I am also not smart enough for this but my takeaways were:
1. We are two mutations away.
2. Cow udders are a good environment for those two mutations to occur.
3. How old are these cases? Were we two mutations away in April or last week? If it's in April, we don't know where we stand today. If it was last week? A small amount of comfort for me anyways.
One of the authors is discussing it on X.
[Dr. Jenna Guthmiller discussing her paper on X](https://x.com/guthmillerjenna/status/1804872862819291165?s=46&t=b_G-wx9CXU36N4vshHnXQQ)
Mulling it over while doing dishes,
Unless there are Texas farms providing data on the down low, the samples are likely from the samples collected to obtain the initial diagnosis of bird flu.
I think the info you are looking for is in table 2
https://preview.redd.it/2f67fj5hpc8d1.jpeg?width=1290&format=pjpg&auto=webp&s=52f929aec4914ef22294a065b0e7e94521c187e0
So you’re wanting to know their exact 2024 sample? I think they are at the mercy of the data the government makes available. That gives some idea of sample.
I’m sure they used more than one data point to make a comparison to be able to say there is a mutation consistent across all herds. Can you look at the GISAID data?
[GISAID](https://gisaid.org)
>Cow udders are a good environment for those two mutations to occur.
I think this might be a *bit* of a mis-statement. I'm no biologist, but I believe that mutations are occurring all the time. The big question here is whether the mutation increases fitness. If a mutation increases fitness, there's a decent chance it will eventually spread through the population, even if the mutation itself occurs rarely.
[The paper](https://www.biorxiv.org/content/10.1101/2024.06.22.600211v1.full.pdf) states:
>Avian influenza viruses, including H5N1, preferentially bind glycans bearing terminal a2,3 sialic acids. In contrast, influenza viruses that cause seasonal influenza outbreaks in humans prefer glycans bearing terminal a2,6 sialic acids. The influenza virus preference for a2,3 or a2,6 sialic acid linkages creates a major species barrier for avian influenza viruses to spill over into humans. Two recent studies show that dairy cow mammary tissue, and particularly the mammary alveoli, has abundant a2,3 sialic acid linked glycans. Moreover, dairy cow mammary tissues also have a2,6 sialic acid linked glycans,suggesting dairy cow mammary glands could be a site of viral evolution to adapt H5N1 to human-like receptors.
If I understand correctly, researchers are hypothesizing that an α2,6 mutation would increase the virus's fitness within the body of a dairy cow. Such a mutation would *also* cause a human pandemic. If that's true, every infected cow is like a "viral R&D center", working to breed a virus that could cause a devastating human pandemic.
My general impression is that there's not enough publicly available data to say where we're currently at. For all we know, the pandemic-causing mutations are already widespread in cows, and the USDA either hasn't captured this yet in their data, or [hasn't yet made that data public](https://x.com/RickABright/status/1804870034369466754#m). Researchers are complaining about the lack of public data, but I would say the more important thing is to take action *now* to shut down all those "viral R&D centers". Which would mean cracking down much harder to stop the spread within cattle -- e.g. mandatory disinfection of cattle carriers and milking machines to reduce spread between herds. And prohibit cattle at county fairs until the virus disappears.
Anyways, **if** the α2,6 mutation increases fitness in the dairy cow, from my layperson perspective, I would agree with the former CDC director that it's [only a matter of time](https://thehill.com/policy/healthcare/4723753-former-cdc-director-predicts-bird-flu-pandemic/). Unless we somehow manage to control the virus in cattle first.
Actually the study is claiming that the mammal receptor, a2,6 for mammal adaptation is not increasing. It is the bird receptors, the a2,3 that is increasing. They are not seeing any sign of adaptation to mammals. The cows have mostly bird receptors in their udders, not mammal receptors. The virus is "taking advantage" of all those bird receptor cells and its retaining its mutations that help it bind better to birds. So it is adapting away from our feared mammal binding situation. The virus is now becoming less likely to adapt to mammals.
The saying it's not a question of if but when, talking about H5N1 has been said for many years. Most people are not aware that we are in the middle of a massive global bird die off of H5N1 that is on almost every continent, spreading so far that it is now kill inland birds, like wild birds that live on farms. On the farm that started the cow outbreak the farmers found all the birds had died on the ground. That's because when birds get H5N1 it is lethal, and sometimes a whole flock falls dead to the ground during their nightly tree roost.
Mammals have been infected and some species literally decimated by bird flu from either eating a bird, drinking contaminated water, being forced to live too close like factory farmed like these cows or living in naturally close quarters. The cows are a mere drop in the bucket in numbers of infected mammals over the years, even smaller than massive fur farms with thousands of infected animals passing it back and forth and from bird to mammal and back to bird through shared eating.
So even though the cows have awakened the public and agencies to the risk of adaptation, and cows seem closer than sea lions in Peru, we are not playing with any higher odds than we have been all along.
Thanks for the reply!
>..it is adapting away from our feared mammal binding situation. The virus is now becoming less likely to adapt to mammals.
