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Speaker 1: What's RSV?

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Speaker 2: Yeah?

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Speaker 3: What is RSV? Indeed RSV respiratory sensicial virus. To a

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Speaker 3: lot of us, it's just a nasty cold, a.

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Speaker 1: Nasty cold, and a weird name, right, sensicial, sensicial, sensicial.

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Speaker 3: It's not that hard if you don't look at the word.

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Speaker 1: Respiratory sensicial virus is super common. We've all had it.

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Speaker 1: Sometimes we don't even know we have it, but it

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Speaker 1: can make babies and the elderly really really sick. Researchers

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Speaker 1: struggled for decades to develop vaccines for RSV, and as

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Speaker 1: of this year, we finally have them. I'm Jacob Goldstein,

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Speaker 1: and you're listening to Incubation on today's show. We're talking

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Speaker 1: about RSV, specifically the long search for a vaccine that

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Speaker 1: can protect those who are most vulnerable to the virus

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Speaker 1: and maybe the rest of us is well. Well, here

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Speaker 1: from two scientists who spent their careers trying to solve

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Speaker 1: the surprisingly difficult puzzle of how to develop a vaccine

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Speaker 1: for RSV, and well hear how in solving that puzzle,

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Speaker 1: they may have also helped to create a powerful new

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Speaker 1: way to develop vaccines for loss of diseases. But before

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Speaker 1: we get to the story of the vaccine, I wanted

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Speaker 1: to learn a little bit about RSV itself and the

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Speaker 1: damage it can do. So I called up Karen Landman.

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Speaker 1: She's an infectious disease doctor and an epidemiologist, and she

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Speaker 1: also writes for vox. So what happens when a baby

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Speaker 1: or an old person with a weak immune system gets RSV?

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Speaker 3: So the virus infects cells in the respiratory tract. And ideally,

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Speaker 3: what happens when your body gets infected by a virus

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Speaker 3: is that your body mounts what's called a cytotoxic response.

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Speaker 3: It deploys various soldiers from its immune system to go

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Speaker 3: and kill the cells that have gotten infected by this virus.

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Speaker 3: That's a little bit different from some of the other

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Speaker 3: things that the immune system does, like cite A. Toxic

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Speaker 3: responses really go in and murder, like they go in

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Speaker 3: and explode the cell or they fully eat the cell.

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Speaker 3: And it's a different part of the immune system.

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Speaker 1: Okay, And why is that important?

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Speaker 3: Well, because that section of the immune system is not

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Speaker 3: developed yet in newborn babies h and it's waning in

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Speaker 3: older adults. So you have cells that are getting infected

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Speaker 3: by viruses and that are dying right where they stand,

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Speaker 3: sort of in the respiratory tract. And when we talk

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Speaker 3: about the respiratory track, this is a very complex kind

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Speaker 3: of upside down tree that runs all the way from

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Speaker 3: the nose and mouth down to the very bottom of

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Speaker 3: the lungs and at the parts of the lungs that

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Speaker 3: connect to your trachea, they're pretty narrow. So the narrower

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Speaker 3: those tubes are, the easier it is to clog them.

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Speaker 3: When this debris accumulates, and baby's chest wall a weaker,

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Speaker 3: they're bendy, they're not as good as adults chest walls

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Speaker 3: are at hacking up the stuff that's in there. So

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Speaker 3: put all of this together, and you have a situation

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Speaker 3: where you have a lot of junk clogging up the

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Speaker 3: airways and the lungs, making it difficult for air to

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Speaker 3: move through the spaces that it normally would move.

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Speaker 1: Through, meaning it's hard to breathe.

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Speaker 3: It's really hard to breathe in that situation.

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Speaker 1: Absolutely obviously a very bad situation. What happens, how do

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Speaker 1: you treat that person?

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Speaker 3: So they wind up in the hospital. Sometimes you'll see

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Speaker 3: them first in the emergency room, and you know the

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Speaker 3: sounds are I won't say unmistakable, but the disease is

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Speaker 3: so severe, and the babies who have it, they make

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Speaker 3: such awful sounds when they have these infections. And you'll

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Speaker 3: see also, it's not just the sounds they make, it's

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Speaker 3: the way they look. So you'll see their chests kind

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Speaker 3: of cave in with every breath they're trying to take

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Speaker 3: as they're sucking hard on the air around them and

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Speaker 3: failing to get enough in.

