20 ms·

SARS-CoV-2-specific immunity in Covid-19 and SARS cases, and uninfected controls

72 points by guscost 6y ago

gridlockd 6y ago
Unfortunately, it doesn't go into detail where exactly these samples come from. It's seems plausible that animal coronaviruses induce an immune response in humans that can later help against SARS-CoV-2. If so, there should be a correlation between animal contact and COVID-19 severity.
- christkv 6y ago
  There are human beta coronavirus as well. One question nobody has answered yet is if parents with young kids are getting less ill due to cross immunization from all the colds young children bring home
  - war1025 6y ago
    I've been (perhaps naively) banking on this. We've had just about everything pass through our house in the past four years since we had our first kid. Have to imagine something in there is good for immunity.
    - deleted 6y ago
      [deleted]
- __blockcipher__ 6y ago
  No need to bring in animals to explain this. There are a handful of human coronaviruses - I think 4 that are not SARS-related, but I’m on mobile so will have to dig up the study later. Besides, once a virus jumps from an animal it either becomes a human virus (capable of spreading), or somehow is a one-off virus that can jump from animal->human but not subsequently to another human. If the latter, that effect is so negligible it would not explain 20-50% of SARS-CoV-2-naive individuals having t cell reactivity. —- While I’m at it, just a reminder to all that SARS-2 overall is a fairly mild virus, and the level of hysteria and death-inducing counterproductive response (lockdown, suspension of elective surgeries like Newsom did for a month here in California) is completely divorced from the fundamentals of this virus. Also a reminder that unlike flu, SARS-2 primarily kills the very old / very unhealthy, whereas flu kills the very young and the very old. Thus when you run the math on population dynamics / herd immunity, the recurring yearly deaths will be vanishingly low (unlike flu) and thus amortized across years, SARS-2 is even leas deadly than the current numbers imply. This is because once it has passed through the population, the set of SARS-CoV-2 naive individuals becomes dominated by new entrants to the world (babies/toddlers) who essentially have 0 risk of dying from COVID (it’s basically a rounding error). Thus while SARS-CoV-2 is and will remain endemic (circulating in the population), it will barely kill anyone once the current world population is largely exposed to it. — Finally, a reminder that mentioning stuff like the above tends to result in censorship from social media platforms, which combined with the incredible bias of “news” organizations like CNN etc, means that those who are plugged into the matrix will never encounter real information about this threat. And surprisingly (although in retrospect it shouldn’t have been surprising to me), there are a lot of people on HN that have dranken that very kool-aid and thus will reactively downvote or even flag commenters who present their beliefs (however founded or unfounded) about the true danger of this virus versus its purported impact. Also, since I’m already ranting, I just want to throw out that the narrative around “long-term damage” (often stated to be lifelong) is completely unfounded and contradicted by the research we already have about SARS-1, which is SARS-2’s much more deadly yet much less popular older brother.
  - berdon 6y ago
    > Thus while SARS-CoV-2 is and will remain endemic (circulating in the population), it will barely kill anyone once the current world population is largely exposed to it. You mean once _all_ the people who could die from it, have died from it?
    - __blockcipher__ 6y ago
      Once all the people who exist today, yes. I anticipated this response of yours. It sounds like a great gotcha in its surface, until you realize that every fast-spreading respiratory virus works like that. It's happened with every flu pandemic, including the recent H1N1. SARS-CoV-2 appears to be an incredible spreader and a poor killer. What that means is the cost of perpetually trying to avoid infection are very high, whereas the benefits (avoided mortality) are quite low. Case in point, SARS-CoV-2 exhibits a fairly high degree of pre-symptomatic spread. I believe that this is almost certainly due to the findings of interferon-mediated early-course immunosuppression (read: in the early days of infection it prevents your immune