This Podcast Will Kill You - Ep 110 Influenza, Take 2: Fowl Play

Episode Date: November 22, 2022

Ep 110 Influenza, Take 2: Sitting Ducks; Fowl PlayOver five years ago, on October 31, 2017, the very first episode of This Podcast Will Kill You premiered, an action-packed (and mildly disorganized) tour of the influenza virus and the 1918 flu pandemic. So much has happened since that episode’s release, both within the podcast and in the world of public health, not the least of which is a respiratory virus pandemic. Given this distance from the podcast’s beginning and the added perspective of experiencing a pandemic firsthand, we decided to circle back to where we started by revisiting influenza for our fifth season finale. In this episode, we provide a bird’s eye view of influenza viruses overall, from how they make you sick to the long history of influenza pandemics and where we stand with case numbers in recent years. Then we dig deeper by giving you a different kind of bird’s eye view: a close examination of highly pathogenic avian influenza, especially H5N1. How is this virus different from your standard seasonal influenza strain, where did it come from, and how worried do we need to be? Are we just a bunch of sitting ducks? Tune in to find out. See omnystudio.com/listener for privacy information.

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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 counterattack 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. Evermore 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 mucus 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 very 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 and 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 more of a respect or appreciation for flu? I think both. I think in large part it's probably COVID. I think it's living through 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't 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 Cypress and it was published in 2009. 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 Aaron Alman Updike. 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 And that is so utterly terrifying. And there is 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 2017 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 quarantini time? We should. We certainly should. What are we drinking this week? Well, we're drinking none other than H1 Drink 2. I love it. We could not. For those of you who haven't listened to our very first influenza episode, we can't blame you.

First of all, second of all. Not necessarily recommending it. Nope. But it is maybe pertinent to this part of the episode to know that our very first quarantini was called H1 Drink 1. So this time, it's H1 drink 2. Yeah. And what is in H1 drink 2, Aaron? It is kind of a play on the corpse survivor.

So we did the corpse survivor number two for our H1 drink 1, our very first quarantini. And this one we're kind of just doing a variation. It includes apricot liqueur, light rum, lemon juice, and lilip blanc. And we will post the full recipe on our website. This podcast Will Kill You.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 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.

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to get free shipping on your order and 365-day returns, now available in Canada too. That's Q-U-I-N-C-E dot com slash this podcast to get free shipping and 365-day returns. Quince.com slash this podcast. 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. I called it a retrovirus on the Internet forever.

It's in our transcript. I did see it in the transcript, but 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 co-infected 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, A, B, C, 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 it 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 of- 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 H1N1 or H3N2.

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-antogen, hemaglutinin, and the N-antogen, neuraminidase. You don't have to remember those names. You could just remember H-N-N. So the H proteins, you can think of these as the proteins that bind to ourselves and allow influenza virus to actually enter ourselves. 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 ourselves entirely. Question.

Okay. So the difference between upper and lower respiratory tract and the differences in the H's 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 yeah that's classic yeah because let me keep going and we'll see not just how much variation there is but like how terrifyingly much variation there 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 influenza virus actually release from inside of our cells. 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 hemaglutinins. Right.

But the neuraminidase, like, what is the variation in that functionality? Oh, 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 N1 versus N2? Is there a functional difference? Or is it just these are different enough to be called different, right? Yeah. Yeah. It's a good question. So there are 18 different major H antigens. 16, if you don't count the ones that are mostly only found in bats. And there are 11, 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 N's in pretty much any configuration, that alone is a huge amount of potential for recombination and change, right? 18 and 11, or even 16 and 9. That's a ton of variation. I can't do that math. No air in math? No air in math this episode.

But on top of that, you asked, like, what are the differences between the different H antigens? Yeah. There is not just a difference between, say, H1 and H2, but because of the buildup of changes to these H&N antigens via that antigenic drift, via those small point mutations, what that means is that not every version of H3N2 is exactly the same. there are parts of the H antigen and parts of the N antigen that are more conserved, and there are other parts that are much more variable, even within, like, say, H1 or H5. 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 H5N1 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 that 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, etc. 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, fomites, 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, Erin, 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, like the relative contribution of this transmission rate versus that transmission route. Does that make sense? Yeah, you know me so well. Those were literally the two questions I was brimming like on the

top of my time. I preempted 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 titers in their nasal epithelium, up to 24 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 our cells 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 65. that are at highest risk of severe infection and death. It's that classic U-shaped mortality curve. In all but the 1918 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 failure, pulmonary disease of various kinds, cigarette smoking, immunocompromising 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. 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. We think we should know that and I just somehow missed it. But I didn't see it. I mean. But presumably there are, there's a subset of people who.

