against this new virus, would be more than “partially protected?” Like fully protected, i.e., immune? Obviously, even if it were “some” that would be huge. Also, do you know what additional studies/data are required to determine if there truly is any level of SARS-CoV-2 immunity in the kinds of patients showing this kind of cross-reactivity?

    1. RA says:

      The corollary to this question is whether a somewhat widely available test could/should be developed to let people know if they have these reactive cells?

      1. johnnyboy says:

        Detecting CD4+ cells is already fairly involved type of lab work, detecting CD4+ cells recognizing a specific antigen is even more. Not something that could be made available to the wider population, like an antibody test is.

        1. RA says:

          Thank you! That’s too bad…essentially a lot of people might have some level of protection, but there is no way for them to know they have it. Makes policy decisions hard!

        2. Erik Dienemann says:

          I can imagine it being difficult to evaluate CD4+ cross-reactivity in unexposed people to assess potential immunity (if that is possible). However, it would certainly be worth knowing more about what that cross-reactivity might do for people with that characteristic. I also wonder if there was anyone in the study under 18, given how much less susceptible that age group is to having serious illnesses from the virus – might they have, on average, higher levels and higher frequency of cross-reactivity than other age groups?

  18. johnnyboy says:

    Another good piece of news from the article is that all patients tested (who all had relatively mild cases) had circulating antibodies to the virus. It’s a pretty small n, but still nothing to indicate that Covid infection would not be associated with detectable antibody (which would greatly complicate detection of immune individuals)

    1. RA says:

      That is good news! I do wonder what the results of this study would be like in a sample of completely asymptomatic cases identified through screening.

  19. Chemist says:

    Thanks, Derek for being the Light House in this storm! All the sensible commentators also to be commended for guiding the rest of us. Anyhow, as a small molecule Natural Product-based medicinal chemist, I wonder as to whether there is any way to increase CD+4 cells/ immunity either with single small molecules or cocktails of NP extracts? Thanks in advance

    1. Barry says:

      not strictly a “small molecule”, but yes CpG alone will boost DC+4 activity. Whether that’s a good general strategy is not as clear. It’s a whopping potent adjuvant. Activating TLR9 revs up an impressive immune response.

  20. Anon says:

    Does ADE happen only with vaccine immunization? Why?

    Why is it not seen with immunization resulted from infection?

    1. sgcox says:

      It does.
      Here is one of the papers, there are many more.

    2. RA says:

      I am also curious about how the risk of ADE would potentially vary based on the different vaccine types being considered (i.e. viral, viral vector, nucleic acid, protein-based?) Do we know enough to think that some types would have less of an ADE risk than others?

  21. steve says:

    Immunologist – I’m afraid you’re wrong. I’m an immunologist as well and other vaccines have indeed shown ADE. Dengue is the classic but the RSV vaccine was halted because of it as have other flavi-, paramyxo-, and lentivirus vaccines. More alarmingly, the first SARS vaccine also had to be halted because of ADE. It’s a real concern and the rush to get a vaccine out for SARS-CoV-2 has definite dangers associated with it.

    1. Immunologist says:

      Very interesting Steve! Can you point me to a SARS vaccine ADE reference? I had never seen any data from vaccine trials or human epidemiology for any diseases besides dengue (or RSV, but more on that below), but very happy to learn more. I’ll reiterate that I think a smaller Ph1 showing that the vaccine induces a strong, neutralizing response is absolutely necessary. If that’s the case, my best hypothesis from all the experience and data I’ve seen is that that kind of vaccine is going to be safe (from an ADE perspective) and effective and epidemiologically useful to shut down this pandemic and that warrants going ahead very quickly once that first key step is established. Real evidence of ADE *in humans* (not in vitro, not in animal models) with a *good* (capable of inducing robust neutralizing antibody response) SARS vaccine would change my mind and make me want more caution.

      On RSV, my impression was that enhanced RSV disease was due to immune complex formation with non-neutralizing antibodies (happening even without vaccines in the case of maternally transferred antibodies in some cases) and/or Th2-skewed immunity (as mentioned above) from the vaccine dose, and the subsequent inflammation was particularly dangerous in infants – which in the case of RSV happens to be the population of concern. This is distinct from increased infection of Fc-receptor expressing cells, and therefore not really something that’s tied to or predictable the in vitro macrophage-infection kind of experiments that are normally done to suggest ADE. So it’s an antibody-dependent enhancement of disease, but not infection, and most of the conversation that I’ve heard around SARS-CoV-2 has focused on the second and is being justified by those type of in vitro experiments.

      There’s other complicated aspects of ADE – like this suggestion that antibody-mediated transcytosis through FcRn drove placental infection in a pregnant woman with COVID-19 ( That event happened with a naturally induced high-titer response. I honestly have no idea if vaccination (again, I’m only talking about “good” vaccination) would increase the rate of this kind of event, or decrease it by preventing maternal infection in the first place. My guess would be decreasing circulation / infection burden by widespread vaccination probably outweighs the odds of increased events like this, but honestly that’s just a guess.