system from reacting strongly, meaning that unlike many other diseases there is a period where you have enough viral load to spread it yet don't express symptoms). Also note that it does not exhibit asymptomatic spread, which would be even "worse" since pre-symptomatic spread only gives you a window of maybe days whereas asymptomatic is by definition across the whole disease course. Now factor in the fact that many people are either completely asymptomatic or paucisymptomatic (few symptoms). For those people, which may even be the majority of cases, it's such a not-big-deal that most don't ever realize they've had it. Some will have more of an actual cold, and some will have symptoms comparable to a run-of-the-mill flu. A small fraction of those infected will go on to experience increasingly severe symptoms, probably comparable to a normal SARS-1 infection (since SARS-1 is quite nasty), culminating in the worst cases in the need for invasive ventilation at which point death is incredibly difficult to avoid. (This is obviously an area of active research but it appears that the severe form of the disease is related to a state of immune disregulation where pathological cytokine release syndrome, the tissue damage from widespread neutrophil infiltration, etc wreak havoc). So, we have a virus that spreads incredibly well, yet is overall incredibly mild, and has very well-defined populations who are at real risk of severe outcomes. That is precisely the type of virus that is a horrible candidate for lockdown, which damages the entire society in the attempt to prevent what is perceived as a greater threat (but is actually not, in my opinion). So, as a society we saw a papercut and chopped off our hand. Oops. I am happy to provide sources for pre-symptomatic spread, interferon-mediated immunosuppresion, etc, but first I wanted to make sure that you were here to engage in good faith dialogue; i.e. whether I can convince you or not, you are actually willing to read (or try to read) the papers. I'm a bit scarred by numerous times (here and elsewhere) where I've invested a bunch of time into detailed posts and then quickly realized that the person on the other end was never serious about addressing the problem of SARS-2 but instead was there to toe the party line and reinforce their pre-existing conclusions.
jhayward 6y ago
Derek Lowe's latest commentary on SARS-COV-2 immunity and this paper specifically: https://blogs.sciencemag.org/pipeline/archives/2020/07/15/new-data-on-t-cells-and-the-coronavirus https://blogs.sciencemag.org/pipeline/archives/2020/07/15/ne...
notatoad 6y ago
I know that as somebody who isn't a scientist, i'm not the intended audience for pre-print articles in scientific journals. would anybody mind providing a summary of conclusions for the general audience here?
- guscost 6y ago
  Derek Lowe's blog (linked by jhayward, thanks) has a good rundown of the recent T Cell research and what it means in general: https://blogs.sciencemag.org/pipeline/archives/2020/07/15/new-data-on-t-cells-and-the-coronavirus https://blogs.sciencemag.org/pipeline/archives/2020/07/15/ne... But, he (and the paper authors!) seem to skim right over what might be the most important conclusion: > Recognition of the nsp7 and nsp13 proteins is prominent, ~as well as the N protein~. And when they looked at that nsp7 response, it turns out that the T cells are recognizing particular protein regions that have low homology to those found in the “common cold” coronaviruses – but do have very high homology to various animal coronaviruses. This "NP" or "nucleocapsid protein" has high homology to "common cold" human betacoronaviruses (OC43 and HKU1), so this basically means that previous exposure to these colds should confer some degree of immunity to SARS-CoV-2. The novel result that everyone seems to be dwelling on is interesting too, it raises the possibility that coronaviruses are transmitted from animals to humans more often than had been previously thought.
solinent 6y ago
I remember at the start of this an infectious diseases professor commented how if you had the antibodies already against CoV you'd be fine, but if you had only half, you were at a significantly higher risk of death. I guess the immune system can misidentify as well--I bet we haven't taxonomized everything fully yet so eventually we'll have a new name for what immunity is required.
- EGreg 6y ago
  Sorry can you rephrase? What do you mean by half?
  - solinent 6y ago
