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Hello, beautiful people, and welcome to episode two of the Filth in America podcast. I'm Brandon Hewley, your host, and today we're going to be talking about vaccination and its history, where did it come from? Why do we vaccinate? What's the future of vaccination look like? A lot of this can be determined by the past of vaccination. You know, we, I think, mostly associate vaccination with childhood vaccinations in the United States. And of course, recently think about it in terms of COVID pandemics, and there's a lot of back and forth about safety and efficacy and where do these come from, and using, quote, experimental technology. One of the things about the story of vaccination that I think isn't widely known is that it is very much an American story, while the concepts of vaccination and the development of vaccination are very much things that took place outside of America, and indeed before the United States was itself a country. The embracing of this technology and the widespread application of vaccination is uniquely American and was practiced in the United States on a much larger scale than in Europe or China or India where these things come from. So today we're going to take a look at vaccination. If you come in contact with a germ, a virus, a bacteria, whatever that's going to cause a disease, it will infect you. And there's a certain dose of these pathogens, as we call them, that are required to cause both a disease, to set up the infection, and ultimately to cause symptoms. And you, as most folks know, have your immune system, largely white blood cells, that are actively going around your body at any given time to try to deal with these pathogens. Now, it's important to note that our bodies are not designed to live in sterile environments. We tend to think of germs and disease. If we get rid of the germs, we won't have disease, but you are coming in contact with lots and lots and lots of microbes. Your gut is full of microbes, and indeed some of the ones in your gut could cause disease if they got out of your gut and into another part of your body. The environment that we live in has lots and lots of germs, more and less depending on the environment. So you're really well set up to manage interactions with the microbial world. And indeed, we're increasingly finding that the microflora, the bacteria in your gut or on your skin, or elsewhere that you have do shape your health. In fact, keeping them viable with things like probiotics and dietary things and bathing practices and all of this is actually really important to maintaining health. But every now and again, a new type of organism makes its way to you in one way or the other, or the balance gets off, and some get where they're not supposed to be, or where you can't deal with them. And your immune system has to protect you. Now, the immune system is an insanely complicated thing. The way it works, it's got all these different pathways and different cell types, and this turning on that and turning off this, and it's extremely powerful, and it can manage everything from infectious diseases to cancer to pain and arthritis. All of these things have an immune system component. So we're going to just talk about that in high-level terms. When your body begins to be infected by a microbe, right? That microbe does what it does inside your body or on the surface of your body. It tries to make copies of itself, whether it's a bacteria that basically takes nutrients from you and uses that to replicate and make more copies of itself. Certainly in the process, it can create toxins that destroy your cells to help free up nutrients or things like that. It is somewhat, you can think of it, as eating you. Or viruses which infect a given cell, and they take that cell from being whatever kind of cell it was, doing whatever its job was, and turn that cell by changing the DNA a little bit into a virus factory. So that cell stops doing whatever it was doing or does less of whatever it was doing and starts producing virus, which then come out and infect other cells, and the process continues. So you have the white blood cells of the immune system always going around and looking for these processes happening because you're in contact with bacteria and viruses and microbes all the time, some of which can cause disease. And so those cells are pretty good. They can eat up the bad cells, get rid of them, kill them, they can issue their own toxins that will destroy things, they can kill your own cells that are infected with virus, so they don't produce anymore, and all of these things. But there's levels of function that they engage. There's kind of your normal level that you have right now if you're healthy listening to this podcast, or just in daily life, right? You have you have a level. And that is fairly calibrated to keep you kind of on an even queue. You really don't want, unless you've got an infection going on, the level of activity of the white blood cells, your immune system, to go up. Because, as we said, in the case of viruses, the one of the ways that it stops viruses is to destroy a cell that's got a virus in it. If those destruction chemicals are released all the time, right, it would be destroying cells that maybe are not infected with a virus. And so you're damaging yourself. You don't want to do that. You need other cells. You don't just need white blood cells. So if you're producing one kind, you might not produce others. And there's different ones that you need. Some are more prone to getting rid of viruses, others are more prone to getting rid of bacteria, others are prone to get rid of fungi or parasites. If the ones that are involved with getting rid of parasites become overactive, that's a very common way people develop allergies. So, you know, when you have allergies, that is the immune system responding to things that it shouldn't, things that are not going to kill you. And so, of course, it never gets rid of them, so you constantly feel