I also wanted to say that the situation is very different from what we had with COVID-19. When COVID-19 started, we didn't have any vaccines, we didn't have any antiviral medications, we didn't know much about the virus that caused COVID-19. So that was a pretty bad situation. With age 5 and 1, the situation could be really bad too, right? If the virus causes a pandemic, it's very likely that a lot of people would die, but we would also be better prepared. Biological with Florian Kramer Hello and welcome to this episode of Virological. This was recorded on February 22nd of 2026 in New York. And today we're going to talk about even influenza or bird flu. So there are many types of even influenza that will get into this a little bit. However, if people hear about even influenza in the media, it's mostly about age 5 and 1, or sometimes age 7 viruses. And as I mentioned, I'm going to explain in a little bit more detail what makes these viruses special. But let's start with some basics about influenza viruses and influenza evauses, specifically. Inflanta evauses include seasonal influenza, swine flu, bird flu, and influenza viruses that infect many different animal species. Actually, influenza evauses can even infect alligators. People have tried that and they actually do get infected. Inflanta evauses are orthomixovaruses. They're related to influenza p-viruses, influenza c-viruses, and influenza d-viruses. Inflanta p-viruses only infect humans. Inflanta c-viruses also circulate in humans and other animals. And inflanta d-viruses are typically found in cows and sheep, for example. All of these viruses have a -sense single stranded RNA genome. That basically just means that RNA is in the entire sense direction. So the virus needs to turn it into a positive sense direction before a protein can be translated from the genome. And the special part here is that it is a segmented genome. Inflanta a and p-viruses have a genomic segments. Inflanta c and t-viruses have seven genomic segments. And you can imagine that a little bit like chromosomes that humans or other animals have. This allows these viruses to actually exchange these genomic segments. If two different viruses infect the same animal and the same cell, this typically can happen between influenza e-viruses or between influenza p-viruses. Influenza a and b, for example, don't mix. So it needs to be within the - within influenza a or within influenza p-viruses. But they can do that. And they can just exchange these genomic segments. And that can lead to new viruses. Basically, that have different combinations of these genomic segments. We call this mechanism reassortment and the viruses that come out of it, reassortment viruses. And these new viruses can have new traits. And they can be more dangerous than their parents. And that is one of the issues that we have with influenza viruses. In terms of structure, we have these genomic segments of the inside. In terms of structure, we have these genomic segments on the inside of the virion. They are covered by a nuclear protein that protects the RNA. And there's also a polymerase complex associated with the genomic segments. And then we have a matrix protein that stabilizes the virion from the inside. And this attaches to the lipid envelope. And in the lipid envelope, we have two spike proteins. They're hemogloutinin and the nerve-inities. And we'll get to those two in a second. In terms of size, the particles are 80 to 120 nanometers in diameter. They're kind of round but more bleuomorphic, some are x-shaped, some are really round, some are elongated. And usually when we have lab strains of influenza, they're more round. But patient isolates of influenza viruses can be pretty elongated, really filamentous. And they look more like Ebola viruses. So we have these two spike proteins, right? The first one is the hemogloutinin or in short, HA. This protein is important because it binds to our cells. It actually binds to sugar structures on the surface of our cells. So they allow the virus to etched to our cells. And specifically, it binds to xialic acids on sugar structures. So the first function of the hemogloutinin is binding. And then once the virus is bound to the cell surface, the cell takes it up and gals it into an endosome. And then the second function of HA comes or hemogloutinin comes into play. And that's fusion. So the hemogloutinin is basically a little machine that can fuse the viral membrane with the endosomal membrane. And that then allows the viral genome that sits inside of the virus to move into the cell and start the replication cycle and start the infection. So two important functions. The second spike protein, the norm in it is, is actually an enzyme. And that cleaves this sugar residue of the xialic acids from the cell surface. And that allows newly formed virus to get released from the cells and spread to other cells. So both of these proteins are very important for the virus. And actually, influenza viruses are, influenza evaresis are named and typed after these two different spike proteins. So for example, when you think about seasonal influenza, we have H1N1 and H3N2 strains. H1N1 is basically named after type 1 hemogloutinin. So H1 and type 1 norm in it is so N1. H3N2 is called H3N2 because it has a type 3 hemogloutinin and the type 2 norm in it is so H3N2. For H5N1, it would be a type 5 hemogloutinin and the type 1 norm in it is. And typically, we have 19 HAs subtypes that exist in the animal reservoir and 12 norm in it is subtypes. 