H five N one is an interloper, an unrefined newcomer, all fury without the seasoning of age in human cells. It has discovered a fresh target, and it pursues its prey deep into the body, penetrating much farther than ordinary flu. This novel virus advances on the lungs themselves, attacking the branches of the bronchial tree and the myriad little buds on their tips called alveoli, where the life sustaining task
of exchanging carbon dioxide for oxygen occurs. The pathogen infects the coating of mucus that protects the membranes of the lungs. This newcomer penetrates into the tissue itself. It spreads farther, often infecting both lungs at nearly the same time. As the pathogen relentlessly erodes the cells of the deep lung, you find yourself increasingly short of breath. Your cough is often bloody, and you may bleed from your nose and
even gums. The human body, which has never encountered anything like it, has no ready arsenal of antibodies to choke off the process. The body can still marshal its innate all purpose defenses, but in doing so, it mounts a counter attack so furious that some scientists believe it's more lethal than the virus itself. The body throws everything it has at the intruder, without regard to the tremendous collateral damage. This causes the lungs themselves ever more. Immune cells are
summoned to the front and continue to blast away. The carnage mounts. The lung cavities fill with dead and damaged tissue, mutilated mucous cells, and other cellular wreckage. The lungs become rigid as the cells that make the liquid to keep the lungs flexible are annihilated. The seal between the bloodstream and the air passages ruptures, red blood cells and plasma leak into the lungs. The alveoli sacs are swamped with fluid and debris and are no longer able to exchange
carbon dioxide for oxygen. If you listen closely, you can hear the liquid crackling. Your breathing accelerates. You desperately press all your chest muscles into helping you suck down precious oxygen. You're gasping for air. You're drowning. But the virus is not content to remain a solely respiratory disease. It invades the digestive tract, often causing diarrhea and sometimes vomiting. It can assault the liver in kidneys, it can provoke heart failure.
It can attack the eyes. It can even breach the brain and spine. Yet, in the end, the lungs are where this microbe concentrates its energies and takes its heaviest toll. The lungs are also the means by which it casts its net for further prey. In this one regard, it is much like its seasonal cousin. They both spread their sickness through contaminated droplets coughed or sneezed into the air, one of the most efficient forms of transmission known.
It is so terrifying.
Is it somehow scarier because of covid or just scarier because we've read more about other pathogens and finally have a like more of a respect or appreciation for flu I think both.
I think.
I think in large part it's probably COVID. I think it's living something that is in many ways so similar and so terrifying, and knowing that it not just has happened again historically, but like it just happened, and now we're going to talk about how it can happen again and potentially be much worse.
Yeah, And by can happen again, likely will happen again. Yeah, it's yeah. So that first hand account was from a book titled The Fatal Strain on the Trail of Avian Flu and the Coming Pandemic, and that was written by Alan Cipres and it was published in two thousand and nine.
I think I read that for our first influenza episode.
I think you did. I think it's on our sources. Yeah. Hi, I'm Aaron Welsh and I'm Erin Alman Updyke, and this is this podcast will Kill You, And.
Today we're revisiting our very first ever topic, influenza.
We are.
It's our season finale celebration. Yeah, kind of a somber celebration. But I think that, you know, given the news about Avian influenza this year and the timeliness of this, we really wanted the opportunity to kind of go back and redo re explore this pathogen that is is so utterly terrifying and there's so much information out there about it that it really deserves not only like just a second episode, but also an entire series.
Yes, one could certainly argue that.
Yeah, yeah, so that's what we're doing this episode, kind of like talking about all of the different bits that we didn't cover in our first episode, which is quite a lot. And I think also one of our aims is to bring us up to speed more about today with a particular focus on Avian influenza.
Yeah, a lot has changed since Tantine and we've learned a lot more, so it's going to be exciting to kind of bring it all back together.
Well, should we start off with quarantiny time?
We should?
We certainly should.
What are we drinking this week?
Well, we're drinking none other than H one Drink Too.
I love it.
So for those of you who haven't listened to our very first Influenza episode, we can't blame you.
First of all necessarily recommending it, Nope, But it is maybe pertinent to this part of the episode to know that our very first Quarantini was called H one Drink one.
So this time stage one drink two. Yeah, and what is in H one drink too?
Erin it is kind of a play on the Corpse Survivor, So we did the corp Survivor number two for our H one Drink one, our very first quarantini, and this one we're kind of just doing a variation includes Apricot Liquor, light rum, Lemon juice, and lil Itt Blanc and we will post the full recipe on our website. This podcast will kill You dot Com as well as on all of our social media channels, so check it out.
And as a reminder, this is our season finale, so do make sure that you are subscribed to whatever podcast app you're listening to this on and to our social media so that you don't miss when we drop our next season.
We don't have an exact date for you yet. We're sorry, but don't be worried. It won't be too It won't be too long.
Yeah, any other business here?
I feel like there should be, but I don't think there is. So let's just get started.
We've got a lot to cover.
Let's take a break and get started. So today we're not going to repeat everything that you may have learned in our very first episode, which covered influenza. But what I do want to do in this biology section is take what we learned in that episode and then expand on it, but also realizing that that was five years ago, and so most of us have probably forgotten or maybe.
Skipped over the first episode.
So what I'm going to do in this section is talk about influenza viruses in general and then focus primarily on bird flu or highly pathogenic avian influenza strains.
So it's going to be a lot of fun and fun meaning.
Terrifying, okay, as we usually mean, but fascinating all right. So, as a perhaps recap for many of us influenza viruses, these are RNA viruses, not retroviruses, as I called them in our very first ever episode. One of the most biggest embarrassments of my life.
To this day.
Is it like one of those things that pops into your head as you're trying to fall asleep.
Yeah, sometimes.
I called it a retrovirus on the internet.
Forever is tscript.
I did see the transcript that I was like in the transcript, I like made jokes about it, like I full on like went hard.
Okay, it's not a retrovirus, but it is.
They are RNA viruses in the family Orthomixoviridae, and RNA viruses in general not always, but is true for influenza viruses tend to mutate much more rapidly than, for example, DNA viruses, in large part because they lack good proofreading mechanisms. So what happens very commonly with influenza viruses is that
small mutations can accumulate over time. And if these mutations happen to be in regions of the genome that encode the major surface proteins of influenza we'll talk about those more in a second, aka the antigens, then that can make it harder for our immune system to recognize those antigens or recognize that virus, and this process is known as antigenic drift.
This is one of the ways that influenza.
Viruses are particularly adept at evading our immune system and why they're so tricky to target and interesting. But on top of that, influenza virus genomes are made up of multiple short strands of RNA rather than one big long strand. And because as we'll talk in a lot of detail about, there are so many different strains of influenza viruses. If an animal like say a bird, is coinfected with multiple strains,
which is not at all uncommon. These segments of RNA can mix and match inside of their cells and recombine to form essentially brand new versions, brand new, unrecognizable strains of influenza.
This is the.
Process of antigenic shift, and this amazing amount of variation in viral strains is why influenza remains such a challenging virus to combat in the form of vaccines, etc. But let me actually back up even further for a second, because when we say influenza virus, we're not talking about
a single influenza virus. There's actually four major classes of influenza viruses ABC and also D, and when we talk about influenza viruses in humans, we mostly mean influenza A and to a lesser extent, influenza B. Influenza C does circulate and causes disease in humans, but it's more like a mild cold rather than what we think of as the flu, and influenza D is mostly in cattle. Okay, So influenza B has two major lineages that circulate only
among humans. It's not a zoonotic virus, and while it can cause a decent amount of disease in epidemics, seasonally it's not a zoonotic virus, and it's not like the major player in general when we think about influenza.