a little bit sick, as if you were fighting an infection. So when that gets up, you have these other problems. So you want to keep it in balance. But when a pathogen infects your body, as it if it gets going and gets kind of past the first line of defense, now it is a race. Your body will sense this and through these complicated immune pathways start producing antibodies. Antibodies serve the purpose of enhancing and revving up the immune system activity. You have lots of different kinds of antibodies that your body can produce, different in the sense of what type of pathogen, what type of germ that they will react to, bind to, or different types, there's different sizes that do different things. As you go through the process of producing more and more antibodies, as you've had a disease for longer and longer, you produce bigger and bigger antibodies. The antibody molecule is larger and shows up later in the disease process, because it just simply takes your body longer to make that type of antibody. An IgG has got lots of binding sites as opposed to, say, an IgA, which only has two. So you change over time, IgG, IgM, all these different antibody types. Eventually, you have enough antibodies that they start really impeding the activity of the pathogen that's affecting you. Some of them will bind to the surface of that pathogen and keep it and block that site where it is trying to attack your cells. Some of them will bind to chemicals produced, so those chemicals no longer go out and damage things. Others will bind to the surfaces of the pathogens and say, hey, look here, come kill here. This is the thing you want to get rid of. Other ones block it up and make it easier for you to get rid of through the normal pathways that your body gets rid of things. Others will signal to the immune system that says it come kill this cell, it's got viruses in it, it's not working. There's all these things that are happening simultaneously. And again, as the disease process comes on, you make more different types of antibodies that do more different things. Eventually, you hope anyway that the number of antibodies and the types of antibodies overwhelm the pathogens. So you start making really hundreds and thousands, indeed millions of copies of antibodies, and that gets ahead of the growth of the pathogen, right? The viruses infecting more cells of the bacteria, making more copies of themselves, and then start to clear it from the body, and you get better. However, the catch is that these pathogens, the viruses, the bacteria that are in there, why you know they're trying to do their thing too, and there could be quite a lot of them. And if you don't get ahead, the disease continues and it keeps damaging your body, and you are sick. And sometimes this can take months for you to make enough of these antibodies to clear your body of all the different pathogens. And so the whole time the disease is hurting your body, in the case of something like smallpox, right? It's making a pox that scars on your skin and has a disfiguring pox there that you don't necessarily want. Hepatitis viruses can damage your liver. All of these things, some of them have things that they don't do at first, say like streps, streptococcal bacteria that get in your throat. Usually it gets in the throat, you would have strep throat for up to, say, nine days. After that, if you still have strep throat, if you haven't quite made enough antibodies to get rid of it, then it can move through the body and infect other parts, like the heart. And in that case, that can cause rheumatic fever, that even once you have cleared the streptococcal bacteria from your body, the damage to the heart valves and other things that go with rheumatic fever are with you forever, even though you didn't die. And unfortunately, if you get too far behind for too long, the pathogens can do so much damage to your body that the organ systems themselves can't keep up with their normal function, and you ultimately die. So the idea of vaccination is to stimulate this antibody production without giving you the downsides or much of the downsides of the infection, to find a way to get the antibody production going, to get it jumpstarted, so that you're already producing lots and lots of antibodies by the time your body comes in contact with this pathogen that can do all these bad things to you. So you're you prevent it another way from ever getting down that road, ever getting to the point that it's causing you symptoms, that you are getting sick and ultimately going through that process, right? So it's a little bit of a race. And of course, you want to engage in that race, engage in that natural stimulation of the immune system without causing a whole lot of damage or disfigurement or whatever to the person that you're vaccinating, right? They kind of defeat the purpose. So there's always been this thinking about how can we naturally stimulate the immune system without causing damage, and that's where vaccination in its various forms came to be. One of the really neat things about your body is that once it has started making antibodies on a significant scale, it remembers how to do that. It may not be making quite as much at any given time, but it has a certain cell called a memory B cell that just hangs out, floats around in your body, and it's ready to ramp up making all these antibodies at the first sign of the invader returning. And these are very long-lived cells. So once you get them there, you've got them in many, in some cases forever. So a vaccine or about with a disease can render you immune for the rest of your life. Now, that's really, really good if we have one exposure and you no longer get the disease. So, gee, wouldn't it be great if we could control this one exposure, make you immune to the disease forever, and then go about our lives not worrying about this particular disease. And that's really the story of vaccination. In historical terms, not every disease provoked as much interest on the part of people as others