Then after a few hundred years, the human population will have undergone enough selection that all the bad HLA alleles that make T-cell responses difficult are low in the population and all the formerly rare ACE2 alleles are widespread. Here, check out these papers:
https://elifesciences.org/articles/12469
https://www.biorxiv.org/content/10.1101/2020.03.18.997346v1.full
Looking at signatures of natural selection in the human population, by FAR some of the strongest signals in the past few tens of thousands of years is proteins that interact with viral proteins - the HLA alleles and all the parts of the interferon response and everything else that all those tricksy accessory proteins sequester and alter.
This is nothing new. We just have somehow decided that we expect better.
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As for other things:
The virus apparently has a mutation rate which is on the high end, unexpectedly large rate of mutation. This makes the vaccine less probable. How much less? No idea.
This is simply not true. Coronaviruses actually proofread their polymerases unlike almost all RNA viruses. The only interesting mutations I am aware of in the current outbreak is two independent origins of a particular missense mutation away from the receptor-binding-domain of the spike protein (that thus dont affect neutralizing antibodies), and a few strains that have up and LOST whole accessory proteins that are part of how the virus evades the innate immune response (because they are so damn good at evading it in humans because the bat response is so absurdly fast that they don't need half of what they have).
Following the vaccine development scene, I am actually absurdly optimistic. All the stuff entering human studies are basically just repurposing already-researched SARS and MERS vaccines that work in monkeys, and swapping out the sequence. The preliminary data is already coming in in these animals and is good.
Thanks for those links. I'll need time to read properly.
I've wondered for a while about the influence of viruses on evolution (just looking at the effects of something like Zika virus for a start) or genomes picking up "new DNA" from RNA templates etc....
It is mostly just retroviruses that wind up entering the genomes of their hosts. RNA viruses leave a very different imprint: high rates of evolution of the proteins that their proteins interact with, as they race to deactivate their hosts immune responses and their hosts race to deactivate or evade the viral proteins.
There is also a constant, diversifying selection on the components of the immune system (HLA/MHC) that display viral proteins from within cells on cell surfaces for the immune system to be sensitized against. Viruses always evolve to take better advantage of the most common of these alleles, and the rarest of these genes are always selected for in populations as result. The end result is what is called 'balancing selection', where rare things become more common and common things become less common leading to the maintenance of great diversity. This is why tissue typing for transplants is so difficult - there is such immune system diversity that most people don't have the same alleles at these loci as each other. Of course, if something new enters the population that a subset of these alleles isn't great against, that set of alleles will become less common over time.
Most biotech companies in the world have pivoted to working on coronavirus. Failure to win in a year or two seems possible but failure to win over the course of a decade is much less likely, and wins could include safe genetic engineering solutions that cure both the common cold and HIV.
The probability of this happening is very low. We have effective coronavirus vaccines for pigs (although not for COVID-19). For most viruses people recover from, they keep immunity and we don't have good evidence that COVID-19 is different. While COVID-19 might do some harm to most people that recover, if the harm was on average significant we should have a lot more evidence of this. Also, the space of possible effective treatments is huge and it seems likely that within 2 years (perhaps even two months) we will be able to greatly improve outcomes for the infected. Finally, keep in mind that we have just started to fight COVID-19, and so we have not already tried and failed with all the obvious approaches and this should make us relatively optimistic about coming up with effective treatments or vaccines.
Some info. on coronavirus vaccines in pigs:
Vaccines for porcine epidemic diarrhea virus and other swine coronaviruses 2016
Coronavirus (and other viruses) causes severe disease in neonatal piglets. Vaccination of pregnant sows in order to confer "lactogenic immunity" i.e. antibodies in the milk is, as far as I'm aware, the main use of coronavirus vaccines in swine.
(I was a veterinary surgeon but I've not treated pigs in over a decade.)
Some others are talking about it, but most people don't want to hear it, so it's not getting signal boosted and the public is generally still hoping for a vaccine to fix it all. Certainly the authorities aren't ready to acknowledge otherwise. I don't think anyone has a clear picture, and you have to hunt around and sift information. I had the best luck on Twitter--lots of nonsense, but eventually I sorted out the people who seemed on top of things and saw what they called attention to and agreed upon. I think the probability of this scenario is high enough to be quite worrying...I could be wildly off, but as you asked for a probability estimate, at least 10%. My reasoning:
1) We develop no long-term immunity, no vaccines, perhaps because the mutation rate is too high.