SO, I have a question about influenza B. So, from my understanding, the vaccines that target you know, seasonal influenza A, the influenza A strain that's in there might change from year to year depending on what is predicted. But B doesn't really seem to change. Why doesn't really change that much?
That's a good question.
There's only two major lineages of influenza B, so I don't know as much detail because I didn't dig hardcore.
Into influenza B.
But it's likely just that there simply isn't as much variation as what we see with influenza A.
Okay, so like fewer opportunities for combination are exactly gotcha.
Because it's not a zoonotic virus, it's only circulating among humans. Right. Interesting, But let us now focus for pretty much the rest of this episode on the biggest player, and that is influenza A. So most people are probably familiar with classifications of influenza A viruses, and those are H one N one or H three N two. You've probably heard those circulating around every time that there's a new strain that
causes an epidemic. Right, So those letters H and N refer to two specific antigens on the influenza virus surface itself, the H antigen hemaglutinin and the N antigen neuraminidase. You don't have to remember those names, you could just remember HNN. So the H proteins, you can think of these as the proteins that bind to our cells and allow influenza virus to actually enter our cells. Remember, of course, that all viruses have to get into our cells in order
to be able to replicate. They rely on our machinery to finish that process of replication. Influenza viruses are respiratory viruses, right, so they predominantly are infecting the cells that line our
upper and lower respiratory tract. These H proteins on their surface are what allow them to bind to these cells in particular and enter those cells, Which means that these H antigens especially are the ones that in theory and in practice our immune system recognizes and if we are able to block it, we can stop this virus from entering our cells entirely.
Question. Okay, so the difference between upper and lower respiratory tract and the differences in the HS, and are some more adept at invading both the upper and lower or just.
The upper or yeah, a thousand percent?
Yes, okay? Which ones?
Okay?
I can't give you an easy answer on that because it varies. The answer to all of these questions of detail are probably going to be it depends because let me keep going, and we'll see not just how much variation there is, but like how terrifyingly much variation is Okay, love it? So we can't also forget about the n antigens.
These are involved in the process of once that virus has replicated in our cells and is all packaged up and ready to burst forth to go infect more cells, the n antigens are what help influence a virus actually release from inside of ourselves. That's what the n antigens are doing. So another potential target, but a harder one given that it's an intracellular site of action.
So it's really this.
H antigen that is the one that when we think of vaccines, we're predominantly potentially targeting. And we'll get to all of that much later in the episode.
It's interesting to think about from an evolutionary perspective, because it seems clear why there would be variation in H in the hema glutenants, right, but the neuromidida is like, what is the variation in that functionality?
Ooh, that's a really good question. Yeah, I don't know, Okay, Yeah, it's really interesting though, Like what's the benefit of like having different receptors to do the binding and releasing?
Right?
What is N one versus N two? Is there a functional difference or is it just these are different enough different?
Right?
Yeah, yeah, it's a good question.
So there are eighteen different major h antigens sixteen if you don't count the ones that are mostly only found in bats, and there are eleven or again nine if you don't count the ones that are mostly only in bats major n antigens. Knowing that you can combine h's and ns in pretty much any configuration, that alone is a huge amount of potential for recombination and change, right, eighteen and eleven or even sixteen and nine, that's a ton of variation.
I can't do that.
Math no air and math, no air and math this episode. But on top of that, you asked, like, what are the differences between the different H andigens. Yeah, there is not just a difference between say H one and H two, but because of the buildup of changes to these H and antigen via that antigenic drift, via those small point mutations. What that means is that not every version of H
three and two is exactly the same. There are parts of the H antigen and parts of the end antigen that are more conserved, and there are other parts that are much more variable even within like say H one or H five. Interesting, it's fascinating, and yes, absolutely, these different H antigens are going to have different affinities for specific receptors on our epithelial cells, and that is going
to determine which cells they invade and how readily. So as we see with particular strains like H five N one in our first hand account that are able to invade lower respiratory tract very rapidly and even invade beyond our respiratory tract, that's likely something that's largely mediated by particular changes to H or possibly N antigen, allowing it to release more readily from certain cells than others.
So that's all of this variation.
Let's get into more details of what we know about influenza as a as an illness.
Okay, yeah, So.
Influenza viruses, of course are respiratory viruses, which means that they're transmitted by droplets or aerosols when we cough, sneeze, talk, laugh,
et cetera. There is also a lot of indirect transmission via fomites like door handles, shared coffee cups, whatever you like, lick your hand and then touch, and this route of transmission, in particular fomtes or like in more indirect transmission seems to be and is thought to be a pretty important route of transmission, although because I figured you were going to ask aarin, I did not get a sense. And the papers that I read actually suggested that influenza is
not actually a very environmentally stable virus. And despite how much we know about influenza, we still don't know enough to be able to say, like the relative contribution of this transmission rate versus that transmission route.
Does that make sense? Yeah?
You know me so well. These were literally the two questions that was brimming like on the top of my touch.
Yeah, preem to do you this time?
You did?
But in any case, you're breathing and sneezing this stuff out because this is a virus that's primarily infecting our respiratory cells, the respiratory epithelium, and in general, the incubation
period for influenza is remarkably short. People are often symptomatic by day two after inoculation, sometimes by day one, and almost always by day four, So like very short incubation period, especially compared to a lot of things we've covered recently, and people are generally infectious that is, high viral tiders in their nasal epithelium up to twenty four hours before symptoms begin.
Which is where the trouble starts.
It sure is, And if you think about it too, that's like incredibly rapid how quickly this virus gets into ourselves, starts replicating, bursts out, and is ready to spread. In terms of who gets infected, everybody gets infected with influenza. Some data suggests that it's actually children who are the most likely to become infected, and the older you are,
the less likely you are to become infected. But when it comes to severe infection and mortality, it's both children and older adults over age sixty five that are at highest risk of severe infection and death.
It's that classic U shaped mortality.
Yeah, yeah, in all but the nineteen eighteen pandemic.
And of a few others.
But yeah, other people who are at particularly high risk of severe infection include people who are pregnant, and then a lot of other comorbidities like heart failailiar pulmonary disease of various kinds, cigarette smoking, immunal compromising conditions. All of these things essentially just make it harder for our bodies to fight off this infection or easier for us to
get infected with it in the first place. And I think we're all probably familiar with the symptoms of the flu, although I think a lot of people might confuse it with any of another million viruses that we just call the common cold, because influenza is not the common cold. No, with influenza, you are sick. You are if you are symptomatic, which not everyone.
Is, right, Okay, question real quick, well how many? Yeah, thank you?
I don't know.
I actually didn't see that number reported very commonly.
That's so interesting because I feel like we know that so well now for things like COVID.
Yeah, like we should know that, and I just somehow missed it, but I didn't see it.
I mean, I mean, but presumably there are there's a subset of people who are asymptomatic.
Absolutely, and asymptomatic carriers can still shed for even up to six days, which is generally how long people shed.
Okay, but yeah, you're sick.