did. In the case of the story of vaccination, it is smallpox, far and away, one of the great scourges of mankind, one of the great epidemic diseases out there, and one that we have had in the modern era great success in eradicating with vaccine technology. But it is the story of smallpox that has driven much of the vaccine story historically. And so that's really what we're going to talk mostly about on this episode of the podcast. The first real vaccine concepts happened quite a long time ago. Certainly by about 1,000 A.D., the year 1000, there is an inoculation concept in the East. There is some debate among historians over whether it originates in China or it originates in India. It was not initially written down in a way that modern historians can trace back and say, okay, this particular guy came up with it on Tuesday. It was really a mixture of medicine and technique and magic and spells that were transmitted orally. So we have references to inoculation that go way, way back, but we don't completely know who invented it and when, right? It was about the year 1000. There were monks, a Taoist or Buddhist monk, possibly none, that would pass this down. The Taoists definitely practice it. But in China, this was going on for at least 500 years or so before it expanded outward in the case of smallpox and became the basis of the vaccination concepts that we have today. It was certainly a secret, orally transmitted. And generally what they noticed was if you take the scabs from the lesions that occur on a smallpox victim, smallpox typically has a disease progression where you get infected, you kind of feel bad, maybe a flu-like prodrome, and then certain pox sores start appearing on the body, and they appear ultimately all over the body. Those sores grow and disseminate, then eventually scab over. The scabs dry and do contain quite a lot of the virus, viral particles. If the antibody response in somebody who has smallpox gets ahead of it, those scabs will ultimately fall off. The lesions will shrink a little bit, they won't be as red, and they'll be a little bit smaller, but there may well be a scar at every spot that one of these lesions erupted. And when you're talking about smallpox, particularly a bad case, you know, you could have a thousand lesions. They can get on your eye, which would render that eye potentially blind. You have scars all over your face, all over your body. And so there was a lot of interest in this particular disease. People could see it, it occurs in waves, and while it's always been with humanity, smallpox tends to occur geographically. You'd see it in one town or one village, then the next one, and then the next one. If you survive a case of smallpox, it was also noted that as successive waves or epidemics of smallpox came through wherever you were, those that had had the disease before did not get it again. They had this immunity. So all these different things kind of go together to make it the disease that really drives the vaccination concept. Most of what we know suggests that the Chinese actually ground up these scabs that would come off of a smallpox patient and blow it into the face of somebody who had not had the disease. They would grind up the scabs into a powder and blow that powder in the face, and of course, exposing you. There are some reports that concubines of the emperor in China were some of the first people to undergo this procedure. And the thinking was, you know, smallpox has the potential to put these disfiguring scars on folks. And so if you're one of the emperor's concubines, the emperor doesn't really want you to be all scarred up, and you probably don't want to be all scarred up either. So that was the first group of people. But it was, it was fairly widely known later on. It was a widely accepted tradition. And secret or not, you know, the practice of this inoculation, also known as variolation, because the later name for the Pox Legions were Variola, travels west towards the Ottoman Empire certainly by the 1500s. It was in Constantinople, modern-day Istanbul in the mid-1600s for sure. And from there does seem to travel to Europe and northern Africa that comes in. For our purposes, looking mostly at the United States, there was an enslaved man named Wonsimus who told the Reverend Cotton Mather, the U history bus out there will recognize the name of Cotton Mather from the Salem witchcraft trials, but he described being inoculated by enslavers to resist smallpox and therefore be able to get better treatment during his enslaved period of time. Now, Cotton asks quite a lot about this and is very interested in this particular practice. He also talks with a local doctor in Boston, and between the two of them, they definitely promote inoculation and are doing this and have communicated this widely by the kind of famous 1721 smallpox epidemic in Boston. Now, you know, again, this is a known practice. It's in kind of folklore. Certainly in the Royal Philistines. Philosophical society, which is our equivalent or the historic equivalent of our modern medical societies, they have descriptions of a procedure known in Greece and Turkey in 1714 and 1716, respectively, where someone takes pus from the pustules of an active smallpox case, makes an incision on a healthy patient's arm, and then sticks the pus in there. That procedure was also referred to as inoculation, and tended to induce a milder case of smallpox that a patient was fairly likely to recover from and therefore be immune for the rest of their lives. Those descriptions indicate that the practice was common in sections of Africa and the Middle East and were around, but really didn't raise a whole lot of interest until certain physicians of Royal Societies in England, particularly a guy by the name of Dr. James Jurin, takes an interest in and they start doing some research and finding really the widespread nature of inoculation in the East. The next thing that happens that's really important for it around the same time in the 1720s, Lady Montague, Lady