As a layperson, I’m increasingly convinced that we’re on a path to a devastating H5N1 pandemic within the next few years, possibly much sooner (writing this in late June 2024). My concern is based on the amount of “biocomputation” that is going towards / will soon go towards parallel search for mutations that have the side effect of triggering a pandemic in humans, plus the risk of viral reassortment with human-native viruses. I’ve been reading a lot about this over the past few days, and I’m eager to defend this position or revise my opinion in light of new arguments.
Lots of cattle biomass = lots of tissue infected with H5N1 = tons of virions (viral density in raw milk is “astronomical” per Nature) = lots of opportunities for a virion to find a mutation that increases fitness in cattle and/or in humans.
Furthermore, as an influenza virus, it has a high mutation rate (which would appear to both lower mutation barriers, and decrease the effectiveness of vaccination).
There are multiple vectors for a mutated virus to spread from cattle to humans: raw milk consumption, poor ag worker biosecurity (see milking parlor discussion here), upcoming county fairs. (Pigs might also serve as an intermediary. Part of why I’m so worried is I see various distinct catastrophe stories.)
Don’t forget about the risk of viral reassortment with ordinary human influenza this fall, given the multiple human/cattle contact vectors I mentioned previously.
On the other hand, perhaps widespread consumption of pasteurized milk could act as “accidental vaccination” (exposure to deactivated virus) and blunt the spread. As a layperson, I am out of my depth here. Could I drink previously-infected pasteurized milk and consume an adjuvant as a method of DIY vaccination?
Clarifying my position here, I’m not claiming there will be a pandemic next week or next month. My claim is more that “common in cattle but not common in humans” is an “unstable evolutionary equilibrium” for H5N1, which is unlikely to persist for an extended period of time.
Another way of putting it is that the ambient risk level for H5N1, in the sense of the number of possible-pandemic dice which are getting rolled every day, seems to have gone up a lot recently. The risk level is likely to stay high, because I expect H5N1 to become endemic among cattle (if it isn’t already). And regulators seem to be dropping the ball, just like they did for COVID. Calling your congressperson and telling them to ask regulators hard questions could be high-impact.
Thanks for tracking this, I definitely think being aware of + extremely up-to-date on “novel pandemics” is one of the things that our community (~GCR-focused EAs) should have at least a few people working on, though it’s a hard thing to do without either under- or over- shooting.
(It’s possible these people already exist and are working quietly. In which case, great! I’m not sufficiently in touch with the space to know either way).
I’m not sure about keeping up to date on potential “novel pandemics” is a great use of resources for above reasons (see reply to Ebenezer). I would like to see us predict in real time even one potential virus moving from animal transmission through human to human pandemic first before committing huge resources. I feel like “general pandemic prevention” stuff (stockpiling, UVA, better diagnostic tools etc.) as well as tracking virus’s we already know can cause epidemics (like Ebola) is maybe a better use of resources but am very uncertain.
Thanks I absolutely love this list and absolutely agree with your reasoning, that points towards H5N1 being one of the most likely (if not the most likely ever identified) situation where a known pathogen could move from a minor issue to disastrous pandemic.
In saying that I still think its very unlikely, based on prior evidence that we will see this happen in real time. I’m not sure that humans have ever actually followed a specific virus that then became a dangerous pandemic. Can you think of an example that fulfils these critreia?
1. Virus identified in advance that was either non-transferrable to humans, or (like H5N1) has very limited human transmission 2. Prediction made that the virus could become dangerous 3. The virus mutates and becomes dangerous, causing an epidemic/pandemic
Previous dangerous diseases that emerged from other animals (HIV, Ebola, Covid, Swineflu) were not predicted in advance.
Because of that I would rate this statement as quite an overstatement.”we’re on a path to a devastating H5N1 pandemic within the next few years, possibly much sooner”. The most likely scenario is that we never get a H5N1 pandemic.
This doesn’t mean we shouldn’t be spending far more money on the issue and focusing on it, there’s obviously a real chance that H5N1 becomes disastrous, I just think well below 50%. I in general though rate priors very heavily, far more heavily than theory so it depends on your prediction methods.