Given the behavior of coronaviruses generally, and what we seem to know of this one, my sense is that long-term immunity is not going to happen, which really complicates things, including vaccines, which depend on activating that immune response. However, a yearly vaccine like that for the flu seems like it could at least help a lot by decreasing cases in those who do produce antibodies, and doesn't seem wildly unrealistic to achieve. Like flu vaccines, it would work better in some years than others, and could realistically only be given to so many people. And we'd need to produce it in huge doses. A quick and easy vaccine is not even something I'm hoping for at this point, I consider it so unlikely, but the news keeps promising a quick fix. A lot of the smart famous people who were scrambling to get a vaccine team together and saying it was our only way out of lockdown back in March have slowly stopped talking about the vaccines or quickly going back to normal.
2) The disease causes permanent lung damage, making each successive infection worse for the patient.
While this doesn't seem to happen to everyone, it seems like a real problem, one also being swept under the rug for the most part. Since I concluded vaccination was a no-go, I had reluctantly resigned myself to the fact that volunteering for variolation or a low-dose infection in a controlled setting was probably in my near future. I'm 30 and healthy, and I know that is no guarantee, but it seemed by far the most realistic scenario. But I had hoped these side effects were very rare, and now I'm not nearly so sure. We don't have enough experience to know what the long-term effects are or their prevalence, but it's much harder to consider voluntary infection knowing about how little we understand the side effects. (This could also be true of a rushed vaccine). I still see little way around it, though--I'm 90% sure I will catch the coronavirus in my lifetime because it won't go away and lockdown will become infeasible, and I'd rather get it young. Even if re-infection is likely, there's a decent chance that severity lessens over time because of immune memory. Out of everything you proposed, I think each successive infection being worse is one of the least likely, but not impossible. It seems like responses vary quite a bit and they think all sorts of genetic things could be involved, so this type of risk might be very uneven, and we might get better at learning who is most at risk and possibly how to mitigate such damage. There's still a lot we don't know, and I think a focus on practical mitigation could do more wonders than people realize, even if we don't eradicate this.
3) No antivirals get developed, or at least not ones which can be produced in extremely large quantities.
I suspect that within a few years, we'll have figured out various treatment protocols that make a significant difference. Not sure if antivirals will be among them. But we're likely to find medications that help with some things in some people, maybe minimizing harmful immune responses that cause lung damage. But getting them to everyone is logistically probably not going to happen, certainly not worldwide, especially if there is a lot of economic and social collapse.
I think groups of people are researching this, but probably not from such an objective perspective. If you knew this would happen, what action would you take? There's almost no one who could use this information, and few want to entertain the idea. Businesses will focus on vaccines and other such things, which get a lot of coverage, but they have to assume a better outcome for this to be worth it, or people won't be able to pay. Major financial players will be trying to strategize, but if this disrupts the whole business environment, they won't be able to exploit it that much. Researchers will look at pieces. All will be incentivized to see significance in narrow solutions that allow them to retain their current position, not apocalypse. High level governments will have to get a general assessment of where things are going, but, especially with the leadership we have, which seems unable to imagine divergence from the status quo, they will be focused in the short-term on suppressing unrest and trying to get the economy restarted. Things may have to collapse pretty badly for them to give up hope of going back to normal, and the American public/economy is not in a good place to process an interruption of its expectations. I agree totalitarian or just third world leaders will be in better shape, largely because in many of those countries people have much lower expectations and are used to widespread death and suffering and disruption. They're better able to adjust socially and psychologically, even if large numbers of them get sick and die, because their cultural frameworks are closer to a time when epidemics were part of daily life. They're used to focusing on survival, and replacing warlords is a straightforward process. Of course, handling it better doesn't mean they'll be in great shape, by any means. Just more functional, at least in the short-term.