      1. sgcox says:

        I am not immunologist and can really judge how good/accurate this cars-1 paper but I guess fears of ADE might have some basis. Lets hope sars-2 vacines will not be compromised.

  22. steve says:

    RSV was prototypical ADE. There’s a ton of articles on ADE and vaccines of all kinds – just go to Pubmed and search on ADE. It’s a well-known issue in the vaccine field and has been well-described for SARS in the first pandemic. In fact, there’s even a theory that the reason some people get such bad C19 symptoms is because they have pre-existing antibodies from exposure to other coronaviruses that cross-react and cause ADE. The Oxford group specifically looked for ADE in their macaque study as did Moderna in their mRNA Ph1 study. Neither saw it but it doesn’t happen with everyone so it will need larger Ph2/Ph3 studies to know for sure.

    1. Immunologist says:

      I’m aware of the hypothesis that pre-existing anti-coronavirus antibodies may exacerbate COVID-19 – it’s been mentioned in the comments on this blog, which is what prompted my initial comment. There’s (admittedly not very strong, given short times and small sample sizes) evidence against the hypothesis of SARS-CoV-2 ADE in humans, and nothing I’ve seen in favor of it. Sinovac also saw no evidence of ADE in NHP (, although again I think that it’s still not strong evidence and disproving things is very hard. I don’t see compelling evidence for ADE of infection *in humans* of anything besides dengue, unless you can point to a specific reference.

      I’ll stand by my statement that there’s nothing to say the risk of ADE is particularly concerning and so we should continue at the fastest prudent pace, check for immediate risks in a small trial, confirm a vaccine does we want in terms of immunogenicity, and scale rapidly while being on the lookout for safety concerns that emerge. There’s not really evidence to say ADE is a higher risk than any of the other potential safety concerns that could emerge when moving quickly (allergies to ingredients, especially with these new modalities like mRNA, etc), so slowing things down for ADE specifically seems unreasonable right now.

      I went on pubmed and searched for RSV ADE – 9 results. The only one with human data is this (, which isn’t fantastic in terms of number or controls but does not show any real relationship between in vitro ADE (enhancement of infection of THP1 or Fc-receptor expressing Vero cells) and severity of disease. Other reading on “enhanced RSV disease” (ERD), which is a far more commonly used term, pops up a lot of things about maternally transferred antibodies acting in a non-typical ADE manner (i.e. most risk at highest titer, immediately after birth, instead of later when levels drop as is observed with dengue and would fit the general model of hook-shaped responses with ADE of infection – this observation goes back a very long way []) and T cell responses ( and to pick a couple), including across animal models.

      Same goes with SARS antibody dependent enhancement – pubmed pulls up 19 results, none of which are human data, and with conflicting results from animal models (no ADE in, even with low titers, no ADE in this one either, but epitope-dependent ADE in this one No ADE results from human clinical trials on pubmed. None after a while of google-scholar-ing either. If there’s actual evidence of worse infection / disease in vaccinated humans, it’d be great to see.

      1. steve says:

        Again, ADE was a problem with the first SARS and the first SARS vaccine so you may stand by your statement but it’s factually incorrect.

  23. steve says:

    And NHLBI halted development of RSV vaccine due to ADE. Here is a review. You are drastically underplaying a problem that everyone who is actually involved in vaccine development knows is a severe one.

    1. Immunologist says:

      Thanks for pointing me to this review. It says what I said (or at least, what I tried to say) – “In essence, two immune correlates are accepted as the main determinants of enhancement: the presence of low-avidity, non-protective antibodies elicited by immunization and a polarization of the immune response toward T helper 2 (Th2) in the respiratory tract after RSV infection. Non-protective antibodies form pathogenic immune complexes in the lung that lead to complement activation and simultaneously fail to inhibit RSV replication.” That’s ADE of disease, not infection. It has nothing to do with increased infection of myeloid cells by uptake through Fc receptors. So seeing antibody-mediated uptake of virus into macrophages in vitro has nothing to do with ERD, according to that review. I pointed to evidence in humans that shows exactly that point, with no strong link between in vitro ADE of infection and severity of disease in RSV. I also pointed to evidence about SARS vaccines showing variable ADE in preclinial NHP models, and multiple examples of vaccines with no evidence of ADE (of infection *or* disease) – so a good vaccine can solve that problem in a model where we know ADE is possible with a bad antibody response.

      I only know several people clinically involved in vaccine development – it’s not my field, but I’m adjacent enough to know and talk to them. Most, but not all, say that ADE is worth watching for (just like any other safety signal) but would probably be highly predictable based on quality of immunogenicity from the early studies. That may not reflect everyone’s opinions. They say that the goal is to get a good vaccine inducing high-titer neutralizing antibodies and is safe from other perspectives (allergies, etc), and they’re happy putting it in as many people as they can get lined up as quickly as possible once that is clearly established. I’m presenting the evidence that I’ve seen that justifies that opinion, which seems to me to be pretty good.