This is a pretty good summary here by the institute for progressalso, where they estimate risk at 4% in the next year, my instincts are it might be even lower. I like their cascade of probabilities, but at a few stages I would have gone with lower probabilities. https://ifp.org/what-are-the-chances-an-h5n1-pandemic-is-worse-than-covid/
No, I can’t think of any examples that meet your criteria. As a layperson I wouldn’t know about them if they existed, anyway.
I could quibble with your implicit method for computing a prior, however. You mention 4 zoonotic pandemics that were not predicted in advance. I’d argue the correct denominator here is pandemics which were predicted in advance. How many times in history have we had an argument this strong for a pandemic which was ultimately a nothingburger? That should be our reference class.
The joke goes that “economists have predicted 9 of the last 5 recessions”. Have epidemiologists predicted 9 of the last 0 pandemics? Furthermore, how does the emergence of modern sequencing technology factor in?
Note that I am not an epidemiologist! So that outside view might not be worth much. I’m a computer scientist, and I’m thinking about this very computationally and probabilistically. See my terminology: “biocomputation”, “parallel search for mutations”, dice rolls, and perhaps an implicit reference to hill-climbing (H5N1 got knocked off its previous local maximum and now it’s searching for a new one). I suspect many epidemiologists do not currently grok this computational/probabilistic argument, which is part of why I wrote my comment. But I know there are big parts of the epidemiological picture that I’m missing.
Anyway, here’s another reference class that might be interesting: Endemic viruses in domesticated mammals. Are there cases where they persisted for many years without becoming endemic in humans? Perhaps canine parvovirus? It’s unclear how to apply this outside view to a virus like H5N1 which (a) has managed to infect so many species, (b) is known to infect humans sometimes, and (c) is currently evolving to better infect mammals (may have lots of low-hanging fruit to capture).
If one wanted to make a serious effort to forecast this, one can imagine a Monte Carlo model which accounts for the H5N1 mutation rate, average case load in US cattle, total virions per infection, fitness advantages and disadvantages associated with various mutations, human contacts, etc. My basic intuition is that many plausible parameterizations for this model will produce a human pandemic some time within the next few years. Maybe there’s some way of doing a quick and dirty monte carlo using Guesstimate.
Thanks yeah I agree with your first question being important, and I would say we have predicted Zero new problematic pathogens ever. I agree with you that the numerator could be pandemics from new zoonotic pathogens which were predicted in advance, and that number I think is zero, making it hard to calculate a prior with this....
You make a decent argument that we could look at pandemics from organisms which we already know have pandemic potential in humans and then see how many of those we got correct. I don’t know the answer to this, but I would imagine its a VERY LOW number (or even zero) again.
My feeling is that there are so many animal diseases out there, the scenarios where diseases combine or mutate to form variants that are dangerous to humans is so hard to predict and random, that even the majority that appear “super close” to being dangerous will never actually become dangerous.
Predicting pandemics is not like predicting volcanic eruptions—at least not yet and you are right that sequencing and other technology will gradually make us better at this—I just think we aren’t nearly there yet.
”If one wanted to make a serious effort to forecast this, one can imagine a Monte Carlo model...” This is basically what the institute for progress did, but in a more simple linear way have you had a look at their calculations?
My feeling is that there are so many animal diseases out there, the scenarios where diseases combine or mutate to form variants that are dangerous to humans is so hard to predict and random, that even the majority that appear “super close” to being dangerous will never actually become dangerous.
I suppose one could create a dataset of various viruses with columns like: Is it endemic in domesticated mammals? How many humans have been infected? Does it appear to be evolving? Can it reassort with human influenza? Etc. etc. and then train a regression or something to predict a pandemic. I suppose data would be extremely sparse, but if you rework the task as “predicting whether a virus will hop from species A to species B” there might be more data, since there are lots of species pairs.
“If one wanted to make a serious effort to forecast this, one can imagine a Monte Carlo model...” This is basically what the institute for progress did, but in a more simple linear way have you had a look at their calculations?
Re: the parvovirus, I’ve been chatting with Elizabeth on LW. She says that flu viruses tend to be unusually good at species-hopping, due to their ability to reassort with viruses native to the target species. Seems like the parvovirus doesn’t have that ability, which could help explain why it’s not a problem in humans.
Replying to the Institute for Progress analysis you linked.
Looks like this was published Feb 2023 and doesn’t account for new developments since then? I don’t see any discussion of mice or cattle, mammals which have more human contact than mink.
