What's RSV?
Yeah?
What is RSV? Indeed RSV respiratory sensicial virus. To a lot of us, it's just a nasty cold, a.
Nasty cold, and a weird name, right, sensicial, sensicial, sensicial.
It's not that hard if you don't look at the word.
Respiratory sensicial virus is super common. We've all had it. Sometimes we don't even know we have it, but it can make babies and the elderly really really sick. Researchers struggled for decades to develop vaccines for RSV, and as of this year, we finally have them. I'm Jacob Goldstein, and you're listening to Incubation on today's show. We're talking about RSV, specifically the long search for a vaccine that can protect those who are most vulnerable to the virus
and maybe the rest of us is well. Well, here from two scientists who spent their careers trying to solve the surprisingly difficult puzzle of how to develop a vaccine for RSV, and well hear how in solving that puzzle, they may have also helped to create a powerful new way to develop vaccines for loss of diseases. But before we get to the story of the vaccine, I wanted to learn a little bit about RSV itself and the damage it can do. So I called up Karen Landman.
She's an infectious disease doctor and an epidemiologist, and she also writes for vox. So what happens when a baby or an old person with a weak immune system gets RSV?
So the virus infects cells in the respiratory tract. And ideally, what happens when your body gets infected by a virus is that your body mounts what's called a cytotoxic response. It deploys various soldiers from its immune system to go and kill the cells that have gotten infected by this virus.
That's a little bit different from some of the other things that the immune system does, like cite A. Toxic responses really go in and murder, like they go in and explode the cell or they fully eat the cell. And it's a different part of the immune system.
Okay, And why is that important?
Well, because that section of the immune system is not developed yet in newborn babies h and it's waning in older adults. So you have cells that are getting infected by viruses and that are dying right where they stand, sort of in the respiratory tract. And when we talk about the respiratory track, this is a very complex kind of upside down tree that runs all the way from the nose and mouth down to the very bottom of the lungs and at the parts of the lungs that
connect to your trachea, they're pretty narrow. So the narrower those tubes are, the easier it is to clog them. When this debris accumulates, and baby's chest wall a weaker, they're bendy, they're not as good as adults chest walls are at hacking up the stuff that's in there. So put all of this together, and you have a situation where you have a lot of junk clogging up the airways and the lungs, making it difficult for air to move through the spaces that it normally would move.
Through, meaning it's hard to breathe.
It's really hard to breathe in that situation.
Absolutely obviously a very bad situation. What happens, how do you treat that person?
So they wind up in the hospital. Sometimes you'll see them first in the emergency room, and you know the sounds are I won't say unmistakable, but the disease is so severe, and the babies who have it, they make such awful sounds when they have these infections. And you'll see also, it's not just the sounds they make, it's
the way they look. So you'll see their chests kind of cave in with every breath they're trying to take as they're sucking hard on the air around them and failing to get enough in.
So, if we zoom out on a national or global scale, like what is the impact quantitatively of RSV?
We see around sixty thousand hospitalizations and kids under five and around one hundred and twenty thousand hospitalizations and adults over sixty five every year, and we see anywhere between one hundred and three hundred deaths in kids and around fourteen thousand deaths in adults every year in the US alone, in the US alone.
And I understand that the infections, the RSV infections, come in waves. So when there is one of these waves, what's it like in the hospital?
Oh, in the hospital, it's like beds in hallways, It's like not enough nurses and doctors to take care of the number of people they're seeing. And not enough respiratory therapists to go around and get people on oxygen and get people intubated.
I mean, that's it's kind of amazing, right that there is this huge problem within the hospital of so many people who basically can't breathe or need help to breathe because they're sick with RSV. I never knew that.
Yeah, Oh, RSV season is something that really in any medical profession you learn to fear. You learn to fear the season because you know it's just gonna be long days and longer nights of many, many very sick people coming to the hospital. You know, tons of babies with RSV, some really really sick kids, and uh and tons of really worried parents. It's a really tough time of year. And it always felt like there was no hope, you know, for vaccinating, for creating a vaccine.