    I have no clue! I just heard this a while back on some random video three months ago from an infectious diseases professor. My knowledge of biology is very low, I really shouldn't be speculating publically, I thought it was less controversial knowledge. I've probably just phrased it badly or remembered it in too simple of a manner due to my lack of background here. I think half is a simplification, it must mean that if you have the wrong type or quantity or some combination thereof, but again I'm guessing and not an expert or even a professional.
    - __blockcipher__ 6y ago
      The closest thing I can think of is https://en.wikipedia.org/wiki/Antibody-dependent_enhancement#Potential_linkage_between_pathophysiology_of_COVID-19_and_ADE https://en.wikipedia.org/wiki/Antibody-dependent_enhancement.... There's no way in which having real antibodies, but a reduced amount of them, would be worse than not having antibodies, but the following is very possible: > It is likely that in older people the production of antibodies is slower and by the time the antibodies are developed in the titer that is sufficient to neutralize the virus, the virus changes its antigenic determinants. In this case, immuno-dominant neutralizing antibodies might start forming unstable complexes with the new form of the virus and start to infect monocytes/macrophages causing ADE. This process can trigger generalized infection of immune cells in multiple organs and cytokine storm
__blockcipher__ 6y ago
First of all, here's the full text in-case anyone isn't aware: https://www.nature.com/articles/s41586-020-2550-z_reference.pdf https://www.nature.com/articles/s41586-020-2550-z_reference.... Before the actual paper, some review. REVIEW SECTION 1 Coronavirus is a family of viruses, viruses being basically pieces of genetic material that swim around, inject their DNA into other cells, which makes the cells produce more copies of themselves until thousands of baby viruses explode out of the cell, killing it and moving on to the next cell. COVID-19 is the condition that results from infection with SARS-CoV-2, which is a novel coronavirus that almost certainly emerged sometime in 2019. Think HIV/AIDS: HIV is the virus, AIDS is the disease, same with SARS-2 vs COVID-19. SARS-CoV-2 while technically novel, is incredibly close related to what we now call SARS-CoV-1, which we used to just call "SARS". SARS-1 was incredibly deadly, but the pandemic fizzled out, presumably because it is quite deadly/quite symptomatic and AFAIK there isn't pre-symptomatic transmission. SARS-CoV-2 structurally is very similar, sharing the same characteristic spike protein, and targetting the same ACE2 receptor which is expressed differentially in different tissue types. But SARS-CoV-2 is like a refined version of SARS-1, it "learned" from SARS-1's mistakes. So, it appears to be adapted to spread quite well, possibly because of cool things it does with interferon-mediated early course immunosuppression, which lets it spread for a few days before you show symptoms. It's also much less deadly than SARS-1. Now, to craft the "optimal" pandemic virus, you want something that spreads easily, has a long incubation time, and isn't too deadly (otherwise it fizzles out by killing its hosts before they spread sufficiently). So in that sense, SARS-2 is perfectly crafted to kill a bunch of people. But please don't fall into fear-mongering, it doesn't kill nearly as many people as most have been led to believe. In my opinion it's really quite a mild virus overall, but some people can have severe COVID-19 which presents very similarly to a more run-of-the-mill SARS-1 infection (remember the original SARS is very deadly, so run-of-the-mill != no-big-deal). REVIEW SECTION 2 We've talked about SARS-1 and SARS-2, but let me briefly butcher the immune system (I can already hear the immunologists stampeding towards me in the distance). Your immune system's job is to distinguish self from non-self, (or more accurately, "non-self that is actually a threat" since you can have bacteria/etc that are not pathogenic/pathological). When it identifies a target, it has a lot of cool ways to kill it, but the specifics of neutrophils and antibodies, etc are out of scope. For now, take it as given that your immune system can detect and kill pathogens. Once it has fought off an infection, you will likely have antibodies, which are little heat-seeker-missiles that are primed to detect and neutralize the pathogen in question. (Note