Mary Montague, who is a British socialite, is living in Constantinople with her husband, who is the British ambassador. She sees the practice of inoculation happening while she is there. And in 1721, she has her three-year-old daughter inoculated. The daughter does pretty well. It's interesting, she seems to do this without her husband knowing, but the husband finds out, and since his daughter was okay, he was kind of good with it. And so when they go back to England and especially Scotland, she asks for other people to be inoculated. And uh it becomes pretty clear from this experience and the study that physicians in the Royal Society had done that inoculation in a controlled setting and under the supervision of a physician was catching smallpox in what they called the natural way. So it became a little more accepted among the upper classes in Britain. The British aristocracy were known to vaccinate their children using this inoculation technique, and there were articles written about it that were shared throughout Scotland, England, and ultimately the Americas. Now, going back to the Boston area, Cotton Mather starts seeing these articles, and of course he's heard, as we said, the information from enslaved people. He urges a Boston physician by the name of Dr. William Douglas to give the practice a trial. Now, William Douglas at this time in the early 1720s is notable because he's the only person practicing as a physician in the area that actually had an MD degree. There were only 10 physicians of all the physicians that had an MD degree, and he was the only one around that was actually trained and had graduated from medical school. Now he was fairly conservative. He doesn't really want to experiment with a deadly disease, as you might imagine, particularly one that does have the possibility of killing the patient. But fortunately, there was another physician by the name of Dr. Zabadil Boylston. Now, Boylston has also heard about this. He talks about it with Douglas, talks about it with Cotton Mather. And in Boston in the spring of 1721, when the first vestiges of what would become a massive smallpox outbreak start appearing in Boston, Boylston, despite some opposition from other physicians and some clergy, and just several random people that lived in Boston and weren't really excited about this, Boylston does inoculate his own children and Cotton Mathers' children to protect them from smallpox. They all do pretty well and are protected as the disease spreads in Boston. Boylston and two of his colleagues in the same neighborhood inoculate around 300 people in Boston as the smallpox epidemic continues to grow throughout 1721. And it's important to note of those undergoing the practice, that is to say, those that underwent inoculation, six of them did die, or about 2%. Among those who acquired the disease, naturally without inoculation, the death rate ran about 14%. Now, Cotton Mather and his physician colleagues extensively documented this so they could show that inoculation could limit the ravages of smallpox when you had an outbreak. But the procedure does remain highly controversial. Not everybody wants it, right? Not everybody is really excited about subjecting themselves to infection with a disease that could potentially kill you. In this case, of course, of very small people, but people nonetheless did die from the inoculation. So there was a lot of debate in America's about this. In Britain, this discussion is really among the learned classes and the aristocracy, not among the regular folks, partly because of kind of the nature of society at that time. But in America's, it's a little more widely discussed across people. And so as other outbreaks happen in other towns, some of them offshoot of the Boston epidemic in 1721, different physicians say that this is a good thing that we should do. We should do it broader. We might put in these smallpox outbreaks. Other physicians say this is a procedure that controverts God's will. God wants to get it. And if you're going to die of smallpox, you know, that that's God's will. There were others that said it was dangerous because you could get smallpox from it, so and therefore unnecessary. There were ministers who said, again, that this contravenes God's will. And so it was a back and forth, but because it was not just the upper echelons of society, but the broader society as a whole that was involved in these discussions that had received this inoculation, by the time of the revolution, the concept of inoculation was pretty widely known and fairly widely accepted in the Americas. It was also, as we said, fairly well known in Europe and widely known in the rest of the world, but it wasn't really practiced on everybody in Europe like it was here in America. Importantly, after his son dies from smallpox in 1736, Benjamin Franklin becomes a champion of inoculation, trying to kind of settle the discussion. It's important to note that the smallpox outbreak that got his son, they saw it coming, as we said. It does tend to occur in geographic waves, and he had kind of discussed getting his son vaccinated several times previously, and they'd just not gotten around to it. Unfortunately, because they hadn't, his son died. So Franklin goes on to write several introductions to written works of the time about it. He in 1759 includes some numbers on the death rates of those who were variolated, who were inoculated, compared to those that weren't, and definitively shows even more proof that the risk of death was lower in those who were inoculated. And of course, by this time, Franklin has a pretty solid reputation of one of the most preeminent scientists, if not the most preeminent scientists of his era. So it really cements the practice in both Europe and North America that this is a thing to do, certainly to contravene, to react to the ever-present smallpox outbreaks that occurred, but also in general. And then, of course, the world in the Americas starts changing pretty dramatically around the same time leading up