This sentence seems to underpin much of the IFP’s optimism:
It is very difficult for R0 of a virus that is currently poorly adapted for human-to-human transmission to have a R0 that exceeds 1.0.
Spread of H5N1 bird flu viruses from mammal to mammal is thought to be rare, but possible.
I’m not sure how to reconcile this claim with H5N1 being present in 20% of grocery store milk samples. I suppose shared milking machines could be creating exceptional circumstances.
It does seem like mammal-to-mammal spread gets you most of the distance from “pure bird flu” to “human flu”, if I’m reading this article (from April 2023) correctly.
In any case, the IFP’s R0 point seems a bit reassuring. It suggests we may get “warning shots” in the form of small-scale human-to-human transmission. It also suggests that much of our focus should be on reassortment: either a cow gets human flu, or a human with the flu gets H5N1.
Raw milk could also be a huge deal. Apparently it can have up to a billion virus particles per mL. Imagine someone drinks a liter of raw milk and consumes a trillion virus particles. How many of those are destroyed during digestion? What are the odds that one of those trillion particles will be viable virus with mutations that happen to make it well-adapted for humans? What if the person drinking the milk has an ordinary seasonal flu, creating the possibility for reassortment?
Yeah I just want to reiterate that I think this is the most prescient pandemic risk that the world has right now and I agree we should be investing a lot more in it than we are right now.
It’s only the probabilities and as not of theory we disagree on I think, which probably doesn’t change much in what we think should happen in practice.
Can you speak on this since Alvea has been wound down?
As a layperson, I’m increasingly convinced that we’re on a path to a devastating H5N1 pandemic within the next few years, possibly much sooner (writing this in late June 2024). My concern is based on the amount of “biocomputation” that is going towards / will soon go towards parallel search for mutations that have the side effect of triggering a pandemic in humans, plus the risk of viral reassortment with human-native viruses. I’ve been reading a lot about this over the past few days, and I’m eager to defend this position or revise my opinion in light of new arguments.
Here’s my basic reasoning:
The virus has been adapting for mammals: https://www.nytimes.com/2024/05/03/health/bird-flu-cows-mutations.html
Grocery store tests suggest it is already very widespread among dairy cattle: https://health.ucdavis.edu/news/headlines/grocery-store-milk-tests-positive-for-bird-flu-why-the-fda-says-its-still-safe-to-drink/2024/04
I believe this represents a shift from past H5N1 behavior, which did not involve transmission amongst domesticated mammals: https://wwwnc.cdc.gov/eid/article/30/3/23-1098_article
Adaptations which increase fitness within a dairy cow are also liable to trigger a human pandemic, e.g. added a2,6 SA receptor binding ability: https://nitter.poast.org/richardhirschs1/status/1804830640418025518
There’s a lot of cattle (the US has around 6% of global cattle): https://xkcd.com/1338/
Lots of cattle biomass = lots of tissue infected with H5N1 = tons of virions (viral density in raw milk is “astronomical” per Nature) = lots of opportunities for a virion to find a mutation that increases fitness in cattle and/or in humans.
Furthermore, as an influenza virus, it has a high mutation rate (which would appear to both lower mutation barriers, and decrease the effectiveness of vaccination).
There are multiple vectors for a mutated virus to spread from cattle to humans: raw milk consumption, poor ag worker biosecurity (see milking parlor discussion here), upcoming county fairs. (Pigs might also serve as an intermediary. Part of why I’m so worried is I see various distinct catastrophe stories.)
For all we know, human-to-human spread is already occurring in states which are doing less testing than Michigan: https://www.michigan.gov/mdhhs/inside-mdhhs/newsroom/2024/05/30/h5n1-updates
Don’t forget about the risk of viral reassortment with ordinary human influenza this fall, given the multiple human/cattle contact vectors I mentioned previously.
And finally, if an H5N1 pandemic happens, it could be really bad: https://www.nytimes.com/2024/06/17/health/bird-flu-pandemic-humans.html
On the other hand, perhaps widespread consumption of pasteurized milk could act as “accidental vaccination” (exposure to deactivated virus) and blunt the spread. As a layperson, I am out of my depth here. Could I drink previously-infected pasteurized milk and consume an adjuvant as a method of DIY vaccination?