Until now, until now. The story of how we got to the RSV vaccine starts in nineteen fifty six. That was the year RSV was discovered, and as you may remember from last week's show, that was just a year after Jonas Salk's polio vaccine was approved to huge acclaim and so naturally, a group of scientists started developing an RSVV vaccine using the same technique that Saulk had used for polio. The idea was to grow the virus, kill it,
and inject it into patients. By the mid nineteen sixties, scientists were ready to launch a clinical trial of their newly developed RSV vaccine, and they gave it to thirty one children in Washington, DC. I talked about this with Barney Graham. He's a virologist and he started studying RSV at the National Institutes of Health in the nineteen eighties. But that earlier work on RSV, that vaccine trial in the nineteen sixties, it had a huge effect on Barney and really on the whole field.
During that winter time of sixty six sixty seven, just after Christmas, there was a big RSV outbreak that occurred, and of the thirty one children who were immunized with this vaccine, about I think twenty were infected, but of those twenty sixteen required hospitization. Two of them died. So it was a really catastrophic failure of the vaccine.
Just to be clear. So that study found that the vaccine not only did it not protect children, it actually made them sicker.
Yes, my first twenty years of research were really focused almost entirely on trying to understand this problem so we could get back to RSV vaccine development.
So what happened with that nineteen sixties vaccine trail? Why did it fail?
So the vaccine that was made in the nineteen sixties, the way that the vaccine was prepared changed the proteins in a way that when that was used to immunize, it created antibodies that could bind the virus but did not block the virus or didn't prevent virus infection. And so having a lot of antibody and a lot of virus to get together without preventing infection can sometimes lead to problems.
And in this instance, it did lead to problems.
Yes, it did lead to problems. And then what was needed to make that vaccine work is having proteins that could make better antibody responses and not so many ineffective antibody responses.
When Barney says proteins there, he's talking in particular about this one protein that sits on the outer surface of the virus. That protein is important because our immune system recognizes that protein and then creates matching antibodies to destroy the virus. The proteins called the F protein or the
F glycoprotein. F stands for fusion because it's the protein that the virus uses to fuse with the cell in the human body, and Barney and his colleagues knew they needed to crack the code of that F protein.
What I knew about the F protein on RSV was that it was a blob on a western blot that just looked like a black ink spot, and you could tell what size it was, but you couldn't really see it. You couldn't really understand how it was folded and how it worked. If you want to make a vaccine, you really need to see the protein and how it interacts with the antibodies and the exact surface contours and the
exact shape of that protein. So if you want to get a virus infection started, you have to figure out a way to get the virus, you know, inside the human cell in order for the virus to start growing. And the way the virus does that it has this interesting protein on its surface that is able to transform. It is able to unravel, reach out, grab the host cell or target cell membrane and pull the membranes back together,
so the host cell and the virus membrane fuse. They merged, then the virus genome can enter the cell and start the replication process.
I mean, that's the crucial bad thing that happens, right, That's the thing we don't want to happen.
If you want to stop a virus infection, if you can stop that F protein from rearranging or from attaching, then you've got a good way of stopping the virus infection.
What did scientists not know about that F protein.
Well, the main thing we didn't know is why it had not worked as a vaccine.
And what did you want to learn about the F protein to try and solve that problem.
Well, we really wanted to know what the F protein looked like in its original state. We wanted to know where the antibodies could bind F protein and how what was the mechanism for neutral the virus. And to understand those things, we needed to know more about the structure off not just in its final rearranged state, but in its original state.
Barney's making a really key point right here that F protein on the surface of rsv it exists in two different shapes. It has one shape when the virus is floating around in the body searching for a cell to fuse with. Then when the virus fuses with the cell, the F protein changes shape. So what our immune system needs are antibodies to that F protein when it's in its prefusion state, before it's fused with the cell in
our body. But when Barney and his colleagues were studying the virus, they always saw the protein in the other shape, in the post fusion shape. That problem went all the way back to that failed vaccine in the nineteen sixties, and it was a problem Barney was still trying to solve in two thousand and eight. That's when Barney had a chance meeting with the scientist who would finally solve the puzzle that r s V researchers had been working on for decades. Well, hear that part of the story
in just a minute. While Barney Graham was working way trying to solve the puzzle of how to create a vaccine for RSV, he met a guy named Jason McClellan, who at the time was a research fellow who worked just down the hall. I recently talked with Jason McClellan and we started with the work he was doing when he met Barney. While Barney had been studying the proteins on the outside of RSV, Jason was studying the proteins
on the outside of a different virus, HIV. This was back in two thousand and eight, and at the time Jason told me he was working in a field called structure based vaccine design.