to the American Revolution. By the time of the resolution, as we said, it was pretty commonly known, pretty widely practiced across the Americas. In fact, it was more commonly practiced in the Americas than in Europe and on a broader swath of people, as we shared. The events start unfolding very rapidly in 1775, 1776, and some of those events include the formation of the Continental Army as well as the integration of militias from multiple states into activities again early on in Boston. And that's when George Washington, of course, is appointed commander-in-chief of all continental forces and heads to Boston to take command of this kind of loosely cobbled together army that would ultimately be the instrument of the revolution. He also had specific knowledge of smallpox. He had had smallpox as a younger man that he'd acquired on a trip in the Caribbean. So he knew how the disease would go, he knew how the recovery, if you did recover, would go. It's one of the little known facts, and something that we'll talk about in a future episode on this particular podcast, that when Washington takes over the Continental Army, the first orders he gives upon arrival outside of Boston are all public health orders. This is how you should organize a camp, this is where washing should be done, this is where latrines should be put, this is where cooking should be done, all of these kinds of things. These are the first orders that he does. And one of the things that really distinguishes the American Army from its inception, way out in front of the European military tradition, is that he makes the health of the soldiers a command priority, not necessarily just a medical priority, but a command priority. Officers are responsible for the health and well-being of their troops. This was a fairly revolutionary concept at the time. Remember, the British Army, and indeed most European armies, the officers came from the aristocracy. They may not have been the firstborn son of a given family that would inherit the title. They may well have been second, third sons that weren't going to inherit the title, but nonetheless came from affluent backgrounds. In England, typically you purchased a commission from the king, and that's how you became an officer, so you had to have the wherewithal to do that. Again, certainly senior aristocrats were oftentimes put in command of things, and what station you are within the officer corps was very much a function of your social status. Whereas the enlisted, the regular troops lined up on the battlefield, they were the exact opposite. They weren't even really the middle classes such as they were, or the working classes of which they were a lot. They were excess population. These were people that were not necessarily needed on the farms to keep the food supply going. They were not necessarily craftsmen that were needed to make the things later, those that were needed to work in factories. So these were oftentimes really the dregs of society. They were enlisted for long periods of time, and European military discipline was very, very, very harsh. Generally speaking, the thinking was that you have discipline so harsh with capital punishment for sure, but whippings and beatings and all this, that a soldier would march forward into battle facing the uncertainty of the battlefield, because even that was a less certain death than not doing what your officer said, to which you would be immediately shot or beaten or so on. So they didn't really, as a group, care about the health and welfare of their soldiers beyond, well, I need so many soldiers today. It was not a command priority. The medical officers, such as they were, particularly in England, did take care of soldiers, and it was kind of just, well, that's one of those things we'll shuttle off to medical people. Whereas Washington very much believes that this is a command priority. And in his first significant winter encampment in Morristown, New Jersey, after a very difficult fighting season that ultimately did result in a few Washingtonian victories, but being pushed out of New York and a lot of areas and losing several battles. In the winter encampment, Washington and his staff get word that yet again there are waves of smallpox that are coming through the area. Again, not uncommon at the time. They tend to occur geographically, come in waves, and the towns, several towns over, we're getting in. So he makes the decision to have his entire army vaccinated. And he does this knowing that some of the soldiers will die, but if he doesn't, most of the soldiers may die. He doesn't know exactly what number, but a lot. And he has come to the realization that without the Continental Army, there is no revolution. There is no future United States. The Army has to continue to exist. So he looks at these public health interventions from that perspective. This is necessary to ensure that the Army continues to exist. And so he sets about an inoculation process there in his winter encampment in Moristown, New Jersey. And it was widely successful. He doesn't have much in the way of death, which works out to be pretty good all in all. But remember, he has to do this not only in a winter encampment in an undersupplied army, he has to do it in complete secrecy. Because if the British find out that Washington is inoculating his army, they would know, gee, all the army would be sick all at the same time. We'll just swoop in and kill them all, and that'll be that. So he has to do it in such a way that those in the surrounding communities do not find out what is going on. And he does it. The British, on the other hand, they know the same things. They do, as we said, know about this process, but don't really equate vaccination and general care of the health and welfare soldiers to be a priority for officers. So they don't inoculate their armies. And in fact, widespread inoculation in the European armies doesn't really occur for, in some cases, another hundred years, whereas it is really ubiquitous in the American Army, starting