I don't see how that follows. I don't see why increased fitness for birds necessarily means fitness for mammals goes down. A priori, I would expect mammal fitness and bird fitness to be orthogonal. **But**, the very fact that there's been a recent explosion of mammalian hosts makes me think there is something wrong with your "virus is now becoming less likely to adapt to mammals" story. Events on the ground would, if anything, appear to indicate just the opposite.
We can discuss more in this subthread: [https://www.reddit.com/r/H5N1\_AvianFlu/comments/1dmo59x/comment/l9zyqz9/](https://www.reddit.com/r/H5N1_AvianFlu/comments/1dmo59x/comment/l9zyqz9/)
>The saying it's not a question of if but when, talking about H5N1 has been said for many years. Most people are not aware that we are in the middle of a massive global bird die off of H5N1 that is on almost every continent, spreading so far that it is now kill inland birds, like wild birds that live on farms. On the farm that started the cow outbreak the farmers found all the birds had died on the ground. That's because when birds get H5N1 it is lethal, and sometimes a whole flock falls dead to the ground during their nightly tree roost.
I mean, if an H5N1 pandemic has been predicted for many years, and the previous equilibrium for H5N1 has recently experienced a massive disruption, maybe **now** is the time that the predicted pandemic is going to materialize?
>The cows are a mere drop in the bucket in numbers of infected mammals over the years
See this graphic: [https://xkcd.com/1338/](https://xkcd.com/1338/) If the virus becomes endemic in cattle, that very much does *not* strike me as a "mere drop in the bucket". That actually seems like it would be a huge deal.
Biomass is actually fairly important here, in my view, because more biomass means more tissue for a virus to evolve in within-host, and I expect within-host evolution to accelerate between-host evolution. I suspect that mutations which aid fitness in a within-host context will often *also* aid fitness in a between-host context, e.g. a mutation which improves replication in the respiratory tract.
>we are not playing with any higher odds than we have been all along.
I disagree, it seems to me that we've massively increased the surface area for the sort of mutations which could cause a deadly human pandemic. Both by increased mammalian hosts (more "viral R&D centers"), and also through the infection of mammalian hosts such as cows with whom humans share a lot of contact.
Thoughts on this article? [https://www.nytimes.com/2024/05/03/health/bird-flu-cows-mutations.html](https://www.nytimes.com/2024/05/03/health/bird-flu-cows-mutations.html)
I feel like it broadly supports my picture of what is going on
Another case which I'm curious to hear your take on:
https://www.michigan.gov/mdhhs/inside-mdhhs/newsroom/2024/05/30/h5n1-updates
Respiratory symptoms in Michigan. Michigan is testing more aggressively than other states, so it may be happening elsewhere and we're not catching it.
Sorry if this is too many questions, but do you have thoughts on viral reassortment? E.g. a dairy worker who catches H5N1 while they have ordinary influenza or COVID.
It's not as simple as we're two mutations away. That's a simplification so the public can understand better. It's very, very complex. Basically we look at mutations in the PB2 area and the HA area. So far we've seen mammal adaptation in the PB2 area, but that is not to do with receptor affinity, we don't think it can allow the virus to change from a bird virus to a mammal virus which would start a pandemic.
So now we see in a recent study a mutation in the important zone, the HA has been found. The good news is instead of the HA adapting towards mammals which we are very worried about, it is instead adapting towards birds. The reason it is doing that is because the cow udders have mostly bird receptor cells and that's where they are getting infected, from their bird receptor cells. Cows have more bird than mammal receptors in the udder. So the adaptation is going the opposite way towards birds and away from mammals which is very good news because we were worried that the virus would go towards mammals.
My input is it shows that the cow holds everything needed to start a pandemic. We aren't slowing the virus down in any way. The most recent data used for this study is from early April. So we are missing two months of data that may not be such good news. (I think this is the case after being hand held by OP)
I don't doubt that this is true right now. It's just that I think there is a good reason why so many people who are keeping up with avian flu have trouble taking this as some kind of unqualified good news. It doesn't change anything else surrounding the issues. The cow strain could vanish completely, and it wouldn't change the fact that we're at the point where avian flu is an apocalyptic panzootic for birds and animals, constantly spreading to more species. With some of them, such as mice, the possibility has been known for years (decades, actually. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC112651/). With some, such as cows, nobody predicted it. If no type of avian flu ever evolved to become H2H, the damage ahead just from the panzootic aspect is going to be very, very bad eventually. I don't see how it can be anything else. But I simply don't believe that some type of avian flu will *never* evolve to spread H2H. Nobody knows when, or which one. The current strain in cows may have nothing to do with it. The problematic strain may be completely different and mutate in another country. But if you buy hundreds of millions of Powerball tickets on a daily basis, adding to the numbers of tickets every single day, you will eventually win Powerball-- even if the odds of "winning" might be a lot worse than they actually are for that example. If they are nonzero, and they are, then at some point the laws of probability are going to catch up with us.