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Speaker 1: So, if we zoom out on a national or global scale,

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Speaker 1: like what is the impact quantitatively of RSV?

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Speaker 3: We see around sixty thousand hospitalizations and kids under five

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Speaker 3: and around one hundred and twenty thousand hospitalizations and adults

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Speaker 3: over sixty five every year, and we see anywhere between

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Speaker 3: one hundred and three hundred deaths in kids and around

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Speaker 3: fourteen thousand deaths in adults every year in the US alone,

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Speaker 3: in the US alone.

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Speaker 1: And I understand that the infections, the RSV infections, come

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Speaker 1: in waves. So when there is one of these waves,

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Speaker 1: what's it like in the hospital?

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Speaker 3: Oh, in the hospital, it's like beds in hallways, It's

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Speaker 3: like not enough nurses and doctors to take care of

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Speaker 3: the number of people they're seeing. And not enough respiratory

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Speaker 3: therapists to go around and get people on oxygen and

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Speaker 3: get people intubated.

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Speaker 1: I mean, that's it's kind of amazing, right that there

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Speaker 1: is this huge problem within the hospital of so many

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Speaker 1: people who basically can't breathe or need help to breathe

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Speaker 1: because they're sick with RSV. I never knew that.

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Speaker 3: Yeah, Oh, RSV season is something that really in any

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Speaker 3: medical profession you learn to fear. You learn to fear

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Speaker 3: the season because you know it's just gonna be long

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Speaker 3: days and longer nights of many, many very sick people

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Speaker 3: coming to the hospital. You know, tons of babies with RSV,

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Speaker 3: some really really sick kids, and uh and tons of

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Speaker 3: really worried parents. It's a really tough time of year.

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Speaker 3: And it always felt like there was no hope, you know,

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Speaker 3: for vaccinating, for creating a vaccine.

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Speaker 1: Until now, until now. The story of how we got

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Speaker 1: to the RSV vaccine starts in nineteen fifty six. That

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Speaker 1: was the year RSV was discovered, and as you may

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Speaker 1: remember from last week's show, that was just a year

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Speaker 1: after Jonas Salk's polio vaccine was approved to huge acclaim

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Speaker 1: and so naturally, a group of scientists started developing an

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Speaker 1: RSVV vaccine using the same technique that Saulk had used

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Speaker 1: for polio. The idea was to grow the virus, kill it,

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Speaker 1: and inject it into patients. By the mid nineteen sixties,

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Speaker 1: scientists were ready to launch a clinical trial of their

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Speaker 1: newly developed RSV vaccine, and they gave it to thirty

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Speaker 1: one children in Washington, DC. I talked about this with

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Speaker 1: Barney Graham. He's a virologist and he started studying RSV

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Speaker 1: at the National Institutes of Health in the nineteen eighties.

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Speaker 1: But that earlier work on RSV, that vaccine trial in

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Speaker 1: the nineteen sixties, it had a huge effect on Barney

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Speaker 1: and really on the whole field.

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Speaker 2: During that winter time of sixty six sixty seven, just

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Speaker 2: after Christmas, there was a big RSV outbreak that occurred,

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Speaker 2: and of the thirty one children who were immunized with

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Speaker 2: this vaccine, about I think twenty were infected, but of

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Speaker 2: those twenty sixteen required hospitization. Two of them died. So

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Speaker 2: it was a really catastrophic failure of the vaccine.

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Speaker 1: Just to be clear. So that study found that the

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Speaker 1: vaccine not only did it not protect children, it actually

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Speaker 1: made them sicker.

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Speaker 2: Yes, my first twenty years of research were really focused

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Speaker 2: almost entirely on trying to understand this problem so we

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Speaker 2: could get back to RSV vaccine development.

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Speaker 1: So what happened with that nineteen sixties vaccine trail? Why

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Speaker 1: did it fail?