17 of these HAs subtypes circulate in birds and 9 and A subtypes circulate in birds. So birds are really the main reservoir for influenza evaresis. Yeah, influenza evaresis that circulate in birds are in generally, in general called avian influenza or bird fluids. Of course, where the name comes from. Most of these viruses are pretty harmless for birds and for humans. They often cause in birds asymptomatic infections. Sometimes infections with mild symptoms. They can grow in the respiratory tract, like seasonal influenza in humans. But very often, they also grow in the gastrointestinal tract in birds. So basically, means the virus just replicates in the gut. And that also explains some of the bird to bird spread. You can imagine if a duck is infected with influenza virus, swimming around in the water and filter feeding in the water. And then it poops in the water. The water gets contaminated in the next duck. That kind of feeds through that, do that water. Takes up the virus and gets infected again. It's pretty disgusting, but that's kind of how the virus can spread in wild waterfall. But there are also strains of avian influenza that can cause severe disease and very rapid death in birds. And that's the bird fluid, typically, here of in the media. And those are usually H5 subtype viruses. Sometimes also H7 subtype viruses. And today I'm going to talk about H5, because this is what we've been hearing about in the last few years when the media talked about bird flu. And I'll try to explain what the issue with this subtype is a little bit about the history and also how the current situation looks like. The H5 subtype is known for quite some time. It was first detected in 1959 in Scotland, where it caused an outbreak in Chichen. Actually, killed a lot of birds there and was a problem for chicken farms. And people realized that there's two versions of this virus. There is low-petogenic avian influenza H5. We call this LPAI, so low-petogenic avian influenza. And then there is a highly-petogenic version that's called highly-petogenic avian influenza, HPAI. And there's actually only a very small difference between these two versions of H5. And that difference is just a few amino acids in the hemoglobin in the spike protein.
protein of the virus. So typically these hemogloutinins have to be cut into two pieces in order to be active and in order to have infectious virus. So there is a cleavage site in the middle of the protein and typically that cleavage site consists of one basic amino acid. And then there is proteins as typically in the airways or the gut that can cleave that hemogloutinins and that means that infectious virus is produced. But that also means that the virus can only replicate in the respiratory tract or the gut where it can be cleaved. It can go to other cells in the body because it can grow there because the hemogloutinins cannot get activated. And that's good. Now there are versions of age 5 where that cleavage site is a little bit different. Instead of having one basic amino acid there is multiple basic amino acids called this poly-basic or multi-basic cleavage site. And now this hemogloutinins can be cut into pieces by proteins and basically all cells in the body. And that's bad because that allows the virus to spread throughout the body including to the brain. And that is what makes these viruses highly pathogenic. And often you have a low pathogenic strain and it spontaneously mutates, often basically through an insertion of a sequence there and it becomes highly pathogenic. And that's really again a problem for chicken farms. It's also a problem for wildlife and it can be a big problem for humans as well. And so most of these low pathogenic age 5 and one strains are basically pretty harmless for birds as I mentioned. But if this virus becomes highly pathogenic and acquires this poly-basic cleavage site, then as I mentioned it can grow throughout the body of the bird including the brain can lead to all kinds of hemorrhagic symptoms. So bleeding throughout the body, it basically looks like Ebola in a chicken but it is actually more deadly than Ebola. If chickens are infected with this highly pathogenic virus, they typically die between 2 and 5 days after getting infected. As I said the virus replicates all over the body and typically kills to 100% of the infected chickens die. So again big problem for poor tree farms but also for wild birds. Until 1997 the idea was that yeah this is a problem if you are chicken but if you are human that's not a problem because this is a chicken virus or a bird virus. But this changed in 1997. In 1997 there was an outbreak of unusual influenza in Hong Kong that was associated with life bird markets. 