The part of the government that needs to deal with reality to at least some extent, the military, seems to be quietly going for some level of herd immunity among its personnel and planning for this to be a seasonal illness. (I think Boris Johnson and his team also immediately recognized this, and caved due to public backlash, not because they realized the models were wrong---the public simply wasn't willing to accept what Johnson felt was inevitable. Sweden's government evidently concluded the same, though it tries to say it's going for containment). I consider that a pretty good indication of where things are going to go in the short-term--if your presence is necessary in public, for whatever reason, you're going to have to take your chances. Politicians, officials, and first responders seem to be quietly resigned to contracting the illness. They know any significant containment will not be accomplished by the lockdowns, so they just have to get to work.
Also, the impact will probably lessen quickly over time. The first few years will take out the most vulnerable in large numbers, if we can't stop it. This will be extremely traumatic. But then the death rates will be far less overwhelming, and there will be at least some level of immunity in a lot of people, so we would expect the rate and severity of spread to decrease. The economic dislocations will also probably be swift and simultaneous, and then we'll have to rebuild. I think there will be a psychological shift eventually where people just accept the situation and live life as functionally as they did for most of human history when this was normal. If you read anything about the Civil War, for example, you'll notice everyone in DC had malaria for half the year, and worked despite migraines and chills and a constant fever. You continually get reinfected with malaria, but it does lessen with each infection over the course of the season. Then you tend to lose immunity over the winter. Some people developed more immunity than others; some were more affected than others. Mild to fatal illness, just like with COVID-19. And these people were always riddled with other infections, because of the lack of antibiotics, so dying in your 60s was common and dying of wrecked lungs much younger than that was also common (tuberculosis was an ugly disease, and was eradicated relatively recently). Plus they had horrific scarlet fever/smallpox/cholera outbreaks with regularity, and child mortality was atrocious. (Lincoln was in the early stages of smallpox when he delivered the Gettysburg address, and one of his kids died in the White House of typhoid fever). Plus, there were the wars killing hundreds of thousands of people. This is not the world I want to live in, to be sure. I'm not tough. But it is evident people are capable of living in it quite functionally, if they have immune systems strong enough to survive in the first place. And I don't think COVID-19 will come anywhere close to wrecking the health of every person on earth. The effects will be very uneven.
Sorry for the long post--wanted to lay out the thoughts that I'd been ruminating on. Hopefully this isn't how things work out. It could go in a lot of different ways that are hard to predict. But I've always felt that a big pandemic was very likely in my lifetime, thinking along the lines of 1918. I hadn't considered a disease that stuck around reinfecting people, not being familiar with other coronaviruses until now. Much scarier, but quite plausible. It's possible that we'll get this under control enough that it will be remembered as something like 1918---a really, really bad flu that killed a ton of older or sick people and then mostly faded into the background among survivors. That one had some scary side effects as well, though.
One source who I think had a realistic view from the beginning is Robin Hanson at overcomingbias.com. He only looks at certain aspects of the situation, but that might be a good place to start.
something like 1918---a really, really bad flu that killed a ton of older or sick people and then mostly faded into the background
The 1918 Flu pandemic's Second Wave killed massive amounts of young, healthy adults. 99% of deaths occurred in people under 65, and half of all deaths were in young adults 20 to 40 years old. Source: Wikipedia.
Apparently the virus had naturally selected in the trenches to become much more deadly. People mildly ill remained in the trenches, and so the virus could not spread. But those becoming gravely ill were taken to military hospitals, were the virus could spread.
This is the opposite of what usually happens: mild cases spread because people still do their usual activities. Serious cases limit because people are too sick to spread it around.
This is the very reason why epidemiologists monitor virus outbreaks in conflict zones: natural selection is reversed, resulting in a deadly virus strain.
Isn't that exactly what we are doing in our lockdown world? We are socially distancing and self-isolating, so mild cases always die out. But when we get critically ill. we have to go to hospitals which, despite our best efforts, are hotbeds of infection.
Sounds to me like we have a good chance for the second Covid-19 wave to be much deadlier.
Apparently the virus had naturally selected in the trenches to become much more deadly. People mildly ill remained in the trenches, and so the virus could not spread. But those becoming gravely ill were taken to military hospitals, were the virus could spread.
Where is the evidence for the increased spreading through military hospitals? It's a nice story, and plausible.