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Speaker 2: So the vaccine that was made in the nineteen sixties,

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Speaker 2: the way that the vaccine was prepared changed the proteins

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Speaker 2: in a way that when that was used to immunize,

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Speaker 2: it created antibodies that could bind the virus but did

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Speaker 2: not block the virus or didn't prevent virus infection. And

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Speaker 2: so having a lot of antibody and a lot of

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Speaker 2: virus to get together without preventing infection can sometimes lead

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Speaker 2: to problems.

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Speaker 1: And in this instance, it did lead to problems.

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Speaker 2: Yes, it did lead to problems. And then what was

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Speaker 2: needed to make that vaccine work is having proteins that

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Speaker 2: could make better antibody responses and not so many ineffective

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Speaker 2: antibody responses.

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Speaker 1: When Barney says proteins there, he's talking in particular about

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Speaker 1: this one protein that sits on the outer surface of

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Speaker 1: the virus. That protein is important because our immune system

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Speaker 1: recognizes that protein and then creates matching antibodies to destroy

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Speaker 1: the virus. The proteins called the F protein or the

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Speaker 1: F glycoprotein. F stands for fusion because it's the protein

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Speaker 1: that the virus uses to fuse with the cell in

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Speaker 1: the human body, and Barney and his colleagues knew they

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Speaker 1: needed to crack the code of that F protein.

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Speaker 2: What I knew about the F protein on RSV was

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Speaker 2: that it was a blob on a western blot that

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Speaker 2: just looked like a black ink spot, and you could

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Speaker 2: tell what size it was, but you couldn't really see it.

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Speaker 2: You couldn't really understand how it was folded and how

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Speaker 2: it worked. If you want to make a vaccine, you

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Speaker 2: really need to see the protein and how it interacts

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Speaker 2: with the antibodies and the exact surface contours and the

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Speaker 2: exact shape of that protein. So if you want to

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Speaker 2: get a virus infection started, you have to figure out

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Speaker 2: a way to get the virus, you know, inside the

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Speaker 2: human cell in order for the virus to start growing.

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Speaker 2: And the way the virus does that it has this

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Speaker 2: interesting protein on its surface that is able to transform.

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Speaker 2: It is able to unravel, reach out, grab the host

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Speaker 2: cell or target cell membrane and pull the membranes back together,

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Speaker 2: so the host cell and the virus membrane fuse. They merged,

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Speaker 2: then the virus genome can enter the cell and start

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Speaker 2: the replication process.

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Speaker 1: I mean, that's the crucial bad thing that happens, right,

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Speaker 1: That's the thing we don't want to happen.

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Speaker 2: If you want to stop a virus infection, if you

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Speaker 2: can stop that F protein from rearranging or from attaching,

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Speaker 2: then you've got a good way of stopping the virus infection.

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Speaker 1: What did scientists not know about that F protein.

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Speaker 2: Well, the main thing we didn't know is why it

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Speaker 2: had not worked as a vaccine.

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Speaker 1: And what did you want to learn about the F

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Speaker 1: protein to try and solve that problem.

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Speaker 2: Well, we really wanted to know what the F protein

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Speaker 2: looked like in its original state. We wanted to know

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Speaker 2: where the antibodies could bind F protein and how what

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Speaker 2: was the mechanism for neutral the virus. And to understand

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Speaker 2: those things, we needed to know more about the structure

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Speaker 2: off not just in its final rearranged state, but in

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Speaker 2: its original state.

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Speaker 1: Barney's making a really key point right here that F

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Speaker 1: protein on the surface of rsv it exists in two

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Speaker 1: different shapes. It has one shape when the virus is

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Speaker 1: floating around in the body searching for a cell to

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Speaker 1: fuse with. Then when the virus fuses with the cell,

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Speaker 1: the F protein changes shape. So what our immune system

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Speaker 1: needs are antibodies to that F protein when it's in

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Speaker 1: its prefusion state, before it's fused with the cell in

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Speaker 1: our body. But when Barney and his colleagues were studying

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Speaker 1: the virus, they always saw the protein in the other shape,

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Speaker 1: in the post fusion shape. That problem went all the

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Speaker 1: way back to that failed vaccine in the nineteen sixties,

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Speaker 1: and it was a problem Barney was still trying to

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Speaker 1: solve in two thousand and eight. That's when Barney had