there's also T-Cell immunity which operates perhaps orthogonally to antibody immunity. This paper talks about T-Cell immunity). Assuming you produced antibodies, eventually your active circulating antibodies will fade. This takes several weeks-a few months for SARS-1, and seems to hold for SARS-2, although I believe antibody prevalence is correlated with disease severity. So eventually you have no more circulating antibodies. Contrary to what doomers will tell you, that's not a bad thing, it's inefficient to perpetually maintain antibodies. So instead your body maintains a living library of the pathogens it has previously encountered. I'd encourage anyone to read about https://en.wikipedia.org/wiki/Immunological_memory https://en.wikipedia.org/wiki/Immunological_memory. I'll summarize briefly. (1) After infection, even when antibodies fade, you still have circulating Memory B Cells which persist across decades, waiting for exposure to the previously-fought-off pathogen at which they ramp up antibody production, leading to a faster, more strong response that results in lower peak viral load, presumably lower transmissibility/symptoms/etc. So, eventually it's possible to get reinfected as far as antibody immunity is concerned, but it takes quite awhile and when it does happen it's not nearly as bad. (2) There's also memory T Cells, which are similar except instead of relying on antibodies, they work with T cells, with basically directly kill pathogens rather than indirectly produce the antibodies with neutralize the pathogen. Okay, now it's time for THE ACTUAL PAPER The first finding is not surprising at all to anyone who has been reading research, but probably surprising to everyone else (read: almost everybody): if you've been previously exposed to SARS-1, you have memory T cells which persist long-term and will happily attack SARS-2. Remember when I said SARS-CoV-2 was a novel virus? Well, it was, but it was also incredibly similar to SARS-CoV-1. So, technically it's novel but in real terms it's only a little bit novel, so previous SARS-1 infection is protective. Well, that's cool, but most of us have never been exposed to SARS-1. But many of us have been exposed to one of the handful of other human coronaviruses that we know about. The somewhat shocking (maybe not shocking to those who have been reading about immunology for years) revelation in this paper is this: > Surprisingly, we also frequently detected SARS-CoV-2 specific T cells in individuals with no history of SARS, COVID-19 or contact with SARS/COVID-19 patients (n=37). In other words, people never exposed to either of the two SARS viruses showed immune activation against SARS-2, meaning that they are either completely or partially immune to SARS-2. Why? Because they've almost certainly been exposed to some of the other human coronaviruses, which basically cause common colds. (Side note: For almost everybody SARS-2 is not any different from the common cold. It's quite rare to have severe SARS-2, but those that do get it experience very bad effects, since their immune system is basically ravaging their entire body) --- So the TL;DR: any model that has assumed that everyone can get infected is completely wrong and will massively overestimate the ultimate death of letting SARS-2 rip through the population. Many people will never be able to get SARS-2 because they've already fought off similar-enough human coronaviruses. (BTW, coronaviruses are very distinctive in structure so that is likely why our immune systems exhibit this cross-reactivity) Implications: (Warning: Strong opinion) As a result any cost/benefit tradeoffs of, say, lockdown, based off those models was off by a huge factor. The good news is, that even with the assumption that everyone was susceptible (capable of being infected), it was still really obvious to anyone with the capacity for rational thinking that containment/lockdown was a terrible idea, so these findings don't really change too much on that front, it just makes it even more overwhelmingly obvious that we collectively lost our shit and chopped off a limb in response to a papercut. So, instead of us (meaning, everywhere except Sweden) being super duper wrong, we now have good evidence that we were actually unimaginably, insanely wrong, to a degree that will be studied by subsequent scientists for decades as an example of where social contagion, groupthink and censorship led to one of the most damaging events in modern human history. Woot!