Why wouldn't it have spread at as well in the trenches where you have repeated exposure to the same group of people? Open air/sunlight, perhaps? Or are you emphasizing the travel aspect (coming into contact with more people total than the mild cases)?
Isn't that exactly what we are doing in our lockdown world? We are socially distancing and self-isolating, so mild cases always die out.
I don't follow your "so ..."
People who have avoided contact since Feb are incredibly more likely to be delaying (perhaps forever) their date of infection. Basically none of them have yet had a mild case.
It's an open question whether the strain we who've avoided it so far eventually are exposed to is more or less severe in symptoms (obviously it will tend to be more contagious) than the one people got in earlier waves. I always expected it would be (because fast onset fatal strains are quarantined more effectively and cannot spread) slower-onset, more lingering, but less severe. I don't have much reason to change my mind, even though you've brought an interesting historical claim into view.
Besides hospital workers, hardly anyone is going to hospitals unless they have covid already, and although it's not perfect, hygiene is practiced. I agree that hospital workers are more likely to contract a severe strain; that's why they should arguably should have been variolated by intentional light exposure already.
The 1918 Flu pandemic's Second Wave killed massive amounts of young, healthy adults. 99% of deaths occurred in people under 65, and half of all deaths were in young adults 20 to 40 years old. Source: Wikipedia.
Oops! Thank you. I was aware of that, but got mixed up while writing and didn't separate my ideas. I meant "like 1918" as in a flu mutation that made it behave much more dangerously. I was thinking the next mutation might be more likely to target the old and sick instead of repeating the cytokine storm thing with the young, but either could easily happen (this one might cause a cytokine storm that attacks the old, in many cases, or at least I've read that is a possibility?). I also figured that in modern times it would be easy to intervene with the young because they weren't in trenches in a world war with a less developed medical system. But COVID-19 is so contagious that it doesn't seem way easier to control.
Those are good and worrying points about natural selection. I'm not at all confident we're handling this intelligently. Maybe there's not much that can be done to help, but making it worse is not good.
Covid seems to leave permanent lung damage even in young people.
It is way too soon to say that. Maybe reason by analogy with SARS. It is widely claimed that SARS caused permanent lung damage. But "permanent" seems to mean 3 or 6 months! Here is a paper showing substantial improvement from 6 months to 9 months.
Even (1),(2) and (3) were proven true in the future, it was not apocalyptic scenario. People only need to wear serious respirators while not at home. It was not a big deal in my opinion.
I have been seeking like minded people. I have been thinking, even just studying the long term effects that we know of already, that nobody is taking this seriously enough. Furthermore, the fact that it immediately travels to the front of the human brain, causing the lack of smell and tatse that people are reporting, means there may be some very serious long term residual brain issues. I tend to read personal encounters with this illness along with preliminary scientific papers on the early findings. The findings that not all are building lasting antibodies is extremely disturbing, the multi organ attack, extreme lmk y disturbing. But, just go to work and wash your hands and you will be fine? Yet it is airborne and reported to be contractes through eyes now? People should be panicking and yet they are instead protesting stay at home orders. The government tends to give less infor.ation, not more, to avoid panic. This is historically true with all large scale issues. They certainly do not WANT us locked down as it kills their profits and our economies. For people that believe they are locking us down to make us compliant by fear are ridiculous. The American president is teykng to send everyone back to work in the midst of this "war zone" with no real protection. If that does not show he is willing to sacrifice human lives for money I do not know what does. Regardless, no one seems to be sounding alarmas at how very bad systemically this virus in fact truly is. In a mild case of a child I recently read about, he recovered and subsequently dropped of a heart attack at age 8( he was revived and saved). This is not a good sign, but this issue, it will be ignored and called "rare", do not worry people! Be the sheep you are and go to work and make the money for your country.
I would like to discuss #2 - there are some reports about that:
https://www.zerohedge.com/health/young-covid-positive-redditors-describe-agony-symptoms-lasting-nearly-two-months-after - these leads to Reddit patient reports, I don't use Reddit that much and I don't know how reliable they are, are those even from real people?