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Speaker 1: a chance meeting with the scientist who would finally solve

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Speaker 1: the puzzle that r s V researchers had been working

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Speaker 1: on for decades. Well, hear that part of the story

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Speaker 1: in just a minute. While Barney Graham was working way

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Speaker 1: trying to solve the puzzle of how to create a

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Speaker 1: vaccine for RSV, he met a guy named Jason McClellan,

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Speaker 1: who at the time was a research fellow who worked

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Speaker 1: just down the hall. I recently talked with Jason McClellan

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Speaker 1: and we started with the work he was doing when

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Speaker 1: he met Barney. While Barney had been studying the proteins

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Speaker 1: on the outside of RSV, Jason was studying the proteins

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Speaker 1: on the outside of a different virus, HIV. This was

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Speaker 1: back in two thousand and eight, and at the time

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Speaker 1: Jason told me he was working in a field called

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Speaker 1: structure based vaccine design.

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Speaker 4: It's really a trying to turn vaccine development into a

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Speaker 4: very rational engineering approach that's guided by the human immune system.

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Speaker 1: That word engineering is good, right, You're like actually trying

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Speaker 1: to build a thing in a certain shape exactly when

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Speaker 1: you so you joined this lab working on this idea

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Speaker 1: structure based vaccine design for HIV. There's this idea, Oh,

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Speaker 1: we have these new tools, we could we could build

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Speaker 1: vaccines in this new, potentially better way. Had anybody done

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Speaker 1: it yet?

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Speaker 4: No. That's really some of the pioneering efforts for structure

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Speaker 4: based vaccine design and its application to HIV, And it

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Speaker 4: quickly became a parent that we're developing really cool approaches,

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Speaker 4: but many of them aren't working, and it's unclear whether

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Speaker 4: the approaches aren't good or the virus is just so

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Speaker 4: difficult to make a vaccine for why don't we sort

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Speaker 4: of apply this to maybe a more tractable virus so

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Speaker 4: we could test some of these techniques. And I was

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Speaker 4: on a different floor from the rest of the lab.

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Speaker 4: I was actually in Barney Graham's floor, and Barney heard

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Speaker 4: of this and he was like, you know, RSV would

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Speaker 4: be perfect for applications of structure based vaccine design. So

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Speaker 4: for the next yeah, the rest of my time next

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Speaker 4: five years or so, I sort of split half my

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Speaker 4: time working on HIV and half my time working on RSB.

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Speaker 1: So this is a good guy for you to meet

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Speaker 1: at this moment. This is a good happy meeting in

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Speaker 1: this science.

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Speaker 4: Scenario, it's very fertuitous happy meeting. It was like December

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Speaker 4: two thousand and eight, when we had sort of formalized

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Speaker 4: the plan. We decided to start working on RSV in

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Speaker 4: structure based design.

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Speaker 1: At this moment, when you decide to do this, what's

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Speaker 1: the key thing you don't know?

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Speaker 4: So we know that the F protein exists in two confirmations.

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Speaker 1: Too, Does that mean two shapes?

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Speaker 4: Two shapes? Yeah, So they had been so it had

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Speaker 4: been imaged by electron microscopy, and it was clear that

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Speaker 4: one form looked like these elongated golf teas and the

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Speaker 4: other was sort of more oval, lollipop shaped with like

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Speaker 4: a little stock. And so it had become appreciated that

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Speaker 4: one of them was the prefusion confirmation, okay, and then

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Speaker 4: the other one is postfusion.

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Speaker 1: And so it's basically, before it's attached to this this

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Speaker 1: protein has one shape and after it's attached to the shell,

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Speaker 1: it has another shape.

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Speaker 4: Yeah, we were unable to make the prefusion state as

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Speaker 4: a purified protein. So if you just purify f it

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Speaker 4: sort of snaps into the postfusion state, which is the

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Speaker 4: lowest energy, most stable state, and people had immunized with that,

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Speaker 4: but it was insufficient to make a vaccine.

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Speaker 1: Well, and that makes sense at some level, right, because

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Speaker 1: what you actually want to immunize against is the prefusion shape.

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Speaker 4: Right.