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 cruddy. 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 staff orias 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&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 H3N2 strain B3.4.5.2 or something like that. So there's like there are like specific. strains. And sometimes, too, 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 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, yeah, 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 L-P-A-I. 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-7 and H-5 and I think H-9 varieties, have emerged as being highly pathogenic, aka H-P-A-I.

And it's very likely that these 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 in a particular population. 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 ruse 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, a 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. Yeah. 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 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, like, 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, H5N1, 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 50 to 60%. 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 firsthand account, is that in the case of H5N1, 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 vivo anything when it comes to H5N1. So we still don't know also how much of the damage of this virus and 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, in fact, 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 our cells in general. Okay. There could be others. Interesting. Yeah. So that is the biology of influenza and influenza A. Erin. Terrifying. Terrifying.

You want to tell me where this sucker came from and, you know, how we got? All the rest. I will do my best right after this break. Anyone who works long hours knows the routine. Wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something. That's why O'Keeffe's working hands hand cream is such a relief. It's a concentrated hand cream that is specifically designed to relieve extremely dry, cracked hands

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Get your free personal training evaluation kit today. Just text lift to 3232 right now. Get certified in as little as six weeks. And ISSA guarantees you'll get a job. Text lift to 323232. Text lift to 32 3232. Lift to 323232. Before getting too deep into the research for what I wanted to cover 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. A hundred percent. 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 2017. Wow. We're recording this in October 2022, 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 1918 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 H5N1. And although we were wrong about the causative agent of the next pandemic, we were right to be scared, to still be scared, frankly. Yeah. My intention today is not to scare you. I don't think our intention is to scare you, but to present what we know about the evolutionary history of influenza viruses, take a brief jaunt 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 H5N1 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 H5N1 virus and the emergence of other pathogens of pandemic potential, things like the 1918 influenza virus, SARS-CoV-1, and of course SARS-CoV-2. 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 prevention seems almost impossible. But before I fall further into this like 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, it's pretty difficult. I can imagine. Despite the fact that, to quote, Will and Holmes 2020, 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.

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 charadroformis, which are shorebirds and goals. 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, goals 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 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 face. Hagfish. I know. And more are likely to be discovered, the more we look, of course. And the patterns in the relatedness of these influences of these influences. influenza viruses suggest that co-evolution 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. Interesting. Yeah. All of the existing diversity, which is high in influenza viruses that we see today in mammals, minus bats and birds, came from a lineage branching off in the late 1800s. 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 additive. advantageous mutation emerges in one strain that leads to all other strains being outcompeted, eliminated, so that all future lineages 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-19 and how the dominant variant of SARS-CoV-2 is constantly changing. We don't really see COVID infections caused by Delta anymore. Delta was

displaced by Omacron, 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 out-compete the rest. And then that's the only lineage that will survive 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. Viruses succeed 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 virus is from previous variants, but also how many people were exposed to those previous ones, how novel the virus is to them. Right. 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 1918 demonstrate this. In 1918, 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 1918 strain.

The 1957, 1968, and 2009 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 H5N1, 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 1957 and 1968 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 H5N1 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 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 parenthis in 412 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 1173 to 1174 CE in 1510 and in 1557, which some argue was a pandemic. But the agreed upon date for the first clear influenza pandemic is 1580.

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. 8,000 deaths in Rome alone. And some Spanish cities were described as being decimated. Two quick asides here. The first has 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. Okay, aside number one over. aside 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. Mm-hmm. I mean, it seems like there should be an easy explanation. Yeah. And generally speaking, people do seem to agree that it comes from Italian, ultimately derived from the Latin word, influenza, 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.

