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April 28, 2020

The artistry of vaccine development

By Conor McKechnie and Dodi Axelson

The artistry of vaccine development

Dodi and Conor chat with a scientist who fulfilled her childhood dreams, a professor with a passion for vaccine design, and a medical doctor turned pharmacovigilante. Tune in to learn what the heck that is and how vaccine development is like ballet.


CONOR: So, Dodi, what is that you're listening to?

DODI: Well, it's actually a video I'm watching of my childhood hero.

CONOR: Oh, sweet and who might that be?

DODI: The ballerina Merrill Ashley, because, you know, I bring up ballet as often as possible in every conversation.

CONOR: Well, I think a background in ballet, the precision and the artistry of it lends itself well to this kind of work.

DODI: Did you know what you wanted to be when you were a kid?

CONOR: I totally knew what I wanted to be. I actually wanted to be a milkman because I thought that the electric milk floats, which are what the milkmen drive in England, were the coolest things ever.

DODI: Always the visionary, Conor.

CONOR: I saw these milk floats. I thought that's the future. That's what I want to be.

DODI: Well, both you and I had our plan A when we were kids that have obviously become something different. Recently I was talking to one of our colleagues who actually has become the plan A she's had since her childhood. She was fascinated with viruses.

CONOR: So, in what kind of way? Like chicken pox and catching viruses, mumps and so on?

DODI: She's interested in how viruses work and what they are good at. I think we should find out more about this.

CONOR: So, I guess this is what matters on today's episode of Discovery Matters.

DODI: Viruses and vaccines.

CONOR: So, who talked so eloquently about viruses to you?

DARIA: Hi, I'm Daria Donati. I've been working first with cell therapies, so a new way of vaccinating, in my first PhD. Then, I moved on to infectious diseases and trying to find ways to prevent infections through vaccination. That's why I'm so interested in that.

CONOR: Okay, so when we typically think about vaccines, and obviously now we're thinking a lot about that, it's a shot in the arm or the buttock and so on.

DARIA: A vaccine is a way to educate our immune system to recognize foreign and dangerous stuff that can be viruses or bacteria. So, for me, vaccination is just a tool to give to our bodies to handle whatever can happen around us. The interesting thing in the immune system is that you can vaccinate people for many different types of diseases. Your immune system is just there to learn.

It's like when you tell people that children can learn many different languages until they're eight years old. They're not only able to learn one but even up to 10. And you just need to expose them to that. And that's the same with the immune system. The difference is that the immune system cannot only learn 10 different ways of reacting diseases, but many, many, many more. Actually, we don't know the upper limit. So, vaccination is a great tool to be able to do that.

CONOR: You could say immunizations are a way of teaching the immune system. So, even for the immune system, every day can be a school day.

DARIA: Definitely. And that's why I spend most of my life working on immunology and trying to see how our immune system can be educated.

DODI: Daria knows her stuff, and she explained to me the incredibly difficult and time-consuming process of bringing a vaccine to market.

DARIA: Everything starts with trying to find the right molecule or technology that you can use as a vaccine tool. That is a very complicated process, probably one of the most complex in the biopharma world. It takes a much shorter time to develop a generic biopharma product than the vaccine product. To bring a vaccine that is already discovered, a known molecule to market, takes up to 10 years. There are many different reasons for that.

Let's think about one major reason. If you have a terminal disease and you need to be treated, you are a sick person and the treatment is perhaps your last chance. So, you don't fear being exposed to a new treatment, and you go in with peace of mind trying to see if you have the opportunity to get cured. When you test vaccines, you test them on healthy people. So, you test a generic biopharma drug on a cohort, a group of people, 200 or 300, or in rare cases, even 20 people. But when you test vaccines, you usually use very large cohorts that are thousands of people.

CONOR: So, it takes 10 years to get a vaccine into market. And of course now we're in the midst of the COVID-19 pandemic, which is oddly ironic given that we've had this episode in the pipe for a good while. How is the industry looking to accelerate that process to shrink that 10 year timeline down to, in this case, months? Can it be done?

DODI: In theory, it can be done.

DARIA: We have been struggling in the industry, trying to reduce the time to market more and more. And in the past years, many, many companies have developed new technologies that would allow the vaccine to be sort of flexible. What does that mean? A vaccine technology, for example, viral vectors, can be used specifically toward a certain type of target pathogen, that will be a disease in larger layman terms. But it can be used as well to defeat another similar or nonsimilar pathogen. How do you do that?

Basically, in the case of viral vectors, if you have a carrier, a little car, where you insert genes that are very specific for an antigen, that is essential to induce an immune response against a specific virus. What if I'm in a condition and capable of changing the same genes expressed by using the same car, the same carrier, to be able to express an antigen that will target another type of disease? In this case, we have been trying to develop a platform of technologies that could, with time, address different types of diseases with the same background, so it's easier to go quickly into development and manufacturing.

CONOR: I suppose it can be done. And that's terrific. But should it be done faster on a regular basis for what you might call normal vaccines? Or is there a good reason for there actually being a really long timeframe to develop these vaccines?

