Dan Snow's History Hit - Vaccine Roll Outs: Tragedy and Triumph

Episode Date: November 23, 2020

Paul Offit is on the US Food and Drug Administration's advisory panel on vaccines. He talked Dan through the history of massive public vaccination programmes in the US, starting with the unprecedented campaign against Polio in 1955. During that vaccination 200,000 children were a form of the vaccine in which the live polio virus had not been sufficiently inactivated and 40,000 of them got polio leading to 10 deaths and 200 cases of paralysis. That 'Cutter Incident' led to the birth of a modern vaccine regulatory framework and far safer vaccines, although, as he points out, vaccines can only be pronounced truly safe when they have been put into enough humans for enough time. This was a fascinating discussion about a topic that could not be more central to the our conversation at present. And yes, Paul will be taking the vaccine.....Subscribe to History Hit and you'll get access to hundreds of history documentaries, as well as every single episode of this podcast from the beginning (400 extra episodes). We're running live podcasts on Zoom, we've got weekly quizzes where you can win prizes, and exclusive subscriber only articles. It's the ultimate history package. Just go to historyhit.tv to subscribe. Use code 'pod1' at checkout for your first month free and the following month for just £/€/$1.

Hi everybody, welcome to Dan Snow's History Hit. Things are getting exciting. I'm talking to you on Monday the 23rd of November 2020. We've just had the preliminary results announced from AstraZeneca and Oxford University's vaccine for COVID-19. They look fairly optimistic, thus joining two other companies who have announced results. We are expecting vaccines to be delivered into the arms of people before the end of December 2020. That's a record, folks. It's a record from identifying a virus to having a vaccine to deal with it in less than 11 months. I was joined on this podcast by an absolute card-carrying legend, Paul Offit. He's an American pediatrician. He specializes in infectious diseases vaccines

immunology virology got all that he's the co-inventor of a vaccine i mean that's big time the co-inventor of the rotavirus vaccine he's a professor at the perilman school of medicine at the university of pennsylvania he is a member of the center for Disease Controls, the CDC's advisory committee on immunization practices. He's a total dude and he's also a wonderful scholar of the history of vaccination programs in the US and around the world. I want to talk to him about the huge campaign to immunize kids against polio, the tragedy and the triumph of that campaign that saw unsafe vaccines given to hundreds of thousands of kids whilst millions more were successfully vaccinated. It feels like an important time to be talking about the history of vaccine development, safety, rollout everybody. Here we go, enjoy. If

you want to go and watch as many history shows as you can possibly stomach, go to History Hit TV. It's like Netflix for History, a new digital history channel we've got going on. It's all kicking off over there at the moment. It'd be great to have you subscribe. Use the code POD1, P-O-D-1. You get a month for free. Your second month is one pound, euro or dollar. Inoculate yourself against boredom by heading over to History Hit TV so you can watch history documentaries. There's also something of a debate has broken out on the Twitter feed. I mean, I'm surprised it's happening. We're selling out of knight's helmets at the moment, knitted knight's helmets, but we've been told they are not knitted knight's helmets. They are in fact crocheted knight's hats. You can get involved

in that debate if you want at history.com slash debate. It's a thing that is now happening, apparently. But in the meantime, everyone, enjoy Paul Offit. Paul, thanks so much for coming on the podcast. My pleasure. It's a huge day. It's a huge month at the moment for vaccines. We'll get on a bit more to the contemporary scene in a second. But let's go back. Let's talk about polio, just how much of a specter. People have forgotten today what polio was like as a haunting prospect in the mid-century, mid-20th century everywhere in the world. Yeah, I mean, I think there are many parallels, actually, from the polio story in the mid-50s to

today. One is parents were scared to death of this virus. I mean, it could paralyze 30,000, 40,000 children a year. It could kill 1,500 children a year, this virus. And what made it particularly heinous, aside from its unique capacity to permanently harm children, was most of the transmission was asymptomatic. You didn't know who you were getting it from, just like SARS-CoV-2 today, where you don't know really where it's coming from. So therefore, you're scared of everyone. The second thing was that in the race to make a vaccine, that was really warp speed one, because basically, it wasn't the government, but it was the March of Dimes in the United States,

the so-called National Foundation for Infantile Paralysis, that said, we'll pay for the phase three trial. We'll pay the millions and millions of dollars for a phase three trial. We'll pay for five companies to make it at risk, not knowing whether it's safe, not knowing whether it's effective. We'll pay for all that. That's what speeded it up. The same reason that this has been speeded up. So there are definitely parallels. And it was a shared national tragedy that was handled that way.