Weird. 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 1357 from an epidemic in Florence, Italy, sometime in the 15th century, 1743 during an epidemic in Rome, or my favorite, favorite quote way way way back in the day unquote that sounds like my answer yeah I know right it's like way back in the day I mean that could be any one of those dates so they're not wrong

they're 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 1729, 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 rapid. rapidly this virus spreads. Mm-hmm. 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, then 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 in the 1700s. Impressive and scary, I guess. Terrifying. Yeah. It's just like, if it 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 1729, which had high mortality, also had recognizable waves of infection with increasing severity. 40 years later, the next pandemic occurred in 1781 to 1782, 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, 30,000 got sick. each day in St. Petersburg. Wow. Yeah. Also, I just thought of something about what you brought up and 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 infectious 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 50 years after that one in 1781. So this was in 1830 to 1833. This one originated in China and spread south to Indonesia and the Philippines. And then west to India, Russia, and on to Europe and the Americas. This pandemic, reportedly, had infection rates comparable to those in the 1918 influenza pandemic, with 20 to 25 percent of the population becoming infected, again in waves.

though not with a super high mortality rate. 60 years went by before the next pandemic in 1889 to 1890. 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 19th 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 on to 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 1.5 billion.

Wow. The world wouldn't have to wait another 50 or 60 years for the next influenza pandemic, though, because a short 28 years later, the deadliest influenza pandemic the world had seen would result in 500 million infections and 50 to 100 million deaths worldwide. Although I'm tempted to redo the coverage of the 1918 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 1918 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 1918 pandemic while it was happening, the technology just wasn't there yet. And it was only in 1933 that the influenza virus was finally isolated. Almost immediately afterwards, research on a possible vaccine began with a live attenuated vaccine first, being produced and used in factory workers in the USSR in 1936. Four years later, the inactivated bivalent vaccine containing H1N1 and influenza B was developed and deployed, likely contributing to reduced influenza morbidity and mortality during World War II.

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 1957 and 1968 influenza pandemics, which had one to four million deaths and one million deaths respectively. And 40 years would pass before the most recent influenza pandemic, which was in 2009, resulting in 800 million to 1.4 billion infections and 120 to 203,000 deaths, although I've seen

higher estimates as well. I do not think that I realized how large those numbers were for swine flu. I didn't either. There's a paper all posts 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. Right. And 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 2009 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 onset 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 whole 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 encephalitis lethargica. I wonder. We must have. We must have. We must have. Maybe we talked about influenza, like 1918. 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-y 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 10 to 50 years,

and that we are due for the next one in X number of years, that travel and increased population size hasn't significantly 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 2001, 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. 100%.

Yeah. Speaking of which, let's now turn to highly pathogenic avian influenza. Mm-hmm. 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 1878, when Perensito 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, it's not 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 1901, and isolated as a virus in 1901, in 1934. 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 1950s. So it took a while to make the connection between like, oh, these are all closely related to one another. Highly pathogenic avian influenza viruses were found in domestic poultry, like H5N1, which was. isolated from a small and self-limiting but extremely deadly outbreak on a chicken farm on the

east coast of Scotland in 1959. 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 1968 H3 and 2 pandemic virus had gotten a couple new genes from an influenza virus found in ducks. Uh-oh. Surveillance studies conducted from 1973 to 1986, involving over 20,000 birds, revealed a prevalence of avian influenza of about 10%, with ducks and geese most infected.

Another study found that 26% of 4,800 ducks about to migrate were infected, and with even higher rates 60% 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 1997. In this spring, Spring of that year in Hong Kong, three-year-old Lam Hoikha 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 kidneys 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 H1 or a weird H3. It was an H5, specifically H5N1, a virus 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 H5N1. 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 Hoikha? The connection wasn't immediately obvious. The family lived in an apartment building 15 miles away from the farms, so how could he have been exposed? It took a turn to him. 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 H5N1, but that classroom exposure seems the likely a source for Lomhoika.

An epidemiologist would have more opportunities that year to track down cases of H5N1 spillover from domestic poultry to humans. Because over the course of that year, 18 people became infected with the virus, six of whom died. In this outbreak, even though it seems really small in size, only 18 people, it sent the world into high alert and for good reason. Could this be the start of the next influenza pandemic? In response, 1.2 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. That 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 1.2 million chickens in Hong Kong arrested the spread of H5N1 to humans. There was no eliminating it from bird populations. Highly pathogenic avian influenza viruses popped up in the early 2000s 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. H5N1 was detected in wild birds in Asia in 2003, and over the next few years, the virus had spread to poultry in Africa, the Middle East, and Europe, causing deadly outbreaks in 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 H5N1, 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 H5N1 have occurred in humans, but I know it's been in the hundreds, maybe 800 or so, with that staggeringly high mortality rate you quoted, like 50 to 60%. 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 H5N1 hasn't yet evolved to be more transmissible

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. 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-CoV-2, the 1918 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, overuse of antivirals or antibiotics and poultry leading to resistant strains, fear of stigma or economic impact leading to 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 SARS. 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 2009, 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's handed 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 avian 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, etc. Three to five million people globally just from epidemic every year seasonal influenza. And it's estimated that anywhere between 290,000 and 650,000 people die worldwide from the flu every year. These are not small numbers.