DARIA: There are very good reasons for longer timeframes. And then we go back to the fact that vaccines are injected into healthy people. So, I think that the regulatory authorities have a very good reason to scrutinize very carefully. At the same time, I think they are demonstrating the willingness to evaluate these stringent regulatory requirements when it's time to respond to emergencies. And I think it is a dichotomy that really speaks to a good approach.

DODI: Okay, Conor, like you said earlier, we are right now in the midst of this COVID-19 crisis. We don't want to delve too much into the specifics there because that situation is changing every day. But we do want to track back to the history of vaccines and understand that better to get more insight into what Daria was talking about. So, we got ahold of this guy.

ADRIAN: I'm Adrian Hill. I'm the director of an institute here at the University of Oxford in England. And I'm particularly involved with vaccines. In fact, our institute is called the Jenner Institute after Edward Jenner, who was effectively the discoverer or the founder of vaccination, way back in 1796. Many years ago in the 18th century, when the first vaccine was discovered, Jenner noticed that milkmaids never got smallpox. So, thinking on that, he figured out that if he could take some of the smallpox fluid from a lesion on a milkmaid's hand and inoculate that into somebody else, they might be protected against getting smallpox.

And lo and behold, that worked the first time. He was lucky. He didn't know what the virus was. He didn't really understand what he was doing. But he produced something that was of enormous public health impact in a very short period of time. So, within five years, his vaccine was being used not just in England, but throughout Europe, in India, in Russia, and even in the United States. That would be very rapid today, let alone in 1796.

DODI: So, to oversimplify that story, Edward Jenner accidentally figured this out.

CONOR: That's right.

DODI: And I started wondering if that's the normal way to discover a vaccine. Are things happening by accident, or have we developed a much more determined and predictable process? Adrian actually answers that question.

ADRIAN: It's a much more scientific process with a lot more scientific understanding of what is going on, particularly in terms of the immune response that's produced by vaccines, but also in terms of the molecular and atomic structure of vaccines. So, these days we literally design vaccines at the atomic level, asking if this is the molecule we want to make an immune response against. Would it be better if we took out this part of the sequence? If we glued together at the atomic level particular domains of the protein and try to ensure the structure was fixed? That's now a standard part of molecular vaccinology. So, that's good news.

Of course, the bad news is that it takes a lot longer, and it's much more expensive and there are people in large pharma companies who will tell that you can't do anything with 100 million pounds to make a vaccine. You need an awful lot more than that, and you need 10 or 15 years on average. Sadly, that is generally right. One of the great topics of discussion these days is whether we can do this much less expensively and much more quickly. And that's been driven by the outbreaks that the world has suffered over the last 10 or 15 years, from swine flu to particularly Ebola. That was a great wake-up call back in 2014. To what we're experiencing as I speak, which is a growing global epidemic of coronavirus. It's a coronavirus we didn't know existed last December, and yet probably 20 different groups around the world are rushing to try and make a coronavirus vaccine in the next few months. And we might need billions rather than millions of doses of that vaccine.

CONOR: So, what does Adrian see happening in the future of vaccines?

ADRIAN: More and more we're going to be using and deploying therapeutic vaccines to treat diseases. There are vaccines and clinical trials to treat blood pressure, to treat high cholesterol, famously to treat Alzheimer's disease. That's proving fairly difficult. But also to treat other immunological diseases like psoriasis and allergies. These are making very rapid progress, and I have no doubt that those vaccines are going to be licensed in the next few years. And probably some of the biggest public health gains, certainly for older individuals, will be through this new approach of vaccinating to often treat rather than necessarily cure chronic disease. I'm convinced that this is the direction vaccinology will be moving in more and more over the next 20 years.

DODI: Right. After talking to Adrian and Daria, I thought, great, that's going to be a fantastic episode about viruses and vaccines. And then I happened to be on an airplane weeks ago before the COVID-19 crisis. And I happened to overhear somebody talking about how she is a doctor of infectious diseases and was on her way to a big convention to talk about viruses and vaccines. I just had to interview her. To be honest, this wasn't something that was planned.

CONOR: So, who is this? Who did you meet on the plane?

REBECCA: My name is Rebecca Chandler, and I am an infectious diseases physician turned pharmacovigilante. I come from the United States. But I met my husband who's German. It still doesn't make a lot of sense. But anyway, I needed to get to Europe and particularly to Sweden because he had gotten his PhD here. And I didn't know any Swedish, but I applied for a job at the Swedish Medical Products agency because they needed an infectious diseases doctor.

And I got it by some miracle. And to be honest, the plan was to work there and learn Swedish. Get my license and then go back to the hospital and take care of patients, because I'm a real people person. I mean, I love to talk to people. I love to hear their stories, but I didn't really anticipate how I would fall in love with this discipline called pharmacovigilance, which is really the overarching term for what I do.

DODI: She is a pharmacovigilante. Isn't that the coolest sounding superhero you've ever heard of?