My mom's family were in Toronto in the 1950s and got wiped out from one dinner party. Several members of the same family developed terrible lifelong, one died and several developed lifelong complications as a result of getting polio. It seemed that there were surges of polio. Does it work like a pulmonary pandemic? Does it kind of come and go or was it just there all the time? No, polio was there all the time. There were three different strains that caused polio. And sometimes one or another strain circulated, but there was polio every year. Every summer, bent polio in the United States. I mean, it started to really rear its head in the 30s and 40s with industrialization, actually, is what happened.

I mean, polio was always around. And what would happen is, you know, everybody got infected. Mothers got infected. They would passively transfer their antibodies that they had from that infection to their newborn. And then because newborns or kids in the first year of life or so would get exposed to polio, it was sort of like this passive active immunity. The antibodies from their mother protected them. And then they would get this active immune response from the virus itself. So they were protected. What happened with industrialization is that the incidence of

polio then started to decrease as people were sanitation improved. So now you weren't exposed to polio until you were five, six, seven years of age and the antibodies you may have gotten from your mother had gone away. So that's when you saw the five to nine year old outbreaks of polio. And what happened in the mid-1950s? Why was there such an effort around this vaccine push? Was it the technology had changed? The money became available? What was it about that key period? Well, the technology had changed. The thing with polio is it reproduces itself in nervous system cells, like cells of the brain, cells of the spinal cord.

If you make a vaccine using cells from the brain and spinal cord, you always run the risk of inducing an immune response against the protein that sort of serves as the sheathing of nerve cells, you know, like the rubber sheathing of a wire, an electrical wire. And so a protein was called myelin basic protein. So when you inoculated people with that, with this sort of nervous tissue-derived poliovirus, you could induce this immune response against your own nervous system, essentially, which could cause paralysis. It could cause coma. It could cause death. It was a problem.

So that was solved by a group at Harvard headed by John Andrews, where they showed you could grow poliovirus in non-nervous system cells, cells like monkey kidney cells. You could grow poliovirus in non-nervous system cells, cells like monkey kidney cells. And with that, you could now, that sort of opened up the field to be able to make a vaccine by the early 50s. And are those breakthroughs taking place? Is there government involvement? Is there government leadership in those vaccines? Or is this just departments at universities, specialists just pursuing this for their own

research interests? You're talking about with polio or today? With polio. No, well, I mean, there were polio vaccines 20 years before the Salk vaccine in the 1950s. In the 1930s, there were two polio vaccines, one made by Maurice Brody in New York, the other by John Comer in Philadelphia, which failed. They actually caused polio because in both cases, although they tried to inactivate the virus with a chemical, in both cases, they failed. They actually caused polio because in both cases, although they tried to inactivate

the virus with a chemical, in both cases they failed. So there were children who got that vaccine who got polio from the vaccine. That set the program back about 20 years, really. Wow. And then we get the great success of this polio vaccine in the mid-1950s. How big was that national immunization push? It was huge. First of all, the study that was done involved giving 420,000 children the vaccine, giving 200,000 children placebo, and then 1.2 million children served as observed uninoculated controls. That was a 1.8 million child study. No medical product, I think, has ever been tested at such a level. I mean, honestly, I think if a 1.8 million child study was done today, I think we'd cost $6 billion, really. And we mass, you know, five companies stepped forward

to mass produce it at risk. It was just an amazing national effort. And it was truly national. I mean, the March of Dimes was a private philanthropic organization where people would send their dimes in to support this. It was our vaccine. It was America's vaccine. It was the American public's vaccine,

even more so than pharmaceutical companies. We paid for that vaccine. And so we felt it was our vaccine. And then there was, however, when you mentioned these private companies that were helping to mass produce it, there was one disaster. Right. So five companies were selected to make that vaccine. One company, Cutter Laboratories of Berkeley, California, made it badly. What they failed to do was they failed to fully inactivate the poliovirus that was in the