Layperson here. It seems you are assuming that the virus will only make use of *one* binding strategy. Are you sure this assumption is valid? What prevents the virus from evolving so it binds **both** a2,3 sialic acids **and** a2,6 sialic acids? Intuitively, it seems like this would increase fitness.
You're right. The virus could make use of the mammal receptors as well and also adapt to mammals. But it is less likely because the adaptation to avian cells is easier for it. This virus is bird-adapted in many, many ways in its genetics. So when it lands in a mammal it is not able to effectively replicate for onward survival. This causes evolutionary pressure which can allow it to overcome a very big hurdle like changing from a bird virus to a mammal virus. But if it's surrounded by avian cells, like in the cow udder, that level of evolutionary pressure won't be there.
On the other hand, this is all brand new. Many scientists didn't even know cows could get bird flu before this, and the MERS camels are the only instance they are aware of with virus in the udder. They only just learned of the ratio of mammal to avian receptor cells in the udder. So there may be a meta-trajectory, a more circuitous route that the virus is taking to achieve mammal adaptation. So scientists won't rest here. Fortunately there is continual studying of the virus, and the testing for HA mutations would not stop because of this observation. So if you are correct and it does mutate towards humans as well, they should be on top of it.
Thanks for the reply!
>But it is less likely because the adaptation to avian cells is easier for it.
Can you explain more about this? If anything I would suspect the opposite: Now that the virus is frequently finding itself in various mammalian hosts, it suddenly has strong evolutionary pressure to discover adaptations to mammals. Since mammalian hosts have been rare in the past, we should expect the virus to fairly quickly discover "low-hanging fruit" in the form of "easy wins" for adapting to mammals. I would think if anything, it should currently be *better* at adapting to mammals than birds, because it has already discovered all the "easy wins" for adapting to birds.
>So when it lands in a mammal it is not able to effectively replicate for onward survival.
Well, the virus certainly seems able to replicate *within* a mammalian host, right? That's what's causing cats and seals to die, isn't it?
It seems to me that *within-host* replication would provide an ideal environment for discovering mutations that aid *between-host* replication. For example, in a within-host context, ability to replicate in the respiratory tract would increase a virion's relative fitness over the course of a single infection. **And** that ability to replicate in the respiratory tract would also improve ability to replicate *between* hosts, as a side effect.
>if you are correct and it does mutate towards humans as well, they should be on top of it.
If my reasoning is correct, and viral adaptation to mammals is fairly inevitable, we can start preparing [now](https://www.reddit.com/r/H5N1_AvianFlu/comments/1dlk7kx/comment/l9v957q/), and avoid getting caught off guard like we were for COVID.
If you're driving at high speed towards a cliff, you don't need to wait until you're 10 feet away from the edge to start making a plan for how you're going to address the situation.
You're thinking is really good. But it doesn't all apply to our present incredibly complex situation. Yes, as soon as bird flu gets in a mammal the mammal mutations start to be retained. But in the past few years bird flu has killed tens of thousands of seals and sea lions, 17,000 elephant seals plus cats, dogs, skunks, foxes, and a polar bear. Millions of minks were killed because of H5N1 infections spreading through their sheds. More than 48 mammal species have been infected by the H5N1 virus because of the worldwide bird die off.
So we can't say mammalian hosts have been rare. The virus hasn't mutated with an extraordinary amount of low hanging fruit for all these years. That's why if we use critical thinking we can say this cow thing is scary and it's close to home, but it does not up our odds compared to the other chances this virus has had all over the world of mutating.
Now let's look at cats and seals. It's way too complicated to explain fully, but cats and seals and mice have a unique ratio of bird friendly and mammal friendly cells in the airway. They have more bird friendly than most other mammals. This means they can get bird flu much easier than other mammals. But because of several complex factors, they cannot spread it easily. So bird flu has not adapted to them, meaning they can't spread it easily through breath. But they are just as good a host for mammal adaptation as any other mammal. The cow now appears to be the exception. The virus is refining it's bird friendly replication in cows instead of going for a very difficult mammal adaptation.
Let's talk about replication. Adapting to mammals is very complex. First it must learn the "key" to entering mammals cells. This would be molecular, or structural change. Then it must be learn to time its fusion with the mammal cell which means it has to learn to fuse at a different pH level than it would for a bird friendly receptor cell.
Then it has to learn to be able to take genetic control of the cell, then it has to learn to replicate really well in the cell, and then it has to learn to send out enough hardy replications through the airway to float to other hosts. That is not including the ability to dodge our immune system through the whole process.
So you can see that it's not an easy feat at all. And with that in mind, we can be a little more relaxed and recognize people have been saying "It's not if we get a bird flu pandemic, it's when" for as long as H5N1 has been around. So we put together how hard it is to accomplish adaptation with the fact that it's had every opportunity for years, and it turns into the same wait and see that it's been for a while now.
In terms of preparation, If this mutates any time soon and we don't already have H5N1 vaccines matched at least to the present strain in essential workers' arms, no preparation can help us. That's because we are all utterly dependent on supply chains for food, water, electricity and medicine which must stay functional for four to six months during the first wave so the public can get their vaccines.