18 people got infected on 6th sti and it turned out this was highly pathogenic age 5 and 1 virus. Actually it post genetically traced back to isolates from the previous year from 1996 when a highly pathogenic virus showed up in the Guangdong province in China. This lineage is called a Guus Guangdong 96 and actually all the age 5 viruses that we have problems with right now trace back to that lineage. The authorities in Hong Kong reacted pretty quickly, basically closed initially the life bird markets and then put in all kinds of frozen regulations to make them safe and initially the virus disappeared. The problem is a few years later it came back in 2003 and it reappeared all over Asia. Initially in Southeast Asia was found in Indonesia, Cambodia, Thailand, Vietnam, China but then also in Mongolia for example so a little bit north, northwest and caused a lot of infections in birds but also human infections and pretty severe human infections including deaths. Back then in 2003 there was already panic about this virus and you know the worry that it could cause a pandemic and you can imagine a virus that is dead severe right if that causes a pandemic you know that could have huge impact. I think back then there were the story about age 5 and 1 even made it to the cover of Times Magazine and you know there was a lot of talk about the potential that this virus could cause a pandemic. So the virus did not cause a pandemic back in 2003 but it started to spread westwards from Southeast Asia through migratory birds. I mentioned earlier that the virus is often very deadly for birds but there are birds species that seem to be relatively resistant to get infected but they don't really become sick and they can still fly very long distances and spread the virus. Malads for example is such a species that's typically pretty unaffected but they spread the virus very well and so this is exactly what happened birds migrated via their flyways towards the west and spread the virus to Central Asia to the Middle East at the Nile Delta for example is a major hub for migratory birds and has been a hotspot for age 5 and 1 for a long time now the virus also spread into Europe and into Africa and over time more and more human infections occurred. Again these infections were typically transmissions from birds to humans not human to human transmission and over time about 900 infections were recorded and out of these approximately 900 infected people approximately half died so that's a case fidelity rate of about 50% which is super high. There have been serological studies to look at how many people actually got infected with the virus in certain areas and it turns out that many more people got exposed to the virus and got infected but basically didn't end up in the hospital, didn't end up developing symptoms and so the assumption is that the infection fidelity rate so basically the true rate of deaths compared to the true rate of infections is much lower than the case fidelity rate and my guess is that it's not that it's closer to 2 to 3% which is still pretty high but nowhere close to the 50% that the case fidelity rate would suggest. Still very dangerous virus and I think it's very bad news if you get infected with it. I think the important point was that this virus spreads well from birds to birds but historically it has not spread from human to human and it actually doesn't spread very well from mammal to mammal. Typically this ability of these viruses to spread from mammal to mammal is tested in the laboratory in ferret model. Ferrets can be infected with influenza viruses and if you infect them with a human influenza virus they transmit the virus onto their cage mates either via direct contact but also through the year but if you infect them with 85 and 1 the infection doesn't spread and so this model is used to assess the risk the ability of a certain virus to spread in humans and so far for for these historic age 5s they didn't do that and that's great and that's probably the reason why we so far haven't had an age 5 pandemic but of course it can still cause very severe infections in humans and death. Okay, influenza viruses are RNA viruses and RNA viruses mutate quite a bit and this is also what age 5 did over time while it was spreading throughout eurasia and africa it was also diversifying and many different variants developed we call these variants Cades. These Cades refer to the hemogloutinine that's important to say because these age 5 viruses can also re-sort and then acquire different meraminidases so often they are age 5 and 1 but they also exist as age 5 and 2 age 5 and 5 age 5 and 6 and age 5 and 8 but the cage always refers to the hemogloutinine. So initially there was Cade 0 then we got Cade 1, Cade 2 and over time as the virus evolved this got more and more complicated and the virus that is now causing issues globally is called Cade 2.3.4.4 B. You don't have to remember that I think it's a complicated, overly complicated number cage. I didn't come up with it but maybe there's somebody who can come up with a simpler a simpler one in the future. So the big trouble maker right now is Cade 2.3.4.4 B but there's also another cage that is locally to Cambodia and Vietnam and that's Cade 2.3.2.1 so if you hear about cases in Cambodia or Vietnam that's typically due to Cade 2.3.2.1. All right but we want to talk about this Cade 2.3.4.4 B. So this virus seems to be very fit especially as age 5 and 1 in the age 5 and 1 constellation and it started to spread widely in 2020 in Europe. In fact that a lot of birds and also species that are often not affected by even influenza not infected by