No, they're not. In the U.S., it's estimated that between 3 and 11 percent, depending on the year, of the U.S. population, is symptomatic from the flu. So not necessarily severely ill, but at least symptomatic. Okay. And the estimated economic burden in the U.S. alone is between $6 to $25 billion a year from both direct medical cost 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 description, 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 2018. And the most recent maps that you can find of HPAI from them at least are actually dated all the way back to 2014. 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 2020, so these numbers are likely from 2019 and maybe early 2020, there have been 883 officially reported highly pathogenic avian influenza cases in humans. 860 of those have been caused by H5N1 and 23 of them from H5N6. And these numbers are only slightly higher than what I actually reported back in 2017 in our very first episode. However, it is also still true that of those over 450 have died as a result of their infection, which is an over 50% mortality rate. And that's terrifying. 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 U.S. alone because it was easy to get really good numbers in the U.S., As of October 13th, 2022, 2 p.m. Eastern, there have been 47,392,498 cases of highly pathogenic avian influenza in domestic birds since January of this year. 47 million across 42 states in 528 different reported outbreaks since January in the United States. Okay. And 2,930 in wild birds in 583 separate outbreaks across 46 states. So some pretty terrible numbers there. Mm-hmm. So far, only one human case.

has been reported in the U.S. in someone who was working directly with calling infected birds back in April in Colorado. Shout out. Shout out. 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 thing that this year is just happening in the U.S.

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 U.S., of course. In Europe, outbreaks have been reported in Bulgaria, Hungary, the U.K., Germany, Netherlands, Russia, Moldova, Spain, France, and Poland. In Africa, outbreaks have been reported in Nigeria. In Asia, they've been reported in Japan, Korea, Taipei, and the Philippines. So far, in 2022. 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 2022 so far. Okay. So there may be countries that had outbreaks early in the year that I missed. But in short, in this year alone, 2022, 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 U.S. 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 hygiene in 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, if we-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. 2022 has been a particularly bad year, especially in the U.S. We haven't seen an outbreak like this since 2015 when we had an outbreak of 50 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. Yeah. Not so. I guess I wouldn't say silver linings, but just like things to look forward to. 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 the end of the end.

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 vaccine, that we have are far from perfect. A, we don't always get the 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 C,

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 10 to 60 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 2020, 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, H1 and 2 and 3, etc. 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.

Anogen, that is the most immunogenic so that we are making the most antibodies towards. Right. So this vaccine, it makes specific Hs that have a less immunogenic head, but a very immunogenic stock that is conserved across all of the. 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, 2022. So we'll see what comes of it. But it's hopeful. That's where we stand. I mean, I feel like that's pretty good. I feel like I was a little bit down on humanity. And that might be from COVID, you know, living through the COVID pandemic. Yeah.

And I think it's reasonable. 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's, 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. A hundred percent. 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.

Boom. Nope. It's complicated. Yeah. Application always is. Well, that was a lot. 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? Oh, Erin. I'm just kidding, because right now I have open on my computer screen, the transcript from our influenza episode from 2017, 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, and then you add, don't hang around birds. Yeah. Love that. Love it. Do you echo those sentiments today? I would say way to go, 2017, Erin. You knew it.

Yeah. Yeah. Yeah. Well. Sources? Yeah. I have, unlike our 2017 episode, a ton of sources for this episode. So embarrassing how few sources we had.

Like, what? We didn't, you know, we had. hadn't hit our stride. Yeah. I will shout out again the book of The Fatal Strain by Alan Cyprus, and I have a ton of papers 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 2021, and it was called Influenza Virus and SARS

COVID-2, pathogenesis and host response in the respiratory tract. Super interesting because it compared influenza virus and SARS-Co-2, so that might be. 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. So kill you.com.

Thanks to Bloodmobile for providing the music for this episode and all of our episodes. Thank you to the Exactly Right Network. And thank you to you, listeners. We really couldn't do this without you. Nope. We wouldn't do this without you. Nope. I hope that y'all enjoyed this season and we're really looking forward to next season.

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