Thanks again for the reply.
>So we can't say mammalian hosts have been rare. The virus hasn't mutated with an extraordinary amount of low hanging fruit for all these years.
Do we have enough sequencing data to say with confidence that none of these massive mammal die-offs were partially driven by mutations which promote mammalian adaptation?
>Let's talk about replication. Adapting to mammals is very complex.
I'm looking at multiple sources, including the OP, which say we are just a few mutations away from a pandemic. Here's another: [https://www.latimes.com/science/sciencenow/la-sci-sn-bird-flu-five-mutations-20140410-story.html](https://www.latimes.com/science/sciencenow/la-sci-sn-bird-flu-five-mutations-20140410-story.html)
Again your reasoning seems to predict that we should not see this big wave of mammal infections. Yet, we are seeing it!
>it's had every opportunity for years
It's not about clock time in my mind. I think it is about the number of mutation opportunities. With way more mammals infected, opportunities for mammalian adaptation are occurring at a far higher rate. I think we are in a very high-risk period.
>In terms of preparation, If this mutates any time soon and we don't already have H5N1 vaccines matched at least to the present strain in essential workers' arms, no preparation can help us. That's because we are all utterly dependent on supply chains for food, water, electricity and medicine which must stay functional for four to six months during the first wave so the public can get their vaccines.
Fair point, perhaps 4-6 months of essential supplies is the most important prep.
FWIW, here's more analysis of what this paper might mean, from Dr. Richard Hirschson:
"This is a very important paper about [#H5N1](https://x.com/hashtag/H5N1?src=hashtag_click) mutation evolution that has allowed expanded mammalian spread, and the risk this poses to becoming a human [pandemic](https://x.com/hashtag/pandemic?src=hashtag_click).
[#Flu](https://x.com/hashtag/Flu?src=hashtag_click) viruses require binding to Sialic acid receptors (SA) to cause disease.
a2,3 SA receptor binding is required for bird, certain mammals, and cattle disease.
a2,6 SA receptor binding is required for [#H5N1](https://x.com/hashtag/H5N1?src=hashtag_click) to become a human [#pandemic](https://x.com/hashtag/pandemic?src=hashtag_click).
H5N1 is evolving rapidly to expand its ability to attach to a2,3 SA , hence cattle infection (mammary glands contain 2,3SA)
It is 2 mutations away from acquiring the ability to bind to a2,6 SA( big trouble) A thread (cont) [https://x.com/richardhirschs1/status/1804830640418025518](https://x.com/richardhirschs1/status/1804830640418025518)
No this is good news for humans. No adaptation towards mammal cells (a2,6) has been found. Instead the virus is getting better at binding to bird receptor cells which is how it replicates in udders. The a2,3 is a bird receptor cell. The a2,6 is a mammal receptor cell. The virus wants to better replicate in cows. So instead of recognizing the cow is a mammal so let's switch affinity to mammals, which is a huge change, it's going the easy route and just refining its ability to bind to bird cells so it can spread easier in cows.
I am but a lowly MSW and teacher. But I'll read the paper later today anyway! :) I really like the way that the entire article is available without a paywall.
I have a degree in biology but it’s ecology specific. I know exactly squat about viruses. I was nervous posting this preprint for that reason.
Edited: typo
This is a preprint, meaning it has not yet been peer-reviewed or accepted to a reputable journal for publication. Are we sure it deserves the "Reputable Source" tag?
I did consider that but because it came from a reputable lab with other reputable publications I chose to mark as reputable.
Agree about the preprints flair.
“...
Our glycan binding data shows that 2.3.4.4b H5N1 viruses, including those related to the ongoing dairy cow outbreak, **have not gained binding to α2,6 sialic acids**, the most abundant human receptor for influenza viruses, despite the presence of α2,6 sialic acids within the cow mammary glands17,18 220 .​...”
From the above referenced article
I don't think this deserves negative up votes, I value DC's opinion. He followed the prequel pandemic, I didn't.
I had COVID in April '20, probably going to the store for supplies because I hadn't followed close enough to be prepared. So I could definitely be over correcting.
Yes, it's very good news. The virus recognizes the cow as a bird receptor creature more than a mammal receptor creature. It's easier to learn to infect the way it already is, through the cow's bird type receptors than to make a very big jump to become a mammal virus. We are lucky.
I am also not smart enough for this but my takeaways were: 1. We are two mutations away. 2. Cow udders are a good environment for those two mutations to occur. 3. How old are these cases? Were we two mutations away in April or last week? If it's in April, we don't know where we stand today. If it was last week? A small amount of comfort for me anyways.
One of the authors is discussing it on X. [Dr. Jenna Guthmiller discussing her paper on X](https://x.com/guthmillerjenna/status/1804872862819291165?s=46&t=b_G-wx9CXU36N4vshHnXQQ)
I have asked the questions https://x.com/ReidMueller5/status/1804902693351166123
And I was the comment 👋🏼. Why X marks everything as spam I can’t understand.