page 5 and 1. So it seems to be pretty fit. And it also then spread into Africa and eastwards to Asia. And in winter 2021, 2022, it spread to North America again via microtory birds. And initially the spread or the intrusion into North America was via Iceland. But there were additional introductions later from Asia as well. And then the virus started to spread relatively quickly in North America, then to Central America, to South America. And it is now even in Antarctica. Actually the only continent that's free of age 5 of this late 2344b currently is Australia. Everywhere else it has been found. I should also say what we see in North America is not just age 5 and 1. There's also age 5 and 5. That is circulating again. That's the same age A. But this virus is resorted and has now is now also present with different neurominities with the n5 neurominities. As I mentioned already, this plate of age 5 seems to be fitted and older. Okay, it's spread into, is able to spread into many different bird populations. It actually has caused really big die-offs of birds and that's a huge problem for endangered species. For example, California and Condors are at risk and they have been actually vaccinated against age 5 to make sure that this is a wife because there's only very few left. And through this well, bird out breaks the virus also made it into bolt-re farms and of course caused huge economic issues there as well. Over the last few years in North America specifically in the US, we have seen this with egg prices going up, for example, but this has happened in other countries too. So big issue in terms of wildlife preservation, big issue in terms of economic losses. What we also see with this plate is that large number of mammals got infected. So these are typically either predators or scavenges that feed on infected or dead birds. And what we see in North America, for example, is that a lot of foxes, raccoons, coyotes, but even bears got infected through that route by eating dead or sick birds. And they can have pretty severe infections. The virus also makes it to the brain. They get neurological symptoms and these age 5 infections in these animals can be pretty deadly. Typically these are dead ant infections, meaning that a predator eats a dead bird or a sick bird gets infected and then dies but doesn't necessarily spread the virus to other other mammals. So that's meant with that dead ant infection. However, mammal to mammal spreads with this new clad of age 5 has been suspected in fur farms in Europe, in Mink, in Spain, and also in foxes in Finland. And mammal to mammal spread is also suspected in marine mammals in North and South America. And that can be problematic, not just because marine mammals are endangered and they die at relatively high rates when they get infected, but if the virus spreads in them, it adapts to mammalian cells. And that means it might actually be getting better at replicating in human cells too. And that's of course an issue. And so that's something that people worry about quite a bit because these viruses that then circulate in marine mammals, for example, might have a much better chance of infecting humans and then spreading from human to human. And then in spring 2024, something surprising happened. Age 5 and 1 was detected in cows in dairy cattle in Texas. And that was surprising because historically, influenza A has not been found in cattle. There's other influenza viruses that can infect cattle in flensady virus, for example, but not influenza A viruses. And so that was super surprising. And the problem was that the virus actually spread quickly across dairy cattle hurts in the US. And the idea is that there's a lot of transport. These are big farms. There's exchange of cows between them and so on and so forth. And so that's how the virus spread between these dairy hurts very likely. And actually more than a thousand farms have been affected over time. The interesting part is that in the cows, the virus doesn't necessarily cause respiratory infections. It actually infects the other. And it replicates in the milk again. And there's actually a lot of virus that's then secreted through the milk. If very high levels of virus in milk often much higher than what you get when you grow the virus in the laboratory, it turned out that the virus actually spreads from cow to cow, mostly by a