It's really a trying to turn vaccine development into a very rational engineering approach that's guided by the human immune system.
That word engineering is good, right, You're like actually trying to build a thing in a certain shape exactly when you so you joined this lab working on this idea structure based vaccine design for HIV. There's this idea, Oh, we have these new tools, we could we could build vaccines in this new, potentially better way. Had anybody done it yet?
No. That's really some of the pioneering efforts for structure based vaccine design and its application to HIV, And it quickly became a parent that we're developing really cool approaches, but many of them aren't working, and it's unclear whether the approaches aren't good or the virus is just so difficult to make a vaccine for why don't we sort of apply this to maybe a more tractable virus so we could test some of these techniques. And I was on a different floor from the rest of the lab.
I was actually in Barney Graham's floor, and Barney heard of this and he was like, you know, RSV would be perfect for applications of structure based vaccine design. So for the next yeah, the rest of my time next five years or so, I sort of split half my time working on HIV and half my time working on RSB.
So this is a good guy for you to meet at this moment. This is a good happy meeting in this science.
Scenario, it's very fertuitous happy meeting. It was like December two thousand and eight, when we had sort of formalized the plan. We decided to start working on RSV in structure based design.
At this moment, when you decide to do this, what's the key thing you don't know?
So we know that the F protein exists in two confirmations.
Too, Does that mean two shapes?
Two shapes? Yeah, So they had been so it had been imaged by electron microscopy, and it was clear that one form looked like these elongated golf teas and the other was sort of more oval, lollipop shaped with like a little stock. And so it had become appreciated that one of them was the prefusion confirmation, okay, and then the other one is postfusion.
And so it's basically, before it's attached to this this protein has one shape and after it's attached to the shell, it has another shape.
Yeah, we were unable to make the prefusion state as a purified protein. So if you just purify f it sort of snaps into the postfusion state, which is the lowest energy, most stable state, and people had immunized with that, but it was insufficient to make a vaccine.
Well, and that makes sense at some level, right, because what you actually want to immunize against is the prefusion shape.
Right.
The virus is floating around in our respiratory tract and it's before it attaches to the cells, it's in the prefusion shape.
Right.
What we really want is for our body to have on the bodies to attack that. So if you're using the postfusion state, it's intuitive that like that's not going to work as well.
Right, Exactly, Our colleague Jose Malero in Spain. What he showed was that most of the neutralizing antibodies did not bind postfusion, suggesting that the majority of the antibodies humans may in response to an RSV infection do not target posts.
And we have the problem that it's hard to isolate pre we don't know exactly what it looks like, like, this is the this is the problem, right.
Yeah, So we assumed that from Hose's data that there are antibodies that bind only to prefusion. So we thought that if we could isolate some antibodies like this, we could make F protein in the presence of these antibodies, and when F transiently adopts prefusion, the antibody binds and locks it, and then we'd be able to purify that complex.
That's very clever. So you're using the body's own response to the prefusion protein, the antibodies to basically make a trap for the prefusion protein. Exactly In the lab, Jason runs an experiment to do just this. He takes an F protein in that prefusion shape, that lollipop shape, and then he binds the protein to an antibody, and once the F protein is bound to the antibody. The protein cannot change its shape. So now Jason has the F protein locked in place in the right shape, and he
needs to see exactly what it looks like. To do that, he uses a technique called xtray crystallography, which lets him see the shape of the protein in incredible detail. He can see the atomic level structure of this prefusion F protein, and Jason knew this was a very big deal.