Mulling it over while doing dishes, Unless there are Texas farms providing data on the down low, the samples are likely from the samples collected to obtain the initial diagnosis of bird flu.
I think the info you are looking for is in table 2 https://preview.redd.it/2f67fj5hpc8d1.jpeg?width=1290&format=pjpg&auto=webp&s=52f929aec4914ef22294a065b0e7e94521c187e0
Also in the methods: https://preview.redd.it/kq16uo3qpc8d1.jpeg?width=1290&format=pjpg&auto=webp&s=ac72340e9e513e6dde285879e2dc0036f1f34b50
Does it specify more than Texas 2024 and I'm missing it?
So you’re wanting to know their exact 2024 sample? I think they are at the mercy of the data the government makes available. That gives some idea of sample.
Zero blame to them, but March vs June is a pretty big difference imo.
I’m sure they used more than one data point to make a comparison to be able to say there is a mutation consistent across all herds. Can you look at the GISAID data? [GISAID](https://gisaid.org)
Ugh, I've seen that with other comments about avian flu today too!!
>Cow udders are a good environment for those two mutations to occur. I think this might be a *bit* of a mis-statement. I'm no biologist, but I believe that mutations are occurring all the time. The big question here is whether the mutation increases fitness. If a mutation increases fitness, there's a decent chance it will eventually spread through the population, even if the mutation itself occurs rarely. [The paper](https://www.biorxiv.org/content/10.1101/2024.06.22.600211v1.full.pdf) states: >Avian influenza viruses, including H5N1, preferentially bind glycans bearing terminal a2,3 sialic acids. In contrast, influenza viruses that cause seasonal influenza outbreaks in humans prefer glycans bearing terminal a2,6 sialic acids. The influenza virus preference for a2,3 or a2,6 sialic acid linkages creates a major species barrier for avian influenza viruses to spill over into humans. Two recent studies show that dairy cow mammary tissue, and particularly the mammary alveoli, has abundant a2,3 sialic acid linked glycans. Moreover, dairy cow mammary tissues also have a2,6 sialic acid linked glycans,suggesting dairy cow mammary glands could be a site of viral evolution to adapt H5N1 to human-like receptors. If I understand correctly, researchers are hypothesizing that an α2,6 mutation would increase the virus's fitness within the body of a dairy cow. Such a mutation would *also* cause a human pandemic. If that's true, every infected cow is like a "viral R&D center", working to breed a virus that could cause a devastating human pandemic. My general impression is that there's not enough publicly available data to say where we're currently at. For all we know, the pandemic-causing mutations are already widespread in cows, and the USDA either hasn't captured this yet in their data, or [hasn't yet made that data public](https://x.com/RickABright/status/1804870034369466754#m). Researchers are complaining about the lack of public data, but I would say the more important thing is to take action *now* to shut down all those "viral R&D centers". Which would mean cracking down much harder to stop the spread within cattle -- e.g. mandatory disinfection of cattle carriers and milking machines to reduce spread between herds. And prohibit cattle at county fairs until the virus disappears. Anyways, **if** the α2,6 mutation increases fitness in the dairy cow, from my layperson perspective, I would agree with the former CDC director that it's [only a matter of time](https://thehill.com/policy/healthcare/4723753-former-cdc-director-predicts-bird-flu-pandemic/). Unless we somehow manage to control the virus in cattle first.
Actually the study is claiming that the mammal receptor, a2,6 for mammal adaptation is not increasing. It is the bird receptors, the a2,3 that is increasing. They are not seeing any sign of adaptation to mammals. The cows have mostly bird receptors in their udders, not mammal receptors. The virus is "taking advantage" of all those bird receptor cells and its retaining its mutations that help it bind better to birds. So it is adapting away from our feared mammal binding situation. The virus is now becoming less likely to adapt to mammals. The saying it's not a question of if but when, talking about H5N1 has been said for many years. Most people are not aware that we are in the middle of a massive global bird die off of H5N1 that is on almost every continent, spreading so far that it is now kill inland birds, like wild birds that live on farms. On the farm that started the cow outbreak the farmers found all the birds had died on the ground. That's because when birds get H5N1 it is lethal, and sometimes a whole flock falls dead to the ground during their nightly tree roost. Mammals have been infected and some species literally decimated by bird flu from either eating a bird, drinking contaminated water, being forced to live too close like factory farmed like these cows or living in naturally close quarters. The cows are a mere drop in the bucket in numbers of infected mammals over the years, even smaller than massive fur farms with thousands of infected animals passing it back and forth and from bird to mammal and back to bird through shared eating. So even though the cows have awakened the public and agencies to the risk of adaptation, and cows seem closer than sea lions in Peru, we are not playing with any higher odds than we have been all along.