Metaculus puts us midway between COVID and the Black Death on a log scale for death rate, perhaps something like the Spanish Flu—one of the worst pandemics in history? https://www.metaculus.com/questions/23762/h5n1-case-fatality-rate-in-us/
Clarifying my position here, I’m not claiming there will be a pandemic next week or next month. My claim is more that “common in cattle but not common in humans” is an “unstable evolutionary equilibrium” for H5N1, which is unlikely to persist for an extended period of time.
Another way of putting it is that the ambient risk level for H5N1, in the sense of the number of possible-pandemic dice which are getting rolled every day, seems to have gone up a lot recently. The risk level is likely to stay high, because I expect H5N1 to become endemic among cattle (if it isn’t already). And regulators seem to be dropping the ball, just like they did for COVID. Calling your congressperson and telling them to ask regulators hard questions could be high-impact.
Thanks for tracking this, I definitely think being aware of + extremely up-to-date on “novel pandemics” is one of the things that our community (~GCR-focused EAs) should have at least a few people working on, though it’s a hard thing to do without either under- or over- shooting.
(It’s possible these people already exist and are working quietly. In which case, great! I’m not sufficiently in touch with the space to know either way).
I’m not sure about keeping up to date on potential “novel pandemics” is a great use of resources for above reasons (see reply to Ebenezer). I would like to see us predict in real time even one potential virus moving from animal transmission through human to human pandemic first before committing huge resources. I feel like “general pandemic prevention” stuff (stockpiling, UVA, better diagnostic tools etc.) as well as tracking virus’s we already know can cause epidemics (like Ebola) is maybe a better use of resources but am very uncertain.
Its a super interesting discussion though.
I’m keeping an eye out for Sentinel’s analyses: https://forecasting.substack.com/p/alert-minutes-for-week-172024
I’m worried too!
Thanks I absolutely love this list and absolutely agree with your reasoning, that points towards H5N1 being one of the most likely (if not the most likely ever identified) situation where a known pathogen could move from a minor issue to disastrous pandemic.
In saying that I still think its very unlikely, based on prior evidence that we will see this happen in real time. I’m not sure that humans have ever actually followed a specific virus that then became a dangerous pandemic. Can you think of an example that fulfils these critreia?
1. Virus identified in advance that was either non-transferrable to humans, or (like H5N1) has very limited human transmission
2. Prediction made that the virus could become dangerous
3. The virus mutates and becomes dangerous, causing an epidemic/pandemic
Previous dangerous diseases that emerged from other animals (HIV, Ebola, Covid, Swineflu) were not predicted in advance.
Because of that I would rate this statement as quite an overstatement.”we’re on a path to a devastating H5N1 pandemic within the next few years, possibly much sooner”. The most likely scenario is that we never get a H5N1 pandemic.
This doesn’t mean we shouldn’t be spending far more money on the issue and focusing on it, there’s obviously a real chance that H5N1 becomes disastrous, I just think well below 50%. I in general though rate priors very heavily, far more heavily than theory so it depends on your prediction methods.
This is a pretty good summary here by the institute for progressalso, where they estimate risk at 4% in the next year, my instincts are it might be even lower. I like their cascade of probabilities, but at a few stages I would have gone with lower probabilities.
https://ifp.org/what-are-the-chances-an-h5n1-pandemic-is-worse-than-covid/
We could also ask serious forecasters here what they think? @Peter Wildeford @NunoSempere
Thanks for the pushback, Nick.
No, I can’t think of any examples that meet your criteria. As a layperson I wouldn’t know about them if they existed, anyway.
I could quibble with your implicit method for computing a prior, however. You mention 4 zoonotic pandemics that were not predicted in advance. I’d argue the correct denominator here is pandemics which were predicted in advance. How many times in history have we had an argument this strong for a pandemic which was ultimately a nothingburger? That should be our reference class.
The joke goes that “economists have predicted 9 of the last 5 recessions”. Have epidemiologists predicted 9 of the last 0 pandemics? Furthermore, how does the emergence of modern sequencing technology factor in?
Note that I am not an epidemiologist! So that outside view might not be worth much. I’m a computer scientist, and I’m thinking about this very computationally and probabilistically. See my terminology: “biocomputation”, “parallel search for mutations”, dice rolls, and perhaps an implicit reference to hill-climbing (H5N1 got knocked off its previous local maximum and now it’s searching for a new one). I suspect many epidemiologists do not currently grok this computational/probabilistic argument, which is part of why I wrote my comment. But I know there are big parts of the epidemiological picture that I’m missing.