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Speaker 1: The virus is floating around in our respiratory tract and

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Speaker 1: it's before it attaches to the cells, it's in the

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Speaker 1: prefusion shape.

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Speaker 3: Right.

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Speaker 1: What we really want is for our body to have

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Speaker 1: on the bodies to attack that. So if you're using

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Speaker 1: the postfusion state, it's intuitive that like that's not going

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Speaker 1: to work as well.

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Speaker 4: Right, Exactly, Our colleague Jose Malero in Spain. What he

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Speaker 4: showed was that most of the neutralizing antibodies did not

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Speaker 4: bind postfusion, suggesting that the majority of the antibodies humans

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Speaker 4: may in response to an RSV infection do not target posts.

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Speaker 1: And we have the problem that it's hard to isolate

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Speaker 1: pre we don't know exactly what it looks like, like,

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Speaker 1: this is the this is the problem, right.

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Speaker 4: Yeah, So we assumed that from Hose's data that there

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Speaker 4: are antibodies that bind only to prefusion. So we thought

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Speaker 4: that if we could isolate some antibodies like this, we

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Speaker 4: could make F protein in the presence of these antibodies,

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Speaker 4: and when F transiently adopts prefusion, the antibody binds and

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Speaker 4: locks it, and then we'd be able to purify that complex.

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Speaker 1: That's very clever. So you're using the body's own response

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Speaker 1: to the prefusion protein, the antibodies to basically make a

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Speaker 1: trap for the prefusion protein. Exactly In the lab, Jason

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Speaker 1: runs an experiment to do just this. He takes an

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Speaker 1: F protein in that prefusion shape, that lollipop shape, and

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Speaker 1: then he binds the protein to an antibody, and once

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Speaker 1: the F protein is bound to the antibody. The protein

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Speaker 1: cannot change its shape. So now Jason has the F

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Speaker 1: protein locked in place in the right shape, and he

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Speaker 1: needs to see exactly what it looks like. To do that,

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Speaker 1: he uses a technique called xtray crystallography, which lets him

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Speaker 1: see the shape of the protein in incredible detail. He

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Speaker 1: can see the atomic level structure of this prefusion F protein,

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Speaker 1: and Jason knew this was a very big deal.

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Speaker 4: It was going to allow us to make prefusion.

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Speaker 1: F okay to use as a vaccine.

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Speaker 2: Aha.

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Speaker 1: Right, So you can make the exact thing as it

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Speaker 1: exists on the surface of an RSV cell and put

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Speaker 1: it into people's bodies in some fashion, and you'll have

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Speaker 1: the perfect protein. You'll have the exact shape of the protein,

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Speaker 1: and the body will make these great antibodies and that

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Speaker 1: body don't get sick with RSV if everything goes according

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Speaker 1: to plan exactly right.

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Speaker 4: It's like, I don't know, we're sculptors, and now we

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Speaker 4: have the model of what we need to make the

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Speaker 4: sculpture of and it allows us to make ideal mimics

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Speaker 4: of these proteins found on the surface of the virus.

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Speaker 1: Amazing. So at this at this moment, do you feel

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Speaker 1: like you've got it, Like you feel like you yet Yeah, okay,

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Speaker 1: what has to happen when we're very excited?

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Speaker 4: We have pre F, but we we have not been

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Speaker 4: able to produce it in the absence of those antibodies

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Speaker 4: the camp it okay, right, So that's the key. We

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Speaker 4: have to modify the F protein such that when we

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Speaker 4: express it in cells in the absence of antibodies, it

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Speaker 4: folds into PREF, stays in pre F, and allows us

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Speaker 4: to immunize with it.

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Speaker 1: So you have to kind of build a version of

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Speaker 1: it from scratch. Now that'll work in this very particular

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Speaker 1: way that it has to work for you're going to

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Speaker 1: make a vaccine, right.

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Speaker 4: I designed several substitutions that ended up working. Four of

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Speaker 4: them in combination allowed the prefusion F protein to be

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Speaker 4: expressed and purified.

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Speaker 1: And this is more sculpting, right, literally like filling holes

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Speaker 1: in the shape of the protein, right, Yeah.