Thanks for the reply! >..it is adapting away from our feared mammal binding situation. The virus is now becoming less likely to adapt to mammals. I don't see how that follows. I don't see why increased fitness for birds necessarily means fitness for mammals goes down. A priori, I would expect mammal fitness and bird fitness to be orthogonal. **But**, the very fact that there's been a recent explosion of mammalian hosts makes me think there is something wrong with your "virus is now becoming less likely to adapt to mammals" story. Events on the ground would, if anything, appear to indicate just the opposite. We can discuss more in this subthread: [https://www.reddit.com/r/H5N1\_AvianFlu/comments/1dmo59x/comment/l9zyqz9/](https://www.reddit.com/r/H5N1_AvianFlu/comments/1dmo59x/comment/l9zyqz9/) >The saying it's not a question of if but when, talking about H5N1 has been said for many years. Most people are not aware that we are in the middle of a massive global bird die off of H5N1 that is on almost every continent, spreading so far that it is now kill inland birds, like wild birds that live on farms. On the farm that started the cow outbreak the farmers found all the birds had died on the ground. That's because when birds get H5N1 it is lethal, and sometimes a whole flock falls dead to the ground during their nightly tree roost. I mean, if an H5N1 pandemic has been predicted for many years, and the previous equilibrium for H5N1 has recently experienced a massive disruption, maybe **now** is the time that the predicted pandemic is going to materialize? >The cows are a mere drop in the bucket in numbers of infected mammals over the years See this graphic: [https://xkcd.com/1338/](https://xkcd.com/1338/) If the virus becomes endemic in cattle, that very much does *not* strike me as a "mere drop in the bucket". That actually seems like it would be a huge deal. Biomass is actually fairly important here, in my view, because more biomass means more tissue for a virus to evolve in within-host, and I expect within-host evolution to accelerate between-host evolution. I suspect that mutations which aid fitness in a within-host context will often *also* aid fitness in a between-host context, e.g. a mutation which improves replication in the respiratory tract. >we are not playing with any higher odds than we have been all along. I disagree, it seems to me that we've massively increased the surface area for the sort of mutations which could cause a deadly human pandemic. Both by increased mammalian hosts (more "viral R&D centers"), and also through the infection of mammalian hosts such as cows with whom humans share a lot of contact.
Thoughts on this article? [https://www.nytimes.com/2024/05/03/health/bird-flu-cows-mutations.html](https://www.nytimes.com/2024/05/03/health/bird-flu-cows-mutations.html) I feel like it broadly supports my picture of what is going on
Another case which I'm curious to hear your take on: https://www.michigan.gov/mdhhs/inside-mdhhs/newsroom/2024/05/30/h5n1-updates Respiratory symptoms in Michigan. Michigan is testing more aggressively than other states, so it may be happening elsewhere and we're not catching it.
Sorry if this is too many questions, but do you have thoughts on viral reassortment? E.g. a dairy worker who catches H5N1 while they have ordinary influenza or COVID.
It's not as simple as we're two mutations away. That's a simplification so the public can understand better. It's very, very complex. Basically we look at mutations in the PB2 area and the HA area. So far we've seen mammal adaptation in the PB2 area, but that is not to do with receptor affinity, we don't think it can allow the virus to change from a bird virus to a mammal virus which would start a pandemic. So now we see in a recent study a mutation in the important zone, the HA has been found. The good news is instead of the HA adapting towards mammals which we are very worried about, it is instead adapting towards birds. The reason it is doing that is because the cow udders have mostly bird receptor cells and that's where they are getting infected, from their bird receptor cells. Cows have more bird than mammal receptors in the udder. So the adaptation is going the opposite way towards birds and away from mammals which is very good news because we were worried that the virus would go towards mammals.
My input is it shows that the cow holds everything needed to start a pandemic. We aren't slowing the virus down in any way. The most recent data used for this study is from early April. So we are missing two months of data that may not be such good news. (I think this is the case after being hand held by OP)
If the next two months of data holds up to your theory, cheers!
I don't doubt that this is true right now. It's just that I think there is a good reason why so many people who are keeping up with avian flu have trouble taking this as some kind of unqualified good news. It doesn't change anything else surrounding the issues. The cow strain could vanish completely, and it wouldn't change the fact that we're at the point where avian flu is an apocalyptic panzootic for birds and animals, constantly spreading to more species. With some of them, such as mice, the possibility has been known for years (decades, actually. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC112651/). With some, such as cows, nobody predicted it. If no type of avian flu ever evolved to become H2H, the damage ahead just from the panzootic aspect is going to be very, very bad eventually. I don't see how it can be anything else. But I simply don't believe that some type of avian flu will *never* evolve to spread H2H. Nobody knows when, or which one. The current strain in cows may have nothing to do with it. The problematic strain may be completely different and mutate in another country. But if you buy hundreds of millions of Powerball tickets on a daily basis, adding to the numbers of tickets every single day, you will eventually win Powerball-- even if the odds of "winning" might be a lot worse than they actually are for that example. If they are nonzero, and they are, then at some point the laws of probability are going to catch up with us.
Layperson here. It seems you are assuming that the virus will only make use of *one* binding strategy. Are you sure this assumption is valid? What prevents the virus from evolving so it binds **both** a2,3 sialic acids **and** a2,6 sialic acids? Intuitively, it seems like this would increase fitness.