Anyway, here’s another reference class that might be interesting: Endemic viruses in domesticated mammals. Are there cases where they persisted for many years without becoming endemic in humans? Perhaps canine parvovirus? It’s unclear how to apply this outside view to a virus like H5N1 which (a) has managed to infect so many species, (b) is known to infect humans sometimes, and (c) is currently evolving to better infect mammals (may have lots of low-hanging fruit to capture).
If one wanted to make a serious effort to forecast this, one can imagine a Monte Carlo model which accounts for the H5N1 mutation rate, average case load in US cattle, total virions per infection, fitness advantages and disadvantages associated with various mutations, human contacts, etc. My basic intuition is that many plausible parameterizations for this model will produce a human pandemic some time within the next few years. Maybe there’s some way of doing a quick and dirty monte carlo using Guesstimate.
Thanks yeah I agree with your first question being important, and I would say we have predicted Zero new problematic pathogens ever. I agree with you that the numerator could be pandemics from new zoonotic pathogens which were predicted in advance, and that number I think is zero, making it hard to calculate a prior with this....
You make a decent argument that we could look at pandemics from organisms which we already know have pandemic potential in humans and then see how many of those we got correct. I don’t know the answer to this, but I would imagine its a VERY LOW number (or even zero) again.
My feeling is that there are so many animal diseases out there, the scenarios where diseases combine or mutate to form variants that are dangerous to humans is so hard to predict and random, that even the majority that appear “super close” to being dangerous will never actually become dangerous.
Predicting pandemics is not like predicting volcanic eruptions—at least not yet and you are right that sequencing and other technology will gradually make us better at this—I just think we aren’t nearly there yet.
”If one wanted to make a serious effort to forecast this, one can imagine a Monte Carlo model...” This is basically what the institute for progress did, but in a more simple linear way have you had a look at their calculations?
Cheers.
Thanks for the reply.
I suppose one could create a dataset of various viruses with columns like: Is it endemic in domesticated mammals? How many humans have been infected? Does it appear to be evolving? Can it reassort with human influenza? Etc. etc. and then train a regression or something to predict a pandemic. I suppose data would be extremely sparse, but if you rework the task as “predicting whether a virus will hop from species A to species B” there might be more data, since there are lots of species pairs.
I haven’t looked, could you provide a link?
I put it in my last reply ;)
https://ifp.org/what-are-the-chances-an-h5n1-pandemic-is-worse-than-covid/
Oh sorry I guess I missed it. I’ll reply to that comment.
Re: the parvovirus, I’ve been chatting with Elizabeth on LW. She says that flu viruses tend to be unusually good at species-hopping, due to their ability to reassort with viruses native to the target species. Seems like the parvovirus doesn’t have that ability, which could help explain why it’s not a problem in humans.
Replying to the Institute for Progress analysis you linked.
Looks like this was published Feb 2023 and doesn’t account for new developments since then? I don’t see any discussion of mice or cattle, mammals which have more human contact than mink.
This sentence seems to underpin much of the IFP’s optimism:
The CDC states:
I’m not sure how to reconcile this claim with H5N1 being present in 20% of grocery store milk samples. I suppose shared milking machines could be creating exceptional circumstances.
It does seem like mammal-to-mammal spread gets you most of the distance from “pure bird flu” to “human flu”, if I’m reading this article (from April 2023) correctly.
In any case, the IFP’s R0 point seems a bit reassuring. It suggests we may get “warning shots” in the form of small-scale human-to-human transmission. It also suggests that much of our focus should be on reassortment: either a cow gets human flu, or a human with the flu gets H5N1.
Raw milk could also be a huge deal. Apparently it can have up to a billion virus particles per mL. Imagine someone drinks a liter of raw milk and consumes a trillion virus particles. How many of those are destroyed during digestion? What are the odds that one of those trillion particles will be viable virus with mutations that happen to make it well-adapted for humans? What if the person drinking the milk has an ordinary seasonal flu, creating the possibility for reassortment?
Yeah I just want to reiterate that I think this is the most prescient pandemic risk that the world has right now and I agree we should be investing a lot more in it than we are right now.
It’s only the probabilities and as not of theory we disagree on I think, which probably doesn’t change much in what we think should happen in practice.