72 points by guscost 6y ago

Unfortunately, it doesn't go into detail where exactly these samples come from. It's seems plausible that animal coronaviruses induce an immune response in humans that can later help against SARS-CoV-2. If so, there should be a correlation between animal contact and COVID-19 severity.

christkv 6y ago
There are human beta coronavirus as well. One question nobody has answered yet is if parents with young kids are getting less ill due to cross immunization from all the colds young children bring home
- war1025 6y ago
  I've been (perhaps naively) banking on this. We've had just about everything pass through our house in the past four years since we had our first kid. Have to imagine something in there is good for immunity.
  - deleted 6y ago
    [deleted]
__blockcipher__ 6y ago
No need to bring in animals to explain this. There are a handful of human coronaviruses - I think 4 that are not SARS-related, but I’m on mobile so will have to dig up the study later. Besides, once a virus jumps from an animal it either becomes a human virus (capable of spreading), or somehow is a one-off virus that can jump from animal->human but not subsequently to another human. If the latter, that effect is so negligible it would not explain 20-50% of SARS-CoV-2-naive individuals having t cell reactivity. —- While I’m at it, just a reminder to all that SARS-2 overall is a fairly mild virus, and the level of hysteria and death-inducing counterproductive response (lockdown, suspension of elective surgeries like Newsom did for a month here in California) is completely divorced from the fundamentals of this virus. Also a reminder that unlike flu, SARS-2 primarily kills the very old / very unhealthy, whereas flu kills the very young and the very old. Thus when you run the math on population dynamics / herd immunity, the recurring yearly deaths will be vanishingly low (unlike flu) and thus amortized across years, SARS-2 is even leas deadly than the current numbers imply. This is because once it has passed through the population, the set of SARS-CoV-2 naive individuals becomes dominated by new entrants to the world (babies/toddlers) who essentially have 0 risk of dying from COVID (it’s basically a rounding error). Thus while SARS-CoV-2 is and will remain endemic (circulating in the population), it will barely kill anyone once the current world population is largely exposed to it. — Finally, a reminder that mentioning stuff like the above tends to result in censorship from social media platforms, which combined with the incredible bias of “news” organizations like CNN etc, means that those who are plugged into the matrix will never encounter real information about this threat. And surprisingly (although in retrospect it shouldn’t have been surprising to me), there are a lot of people on HN that have dranken that very kool-aid and thus will reactively downvote or even flag commenters who present their beliefs (however founded or unfounded) about the true danger of this virus versus its purported impact. Also, since I’m already ranting, I just want to throw out that the narrative around “long-term damage” (often stated to be lifelong) is completely unfounded and contradicted by the research we already have about SARS-1, which is SARS-2’s much more deadly yet much less popular older brother.
- berdon 6y ago
  > Thus while SARS-CoV-2 is and will remain endemic (circulating in the population), it will barely kill anyone once the current world population is largely exposed to it. You mean once _all_ the people who could die from it, have died from it?
  - __blockcipher__ 6y ago
    Once all the people who exist today, yes. I anticipated this response of yours. It sounds like a great gotcha in its surface, until you realize that every fast-spreading respiratory virus works like that. It's happened with every flu pandemic, including the recent H1N1. SARS-CoV-2 appears to be an incredible spreader and a poor killer. What that means is the cost of perpetually trying to avoid infection are very high, whereas the benefits (avoided mortality) are quite low. Case in point, SARS-CoV-2 exhibits a fairly high degree of pre-symptomatic spread. I believe that this is almost certainly due to the findings of interferon-mediated early-course immunosuppression (read: in the early days of infection it prevents your immune system from reacting strongly, meaning that unlike many other diseases there is a period where you have enough viral load to spread it yet don't express symptoms). Also note that it does not exhibit asymptomatic spread, which would be even "worse" since pre-symptomatic spread only gives you a window of maybe days whereas asymptomatic is by definition across the whole disease course. Now factor in the fact that many people are either completely asymptomatic or paucisymptomatic (few symptoms). For those people, which may even be the majority of cases, it's such a not-big-deal that most don't ever realize they've had it. Some will have more of an actual cold, and some will have symptoms comparable to a run-of-the-mill flu. A small fraction of those infected will go on to experience increasingly severe symptoms, probably comparable to a normal SARS-1 infection (since SARS-1 is quite nasty), culminating in the worst cases in the need for invasive ventilation at which point death is incredibly difficult to avoid. (This is obviously an area of active research but it appears that the severe form of the disease is related to a state of immune disregulation where pathological cytokine release syndrome, the tissue damage from widespread neutrophil infiltration, etc wreak havoc). So, we have a virus that spreads incredibly well, yet is overall incredibly mild, and has very well-defined populations who are at real risk of severe outcomes. That is precisely the type of virus that is a horrible candidate for lockdown, which damages the entire society in the attempt to prevent what is perceived as a greater threat (but is actually not, in my opinion). So, as a society we saw a papercut and chopped off our hand. Oops. I am happy to provide sources for pre-symptomatic spread, interferon-mediated immunosuppresion, etc, but first I wanted to make sure that you were here to engage in good faith dialogue; i.e. whether I can convince you or not, you are actually willing to read (or try to read) the papers. I'm a bit scarred by numerous times (here and elsewhere) where I've invested a bunch of time into detailed posts and then quickly realized that the person on the other end was never serious about addressing the problem of SARS-2 but instead was there to toe the party line and reinforce their pre-existing conclusions.

jhayward 6y ago

Derek Lowe's latest commentary on SARS-COV-2 immunity and this paper specifically: https://blogs.sciencemag.org/pipeline/archives/2020/07/15/new-data-on-t-cells-and-the-coronavirus https://blogs.sciencemag.org/pipeline/archives/2020/07/15/ne...

notatoad 6y ago

I know that as somebody who isn't a scientist, i'm not the intended audience for pre-print articles in scientific journals. would anybody mind providing a summary of conclusions for the general audience here?