It was going to allow us to make prefusion.
F okay to use as a vaccine.
Aha.
Right, So you can make the exact thing as it exists on the surface of an RSV cell and put it into people's bodies in some fashion, and you'll have the perfect protein. You'll have the exact shape of the protein, and the body will make these great antibodies and that body don't get sick with RSV if everything goes according to plan exactly right.
It's like, I don't know, we're sculptors, and now we have the model of what we need to make the sculpture of and it allows us to make ideal mimics of these proteins found on the surface of the virus.
Amazing. So at this at this moment, do you feel like you've got it, Like you feel like you yet Yeah, okay, what has to happen when we're very excited?
We have pre F, but we we have not been able to produce it in the absence of those antibodies the camp it okay, right, So that's the key. We have to modify the F protein such that when we express it in cells in the absence of antibodies, it folds into PREF, stays in pre F, and allows us to immunize with it.
So you have to kind of build a version of it from scratch. Now that'll work in this very particular way that it has to work for you're going to make a vaccine, right.
I designed several substitutions that ended up working. Four of them in combination allowed the prefusion F protein to be expressed and purified.
And this is more sculpting, right, literally like filling holes in the shape of the protein, right, Yeah.
Because the structure tells us, oh, there's some pockets and cavities here that are causing instability, so why don't we fill them?
You're really building this physical thing in a particular way.
Yeah, yeah, very specifically. So we have we have like almost an atomic level mimic. And then the next step was to make those proteins and provide them to Barney Graham's lab. And so Barney then immunized mice and then blood was drawn from the mice and they'd performed the neutralization essays. And then that was the exciting day. That's when because Barney told me it's he couldn't believe it. It was the highest neutralizing antibody tighters he had ever seen in his decades of working on RSV.
Meaning the best, right, yeah, it listened, the strongest response. Yeah.
And so at that point we're like, we got it, Like this, this is exactly what we were looking for, this proof of concept for structure based vaccine design.
So now in twenty twenty three, these RSV vaccines based on your research are are coming out. They're a thing in the world, and millions of people presumably are getting this vaccine, are about to get this vaccine. I mean, what's that like for you? That's amazing.
That always wanted to try to have some impact improve people's lives, and you know, you know, it's sort of a long shot to actually help make a vaccine, just given how few vaccines get approved but to actually do it is I mean, it's credible. It's everything you can hope for.
There is one more piece of the Jason and Barney story that's worth telling before we go. In twenty twelve, there was an outbreak of a new disease in Saudi Arabia. The disease was caused by a coronavirus, and it was given the name MERZ for Middle Eastern Respiratory syndrome. Jason and Barney went to work on that coronavirus. Using the engineering and structural biology techniques they'd honed in their work on RSV. They developed an incredibly detailed picture of the
prefusion spike protein. They did that sculpting works to create a stable version of that protein, and they did preliminary work toward developing a vaccine. Then, in twenty nineteen, another new coronavirus emerged, the virus that causes COVID. This time,
Jason and Barney were ready. The work they had done first on RSV then on MERZ meant that just a few weeks after that new virus was discovered, they were able to create a stabilized version of that key spike protein in just the right shape that work played a major role in designing the COVID nineteen vaccines. The protein they created was one of the key reasons it was possible for the vaccines to be developed so quickly. Thanks to my guests today Karen Lanman, Arnie Graham, and Jason McClellan.
Next week on Incubation, the story of the Common Cold Unit, a place where tens of thousands of people went voluntarily for decades to catch a cold. You know, Britain post war. Chimpanzees are not easy to come by to do this type of research, So what's definitely the next best thing are human volunteers, so human guinea pigs. Incubation is a co production of Pushkin Industries and Ruby Studio at iHeartMedia. It's produced by Gabriel Hunter Chang, Ariela Markowitz and Amy
Gaines McQuaid. Our editors are Julia Barton and Karen Schakerjie Mastering by Anne Pope, fact checking by Joseph Fridman. Our executive producers are Katherine Girardeau and Matt Romano. I'm Jacob Goldstein. Thanks for listening.