milking equipment. So basically this cows are milked by these milking machines. And then viruses sticking on these machines. And so that's how it gets transmitted from one cow to another cow. The problem is also that if there's a lot of virus in the milk, the milk is dangerous, right? And if you feed raw milk to cats, for example, this is what happens on farms often, the cats die. And the virus has also been found in mice on these farms. So the mice seem to consume some of the milk and then get infected. And it has also been shown that there is spread from dairy cattle then to bird populations, wild bird populations. And that also fuels a spread of the virus. Of course, if you paste the rice, the milk, if you heat it up, then you kill the virus. It's not infectious anymore. But virus genome has been detected in milk, bought in supermarkets in the US. Again, this is not infectious virus. This is just a genome because of the past realization that the virus not infectious anymore. But it seems that at least at some point, the infections were so widespread that even supermarkets milk had traces of the virus. And very recently, while the situation in the US seemed to have improved, there was also a case of transmission to dairy cattle in the Netherlands. In this case, it doesn't seem like the virus spread from one farm to another, but there was a detection at one farm. Of course, these infections in cows are also problematic because cows are mammals too. And if the virus replicates in the cows and spreads from cow to cow, it might also gain the ability to grow better in human cells. So that's in animals. But we also had human infections so far, a little bit more than 70 human infections with this K2.3.4.4B H5 viruses have been detected globally. Most of them were mild. Most of them were either birth to human or cow to human transmissions. When people get infected from cows, the symptoms often include connectiveitis, so infection of the eye. The reason for that is that when people work with the cows and work with the milking equipment, there might be splashes of milk that end up in their eyes and then the virus can replicate there. There's also a small number of cases where it's not clear how people got infected. And those are worrisome because if there was no obvious contact with infected birds or infected cows, of course there is the risk that this is already human to human transmission. And in these cases, where this was suspected, there was of course investigation and it turned out that there was no human to human spread. So it's just unknown how these people got infected. As I said, most of these infections were mild, which is in contrast to what we historically know about H5 and one infections in humans. But there were also several cases of severe infections in Latin America, in the US, in Canada. And there were also deaths. There's one recorded death in China, basically two, three, four, four, B virus. There's one in Mexico, two in the US, one of them in Louisiana, with H5 and one. And one relatively recent in Washington state and that was within H5 and five virus. So the H5, H8 was from the same plate, but it had resorted and acquired in five neurominides from from another even in flants of ours. And that caused fatal infection. And the virus hasn't spread so far from human to human. So basically that's good because that means if it can't do that efficiently, it can cause a pandemic. But there is of course worry that the virus can't change over time. Right? On the one side, when it grows and replicates a lot and transmits from mammal to mammal like in the cows or in marine mammals, it can actually acquire mutations that make it easier for the virus to grow in humans and jump from humans to humans. And then there's another mechanism that the virus has to gain the ability to replicate better in humans and maybe spread from humans to humans. And this is this reassortment that I mentioned. right so this h5
in one virus, for example, could infect, let's say, a dairy worker. And maybe in the winter season, the dairy worker might be infected at the same time with H1N1 or H3N2 seasonal influenza. And if that happens, the H5N1 virus can exchange genomic segments, genomic information, with the seasonal influenza virus. And you might end up with a virus that it has then H5 on the surface. So that's a hematrotinine to which humans have no or very little immunity. But the replication machinery and the matrix protein, for example, might come from the human, from the seasonal influenza virus, that's very well adapted to growth and transmission in humans. And you might end up with a virus that then actually can spread from humans to humans, but is not detected very well by the human immune system. And of course, this would be problematic because this virus like that could start a pandemic. And so for that reason, it's really important to minimize the contact that humans have with these H5N1 viruses. So people work with potentially infected animals in the dairy industry or in the poultry industry, or if they