vaccine for a number of reasons. And what happened then was that about 120,000 children in the West and Southwest were inoculated with live, fully virulent poliovirus, thinking it was a poliovirus vaccine. About 40,000 of those children developed abortive or short-lived polio, meaning transient weakness, transient paralysis. About 164 were permanently paralyzed and 10 were killed. I think it was the worst biological disaster in this country's history. And it wasn't just Cutter. Wyeth Laboratories also made a vaccine that paralyzed and killed children, just not nearly to that extent. I think more reasonably, it could have been called a scale-up incident. We just weren't

very good at going from sort of 10 or 100 or 1,000 doses to tens of millions of doses. That's the hardest part of vaccines. I mean, as many people say in the vaccine world, the hardest part of making vaccines is making vaccines. I mean, you have to scale them up and make sure that it looks exactly like it did when you were working with it in your laboratory. And that's hard. Well, that seems like a fairly important lesson from history today. Let's talk about what the impact, the legacy of that terrible, the Qatar incident. What was the effect that that had on public health policy and delivery in the US and elsewhere? It was the birth of vaccine regulation in the United States. We went from about 10 people in the federal government who oversaw vaccines to 150 within

a very short period of time. It was the birth of something called consistency lots, which still exists today, where you show you have to make a certain number of lots of vaccine that have the exact same biological characteristics. See, the hard thing about making vaccines is they're biologicals. They're not small molecule drugs. I mean, if you make, for example, amoxicillin, it's very easy to say, I have 50 milligrams of amoxicillin in this tablet from this batch, and 50 milligrams of amoxicillin in this tablet from this batch. But biological is really the process is the product. And so it's the process that gets regulated. It's hard to characterize it otherwise. So therefore, a whole new regulatory system is introduced as a result of this.

That's right. It was the birth of vaccine regulation in the United States. And as is invariably true, there's a historian named Michael Harris who said that the history of drug regulation is built on tombstones. And that's always true. Now, what effect did that have on the public? I mean, is this the beginning of a sort of a mistrust of scientists, a mistrust of big government regulation, the anti-vax movement? Was Qatar instance important in that respect?

Interestingly, not at all. Qatar went to court. I mean, obviously they were held accountable for their tragic mistake and they went to court again and again. But if you look at the exit interviews with the people who served on juries, they actually wanted to find Qatar not guilty or not negligent. The reason being that they thought it was a process of evolution. The defense explained correctly that it wasn't only Qatar that had a problem, that all of the vaccine makers had difficulties in activating the virus on a mass scale. And so the jurors intelligently reasoned that this was a evolutionary process and that we just hadn't gotten to the point of evolution in the science to be able to say that Qatar in sense, knowingly made a mistake.

You know, the safety tests weren't really there yet. The capacity to mass produce consistently wasn't there yet. It just wasn't there yet. And the jurors realized that. And it had very little impact, I think, on the public. The public generally trusted pharmaceutical companies. I know it's hard to imagine there ever was a time like that, that basically the public believed that the pharmaceutical manufacturers were doing the best they could. And in fact, I mean, the people at Qatar Laboratories who made that vaccine gave it to their own children. They didn't think anything was wrong, obviously. Land a Viking longship on island shores, scramble over the dunes of ancient Egypt and avoid the Poisoner's

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There was a vaccine in the late 1990s to prevent a virus called rotavirus, which is a common cause of fever, vomiting, and diarrhea in babies, that was found to be a very rare cause of intestinal blockage called intussusception. This vaccine was on the market for about 10 months when it was very quickly found to cause a problem, and then it was off the market. And that's really been it. In terms of safety, that's probably been the only real safety issue. Even there, the incidence was about one per 30,000 vaccinees. And certainly far more children died, even in the United States, every year of rotavirus than would have ever been hurt by that vaccine. But nonetheless, we were intolerant of any severe side effects, so that vaccine came off the market till it was replaced by a better, safer vaccine seven years later.