You have a fever, you have muscle aches, full body, like your entire body is aching. Your throat is sore and it's red. Your nose is probably runny. You're coughing. You're possibly coughing so hard that you're hurting your ribs. You feel like you're coughing your brains out. And this is if you have a mild infection. In this case, symptoms last seven to ten days, so it's not just a few days that you're feeling creuddy. You're feeling bad for a long time.
Yeah, And if.
Or when this virus makes its way into your lower respiratory tract, it can then cause a viral pneumonia. It can progress to an acute respiratory distress, which can then progress to shock and potentially death. One of the primary drivers that determines if someone is going to have a severe infection versus a less severe infection Besides just what strain of the virus is, it is how far down
into that respiratory tract did the virus invade? And this is probably determined by a whole number of factors, like our individual immune response, largely how well did we tolerate versus resist that virus in the upper respiratory tract before it tried to travel down, What strategies did our immune system employ.
Like and how effective were they?
But then also likely some degree of infectious dose, like how much of the virus were we exposed to, how big.
Of a load did we have to fight off?
And then of course the strain of the virus itself, like how virulent is it, how big of an affinity does it have for those lower cells versus our upper cells. And on top of that, because this virus and our immune response to it can cause so much damage to our lungs, Influenza virus, especially viral pneumonia, can put people at significantly higher risk of a superimposed bacterial pneumonia, especially from a Staph aureus or a Streptococcus pneumonia.
Right, okay, question about the nomenclature I guess of influenza A viruses, So we know the h's, we know the ends, but then there are variations within a particular H and N pairing, So like how does that work and how do we refer to those?
Yeah, there's not good ways to refer to them.
The ones I've seen.
It's usually like H three and two strain B three dot four dot five dot two two two.
Or something like that.
So there's like there are like specific strains and sometimes two they're still named by like the first place that they were discovered or the year that they were discovered. So there's a lot when we have particular strains that have say become epidemics or have caused really big outbreaks in birds, or or spilled over into humans a particular number of times or something like that, then they do
tend to get more specific names. But they're not like nice friendly names, yeah, to like easily be liked, you know, right, They're very very viral names, if that makes sense.
Unfriendly names.
Yeah.
But so this is where I want to kind of shift focus and talk more specifically about the bird flu or highly pathogenic avian influenza strains. So it turns out that when you hear talk about avian influenza in some respects. We're kind of talking about nearly all influenza A strains.
Oh yeah, yeah.
The primary natural reservoirs for influenza A viruses are birds, especially aquatic birds like ducks and geese and swans and gulls and like those cute little sandpiper things on the beach.
Lots of cute little water birds.
With the exception of a few strains that are found predominantly in bats and not really other places, the vast majority of influenza A strains have birds as their natural reservoir. These strains, the vast majority of them in both wild and domestic birds, are what we call low pathogenicity strains or LPAI, So in the birds they infect, they don't cause a lot of disease. They might not cause any disease,
but they can circulate very readily. However, some strains, especially those of the H seven and H five and I think H nine varieties, have emerged as being highly pathogenic aka HPAI. And it's very likely that the strains emerge by a number of mechanisms, but antigenic shift and antigenic drift that I talked about earlier play a really big role, especially reassortment leading to antigenic shift, and this can happen
in a couple different ways. In wild birds. Many of the aquatic bird species that I mentioned, like ducks and geese and gulls, tend to roost in really large numbers, and because many of these influenza virus strains are low pathogenicity, it's easy for a lot of these different strains to
circulate in a particular population. But one thing that can happen is that these low pathogenicity duck strains, for example, can pop over into our lovely food system aka poultry farms, which are also extremely dense, generally quite unsanitary, beautiful mixing grounds for viruses.
In both of.
These scenarios, both in large roots of wild birds and in poultry farms, it's very easy for these different strains to mix in a single animal, recombine, and potentially gain traits that lend themselves to higher pathogenicity or virulence in the process. And what we can see then happen when these highly pathogenic avian influenza strains emerge is kind of
three major things, all of which are terrifying. Number one, it can result in outbreaks in wild birds, which can result in massive die offs of wild birds, which is not good for the environment or the birds. Number Two, we can see outbreaks in poultry at domestic poultry, either directly from spillover events or because these highly pathogenic strains emerged in the domestic birds themselves, which can.
Cause massive die offs.
That also can result in the culling of flocks, which means people might lose substantial income. This can also result in spill back into wild bird populations, so you then have both domestic and wild bird deaths. And then, of course there's the thing that makes public health professionals so worried, and that is number three. These highly pathogenic avian influenza strains can spill over into human populations and potentially cause very severe disease. And this has happened.
Oh, it happens, and it's scary. And I think that we've definitely touched on this topic several times. The evolution of virulence and why not all viruses or not all pathogens will just become nicer to us over time. Yea, they may evolve to become more virulent. And poultry farms are a great example of this. Right when you have like a ton of birds crowding in one space and it's really dirty and they're there's no escaping. Yeah, then it makes more sense to like ramp up as a virus.
It makes more sense to ramp up your replication and just cause widespread infection. And there aren't many drivers for decreased virulence necessarily.
Right, because that virus is going to be able to spread so easily and quickly through a population. It doesn't matter if it kills its host really rapidly, it's still going to have time to spread, especially in the case of an influenza virus which is replicating so rapidly to begin with exactly.
And there have been different estimates of the mutation rate or the rate of evolution of influenza viruses based on different hosts, and certainly domestic poultry is top.
That's terrifying, it is. And what's even more terrifying is, like we said, this has happened one strain in particular. Though several HPAI strains have spilled over into humans, one strain in particular, H five N one has spilled over handfuls of times, dozens of times into human populations, either usually from domestic.
Or wild birds.
And when this strain has spilled over into humans, it has caused severe infections, with mortality rates of fifty to sixty percent. In general, so far, these outbreaks have shown relatively limited human to human transmission, which is good for now. But the real worry is how many additional mutations would it take in a human or even in the bird before it makes it into humans.
For one of.
These highly pathogenic avian strains to maintain that same level of virulence but with more efficient human to human transmission, that would be something devastating. And then there's really interesting questions as to why do these particular strains cause such severe disease in humans? And part of it, as we actually heard in our first hand account, is that in the case of H five N one, we have evidence that this strain in particular causes extra pulmonary infection a
lot more readily than most other influenza viruses. So it's not only infecting the respiratory tract, it's infecting other tissue types as well.
How is it doing that We don't know.
Necessarily, there's a relatively limited number of human cases that have happened so far, and so there's not a ton of data on like in VVO anything when it comes to age five N one, so we still don't know. Also, how much of the damage of this virus in this strain is due to direct viral cytopathic effects versus what a huge amount of immune system response it stimulates. But
in either case, the mortality rate is it's terrifying. Yeah, and we'll talk a lot more later on about how much these viruses continue to circulate and spread among domestic foul populations in particular. So it's really something that worries a lot of public health professionals.
Oh yeah, when we talk about species barriers and why some influenza viruses that infect birds don't infect humans, what is that barrier specifically, Like, what is it about that H or that N or whatever that prevents that virus from infecting humans.
Yeah, a lot of it is likely the H factor, and just what particular residues on, say duck respiratory or GI epithelial cells, because in birds, influenza viruses infect both the respiratory and the GI tract often, So it's probably just that we don't have as many of those same receptors, or we don't have receptors in places that are as easy for that virus to get to and that's the
biggest That would be the biggest barrier. It would be the receptors and being able to actually get into ourselves in general.