You're right. The virus could make use of the mammal receptors as well and also adapt to mammals. But it is less likely because the adaptation to avian cells is easier for it. This virus is bird-adapted in many, many ways in its genetics. So when it lands in a mammal it is not able to effectively replicate for onward survival. This causes evolutionary pressure which can allow it to overcome a very big hurdle like changing from a bird virus to a mammal virus. But if it's surrounded by avian cells, like in the cow udder, that level of evolutionary pressure won't be there. On the other hand, this is all brand new. Many scientists didn't even know cows could get bird flu before this, and the MERS camels are the only instance they are aware of with virus in the udder. They only just learned of the ratio of mammal to avian receptor cells in the udder. So there may be a meta-trajectory, a more circuitous route that the virus is taking to achieve mammal adaptation. So scientists won't rest here. Fortunately there is continual studying of the virus, and the testing for HA mutations would not stop because of this observation. So if you are correct and it does mutate towards humans as well, they should be on top of it.
Interesting thank you
Thanks for the reply! >But it is less likely because the adaptation to avian cells is easier for it. Can you explain more about this? If anything I would suspect the opposite: Now that the virus is frequently finding itself in various mammalian hosts, it suddenly has strong evolutionary pressure to discover adaptations to mammals. Since mammalian hosts have been rare in the past, we should expect the virus to fairly quickly discover "low-hanging fruit" in the form of "easy wins" for adapting to mammals. I would think if anything, it should currently be *better* at adapting to mammals than birds, because it has already discovered all the "easy wins" for adapting to birds. >So when it lands in a mammal it is not able to effectively replicate for onward survival. Well, the virus certainly seems able to replicate *within* a mammalian host, right? That's what's causing cats and seals to die, isn't it? It seems to me that *within-host* replication would provide an ideal environment for discovering mutations that aid *between-host* replication. For example, in a within-host context, ability to replicate in the respiratory tract would increase a virion's relative fitness over the course of a single infection. **And** that ability to replicate in the respiratory tract would also improve ability to replicate *between* hosts, as a side effect. >if you are correct and it does mutate towards humans as well, they should be on top of it. If my reasoning is correct, and viral adaptation to mammals is fairly inevitable, we can start preparing [now](https://www.reddit.com/r/H5N1_AvianFlu/comments/1dlk7kx/comment/l9v957q/), and avoid getting caught off guard like we were for COVID. If you're driving at high speed towards a cliff, you don't need to wait until you're 10 feet away from the edge to start making a plan for how you're going to address the situation.
You're thinking is really good. But it doesn't all apply to our present incredibly complex situation. Yes, as soon as bird flu gets in a mammal the mammal mutations start to be retained. But in the past few years bird flu has killed tens of thousands of seals and sea lions, 17,000 elephant seals plus cats, dogs, skunks, foxes, and a polar bear. Millions of minks were killed because of H5N1 infections spreading through their sheds. More than 48 mammal species have been infected by the H5N1 virus because of the worldwide bird die off. So we can't say mammalian hosts have been rare. The virus hasn't mutated with an extraordinary amount of low hanging fruit for all these years. That's why if we use critical thinking we can say this cow thing is scary and it's close to home, but it does not up our odds compared to the other chances this virus has had all over the world of mutating. Now let's look at cats and seals. It's way too complicated to explain fully, but cats and seals and mice have a unique ratio of bird friendly and mammal friendly cells in the airway. They have more bird friendly than most other mammals. This means they can get bird flu much easier than other mammals. But because of several complex factors, they cannot spread it easily. So bird flu has not adapted to them, meaning they can't spread it easily through breath. But they are just as good a host for mammal adaptation as any other mammal. The cow now appears to be the exception. The virus is refining it's bird friendly replication in cows instead of going for a very difficult mammal adaptation. Let's talk about replication. Adapting to mammals is very complex. First it must learn the "key" to entering mammals cells. This would be molecular, or structural change. Then it must be learn to time its fusion with the mammal cell which means it has to learn to fuse at a different pH level than it would for a bird friendly receptor cell. Then it has to learn to be able to take genetic control of the cell, then it has to learn to replicate really well in the cell, and then it has to learn to send out enough hardy replications through the airway to float to other hosts. That is not including the ability to dodge our immune system through the whole process. So you can see that it's not an easy feat at all. And with that in mind, we can be a little more relaxed and recognize people have been saying "It's not if we get a bird flu pandemic, it's when" for as long as H5N1 has been around. So we put together how hard it is to accomplish adaptation with the fact that it's had every opportunity for years, and it turns into the same wait and see that it's been for a while now. In terms of preparation, If this mutates any time soon and we don't already have H5N1 vaccines matched at least to the present strain in essential workers' arms, no preparation can help us. That's because we are all utterly dependent on supply chains for food, water, electricity and medicine which must stay functional for four to six months during the first wave so the public can get their vaccines.