by a better, safer vaccine seven years later. So that does sound like, though, that there is still, there's still no, well, you tell me, there's no magic, there's no silver bullet on vaccines. A lot of this is just observing its effect in human beings and then drawing judgment from that. It's always trial and error. You never know about whether or not something works

until you put it in people. That's always true. I mean, for people in the vaccine world, the old expression is mice lie and monkeys exaggerate. You never really know until you put it in people. And so how are you feeling about today? First of all, we heard so much, didn't we, at the beginning of this outbreak in January, February. What is the record speed at which a vaccine has gone from identifying the threat to delivery in the doctor's surgery? Right. So from having a virus in hand to a commercial product, the fastest vaccine would be the mumps vaccine, which was that virus was isolated by the researcher who made that vaccine, Maurice Hilleman, in 1963. That was then a vaccine four years later. But there were a lot of things you could do then that you couldn't do

now. I mean, you tested it in far fewer people then. You would test the vaccine in 5,000, 6,000 people before it would get a license. The licensing process was very fast. As I've seen from now, it's much slower. So this vaccine, I mean, this virus was in hand in the United States anyway and sequenced in January of 2020. This will be a vaccine, very likely, that rolls off the assembly line into the arms of the American public and the world probably by the end of December. One year. Remarkable.

And what about then, what about the safety? What about the fact that you haven't observed it in enough people? Are you feeling, has that speed, this is obviously the big question, but has that speed involved compromising on safety? So if you look at the size of the trials, Moderna's is a 30,000-person study. Pfizer's is a 44,000-person study. Johnson & Johnson is a 60,000-person study.

AstraZeneca also is in the tens of thousands. That's typical for any vaccine. That's typical for any vaccine. That's typical for any pediatric vaccine. So if that's true, why not just submit these vaccines for licensure like you always do and just get a biological license application like you always do and get licensed?

And the reason is, is the length of the trial. I mean, the human papillomavirus vaccine was a 30,000-person trial, but it was a seven-year trial. I mean, the rotavirus vaccine that we worked on at Children's Hospital of Philadelphia was a 70,000-person study, but it was a four-year study. But you're not going to do a three- or four-year study for this vaccine. I mean, when it's already killed, say, 250,000 people this year in the United States, you're not going to wait to make sure that it's effective not only for a couple months, which is what you're going to know. sure that it's effective not only for a couple months, which is what you're going to know. I mean, when Pfizer's vaccine, Moderna's vaccine, or AstraZeneca's vaccine, or Johnson & Johnson's

vaccine are approved through emergency use authorization, you're only going to know that they were effective for a couple months. You're not going to know whether it was effective for six months or a year. On the other hand, you're not going to test it for that long because you can't afford to. So are you taking a risk? Have you reduced a critical amount of uncertainty by saying, okay, I know it's effective for a couple months. Is it likely it'll be effective for six months or a year?

And I think the answer is yes. So then the question becomes safety. Well, the rule is, at least in the United States, that you have to test at least half of the vaccine group for at least two months after the last second dose or last dose. Is that enough time to figure out whether or not you have a serious side effect problem? If you look at the history of serious side effects from vaccines, and there certainly are serious side effects from vaccines, like, for example,

a disease called Guillain-Barre syndrome, which is this ascending paralysis that occurs in roughly one per million doses of influenza vaccine, or narcolepsy, a disorder of wakefulness that was caused by a squalene-adjuvanted influenza vaccine that was given in Europe during 2009, 2010. Or polio, caused by the polio vaccine. Albert Sabin's oral polio vaccine, roughly one per every 2.4 million doses, was complicated by paralysis. The measles-containing vaccine can cause a lowering of the platelet count, which can cause you to have these sort of little showers of broken blood

vessels. The yellow fever vaccine can essentially cause something that has a fancy name of viscerotropic disease, which is a nice way of saying yellow fever. I mean, the yellow fever vaccine is a rare cause of something like yellow fever. That too occurs roughly one per million doses. All of those awful side effects occur within six weeks of getting a vaccine. So I think by waiting two months, you have, again, reduced a critical amount of uncertainty. Plus, you know, you are going to have systems in place like the Vaccine Adverse Events Reporting System in the U.S., the Vaccine Safety Data Link, something called V-SAFE, which is an active program that's run by the CDC where you call people on their phone to make sure that they're okay after they've gotten a vaccine. So I think that we have reduced a critical amount