Okay, there could be others interesting.
Yeah, So that is the biology of influenza and influenza a Aaron terrifying, terrifying. You want to tell me where this sucker came from? And you know how all.
The rest, all the rest. I will do my best. Right after this break, before getting too deep into the research for what I wanted to cover or this influenza go around, I figured I should first check back through the transcript from our first influenza episode, our very first episode ever.
Yeah, and then you immediately regretted it, just like I did.
One hundred percent. How how can anyone make any sense of this? It's yeah, But I also wanted to see what I covered, if anything, so that I didn't talk about it again, like you said. Turns out I didn't have to worry all that much about it because there
was just kind of disorganized mess everywhere. But it was really interesting to skim through to see what I didn't cover, like what questions I still had about the history of the influenza virus, especially in terms of its evolutionary history and avian influenza, and then that is sort of what I based this part of the episode on, and it was also really interesting to read it through the lens of today, after we've been in a pandemic for two
plus years. That episode came out in October twenty seventeen. Wow, we're recording this in October twenty twenty two, which is amazing. Yeah, five years later. And at the time of that first recording, we were horrified by the choices that people made during the nineteen eighteen pandemic, like the parade in Philadelphia, for instance. We seemed shocked at the idea of everyone wearing masks.
And we talked about the very real and very scary possibility that the next pandemic that we could see would be caused by an influenza virus, in particular H five N one. And although we were wrong about the causative agent of the next pandemic, we were right to be
scared to still be scared. Frankly, my intention today is not to scare you, and I think our intention is to scare you, but to present what we know about the evolutionary history of influenza viruses, take a brief jount through the history of past influenza pandemics pandemics multiple because there were many of them, and then turn towards the highly pathogenic Avian influenza virus H five and one and
how its epidemiology has changed over the past decades. And it's in this last part that I want to draw attention to the parallels between the emergence of this H five and one virus and the emergence of other pathogens of pandemic potential, things like the nineteen eighteen influenza virus SARS covid one and of course SARS covid two, Because those stories, from initial appearance to sweeping the globe public health responses and political commentary, they're disturbingly similar, I know,
and I say disturbing because even though we know how these pandemics happen, applying that knowledge to prove seems almost impossible. But before I fall further into this pit of pessimism fatalism, let's start back at the evolutionary roots of influenza viruses, specifically influenza A. Like most other pathogens we talk about on this podcast, coming up with a timeline for the origins and evolution of influenza viruses.
That's pretty difficult, I can imagine, despite.
The fact that to quote Will and Holmes twenty twenty quote from an evolutionary perspective, more is known and more sequence data have been generated about influenza viruses than arguably any other group of pathogens and.
Quote I'm not surprised by that.
Yeah, what does seem likely is that influenza viruses have been around for hundreds of millions of years, hundreds of millions of years, and that they have infected their natural reservoirs, these water birds, specifically the orders and Seriformis, which are ducks, and Charadriformis, which are shore birds and gulls. I hope I'm pronouncing that right.
I didn't say those orders because I knew I couldn't pronounce the second one, so I was like, you know, gulls and cute little pipes.
That's actually probably what I should have done. Regretting it now, I think you did a great job. Thank you, Thank you. Anyway, these these influenza viruses have been infecting those birds for thousands and thousands of years, and of course birds aren't the only animals where influenza viruses can be found pigs, bats, amphibians, fish,
even hagfish and more. I know your faces, hagfish, I know, and more are likely to be discovered the more we look, of course, and the patterns in the relatedness of these influenza viruses suggest that coevolution between influenza viruses and their hosts has been going on as long as vertebrates have been vertebrates.
Wow. I know, that's kind of nice. That's pretty fun.
Yeah, But a paper from twenty fourteen concluded that all of the influenza A viruses that we see today in mammals minus bats, and birds descended from a common ancestor dating back to the late eighteen hundreds.
So interesting.
Yeah, all of the existing diversity, which is highah in influenza viruses that we see today in mammals minus bats and birds came from a lineage branching off in the late eighteen hundreds. Okay, but what does this mean? Like, why does this matter? It matters because it highlights a very important characteristic of influenza virus evolution, their tendency to
undergo selective sweeps. Basically, what happens is that a new advantageous mutation emerges in one strain that leads to all other strains being outcompeted eliminated, so that all future come from this one mutant branch.
Oh my gosh, I love this so much.
And also we have a present day example or like a present day illustration of this. Think about COVID nineteen and how the dominant variant of SARS COVID two is constantly changing. We don't really see COVID infections caused by delta anymore. Delta was displaced by omicron, and even the original Omicron lineage has been displaced by a later one.
Yeah.
Yeah, and this will keep happening, like this is just how it's going to go. The one that is the most transmissible and causes the most infections, that's going to outcompete the rest, and then that's the only lineage that will survive and on and on and on.
Okay, love this, I know, right.
And selective sweeps are interesting in light of how we look at existing diversity and evolutionary relationships or the evolutionary history with different influenza viruses, but they're also important from a public health standpoint. Virus is seed when there are susceptible individuals to infect, and the more novel a mutation makes a strain or variant compared to previous ones, the more susceptibility there is going to be in the population. And that holds for humans, or birds, or pigs or
what have you. What determines the level of susceptibility in a population is not just how different the viruses from previous variants, but also how many people were exposed to those previous ones, how novel the virus is to them,
and that's what separates seasonal flu from pandemic flu. With the circulating seasonal influenza viruses, they usually only undergo small changes from year to year, and so most of our immune systems have seen them or have seen similar strains before, either through vaccination or infection, So we don't get infected with this new slightly different strain, or if we do,
we just experience a mild infection. But let's say a new influenza virus strain is introduced, maybe spilled over from pigs or birds, and none of our immune systems have seen it before. That's when you have the potential for a pandemic. The four influenza pandemics that we've seen since
nineteen eighteen demonstrate this. In nineteen eighteen, that usual U shaped mortality curve that we talked about was flipped upside down, hitting the younger and middle aged generations the hardest, which suggested to some that the older generation had encountered an influenza virus similar to the nineteen eighteen strain. The nineteen fifty seven, nineteen sixty eight, and two thousand and nine influenza pandemics were caused by viruses that had undergone reassortment
from previously circulating viruses. And reassortment, by the way, is just when influenza viruses swap bits of their genome and create new strains like antigenic shift. Exactly people hadn't encountered these new reassorted viruses, and so boom pandemic. This is a source of grave concern for highly pathogenic avian influenza H five N one that it will swap genes, maybe with a human influenza strain, gaining high human to human
transmissibility and retaining its highly pathogenic nature. The influenza pandemics of nineteen fifty seven and nineteen sixty eight were caused by viruses that had undergone reassortment between previously circulating avian and human influenza viruses, so it can happen. And let's not also discount the role of the humble pig as a little mixing bowl for influenza viruses.
The humble pig, the humble pig.