interact with potentially infected wild birds, they should protect themselves. This can be done by varying calves, varying masks, varying face shield, many work with cows, and when you're milking cows, what also helps is to get seasonal influenza vaccine, because if you're vaccinated against seasonal influenza, the chances that you have a seasonal influenza infection is lower. And then the chances that you get co-infected with seasonal influenza and H5N1 is also lower. So seasonal influenza vaccines help to reduce the risk. And then in some European countries and also in Canada, H5 vaccines are available. And in some European countries, they are offered to people who work with with potentially infected animals. They're offered to veterinarians, to farmers and so on and so forth. And if you have vaccination against H5, of course, it's also very unlikely that you get infected with H5N1, or that you have done a co-infection with H5N1 for seasonal influenza viruses. For people who are not necessarily professionally interacting with potentially infected animals, it's also important to know that you should stay away from specifically sick birds or dead birds. And it's also important to keep your pets away from sick or dead birds. Dogs and cats can get infected with H5N1. And that also can be problematic. So it's really important to stay away from potentially infected wildlife. One big issue is also live bird markets, right? Where chickens, ducks and so on and so forth are brought to be sold as live animals. And they can of course be infected. And that was, for example, what happened in 1997 in Hong Kong. There was transmission from infected birds at live bird markets to humans. And often when we think about live bird markets, we think about Asian countries. But the truth is we even have live bird markets in New York City. And there have been outbreaks of H5N1 in live bird markets in New York City as well and in other cities in the United States. So I think that's a big risk factor and I think this needs to be closely monitored. So H5N1 comes with risks and there's certainly a risk that this virus could cause a pandemic in the future. But I don't think we're in a situation right now where this pandemic is imminent. I don't think there's huge risk that H5N1 would start in the next weeks or months. But it's certainly a situation that needs to be monitored. With H5N1, the situation could be really bad too. If the virus causes a pandemic, it's very likely that a lot of people would die. But we would also be better prepared. First of all, we understand influenza viruses quite well. Because they circulate in humans, they have caused pandemics in the past. We study even influenza viruses. We know a lot about them. We know that these viruses can be stopped with certain count the measures including masks. But we could also switch vaccine production from seasonal influenza vaccines to this new, to a potential new pandemic H5N1 very, very quickly. There's a lot of production capacity for vaccines globally. And it doesn't have to be new vaccines, right? It doesn't have to be a new generation of mRNA vaccines. We can make old-fashioned inactivated virus vaccines as they are used for a seasonal influenza. We can just switch their strain. And so that's good because in a way we could use relatively established, very safe vaccines that are just switched to this new strain. And in addition to that, we have antivirals that we use for seasonal influenza. And they do work at least in animal models for H5N1 as well, for even flu as well. Specifically, the newer generation like Bologna, which is medication that inhibits a function of the polymerase of influenza virus, has been shown to work very well against H5N1 infections in animal models. So we certainly would also have antivirals already that work against these infections. Of course, again, an H5N1 pandemic would still be severe and problematic, but in a way, we're much better prepared than for COVID-19. But certainly the situation needs constant monitoring and whatever can be done to minimize the exposure of humans to H5N1 should be done. And that includes countermeasures to make sure that the virus is eradicated from dairy farms, but also making sure that there is little outbreaks in poultry farms so that humans don't get exposed. Yeah, that was it. But H5N1, it's a virus that is now around globally in the wild-pert population. We actually, in the North and Hemisphere, see increases in cases every winter. This has not been going on for a few years. We see this in Europe, we see it in North America. In the winter season, you see more infections in wild birds, and then you also see more transmissions to poultry operations. So I guess we have to get used to it, but and we have to keep an eye on it. But if you pay attention, we probably can manage the situation. All right, that's it for today with Virological. Thanks for listening in, and as always, if you have any comments, questions or suggestions, just write an email to
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