It is consistent with the 'silent hypoxia' story - that the virus destroys the lungs in a way that makes them very inefficient it blood oxygenation - but initially still good at expelling CO2. We don't feel low oxygen - we only feel too much CO2 in blood. Here is an example article about that: https://www.nytimes.com/2020/04/20/opinion/coronavirus-testing-pneumonia.html , but googling reveals many more stories.
Another Reddit discussion thread: https://www.reddit.com/r/Coronavirus/comments/g3rv7h/permament_lung_damage_found_in_revovered_patients/ . It leads to some strange German language publication on an Italian web site, again not very reliable. But google for the doctor involved: https://www.google.com/search?&q=Innsbruck%2C+Frank+Hartig and you get more stories.
Overall this does not look very difficult to evaluate more scientifically - so if this is a real phenomenon then there should be peer reviewed research about that and I was kind of skeptical at the beginning, but maybe it is just too early. Of course the anecdotal evidence that we have is consistent with https://www.lesswrong.com/posts/grrMAwJrELry5BhSy/littlewood-s-law-and-the-global-media and might not mean much - so it is very important to have some stats on that.
The virus apparently has a mutation rate which is on the high end, unexpectedly large rate of mutation. This makes the vaccine less probable. How much less? No idea.
Certainly a moving target makes vaccines a bit problematic.
However, I would also be curious about the mutation path. Sounds like the underlying assumption here is that all mutations remain viable for infecting humans. I would be really interested in hearing (to the extent we might have a intuition on this) what the probabilities are for mutations to result in a human incompatibility. In other words, just how much variation is allowed before humans are not compatible with the virus.
What, if any, is the there here? Perhaps we can call this one a related questions, bacteria and in theory some other cellular organisms have formed symbiotic relationships both at the cellular and system/organ level with humans. Any indication that has ever happened with a virus?
Does anyone have any guesses on how long it might have taken to jump from bat to human? Ideally if we could be sure about the intermediate host we could do better but even there we might be able to estimate the time to mutate from any number or potential intermediates.
Any existing models there?
This apocalyptic scenario:
1) We develop no long-term immunity, no vaccines, perhaps because the mutation rate is too high.
2) The disease causes permanent lung damage, making each successive infection worse for the patient.
3) No antivirals get developed, or at least not ones which can be produced in extremely large quantities.
is perhaps the most important consideration right now, and I'm not sure how much discussion there is about it. The probability of it seems hard to estimate, but it should nevertheless be attempted, because the stakes are so high.
Uncertainty
Covid seems to leave permanent lung damage even in young people. Let's say you are 30, get the disease now and recover. Say the vaccine does not get developed, the disease stays with us and you get it again in a few years. Now it's going it be worse. It still may not kill you. Let's say that no effective antivirals get developed which can help you. In a few years you get it again, and this straw breaks the camel's back, now you're dead.
The virus apparently has a mutation rate which is on the high end, unexpectedly large rate of mutation. This makes the vaccine less probable. How much less? No idea.
Some say that antivirals "look promising" but what does that actually mean? No idea. What are they going to cost? What is the theoretical maximum which could be produced on this planet? No idea.
As someone who is not an expert in medicine/biology, every estimate I attempt is going to have a large entropy. Information about this disease we got from various institutions in the past few months was highly biased, because of their incentives. What are the incentives of the people who claim that antivirals look promising? Are the companies just trying to make their product look better, in order to increase the funding provided to them?
The fact that I don't have a clear picture on this bothers me... Where to even get info on this? Are people talking about it but I'm not aware of it? Please, if you have an opinion, leave your subjective probability estimate in the comments, along with the reasoning behind it.
Society
The apocalyptic scenario would surely have huge impact on society. The totalitarian regimes would perhaps deal with this better than free ones, which would either tip the balance of power in favour of China, or it would offer an incentive for the free regimes to turn totalitarian. Even without totalitarianism, a large percentage of the population dying means a lot of people at critical positions (e.g. nuclear power plant engineers) would need to be replaced fast. Also, it means a lot of people at head positions in various organizations would need to be replaced. Will they be replaced successfully?
I hope there is a research group somewhere which is investing, or plans to invest, at least 100 man-hours into investigating the worst-case scenario and estimating the probability of it.