  24. Kevin says:

    I’m no scientist but I came across this article as I am a very curious citizen. I don’t pretend to understand the vast majority of what is being said and it seems that immunology is “dizzying” to say the least (for me), but something stuck in reading all of these responses. ADE is bad when it comes to a vaccine. If that’s true – why the lockdowns when over 99% of people under 60 are likely to live (especially if you don’t have any underlying health condition) – doesn’t natural immunity make more sense to create herd immunity? Are we doing humanity a disservice by waiting for some vaccine that may actually cause more damage if ADE is a concern? I only ask because it just seems that our current leaders aren’t giving us all the details. Sorry if this is a dumb question.

    1. Derek Lowe says:

      Not a dumb question at all! ADE is something that we have to look out for, especially since it was seen on the SARS vaccine work. But we have a good idea of what to look out for, and the hope is that we have so many candidates coming (via so many platforms) that we should be able to get around it.

      The other problem is that it appears that only single-digit percentages of people have been exposed in most populations – only places like Madrid and NYC have higher. That means that a *lot* of people have not been exposed, and we still have the fatalities that we do. “Herd immunity” would need perhaps 70% of people to have been exposed, and that is likely to kill up to several million people in the US. A vaccine is not going to cause more damage than that – we’d see that coming in the clinical trials.

      1. intercostal says:

        I think part of the idea is that we could protect only the elderly – ie 70% or whatever of the population would still get exposed, but it would be the 70% of the population that is under 55, so dramatically fewer deaths and other bad outcomes would result.

        Could you explain a bit more why that wouldn’t work? (I’ve heard that it wouldn’t, and I don’t really doubt that, but would like a better explanation.)

        1. Riah says:

          my thoughts have been going along similar lines to Intercostal’s and Kevin’s. So basically doing what Sweden is doing except protecting the elderly and care homes better than they managed to do(50% of deaths there have been in care homes). Also do you think these two other advantages to naturally acquired immunity may be worthy of more consideration: Firstly, shouldn’t natural infection provide immunity to a wider range of antigens and so possiblly a measure of protection against future viruses with cross reactive antigens? Similar idea to Thiel’s findings that prior common cold Coronovirus infections (from looking at 2015-18 blood)have resulted in 34% of people having T cell cross reactivity to SARS-Cov-2 and therefore hopefully at least some measure of protection. Secondly, wouldn’t natural immunity be longer lasting?

      2. Dr AV says:

        I keep wondering, if a skin test, similar to the Mantoux was for TB, could test the availability of a T cell response (type IV cellular response). Even if just a cross reaction for COVID-19. I think the antibody response may be weak or even wane over time, but the T cell response measured by the skin test may remain, with a longer memory. Even an aspecifically strengthened T cell response may have caused by a remote BCG mitigated the spread of COVID infection in certain countries where BCG is still mandatory.

      3. Nic Lewis says:

        You say that ‘“Herd immunity” would need perhaps 70% of people to have been exposed’. I know that is what simple compartmental epidemiological models (SIR, SEIR) imply, but that is only because they assume (very unrealistically) that the entire population is homogeneous as regards susceptibility and infectivity. In reality these are both highly inhomogeneous because social connectivity affects them both and varies a lot (think of “super-spreaders”: 10% of people are estimated to cause 80% of infections), and susceptibility also varies due to other factors, including biological factors such as general health, immune system state, genetics, etc.

        Inhomogeneity in susceptibility, and in infectivity insofar as correlated with susceptibility, can easily be shown to reduce the herd immunity threshold – quite possibly by a factor of several times. I have written an article explaining this effect and giving illustrative examples of its possible magnitude. It is available here:

  25. joe denney says:

    Great article and interesting comments. And reads like good news. Thanks. I fondly recall the old jokes about scientists not being able to cure the common cold. I think people have a better understanding why this would be so difficult! And I can answer that ADE could be a problem (not that I would try to explain the science). I hope further research is funded in all areas…from pathology of the common cold to tracking of future pandemic culprits. Have found the variety of symptoms, timescale, reactions – the pathology – fascinating to follow. Several cases in my family (with positive test in hospital for one member) ranging from stomach bug with no other symptoms to classic case (me unfortunately) which was like flu+ with a doubling of asthma. How does that happen? Appreciate without thorough testing might not be Covid19. But even the classic cold would not cover the range of symptoms including loss of taste! And disparity in various groups. I look forward to another win for science in the future on this one…

  26. Asking for a friend says:

    There are reports that some people have lingering symptoms (even for over 2 months) – could it be that the virus is long gone but their immune systems are attacking their own bodies causing a variety of weird symptoms?

  27. NICK says:

    We should have a certain portion of the population who is able to use the innate immune system to neutralize Sars COV2 – what percentage and how to measure? Then we have the rest of the population that will use the adaptive immune system (T-cells) about 34% is immune. The rest – majority have none to mild symptoms. Then we have the rest that are hit very hard old with comorbidity and the young children – a very small percentage of the population.

    1. NICK says:

      Not all children. Very small percentage of children who get the multi organ inflammatory syndrome

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