of uncertainty by bringing these vaccines even this quickly. The reason it's so quick is that the pharmaceutical companies basically had the risk taken out of it for them by the government. I mean, the government said, we'll pay for phase three trials, we'll pay for mass production. I mean, companies would never do it that way. The companies would say, we'll do the phase three trial, and if it works, then we'll mass produce it. We're not going to mass produce it at risk. So the interesting thing is for an idiot like me, I assume maybe there was some like supercomputer that was just crunching data quicker. Have we reached the inelastic point past which we're not going to get more speedy vaccines, because we've got to let this work through these human trials. That's correct. You always have to test it. You have to do that. You

can't get to the point, I think, where you have a computer simulation, at least not now, where you say this is I can now accurately predict that this will work in X percentage of people. It'll be this percentage effective. It will have this safety problem that's occurring at this rate. We're not there yet. No. And so historically, what will be the legacy of what do you think the legacy of what is what we're going through at the moment? Is it just a lesson in what can be what can be achieved when you apply an unlimited amount of money to a traditional practice, creating vaccines? Or has have we have we pioneered new ways that will be deeply significant the next time we get one of these pandemics? I think both. I think the amount of money we put into this dramatically drove this

process to be much faster. And we'll see. I mean, you know, the messenger RNA vaccine that's being used, the DNA vaccines, these replication-defective human adenoviruses or replication-defective simian adenoviruses or these replication-competent other viruses that are being used as sort of a Trojan horse to bring that SARS-CoV-2 spike protein into the cell are all pretty novel strategies. I mean, there's no commercial experience with some of them and very little commercial experience with others and none in the developed world. So we're going to learn a lot, I think, over the next couple of years. I mean, if you take a step back, here's what you have. You have a bad coronavirus that just made its debut in the human population a year ago that has caused a number of things that no one would have ever predicted. You would

have never predicted it would cause you to, say, have a weeks-long loss or many weeks-long loss of smell, taste, which says that the virus at some level is going up into your brain, that causes vasculitis, meaning inflammation of blood vessels. And because every organ in your body has a blood supply, every organ can be affected. I mean, what respiratory virus that's typically a winter respiratory virus like influenza or parainfluenza or respiratory syncytial virus, that's how this virus was built. This virus was built out of Wuhan as a winter respiratory virus that causes pneumonia. It causes far more than that. It can cause strokes, heart attacks, kidney disease, liver disease. It causes a very unusual disease in children, this so-called multi-system inflammatory disease of children.

I've never seen that before caused by a virus. I mean, so you have this difficult to characterize virus, which already has a number of clinical surprises and pathological surprises that you are about to meet with a series of vaccine strategies with which we have no commercial experience. I think it's fair to say that we are going to learn a lot over the next couple of years. Some things we would have wished we knew now. So we have to be humble, be open-minded, that when you don't know things, you have to be humble and see how it plays out. You're going to get a vaccine, right? You bet. I mean, I'm a person of a certain age, i.e. over 65, who's at risk of this disease. I

mean, I want to see the data. I mean, right now we're in science by press release time. We will see the data. I'm actually on the FDA's Vaccine Advisory Committee. On December 10th, we will meet and we will go over Pfizer's vaccine. And I then will see all the data, actually before then, I'll see all the data. And so I'll have a much better sense of whether this vaccine meets up to its billing. Well, this is an audio only podcast, but I can tell you, listeners, that I am looking, I am looking at Paul right now. and i'll tell you he's not being honest with us because he's taken the he's taken the youth drug as well because he does not look like he's over 65 paul i think you've got some other drugs up your sleeve you need to approve

buddy um thank you very much for coming on this podcast you've you've been it's been incredible thank you for giving the historical context of this important moment thank you it's my pleasure i feel the hand of history upon our shoulders all this tradition of ours our school history our songs this part of the history of our country all were gone and finished and liquidated hope you enjoyed the podcast just before you go bit of a favor to ask totally understand if you don't become a subscriber or pay me any cash money makes sense but if you could just do me a favour, it's for free. Go to iTunes or wherever you get your podcast. If you give it a five-star rating and give it an absolutely glowing review, purge yourself, give it a glowing review, I'd really appreciate that. It's tough weather, the law of the jungle out there, and I need all the fire support I can get. So that will boost it up the charts. It's so tiresome, but if you

could do it, I be very very grateful thank you