That's going to be the name of my bar whenever I make it. But let me rope those fears of H five and one in a bit and instead take us briefly through the history of influenza, as I didn't really do in our first episode. Although influenza viruses are as old as time, it's unclear when humans were first exposed, but it's certainly plausible that a passing interaction with ducks or with pigs during domestication could have led to small
outbreaks growing in size as settlements got larger. And while some researchers have pointed towards the Hippocratic texts as having the first description of an influenza pandemic, specifically the cough of parenthus in four to twelve BCE, the symptoms don't really match up all that well, and diphtheria has also been proposed as a more likely explanation other possible but debated influenza epidemic descriptions can be found throughout the hundreds
of years that followed in eleven seventy three to eleven seventy four, c in fifteen ten, and in fifteen fifty seven, which some argue was a pandemic, but they agreed upon date for the first clear influenza pandemic is fifteen eighty.
The disease broke out initially in Asia and then spread to Africa and then Europe before being brought to the Americas, and in all places, infection rates were reported as being incredibly high, with a sizable mortality rate eight thousand deaths in Rome alone, and some Spanish cities were described as being decimated who Two quick asides here The first test
to do with assessing historical influenza epidemics. Influenza has some fairly general symptoms, So how can you tell whether a pandemic is caused by influenza in historical accounts When you can't do molecular testing, Of course, you can't be certain, but you can look for clues that are suggestive of influenza.
One is that it occurs in the winter months. Another is its pattern of spread, which has tended to be though not always from somewhere in Asia, to move on then west to Africa and Europe, and then the Americas. That it explodes rapidly, with a high infection rate and often high mortality rate, at least compared to seasonal flu and of course the symptoms have to match. If you've
got all that, influenza seems likely. But those characteristics are not unique to influenza alone, and more recently, some researchers are re examining these past influenza pandemics and asking whether they could have actually been caused by a different respiratory virus, say perhaps a type of coronavirus.
Dump done it now?
Okay, a side number one over a side number two. Here we are the etymology of influenza. Oh, which I didn't talk about. I'm pretty sure I don't think you did either. Okay, Well I'm talking about it now. Surprisingly
difficult to track down. I mean, it seems like there should be an easy explanation, and generally speaking, people do seem to that it comes from Italian, ultimately derived from the Latin word influentia, meaning either to flow into or influence, both suggesting that the influence of the stars, or like the influence of the fluid from the stars would flow into you to make you sick. Huh yeah, yeah, something to that effect. Okay, but when it was first used
seems up for debate. So I've read that it was first used in thirteen fifty seven from an epidemic in Florence, Italy, sometime in the fifteenth century, seventeen forty three during an epidemic in Rome, or my favorite quote, way way way back in the day.
Quote that sounds like my answer. It was like way back in the day.
I mean, that could be any one of those dates.
So they're not wrong, they're not.
It's true.
It's the most correct answer.
Technically, right is the best way to be right. The precise year that it was first used may not really matter all that much, but I do think it would be helpful to understand how well known or distinguishable this disease was. Yeah, yeah, okay, But back to pandemics. The next influenza pandemic occurred in seventeen twenty nine, starting in Russia, before covering the entirety of Europe within six months and the rest of the world within three years.
It's also so impressive to think of these influenza pandemics so long ago when travel was not as easy, given how rapidly this virus spreads, and that the vast majority of people are not infectious for that long after they start to show symptoms.
But if it is that infectious of a virus or that transmissible that anyone you come into contact with.
I know, it's just still so impressive that you can make it from Russia to like anywhere else, I know, in the seventeen hundreds.
Impressive and scary. I guess it's just like, but did it then, Like, you know, does air travel really make that much of a dent?
We've all seen contagion.
Anyways, yep, I have not watched that since COVID, But yeah, Interestingly, this pandemic, the one starting in seventeen twenty nine, which had high mortality, also had recognizable waves of infection with increasing severity. Forty years later. The next pandemic occurred in seventeen eighty one to seventeen eighty two, beginning in China, spreading to Russia within a few months, and then onto Europe and the rest of the world within eight months.
As is characteristic of influenza, pandemics attack rate was super high, especially among young adults, notably with two thirds of the population of Rome falling ill three quarters of the population of Britain, and at its peak, thirty thousand got sick each day in Saint Petersburg.
Wow. Yeah.
Also, I just thought of something about what you brought up in global travel and how long it would have taken to get from Russia to Europe. For instance, we may not be dealing with the same influenza viruses that we see today, so you could have potentially been infections so longer.
That's a really good point. Yeah, yeah, yeah, or shedding. Yeah.
But anyway, Okay, So going back to pandemics. So the next pandemic happened about fifty years after that one in seventeen eighty one. So this was in eighteen thirty to eighteen thirty three. This one originated in China and spread south to Indonesia and the Philippines, and then west to India,
Russia and onto Europe and the Americas. This pandemic reportedly had infection rates comparable to those in the nineteen eighteen influenza pandemic, with twenty to twenty five percent of the population becoming infected again in waves, though not with a super high mortality rate. Sixty years went by before the next pandemic in eighteen eighty nine to eighteen ninety and this was the first since the rise of germ theory and the enormous shifts in medicine and medical training that
had occurred in the nineteenth century. And this marks the first influenza pandemic for which we have detailed records, statistics, timing, and a better sense of the pathology. For this disease, the virus reached Europe from Russia and spread across the Atlantic to the Americas, then onto Australia and New Zealand, Southeast and Southern Asia, and Africa, all within about a year, which is again pretty fast. Infection rates were high, but
the case fatality rate was low. Despite this, the scale of death was enormous one million people in a global population of one point five billion.
Wow.
The world wouldn't have to wait another fifty or sixty years for the next influenza pandemic, though, because a short twenty eight years later, the deadliest influenza pandemic the world had seen would result in five hundred million infections and
fifty to one hundred million deaths worldwide. Although I'm tempted to redo the coverage of the nineteen to eighteen influenza pandemic from our first episode, I want to make sure that I get to what I really want to talk about today, which is the emergence of highly pathogenic avian influenza, and so I'm just going to glance over it. Essentially. So, the nineteen eighteen influenza pandemic left the world reeling, and if you want to read more about it, there are
countless resources. I'll post them. And although many researchers tried to isolate the causative agent of the nineteen eighteen pandemic while it was happening, the technology just wasn't there yet, and it was only in nineteen thirty three that the influenza virus was finally isolated. Almost immediately afterwards, research on a possible vaccine began, with a live attenuative vaccine first being reduced and used in factory workers in the USSR
in nineteen thirty six. Four years later, the inactivated bivalent vaccine containing H one N one and influenza B was developed and deployed, likely contributing to reduced influenza morbidity and mortality during World War Two. The history of influenza viruses could genuinely be an entire episode all of its own. Oh I bet, and I'm definitely not doing it justice here.
But essentially, it was a good thing that influenza vaccines were around for the nineteen fifty seven and nineteen sixty eight influenza pandemics, which had one to four million deaths and one million deaths respectively, and forty years would pass before the most recent influenza pandemic, which was in two thousand and nine, resulting in eight hundred million to one point four billion infections and one hundred and twenty to
two hundred and three thousand deaths. Although I've seen higher estimates.
I do not think that I realized is how large those numbers were. I didn't swine flu.
I didn't either yet. There's a paper all post that sort of modeled these estimates.
Okay, yeah, because yeah, that's I mean, you always hear like it wasn't as bad as we expected.
Right, Those are likely not confirmed cases, but estimated and modeled.
But interesting though, Yeah, that's a lot.