here at the Revolution and continuing on to today. It never really fades out. So it's pretty common. There were continued discussions, and different towns look at vaccination. I mean, without a doubt, smallpox is the most feared disease in the colonial period, and it really inspires a lot of what would become public health measures. There are, because of the hazardous, some debates as to whether you should universally inoculate people or should just wait till you know a outbreak, an outbreak of a disease is coming. But this process continues both in society and in the Army across the Americas. And in that case, in that sense, America comes very uniquely a vaccinating population, which was unlike the broader population in Europe. Now, by the late 1700s, our more modern concept of true vaccination, not inoculation, comes to be. Edward Jenner observes that milkmaids and other folks that had been previously exposed to, or in some cases, infected with cowpox did not seem to develop smallpox when waves of smallpox come through a given area. He really notices that milk manes in particular seem to have very fair skin. They don't seem to have much in the way of these smallpox lesions, which were very, very common. And of course, once you've got this scar in your face, right, it lasts forever. The cowpox disease does cause some lesions, but they're localized. The disease is really much, much, much milder. It's not considered deadly at the time. So he starts looking and sees this pretty common practice of inoculation. So he devises a series of experiments in which a person who had not had smallpox, nor cowpox, would be first inoculated with cowpox, allowed to recover. And again, this is a very mild disease. They may not really show much in the way of symptoms, and then later be challenged or attempted to be infected with smallpox. Now, this is a little bit of a gamble. Remember, germ theory of disease won't happen for another hundred years or so until 1878 or so. There's really not much understanding of what happens microbiologically or immunologically, but there is an understanding of this disease clinically. They know the process, they know the lesions, they know somebody who's got it, they know where to get this material. And so this is a pretty significant gambit. I mean, if you think about what Jenner was doing, he does it to his own kids and he does it to community people. Certainly, this is probably research that would not pass IRB or other scrutiny today, but the subjects of these experiments do generally show this mild cowpox reaction. And then later, when challenged with smallpox, showed no reaction nor disease when they were inoculated. So Jenner's the one who writes up this concept of true vaccination, where you're giving somebody something to stimulate that natural immune response, except it is not the thing that causes the disease. So you won't get the disease that you are protecting someone from from the exposure, right? So rather than inoculation, where I am intentionally infecting you with a disease-causing agent to give you a milder case so that your likelihood of getting better is greater. In this case, I am exposing you to something that does not cause the disease, but does stimulate that antibody reaction. Now, again, they don't know about antibodies, but they do know that after Jenner, that cowpox will stimulate people in such a way that they won't get smallpox. And so that is really the first true vaccine that was not a straight inoculation. For almost 80 years after his experiments, cowpox vaccination against smallpox remains the primary vaccine that is in use around the world. Science and technology just really weren't to the point where they could understand the microbiologic basis and therefore the cause of agents of several other diseases. So there really wasn't the knowledge base needed in many cases to create a vaccine for other diseases, although some people did try. One of the people that most famously tries is Louis Pasteur, much, much later after Jenner. He had been experimenting, as many people know with microorganisms, for lots of things. He was also a very detailed record keeper, so we know quite a lot. He develop both an animal vaccine and a human vaccine. He works most famously at first on chicken cholera and finds a way to give chickens exposure to milder forms of disease and prevent chicken cholera, which would destroy flocks, which was a significant threat to the food supply in France at the time. But what I think he's most known for in the vaccination sphere was his work with rabies. Rabies was of great concern in European cities at his time. Rabbit animals from the forest would bite and infect kind of the roaming street dogs or cattle or other animals that were around. Remember, this is a time, unlike today, where animals and humans occupy very, very close quarters. It's not uncommon at all for people to have animals sleeping in their house or sleeping in the same vicinity animals. And this is not like my dog getting up on the bed and sleeping. These are the farm animals. These are all kinds of things, you have sheep and ducks and cows, and they all may be in the same structure. So these animals would get rabies from, usually from wild animals in the forest. And then, of course, there's really no effective treatment for rabies at that time. Even today, it's a very difficult disease to manage. And so people would then be bitten by these rabid dogs or exposed through cattle or whatever. They would develop rabies, which is a really, really difficult way to go. Again, most people don't know a whole lot about the natural history or certainly the viral origins of this disease. And so there's a lot of fear around rabies. And Pasteur theorized that something in the saliva of rabid animals caused the rabies, although he couldn't at that time see the rabies virus. Now there were some early microscopes that existence, but the rabies virus is too small for them to see. He proves the disease is communicable and he gets to