guscost 6y ago
Derek Lowe's blog (linked by jhayward, thanks) has a good rundown of the recent T Cell research and what it means in general: https://blogs.sciencemag.org/pipeline/archives/2020/07/15/new-data-on-t-cells-and-the-coronavirus https://blogs.sciencemag.org/pipeline/archives/2020/07/15/ne... But, he (and the paper authors!) seem to skim right over what might be the most important conclusion: > Recognition of the nsp7 and nsp13 proteins is prominent, ~as well as the N protein~. And when they looked at that nsp7 response, it turns out that the T cells are recognizing particular protein regions that have low homology to those found in the “common cold” coronaviruses – but do have very high homology to various animal coronaviruses. This "NP" or "nucleocapsid protein" has high homology to "common cold" human betacoronaviruses (OC43 and HKU1), so this basically means that previous exposure to these colds should confer some degree of immunity to SARS-CoV-2. The novel result that everyone seems to be dwelling on is interesting too, it raises the possibility that coronaviruses are transmitted from animals to humans more often than had been previously thought.

solinent 6y ago

I remember at the start of this an infectious diseases professor commented how if you had the antibodies already against CoV you'd be fine, but if you had only half, you were at a significantly higher risk of death. I guess the immune system can misidentify as well--I bet we haven't taxonomized everything fully yet so eventually we'll have a new name for what immunity is required.

EGreg 6y ago
Sorry can you rephrase? What do you mean by half?
- solinent 6y ago
  I have no clue! I just heard this a while back on some random video three months ago from an infectious diseases professor. My knowledge of biology is very low, I really shouldn't be speculating publically, I thought it was less controversial knowledge. I've probably just phrased it badly or remembered it in too simple of a manner due to my lack of background here. I think half is a simplification, it must mean that if you have the wrong type or quantity or some combination thereof, but again I'm guessing and not an expert or even a professional.
  - __blockcipher__ 6y ago
    The closest thing I can think of is https://en.wikipedia.org/wiki/Antibody-dependent_enhancement#Potential_linkage_between_pathophysiology_of_COVID-19_and_ADE https://en.wikipedia.org/wiki/Antibody-dependent_enhancement.... There's no way in which having real antibodies, but a reduced amount of them, would be worse than not having antibodies, but the following is very possible: > It is likely that in older people the production of antibodies is slower and by the time the antibodies are developed in the titer that is sufficient to neutralize the virus, the virus changes its antigenic determinants. In this case, immuno-dominant neutralizing antibodies might start forming unstable complexes with the new form of the virus and start to infect monocytes/macrophages causing ADE. This process can trigger generalized infection of immune cells in multiple organs and cytokine storm