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Speaker 4: Because the structure tells us, oh, there's some pockets and

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Speaker 4: cavities here that are causing instability, so why don't we

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Speaker 4: fill them?

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Speaker 1: You're really building this physical thing in a particular way.

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Speaker 4: Yeah, yeah, very specifically. So we have we have like

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Speaker 4: almost an atomic level mimic. And then the next step

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Speaker 4: was to make those proteins and provide them to Barney

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Speaker 4: Graham's lab. And so Barney then immunized mice and then

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Speaker 4: blood was drawn from the mice and they'd performed the

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Speaker 4: neutralization essays. And then that was the exciting day. That's

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Speaker 4: when because Barney told me it's he couldn't believe it. It

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Speaker 4: was the highest neutralizing antibody tighters he had ever seen

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Speaker 4: in his decades of working on RSV.

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Speaker 1: Meaning the best, right, yeah, it listened, the strongest response. Yeah.

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Speaker 4: And so at that point we're like, we got it,

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Speaker 4: Like this, this is exactly what we were looking for,

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Speaker 4: this proof of concept for structure based vaccine design.

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Speaker 1: So now in twenty twenty three, these RSV vaccines based

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Speaker 1: on your research are are coming out. They're a thing

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Speaker 1: in the world, and millions of people presumably are getting

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Speaker 1: this vaccine, are about to get this vaccine. I mean,

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Speaker 1: what's that like for you? That's amazing.

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Speaker 4: That always wanted to try to have some impact improve

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Speaker 4: people's lives, and you know, you know, it's sort of

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Speaker 4: a long shot to actually help make a vaccine, just

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Speaker 4: given how few vaccines get approved but to actually do

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Speaker 4: it is I mean, it's credible. It's everything you can

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Speaker 4: hope for.

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Speaker 1: There is one more piece of the Jason and Barney

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Speaker 1: story that's worth telling before we go. In twenty twelve,

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Speaker 1: there was an outbreak of a new disease in Saudi Arabia.

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Speaker 1: The disease was caused by a coronavirus, and it was

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Speaker 1: given the name MERZ for Middle Eastern Respiratory syndrome. Jason

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Speaker 1: and Barney went to work on that coronavirus. Using the

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Speaker 1: engineering and structural biology techniques they'd honed in their work

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Speaker 1: on RSV. They developed an incredibly detailed picture of the

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Speaker 1: prefusion spike protein. They did that sculpting works to create

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Speaker 1: a stable version of that protein, and they did preliminary

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Speaker 1: work toward developing a vaccine. Then, in twenty nineteen, another

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Speaker 1: new coronavirus emerged, the virus that causes COVID. This time,

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Speaker 1: Jason and Barney were ready. The work they had done

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Speaker 1: first on RSV then on MERZ meant that just a

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Speaker 1: few weeks after that new virus was discovered, they were

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Speaker 1: able to create a stabilized version of that key spike

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Speaker 1: protein in just the right shape that work played a

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Speaker 1: major role in designing the COVID nineteen vaccines. The protein

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Speaker 1: they created was one of the key reasons it was

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Speaker 1: possible for the vaccines to be developed so quickly. Thanks

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Speaker 1: to my guests today Karen Lanman, Arnie Graham, and Jason McClellan.

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Speaker 1: Next week on Incubation, the story of the Common Cold Unit,

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Speaker 1: a place where tens of thousands of people went voluntarily

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Speaker 1: for decades to catch a cold. You know, Britain post war.

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Speaker 1: Chimpanzees are not easy to come by to do this

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Speaker 1: type of research, So what's definitely the next best thing

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Speaker 1: are human volunteers, so human guinea pigs. Incubation is a

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Speaker 1: co production of Pushkin Industries and Ruby Studio at iHeartMedia.

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Speaker 1: It's produced by Gabriel Hunter Chang, Ariela Markowitz and Amy

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Speaker 1: Gaines McQuaid. Our editors are Julia Barton and Karen Schakerjie

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Speaker 1: Mastering by Anne Pope, fact checking by Joseph Fridman. Our

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Speaker 1: executive producers are Katherine Girardeau and Matt Romano. I'm Jacob Goldstein.

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Speaker 1: Thanks for listening.