I didn't read too much about the two thousand and nine pandemic because there were just way too many rabbit holes to fall down into in this entire episode. But I did come across something very interesting that I don't remember if we've ever mentioned, and I think that we did, and that is the apparent increase in narcolepsy on set following the pandemic.
I don't remember ever talking about that.
Okay, Well, that of course brought to mind the encephalitis lethargica episode and that thing, and so it made me really really want to do a narcolepsy episode next season, definitely.
And maybe we did talk about it a little bit in cephalitis lethargica.
I wonder we must have.
We must have, we must have.
We talked about influenza like nineteen eighteen. Yeah, okay, all right, yeah yeah, narcolepsy okay.
Yeah, all right, back to pandemics. Maybe it's just been a while since we've covered a really pandemic ye pathogen. But I was struck by just how many pandemics that influenza viruses have caused, and it made me wonder whether we could draw any patterns at all, and what those patterns might be from these pandemics. Yeah, so some researchers have suggested that there's a set interval between flu pandemics, ranging from ten to fifty years, and that we are due for the next one in X number of years.
That travel and increased population size hasn't seen unificantly impacted this interval, so it must be something intrinsic to the virus itself. Yeah, your face and my face. I'm also inclined to disagree. I don't believe that pandemics happen on a schedule, or that influenza virus evolution is anywhere near
predictable enough to know when the next pandemic strain might emerge. Yeah, but to borrow a quote from a paper by Potter from two thousand and one, quote, it is self evident from the history of pandemics that each year that passes brings the next pandemic one year closer.
That I would agree with.
One hundred percent. Speaking of which, let's now turn to
highly pathogenic avian influenza. It may be futile to seek to predict exactly when the next pandemic influenza will occur, but we already know some of the likely circumstances under which the next pandemic virus could emerge, namely humans interacting with domestic foul Most papers put the first recognition of avian influenza in eighteen seventy eight, when Parencido described a deadly disease sweeping through chickens and other poultry in Italy.
It's really unlikely that this is the first actual instance of avian influenza, but as often happens, this publication and the nickname foul plague led to Isn't that Great? Led to additional reports of the disease, which was distinguished from other well known avian infections like foul cholera. The pathogen responsible for causing foul plague was found to be a filterable transmissible agent in nineteen oh one and isolated as
a virus in nineteen thirty four. Of course, the more people looked, the more foul plague viruses they found, which were recognized as influenza viruses but not demonstrated to share internal antigens with influenza A viruses infecting mammals until the nineteen fifties, so it took a while to make the connection between like oh, these are all closely related to one another, highly pathogenic av and influenza viruses were found in domestic poultry, like H five N one, which was
isolated from a small and self limiting but extremely deadly outbreak on a chicken farm on the east coast of Scotland in nineteen fifty nine, and these viruses were also found in wild birds, particularly migratory birds. The more viruses that researchers found, and the more birds they found these viruses in, the more they realized they had to worry about, especially with the evidence suggesting the nineteen sixty eight H three and two pandemic virus had gotten a couple new
genes from an influenza virus found in ducks. Surveillance studies conducted from nineteen seventy three to nineteen eighty six involving over twenty thousand birds revealed a prevalence of avian influenza of about ten percent, with ducks and geese most infected. Another study found that twenty six percent of forty eight hundred ducks about to migrate were infected, and with even
higher rates sixty percent in juveniles. The high prevalence, incredible diversity, and extreme virulence of some influenza viruses in domestic and wild birds did ring alarm bells for many public health researchers, but that ringing was kind of faint for a while because there had been no apparent instances of these deadly viruses being transmitted directly from birds to humans. But that ringing would grow a whole lot louder in nineteen ninety seven.
In the spring of that year, in Hong Kong, three year old lamb Hoycob became increasingly sick with what seemed like a severe respiratory infection fever, cough, sore throat, and the infection wasn't getting any better. Although doctors tried everything they could, he got worse and worse, his lungs, liver, and kidney's failing, and a week after he was admitted
to the hospital he died. Samples had been taken from Hoyka while he was still alive and sent to the lab, where they were expected to confirm that his illness was caused by seasonal influenza, which is generally mild but can cause severe infection in some cases, of course, but nothing
was a match. The virus was definitely influenza A, but it didn't seem to be any of the subtypes they were testing against the chief of the virology lab at the Queen Mary Hospital sent off the samples to other researchers around the world to see if someone else could solve the puzzle. Two months later, one of those researchers showed up in person to reveal what they had found. It wasn't an H one or a weird H three.
It was an H five, specifically H five N one, that had up to that point only been known to cause infections and deadly ones in birds. It turned out that earlier that year, a horrifically deadly disease had swept through some poultry farms northwest of Hong Kong, killing most, if not all, of the chickens at these farms. That virus turned out to be H five N one, but this news didn't really register as public health news. After all,
this strain had never been known to infect humans. Could this poultry outbreak have been the source of infection for lam Hoyca. The connection wasn't immediately obvious. The family lived in an apartment building fifteen miles away from the farms, so how could he have been exposed. It turned out that a few weeks before he had gotten sick, the teachers at his nursery school brought in baby chicks and ducklings into the classroom to keep his class pets. They
didn't last long. Over a couple of weeks, both ducklings and two of the three chicks had died. The remaining chick was long gone by the time epidemiologists arrived on
the scene to test for H five and one. But that classroom exposure seems the likeliest source for lam hohoica, and epidemiologists would have more opportunities that year to track down cases of H five and one spillover from domestic poultry to humans, because over the course of that year, eighteen people became infected with the virus, six of whom died.
In this outbreak. Even though it seems really small in size, only eighteen people, it sent the world into high alert and for good reason, could this be the start of the next influenza pandemic? In response, one point two million chickens in Hong Kong were called to try to stop the spread, which was a controversial and unpopular decision for many people because of the tremendous economic impact. It was
your livelihood gone. But it turned out that one in five of those chickens had been infected with the virus, and once the culling had ended, the human deaths and infections also seemed to stop, but the worry remained. This outbreak turned what we thought we knew about avian influenza on its head. We thought that a species barrier prevented avian influenza from infecting humans and human influenza from infecting birds.
Not so the other assumption that spillover could happen, but human to human transmission of an avia influenza virus was unlikely. That was also about to be challenged. Even though the culling of those one point two million chickens in Hong Kong arrested the spread of H five and one to humans,
there was no eliminating it from bird populations. Highly pathogenic avian influenza viruses popped up in the early two thousands, again in domestic poultry, after causing huge outbreaks, some of which were successfully controlled by culling, but the cat was long out of the bag. H five and one was detected in wild birds in Asia in two thousand and three, and over the next few years the virus had spread
to poultry in Africa. The Middle East and Europe, causing deadly outbreaks and birds, as well as spilling over to humans where instances of human to human transmission seem to occur, although in very limited chains. Up to this point, it's somewhat debated what led to the spread of H five and one, which is now globally distributed, but it seems
likely that it was migratory birds. Outbreaks on domestic poultry farms seem to follow the timing and location of where migratory birds are flying over, as do some human cases. And Aaron, I'll leave it to you to give us the final numbers on how many cases of H five and one have occurred in humans, but I know it's
been in the hundreds, maybe eight hundred or so. With that staggeringly high mortality rate you quoted, like fifty to sixty percent in the age of COVID, A thousand or so infections may seem like nothing at all, just a day in your county, but it's truly not, especially when the mortality rate is so high. Some people take comfort in the fact that H five N one hasn't yet evolved to be more transmissible of human to human, while others feel it's just a matter of time. Complacency is
not acceptable. COVID showed us just how unprepared we were and I worry still are for a pandemic. Public health isn't just about control and containment. It's also about prevention. It's the centers for disease control and prevention. Although people often forget to include that last part, including us, we
often leave it off. Some viruses are extremely difficult to control or contain once they emerge, especially if they're infectious before causing symptoms, which makes them great pandemic viruses, as we saw with SARS, Coby two nineteen eighteen, influenza virus, and many other pandemic viruses, and so our best shot lies in preventing them from emerging in the first place.