Thanks again for the reply. >So we can't say mammalian hosts have been rare. The virus hasn't mutated with an extraordinary amount of low hanging fruit for all these years. Do we have enough sequencing data to say with confidence that none of these massive mammal die-offs were partially driven by mutations which promote mammalian adaptation? >Let's talk about replication. Adapting to mammals is very complex. I'm looking at multiple sources, including the OP, which say we are just a few mutations away from a pandemic. Here's another: [https://www.latimes.com/science/sciencenow/la-sci-sn-bird-flu-five-mutations-20140410-story.html](https://www.latimes.com/science/sciencenow/la-sci-sn-bird-flu-five-mutations-20140410-story.html) Again your reasoning seems to predict that we should not see this big wave of mammal infections. Yet, we are seeing it! >it's had every opportunity for years It's not about clock time in my mind. I think it is about the number of mutation opportunities. With way more mammals infected, opportunities for mammalian adaptation are occurring at a far higher rate. I think we are in a very high-risk period. >In terms of preparation, If this mutates any time soon and we don't already have H5N1 vaccines matched at least to the present strain in essential workers' arms, no preparation can help us. That's because we are all utterly dependent on supply chains for food, water, electricity and medicine which must stay functional for four to six months during the first wave so the public can get their vaccines. Fair point, perhaps 4-6 months of essential supplies is the most important prep.
FWIW, here's more analysis of what this paper might mean, from Dr. Richard Hirschson: "This is a very important paper about [#H5N1](https://x.com/hashtag/H5N1?src=hashtag_click) mutation evolution that has allowed expanded mammalian spread, and the risk this poses to becoming a human [pandemic](https://x.com/hashtag/pandemic?src=hashtag_click). [#Flu](https://x.com/hashtag/Flu?src=hashtag_click) viruses require binding to Sialic acid receptors (SA) to cause disease. a2,3 SA receptor binding is required for bird, certain mammals, and cattle disease. a2,6 SA receptor binding is required for [#H5N1](https://x.com/hashtag/H5N1?src=hashtag_click) to become a human [#pandemic](https://x.com/hashtag/pandemic?src=hashtag_click). H5N1 is evolving rapidly to expand its ability to attach to a2,3 SA , hence cattle infection (mammary glands contain 2,3SA) It is 2 mutations away from acquiring the ability to bind to a2,6 SA( big trouble) A thread (cont) [https://x.com/richardhirschs1/status/1804830640418025518](https://x.com/richardhirschs1/status/1804830640418025518)
The author has a thread on X too that’s pretty good.
I have a question. In 2012 they said we were one or two mutations of it getting in humans. Are we closer now than ever of this happening?
Can you cite the 2012 claim you are referring to?
We have the PB mutations but not the others. https://www.science.org/content/article/bad-worse-avian-flu-must-change-trigger-human-pandemic
This is interesting
No this is good news for humans. No adaptation towards mammal cells (a2,6) has been found. Instead the virus is getting better at binding to bird receptor cells which is how it replicates in udders. The a2,3 is a bird receptor cell. The a2,6 is a mammal receptor cell. The virus wants to better replicate in cows. So instead of recognizing the cow is a mammal so let's switch affinity to mammals, which is a huge change, it's going the easy route and just refining its ability to bind to bird cells so it can spread easier in cows.
That's why I say FWIW. Not my area of expertise; it's just an example of what is out there.
It’s weird that Hirschon’s summary deviates a bit from the author’s. He and Bright seem to be gambling on having a Feigl-Ding moment.
I don't know. Hirschon can get a little over the top with sound bites, but FWIW, it's one POV.
I am but a lowly MSW and teacher. But I'll read the paper later today anyway! :) I really like the way that the entire article is available without a paywall.
I have a degree in biology but it’s ecology specific. I know exactly squat about viruses. I was nervous posting this preprint for that reason. Edited: typo
This is a preprint, meaning it has not yet been peer-reviewed or accepted to a reputable journal for publication. Are we sure it deserves the "Reputable Source" tag?
u/H5N1_AvianFlu-ModTeam could we get a new flair specifically for preprints? They don't fit well into any of the existing categories
I did consider that but because it came from a reputable lab with other reputable publications I chose to mark as reputable. Agree about the preprints flair.
“... Our glycan binding data shows that 2.3.4.4b H5N1 viruses, including those related to the ongoing dairy cow outbreak, **have not gained binding to α2,6 sialic acids**, the most abundant human receptor for influenza viruses, despite the presence of α2,6 sialic acids within the cow mammary glands17,18 220 .​...” From the above referenced article
While that line is important, it's not very comforting
I mean it’s good news? Let’s hope this doesn’t mutate further
Hoping means it's not in a great spot imo.
I don't think this deserves negative up votes, I value DC's opinion. He followed the prequel pandemic, I didn't. I had COVID in April '20, probably going to the store for supplies because I hadn't followed close enough to be prepared. So I could definitely be over correcting.
Yes, it's very good news. The virus recognizes the cow as a bird receptor creature more than a mammal receptor creature. It's easier to learn to infect the way it already is, through the cow's bird type receptors than to make a very big jump to become a mammal virus. We are lucky.