CONOR: That is extraordinary. So, let her explain exactly to us what pharmacovigilance is and why it's important.

REBECCA: I spend my days monitoring the safety of medicines, vaccines, and other medicinal products. And I think it makes perfect sense that I love it, because so much of what I do is very similar to infectious diseases, particularly infectious disease epidemiology. I consider a safety concern, a safety signal, like narcolepsy, like an outbreak of an adverse event. It's very similar to an outbreak of a disease. So, it's something you don't expect. It's in a cluster of people. You've got to figure out, why did it happen? What caused it? And so the parallels are uncanny.

I think that's why I love pharmacovigilance in particular. I chose this field almost 20 years ago, and even back then people thought, we're not going to need infectious diseases doctors much anymore because we figured everything out. And you know, even in 20 years, so many infectious disease emergencies, if you want to call it that, have happened. We've had monkey pox, we've had SARS, and we've had MERS. Now we have coronavirus. We've had Ebola. It's such a social science, because infectious diseases are tied so closely to the way people behave and how they live.

DODI: And Rebecca mentioned adverse events and narcolepsy, so I asked her to take us back. In 2008, Rebecca started working at the Swedish Medical Products agency as a safety assessor. A year into the job we had the experience with pandemics and the safety signal of narcolepsy.

2009 NEWSCASTER: One rare, and we should emphasize rare, side effect of flu vaccines is starting to show up around the country. Dr. Jennifer Ashton is here to tell us all about it.

DODI: Do you remember this case?

CONOR: I do. As a matter of fact, fresh off the back of the 2008 SARS epidemic. Yeah, narcolepsy seemed to make a comeback, or there seemed to be a rise in narcolepsy in some places.

DODI: H1N1. Yeah. That's right. In 2009. A whole lot of young people started to suffer from narcolepsy out of nowhere. And some doctors started describing it as an epidemic.

CONOR: Did they get to the bottom of what was causing it?

DODI: It was swine flu. A vaccine had been approved for use for H1N1. It had been accelerated through clinical trials, and the manufacturer was given an indemnity by the UK government. 850 000 vaccinations. Think about the scale of that. So, children who were six months old up to 16 years were getting this vaccination. Then after the pandemic in 2010 en 2011 what happened, and this is interesting, is this vaccine that was used for H1N1 was used in place of the seasonal flu vaccine on a further 170 000 adults and children. And then doctors noticed an increased incidence of narcolepsy. So, they did a study and found that one in every 55 000 of these vaccines was associated with this adverse development.

CONOR: So, all of the people that had been given the vaccine, one in every 55 000 of those people, had some association with narcolepsy. It doesn't sound like a lot. But you know, it's more than you would really accept as an adverse event in a mass vaccination campaign.

DODI: So, Rebecca takes that up again.

REBECCA: That really changed my life as an infectious diseases physician turned regulator. It was very interesting to go from a situation where infectious disease doctors think about vaccines as one of the greatest medical interventions possible, which they are, but to have an experience where we see that there are instances of harm. That was a turning point for my career, to really spend my life trying to understand, why do vaccines cause harm in a few people?

DODI: I think it's important to note that it is so important to consider safety and that developing vaccines is overall better than not having a vaccine.

CONOR: So, just in case anyone thinks that we're going anywhere near anything that's remotely smells like a debate about the value of vaccination... Vaccination is the single biggest, most important health intervention that you can make in a population's health. So, let's not be coy about that, right?

DODI: Utterly. And it's a huge issue. So, somebody like Rebecca has to consider on a daily basis how to prioritize what to look at.

REBECCA: Typically, when regulators need to focus on a vaccine or a drug or a public health issue, we will prioritize based on the newness of the product. I just spent a couple of days reviewing all the reports in our global database for a new malaria vaccine that they're piloting in three countries of Africa. So, that comes under quite close review. You can prioritize by the drug or the vaccine, but you can also prioritize by the event. You might want to look in your database for all serious adverse events. When we talk about a harm from a drug or a vaccine, they're usually classified as nonserious or serious. A serious event would be one that resulted in hospitalization, caused a death, or caused a congenital malformative malady. So, you might prioritize how to look at harms based on the seriousness of the event.

DODI: That's how Rebecca considers what's important. And I think, Conor, this is what brings us back to what we were talking about at the beginning here, you know, considering viruses and vaccinations, Really, you have to be an artist, you have to be a ballerina. Somebody like Rebecca, somebody like Adrian, somebody like Daria, they are training day in and day out. They are constantly learning more about viruses, constantly trying to develop vaccines. There's always something better around the corner, and it is a never-ending process of being a great artist.

CONOR: Okay, I get it. So, it's about putting in the hard work that makes you good at what you do. It's about dedication and commitment to a cause that kind of subsumes your entire life.

DODI: And then you get on stage, and also it's in the moment. It either happens or it doesn't.

CONOR: Flow states coming to you soon. Thank you for listening, and we hope you enjoyed this episode. Rate us and recommend us to your friends and colleagues, and we'll see you next time.

DODI: Stay safe. Wash your hands.

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