The good news is that we know the circumstances under which these viruses are most likely to emerge and the places where viral evolution and spillover is most.
Likely to happen.
The bad news is that these circumstances, the breeding grounds for pandemic pathogens, not only still exist, but are likely increasing in size and number, making spillover more likely and monitoring for these pathogens more difficult. That combined with globalization. Well, we know the rest massive unregulated farms where poultry or pigs or cows all crowd together, wet markets where viruses
can commingle freely before spilling over to humans. Over use of anti virals or antibiotics, and poultry leading to resistant strains, fear of stigma or economic impact into the suppression of disease reports. What's shocking to me is not that avian influenza has spilled over into humans, but that there hasn't yet been a pandemic. Reading about highly pathogenic avian influenza filled me with such a creeping dread because it's the
same thing that we've seen time and time again. It's what we saw with stars, it's what we saw with COVID, and it's what we're going to see with the next influenza pandemic. From the book I read that was published in two thousand and nine, quote, the moral of SARS is clear. The flu virus must be controlled in birds, whatever it takes. The microbial agent must be extinguished before a readily transmissible flu strain jumps to people, because once
it does, global spread is inevitable. There won't be any way to stop it.
End quote.
I think the biggest question that remains is what exactly will it take to prevent the next influenza pandemic? And are we equipped to do those things? Are we equipped to do more than just react?
I don't know.
I don't have the answer to that either, so I hope you're not.
I'm not I can answer that.
I don't know if anyone has the answer. I hope people do. I won't ask you to answer, but I will hand it over to you at this point to fill me in on where we stand with influenza today.
Oh my gosh. I will try and do my best.
Right after this break, we'll talk briefly because I think it's still deserving about epidemic flu and then get into the details on the status of highly pathogenic Evian influenza, and I will try to not end on the most of downers, but no guarantees, so sorry. Every year, World Health Organization estimates that anywhere from three to five million people worldwide become severely ill from influenza. So I'm not
just talking like global numbers. I'm talking like sick enough to matter to things like hospital systems and work systems, et cetera. Three to five million people globally just from epidemic every year seasonal influenza. And it's estimated that anywhere between two hundred and ninety thousand and six hundred and fifty thousand people die worldwide from the flu every year.
These are not small numbers, no, they're not.
In the US, it's estimated that between three and eleven percent, depending on the year of the US population is symptomatic from the flu, so not necessarily severely ill, but at least.
Symptomatic, okay.
And the estimated economic burden in the US alone is between six to twenty five billion dollars a year from both direct medical costs as well as indirect like time missed from work, et cetera type costs. Dang, So, I hope that we can all be on the same page that even apart from the terror that is highly pathogenic avian influenza, even apart from novel strains and pandemic potential, annual flu epidemics are a big deal, and they're incredibly costly in terms of.
Lives and dollars. So that's flu. It matters.
But then, of course there is highly pathogenic avian influenza, and there is like you described, aaron massive pandemic potential, and we all probably not just from your terrifying descriptions, sorry, but also from currently living through a global respiratory viral pandemic. I think we have a renewed appreciation for just how
serious and real this threat really is. So there is a group of organizations, the World Health Global Influenza Program developed a tool that's called the Tool for Influenza Pandemic Risk Assessment, which basically joins together the World Health Organization, the World Organization for Animal Health WOE like their acronym used to be called the OIE, as well as the Food and Agricultural Organization or the FAO, and these groups together, and I would say predominantly the WOE attempt to monitor
and assess the risk of pandemic influenza from a one health perspective.
We love to see it right.
One health is.
Great, One health is great.
But I will say, as much as I did find data on the WOE page, I was a little bit disappointed that the World Health Organization page on Avian influenza hasn't been updated since twenty eighteen, and the most recent maps that you can find of HPAI from them at least are actually dated all the way back to twenty fourteen, so it's a little bit difficult at least if you're just going directly to the World Health Organization to try and access the more current data.
That's disappointing.
It's a little disappointing. Let's move on.
When we look at human infections as of a paper that was published in twenty twenty, so these numbers are likely from twenty nineteen and maybe early twenty twenty, there have been eight hundred and eighty three officially reported highly pathogenic avian influenza cases in humans. Eight hundred and sixty of those have been caused by H five and one, and twenty three of them from H five and six. And these numbers are only slightly higher than what I
actually reported back in twenty seventeen in our very first episode. However, it is also still true that of those over four hundred and fifty have died as a result of their infection, which is an over fifty percent mortality rate, and that's terrifying. Yeah, But where it gets way more terrifying is just if we look at what's happening in birds. So if we look just at the US alone, because it was easy to get really good numbers.
In the US.
As of October thirteenth, twenty twenty two, two pm Eastern, there have been forty seven million, three hundred ninety two thousand, four hundred ninety eight cases of highly pathogenic avian influenza in domestic birds since January of this year, forty seven million across forty two states in five hundred twenty eight different reported outbreaks since January in the United States, and two thousand, nine hundred and thirty in wild birds in
five hundred eighty three separate outbreaks across forty six states.
So some pretty terrible numbers there h So.
Far, only one human case has been reported in the US, in someone who was working directly with calling infected back in April in.
Colorado Shout out and shouta yep.
They survived and had a relatively mild infection. But this is continuing to spread, including among wild birds, many of which have now begun their migrations south, and therefore this is not the end. If we look globally, this is not something that this year is just happening in the US. According to the WOE, the World Organization on Animal Health, there have been outbreaks either singular or more commonly plural, that are ongoing in Mexico, Canada, the US of course.
In Europe, outbreaks have been reported in Bulgaria, Hungary, the UK, Germany, Netherlands, Russia, Moldova, Spain, France, and Poland. In Africa, outbreaks have been reported in Nigeria. In Asia, they've been reported in Japan, Taipei, and the Philippines so far in twenty twenty two.
And to be.
Completely honest, that might not actually be all of them, because the way that the WOE reports things out is monthly or sometimes every couple of months, but they report out current outbreaks that have new cases and new outbreaks, but not necessarily if there were outbreaks that don't have new cases reported and I couldn't find nice like cumulative summary reports from twenty twenty two so far, Okay, so there may be countries that had outbreaks earlier in the
year that I missed, But in short, in this year alone, twenty twenty two, we are looking at hundreds, if not thousands, of individual outbreaks.
Accounting for millions.
Of cases in both wild and domestic birds in dozens of countries across the globe.
I mean how many more times this episode can we say it's terrifying.