work on a vaccine. Now that work involved exposing animals to small doses of rabies, much like virulation that had happened in the past, although interestingly, this did not work. The rabies virus was just too infectious, too virulent, it really causes a lot of disease. As a result, Pasteur approaches the problem differently. He sets out to come up with a way to weaken the infection agent somehow before giving it to a person. So rather than taking it from another person or from an animal, as had been done in the past, he wants to take these samples, process them somehow, and then give it to someone. It was believed that drying the material might make it less virulent, again, with smallpox virulation. Some versions did involve taking scabs and drying them and then using that to generate an inoculation. So there was kind of a basis. So Pasteur tries with the brains and spinal cords of affected rabbits, infects them with the rabies virus, and puts them down, dissects them down, gets the brains and spinal cord, pulls them out, drives. It was certainly understood by Pasteur and others that at least some point in the natural history of rabies infection, it attacked the central nervous system of animals. So even if he couldn't see the virus, he could see the damage. So he would take these dried brain, dried spinal cord uh products, and then give them to another rabbit. And he did this successively, right? So he he takes it and he gives it to a rabbit, and then he sees what happens, and then he takes that brain and spinal cord, dries it, and gives that the that. So he goes down the line and keep repeating the process with a third, fourth, down it. Now, later down the chain, the rabbits that had gotten extracts of brain or spinal cord that had been from the fifth rabbit or the sixth rabbit that was infected didn't seem to be getting sick, but they also resisted any attempts at infection through fresh specimens of saliva. So you could give them these dried brain or spinal cord extracts and then challenge them with the saliva of an infected person or infected rabbit, and the rabbit would not get sick. So he thinks that this is the answer. If you take it and you do these kind of serial infections in laboratory animals, you can create a concoction of rabbit brain or rabbit spiranal cord that will stimulate resistance to the disease without killing you. That's really good. So before he goes public with his findings, Pasteur, very much like Jenner, takes a gamble and he exposes human subjects to the dried material in his experiments. He started with a dried brain spinal cord from the last rabbit to be inoculated. And he definitely starts seeing a similar effect. He kind of works backwards. He doesn't really know how many series of infections of rabbit to rabbit to rabbit it takes. So he does do some experiments before he publishes, looking at, all right, well, this is one from the fifth rabbit in the chain, and this was one from the fourth rabbit in the chain, this is one from the third rabbit in the chain, and so on. The most well-known human subject was a guy by the name of Joseph Meister, who was a young man that had been bitten by a rabbit animal to save Joseph's life. You know, the physicians basically allowed Pasteur to do whatever, including this procedure, because they all knew there's no real cure, there's no real treatment for rabies. Joseph was certainly going to die, and it's, like we said, a really not bad death. So after the expected incubation period, he was going to be watched. So Pasteur gives him a rabbit pre reparation, and then after 21 days, he noticed that Joseph didn't uh develop any signs or symptoms of the disease. So Pasteur's vaccine was successful not only at preventing it before exposure, but immediately after exposure. And this is the hallmark to the way we use rabies vaccine today. If you're bitten by an animal, you may well get rabies vaccine after the bite to ensure that you don't develop rabies, which we don't still to this day have a whole lot of therapeutic options for. Other people at high risk for rabies exposure, like veterinary folks, uh, tend to get it preventively. Military folks that go to areas where there are quite a lot of rabid animals around get it. That's when I personally got the rabies vaccine. It was before a trip to Africa where there was an area there's a lot of wild, naturally occurring rabies. But in this case, it was very clear that Pasteur's technology was a success. This is the first time where a scientist uses an analog to an infectious agent that they hadn't made, right? So Jenner makes a leap of cowpox for smallpox, and Pasture makes rabies vaccine less virulent or what we call attenuated. And then other vaccines were developed, and many of our vaccines today are live attenuated vaccines. We have lots of ways of taking a pathogen and making it defective. We can do this genetically or so on, or in some cases killing it. Traditionally there was heat killing, but there's chemical killing so that the viral particle or the bacterial cell is still intact and will stimulate an immune response, but it is not alive so that it will not cause the actual disease. We can weaken them, as we said, so maybe they are alive, but they don't infect cells particularly efficiently. So we can stimulate the natural immune processes very, very quickly without putting somebody at much risk of disease. And these are the ways that vaccines come to be. Now, in the modern era, you know, as we go forward in time, we start looking at more and more pathogens. Some of them we have to attenuate to get worse. Some of them they come up ways to kill without developing the disease. So you're going to kill this germ, but you're not going to break it down so the immune system still responds to it. It's important, I think, historically to note that while this is widely known, really from the Jenner era on, where we have true vaccination, remember he's using cowpox, there was still a lot of debate. A lot of people were not really excited about