__blockcipher__ 6y ago

First of all, here's the full text in-case anyone isn't aware: https://www.nature.com/articles/s41586-020-2550-z_reference.pdf https://www.nature.com/articles/s41586-020-2550-z_reference.... Before the actual paper, some review. REVIEW SECTION 1 Coronavirus is a family of viruses, viruses being basically pieces of genetic material that swim around, inject their DNA into other cells, which makes the cells produce more copies of themselves until thousands of baby viruses explode out of the cell, killing it and moving on to the next cell. COVID-19 is the condition that results from infection with SARS-CoV-2, which is a novel coronavirus that almost certainly emerged sometime in 2019. Think HIV/AIDS: HIV is the virus, AIDS is the disease, same with SARS-2 vs COVID-19. SARS-CoV-2 while technically novel, is incredibly close related to what we now call SARS-CoV-1, which we used to just call "SARS". SARS-1 was incredibly deadly, but the pandemic fizzled out, presumably because it is quite deadly/quite symptomatic and AFAIK there isn't pre-symptomatic transmission. SARS-CoV-2 structurally is very similar, sharing the same characteristic spike protein, and targetting the same ACE2 receptor which is expressed differentially in different tissue types. But SARS-CoV-2 is like a refined version of SARS-1, it "learned" from SARS-1's mistakes. So, it appears to be adapted to spread quite well, possibly because of cool things it does with interferon-mediated early course immunosuppression, which lets it spread for a few days before you show symptoms. It's also much less deadly than SARS-1. Now, to craft the "optimal" pandemic virus, you want something that spreads easily, has a long incubation time, and isn't too deadly (otherwise it fizzles out by killing its hosts before they spread sufficiently). So in that sense, SARS-2 is perfectly crafted to kill a bunch of people. But please don't fall into fear-mongering, it doesn't kill nearly as many people as most have been led to believe. In my opinion it's really quite a mild virus overall, but some people can have severe COVID-19 which presents very similarly to a more run-of-the-mill SARS-1 infection (remember the original SARS is very deadly, so run-of-the-mill != no-big-deal). REVIEW SECTION 2 We've talked about SARS-1 and SARS-2, but let me briefly butcher the immune system (I can already hear the immunologists stampeding towards me in the distance). Your immune system's job is to distinguish self from non-self, (or more accurately, "non-self that is actually a threat" since you can have bacteria/etc that are not pathogenic/pathological). When it identifies a target, it has a lot of cool ways to kill it, but the specifics of neutrophils and antibodies, etc are out of scope. For now, take it as given that your immune system can detect and kill pathogens. Once it has fought off an infection, you will likely have antibodies, which are little heat-seeker-missiles that are primed to detect and neutralize the pathogen in question. (Note there's also T-Cell immunity which operates perhaps orthogonally to antibody immunity. This paper talks about T-Cell immunity). Assuming you produced antibodies, eventually your active circulating antibodies will fade. This takes several weeks-a few months for SARS-1, and seems to hold for SARS-2, although I believe antibody prevalence is correlated with disease severity. So eventually you have no more circulating antibodies. Contrary to what doomers will tell you, that's not a bad thing, it's inefficient to perpetually maintain antibodies. So instead your body maintains a living library of the pathogens it has previously encountered. I'd encourage anyone to read about https://en.wikipedia.org/wiki/Immunological_memory https://en.wikipedia.org/wiki/Immunological_memory. I'll summarize briefly. (1) After infection, even when antibodies fade, you still have circulating Memory B Cells which persist across decades, waiting for exposure to the previously-fought-off pathogen at which they ramp up antibody production, leading to a faster, more strong response that results in lower peak viral load, presumably lower transmissibility/symptoms/etc. So, eventually it's possible to get reinfected as far as antibody immunity is concerned, but it takes quite awhile and when it does happen it's not nearly as bad. (2) There's also memory T Cells, which are similar except instead of relying on antibodies, they work with T cells, with basically directly kill pathogens rather than indirectly produce the antibodies with neutralize the pathogen. Okay, now it's time for THE ACTUAL PAPER The first finding is not surprising at all to anyone who has been reading research, but probably surprising to everyone else (read: almost everybody): if you've been previously exposed to SARS-1, you have memory T cells which persist long-term and will happily attack SARS-2. Remember when I said SARS-CoV-2 was a novel virus? Well, it was, but it was also incredibly similar to SARS-CoV-1. So, technically it's novel but in real terms it's only a little bit novel, so previous SARS-1 infection is protective. Well, that's cool, but most of us have never been exposed to SARS-1. But many of us have been exposed to one of the handful of other human coronaviruses that we know about. The somewhat shocking (maybe not shocking to those who have been reading about immunology for years) revelation in this paper is this: > Surprisingly, we also frequently detected SARS-CoV-2 specific T cells in individuals with no history of SARS, COVID-19 or contact with SARS/COVID-19 patients (n=37). In other words, people never exposed to either of the two SARS viruses showed immune activation against SARS-2, meaning that they are either completely or partially immune to SARS-2. Why? Because they've almost certainly been exposed to some of the other human coronaviruses, which basically cause common colds. (Side note: For almost everybody SARS-2 is not any different from the common cold. It's quite rare to have severe SARS-2, but those that do get it experience very bad effects, since their immune system is basically ravaging their entire body) --- So the TL;DR: any model that has assumed that everyone can get infected is completely wrong and will massively overestimate the ultimate death of letting SARS-2 rip through the population. Many people will never be able to get SARS-2 because they've already fought off similar-enough human coronaviruses. (BTW, coronaviruses are very distinctive in structure so that is likely why our immune systems exhibit this cross-reactivity) Implications: (Warning: Strong opinion) As a result any cost/benefit tradeoffs of, say, lockdown, based off those models was off by a huge factor. The good news is, that even with the assumption that everyone was susceptible (capable of being infected), it was still really obvious to anyone with the capacity for rational thinking that containment/lockdown was a terrible idea, so these findings don't really change too much on that front, it just makes it even more overwhelmingly obvious that we collectively lost our shit and chopped off a limb in response to a papercut. So, instead of us (meaning, everywhere except Sweden) being super duper wrong, we now have good evidence that we were actually unimaginably, insanely wrong, to a degree that will be studied by subsequent scientists for decades as an example of where social contagion, groupthink and censorship led to one of the most damaging events in modern human history. Woot!