Well, we can say it one more time after this, because right now it's October, and September tends to be the lull of cases, and then it often picks back up in October with peaks in February. And what's been really scary about this season in particular is that what we saw throughout all of these outbreaks is that they
didn't go away in the summer. Even in places like the US, where usually you would see like really low, almost no numbers of avian influenza across the summer months, we didn't see like complete elimination during those months like we usually have in the past. Why they just have continued to spread. Why they've made it into particular bird populations.
That have allowed it?
Why?
Why?
And like you said, Aaron, prevention.
Is incredibly difficult.
Of course, there are recommendations things like separating wild and domestic birds to reduce contact between these populations, ensuring good hygienes and poultry facilities, but we know that's very difficult.
It doesn't always happen.
Vaccination of birds can be helpful to some extent, but it doesn't do anything for wild bird populations, and the same limitations on vaccines for birds exist as those for humans, which I'll talk more about in just a minute. But our vaccines are not perfect, and rapid containment once we've identified outbreaks is really important. But like you mentioned, Aaron, this usually involves culling, which is a difficult thing to
ask of people because that's a huge financial stressor. And not everywhere, like not every government financially compensates people for the loss of their flocks.
Yeah.
On top of that, just to make it a little bit worse, is pile it on you want to pile it. Urbanization and habitat loss for wild birds, especially waterfowl, means that both humans and our domestic animals are naturally put into closer and closer contact with these birds on a regular basis, and so it's just so much easier for transmission to cross species.
Yep. So none of that was.
Good news, but that is the truth of where we stand with highly pathogenic avian influenza. Twenty twenty two has been a particularly bad year, especially in the US. We haven't seen an outbreak like this since twenty fifteen, when we had an outbreak of fifty million birds, and we're almost there and it's October. So let's see if we can find any good news, any silver linings.
Vaccines.
But yeah, not so, I guess I wouldn't say silver linings with just like things to look for.
Would do things to have to cling to hope, There we go, hope clingers. Yeah, vaccines, you're right erin so everyone knows that every year we have to get a new flu shot. Every year, your doctor's like, did you get your flu shot?
And every year, at the end of flu season, we find out how effective or not so effective that year's vaccine was. The reason that we have these different shots every year is because of how much variety there is in the genome of influenza viruses, because of that antigenic drift, especially those small mutations that are happening every year, and so every year the vaccine aims to cover the most likely circulating strains. But the current vaccines that we have
are far from perfect. A. We don't always get strains right. Sometimes they continue to mutate and we get them wrong. B. The vaccines themselves are not the most immunogenic, and so we don't actually mount like that incredible of an immune response to them and see, because of the way that we currently produce influenza vaccines, which is using eggs as incubators, sometimes these viral strains actually mutate in the eggs to become less effective during the process of replication.
Fantastic.
Yeah, So that's why effectiveness can vary anywhere from ten to sixty percent year to year. Now, I will say that even a less effective flu vaccine tends to still provide good protection against severe disease and death and hospitalization, even though it may not protect as well against infection itself. So don't think that I'm saying don't get your flu shot. It is imperfect, but for right now, it's the best that we have, and something is a lot better than nothing.
But the real question is, and has been for a long time, like can we do better, and especially can we develop a universal flu vaccine, something that protects against a wider variety of strains and does so more effectively, a vaccine that could, in theory even protect against these pandemic potential strains that we don't even know about yet. And the answer is, there's a lot of people who think we can, and so they've dedicated their lives to
working towards it. We still don't have one that I can say in the next X number of months or years, we're going to have a universal flu vaccine.
There are I think two that.
I found in the last couple of years that have made it either two or through phase one clinical trials that have a lot of potential. One of them is from a paper that was published in twenty twenty and I tried to get a sense of where it stands today, but I couldn't quite, but I'll post the paper so that you can read it. It's a really interesting vaccine
that is made of chimeric h antigens beautiful. So what they did is that they linked those conserved portions of the H antigen which are similar across a whole bunch of different strains H one and two and three, et cetera.
But usually isn't.
The part that our immune system responds to and makes antibodies against, because it's usually the head, the different part of the H anigen that is the most immunogenic, so that we are making the most antibodies towards.
So this vaccine it makes.
Specific hs that have a less immunogenic head, but a very immunogenic stock that is conserved across all of these different strains, so it allows for you to mount a really good amount of immune response against that stock.
Interesting.
I love it. And so in phase one trials it did really well. People mounted a really great immune response. But what we don't know yet, because we need more trials, is to know how does that play out in actual flu infections? How well does that protect you against actual infection? Right,
but it's exciting. The other vaccine that actually started phase one trials with NIH this year is a whole virus vaccine that is made of low pathogenicity avian influenza viruses, and the hope at least this is what happened in mice, is that these mice mounted very robust immune responses that then actually were protective against a wide variety of strains, including those not included in.
The vaccine, which is fascinating.
That's cool.
Yeah, And so that vaccine is currently undergoing phase one trials right now twenty twenty two, so we'll see what comes of it.
But it's hopeful. That's where we stand.
I mean, it's I feel like that's that's pretty good. I feel like I was a little bit down on humanity and that that might be from COVID, you know, living through the COVID pandemic.
Yeah, and I think it's reasonable. I think I think that the idea of in the paper or the book that you cited of like we must eliminate this microbe, like that's not realistic. No, I don't think that that's a thing that is possible, given how widespread influenza is, given how rapidly it mutates, it's just not possible. I do think that creating a vaccine that does a really good job at preventing severe illness, at preventing death, I do think that that's possible, and so I have hope.
I think that's possible. I think that raises the issue of access and equitability across different countries. And so you're right in that it's in the birds. It's not going to leave the birds. It's going to keep evolving and mutating in the birds and spreading and so on and so forth and more spillovers. And I think that the most important thing to target is those opportunities for spillover and the opportunities for mixing and like reassortment of different viruses.
And that's difficult to do. There are a lot of different drivers. It's not just about Okay, we'll just stop.
This right, Nope, it's complicated.
Yeah, application always is.
Well, that was a lot.
That was a lot.
That was a lot of influenza talk.
I have one more question. Okay, how scared do we need to be? Oharin, I'm just kidding because right now I have open on my computer screen the transcript from our Influenza episode from twenty seventeen to quote you.
Okay, what did I say? Go ahead and.
Get your seasonal flu shot, wash your hands, and just be a little afraid. I guess. Oh, then you add don't hang around birds?
Yeah? I love that, love it.
Do you echo those sentiments today?
I would say, way to go twenty seventeen, Aarin, you knew it? Yeah, yeah, yep.
Well sources, yeah, I have, unlike our twenty seventeen episode, a ton of sources for this episode.
So embarrassing. How few sources we had for like what we didn't?
You know?
We hadn't hit our stride. Yeah, I will shout out again the Book of the Fatal Strain by Alan Cippras. And I have a ton of paper that I will post on our website post for this episode.
I also had quite a number of papers for this episode. One that I did really like was actually from twenty twenty one and it was called Influenza virus and SARS CoV two Pathogenesis and Host response in the Respiratory Tract. Super interesting because it compared influenza virus and SARS CoV two, so that might be of interest to a lot of people.
Had a number of other papers on the specific pathogenicity and a few if anyone wants to deep dive, especially on the transmission aspects of influenza viruses, and then of course a number of other papers on the current status as well as where we stand with universal flu vaccines.
So we will post all of.
Our sources from this episode and every one of our five entire seasons on our website, This podcast will kill You dot Com.
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