it, and they were coming up with every excuse in the book not to get this. There's some really funny cartoons describing Jenner's findings, where people have cow heads growing off of their body where at the site where he vaccinated, you know, the name vaccination, vaca is Latin for cow. So he had variolation from the variola, which is the Latin name for the pox itself, and now vaca because it was the cow pos of vaccination. But a lot of this, and it was for a lot of the same reasons. People were afraid, they didn't understand, there were any number of folks. Remember, this is an era before the Food and Drug Administration in the United States and comparable agencies in Europe that wanted to sell their usually ineffective compound to deal with whatever illness. So if you were getting vaccinated and no longer cared about smallpox, you know, you're not going to buy Dr. Smith's snake oil or whatever it is to treat or protect yourself. And so they would come up with what we now would call misinformation or disinformation about these things to try to get you to avoid using vaccines. By 1806, French Emperor Napoleon Bonaparte and American President Thomas Jefferson both acknowledge Dr. Jenner's work and endorse the smallpox vaccine. And really from that time forward in the United States, a reservoir of smallpox vaccine is maintained by the federal government. This definitely is thought of as a governmental, a public health effort. And local physicians and later local health departments could then send off to the federal government to get this material and set up localized inoculation procedures if they need to. And of course, the number of vaccines developed start to grow. And so in a subsequent episode, Vaccination Part II, we'll talk about the use of these vaccinations once the technology is worked out, as we've talked about today, and the broadening number of vaccines and how it changes public health policy. This increasingly becomes thought of as a governmental responsibility, as we say. It affects wars, particularly World War I, but also other things like the Civil War and certainly World War II. We start seeing broader and broader swaths, and then we see other disease outbreaks that come along, and really vaccination saves the day. It's important to think, as we close out this episode, that smallpox episode smallpox vaccination in different forms continues to be used throughout the United States and indeed the world up until the post-World War II. After that, there's so little smallpox in certain countries that smallpox vaccination isn't widely done any longer. And the United States is among these. And large international organizations like the World Health Organization, which now exists at that time, start certifying countries as smallpox-free. And so they can start getting away from routine or regular vaccination, although most of the countries do maintain a reservoir. This continues up until the 1970s, where the decision is made to eradicate smallpox from the world itself. In 1967, global max vaccination from the World Health Organization begins with the specific intent of eradicating smallpox. More than 30 countries, many of which no longer have smallpox within their own borders, commit and sign on to this. At that time, of course, we said it's been mostly eliminated in Western Europe, North America, and Japan by that time. The WHO defines it as a permanent reduction to zero of this specific pathogen, the result of a deliberate effort, no more risk of reintroduction. So they very much change to try to eradicate smallpox, other diseases they start looking in, and then they go once we've had broad, then they start doing what we call ring vaccination, when a case pops up, and cases were occurring in more and more remote areas by the 70s. And so you had teams out looking for these cases, and what they would do is they would vaccinate all those people around the location where that case was so that it would not spread. And that happens until again the late 1970s, and then you stop seeing any cases of smallpox. The last case was in the late 1970s. And in 1980, uh the World Health Assembly, acting on a recommendation from the World Health Organization Global Commission on the Eradication of Smallpox, declares smallpox eradicated. The first time that we have truly been able to intentionally eradicate an infectious disease from the earth. And there was a lot of debate at the time. Should we keep smallpox virus around? Do we really want to be responsible for completely destroying a species? There's a lot of people said, well, even though this is a species that's really bad for humanity, we don't want to eradicate a species. There was some fear, rightly so, that smallpox could be made into a biological weapon, especially when we had large swaths of the population that were, again, vulnerable because vaccination had stopped. And so, in kind of a Cold War peace way, it was agreed upon that there would be two labs in the world that kept stocks of the smallpox virus around for research purposes. One would be the U.S. CDC in Atlanta, and one would be in a comparable facility in Moscow. To this date, those are the only two official stockpiles of smallpox virus anywhere in the world, and they are used to continue some research under very tightly controlled conditions, although many folks have theorized that there may be illicit stocks used in rogue nation biological weapon programs, but we haven't seen those weapons with smallpox in particular utilized in the modern era. So this is really a milestone from inoculation, variolation all the way up through vaccination, attenuated modern vaccines, and the eradication of disease and the prevention of untold human suffering all through these scientific and public health efforts. In a future episode, so we're going to talk about some other vaccines and how they have worked and where we have fallen short of the success of smallpox vaccination in the world. So until next time, stay healthy and we'll see you on the next episode.