WEBVTT - RSV: The Quest for a New Vaccine 0:00:03.840 --> 0:00:04.600 What's RSV? 0:00:05.400 --> 0:00:05.600 Yeah? 0:00:06.559 --> 0:00:12.760 What is RSV? Indeed RSV respiratory sensicial virus. To a 0:00:12.800 --> 0:00:15.120 lot of us, it's just a nasty cold, a. 0:00:15.160 --> 0:00:20.680 Nasty cold, and a weird name, right, sensicial, sensicial, sensicial. 0:00:21.000 --> 0:00:22.840 It's not that hard if you don't look at the word. 0:00:24.560 --> 0:00:28.920 Respiratory sensicial virus is super common. We've all had it. 0:00:29.360 --> 0:00:31.600 Sometimes we don't even know we have it, but it 0:00:31.600 --> 0:00:36.000 can make babies and the elderly really really sick. Researchers 0:00:36.040 --> 0:00:40.160 struggled for decades to develop vaccines for RSV, and as 0:00:40.200 --> 0:00:47.199 of this year, we finally have them. I'm Jacob Goldstein, 0:00:47.280 --> 0:00:50.760 and you're listening to Incubation on today's show. We're talking 0:00:50.840 --> 0:00:55.279 about RSV, specifically the long search for a vaccine that 0:00:55.320 --> 0:00:58.080 can protect those who are most vulnerable to the virus 0:00:58.440 --> 0:01:01.560 and maybe the rest of us is well. Well, here 0:01:01.600 --> 0:01:04.479 from two scientists who spent their careers trying to solve 0:01:04.520 --> 0:01:07.679 the surprisingly difficult puzzle of how to develop a vaccine 0:01:07.720 --> 0:01:11.319 for RSV, and well hear how in solving that puzzle, 0:01:11.600 --> 0:01:14.000 they may have also helped to create a powerful new 0:01:14.040 --> 0:01:18.600 way to develop vaccines for loss of diseases. But before 0:01:18.640 --> 0:01:20.680 we get to the story of the vaccine, I wanted 0:01:20.680 --> 0:01:23.320 to learn a little bit about RSV itself and the 0:01:23.440 --> 0:01:26.280 damage it can do. So I called up Karen Landman. 0:01:26.680 --> 0:01:29.840 She's an infectious disease doctor and an epidemiologist, and she 0:01:29.880 --> 0:01:35.800 also writes for vox. So what happens when a baby 0:01:35.880 --> 0:01:39.000 or an old person with a weak immune system gets RSV? 0:01:40.000 --> 0:01:45.080 So the virus infects cells in the respiratory tract. And ideally, 0:01:45.120 --> 0:01:50.080 what happens when your body gets infected by a virus 0:01:50.360 --> 0:01:54.320 is that your body mounts what's called a cytotoxic response. 0:01:54.720 --> 0:01:58.720 It deploys various soldiers from its immune system to go 0:01:58.760 --> 0:02:02.000 and kill the cells that have gotten infected by this virus. 0:02:02.200 --> 0:02:04.640 That's a little bit different from some of the other 0:02:04.880 --> 0:02:07.960 things that the immune system does, like cite A. Toxic 0:02:08.000 --> 0:02:12.280 responses really go in and murder, like they go in 0:02:12.320 --> 0:02:15.080 and explode the cell or they fully eat the cell. 0:02:15.400 --> 0:02:17.320 And it's a different part of the immune system. 0:02:17.400 --> 0:02:18.919 Okay, And why is that important? 0:02:19.160 --> 0:02:22.400 Well, because that section of the immune system is not 0:02:23.160 --> 0:02:27.040 developed yet in newborn babies h and it's waning in 0:02:27.160 --> 0:02:32.320 older adults. So you have cells that are getting infected 0:02:32.320 --> 0:02:35.760 by viruses and that are dying right where they stand, 0:02:35.840 --> 0:02:38.640 sort of in the respiratory tract. And when we talk 0:02:38.680 --> 0:02:41.200 about the respiratory track, this is a very complex kind 0:02:41.280 --> 0:02:44.040 of upside down tree that runs all the way from 0:02:44.040 --> 0:02:45.959 the nose and mouth down to the very bottom of 0:02:46.000 --> 0:02:48.560 the lungs and at the parts of the lungs that 0:02:48.639 --> 0:02:53.240 connect to your trachea, they're pretty narrow. So the narrower 0:02:53.240 --> 0:02:55.919 those tubes are, the easier it is to clog them. 0:02:56.240 --> 0:03:00.920 When this debris accumulates, and baby's chest wall a weaker, 0:03:00.960 --> 0:03:04.400 they're bendy, they're not as good as adults chest walls 0:03:04.440 --> 0:03:07.240 are at hacking up the stuff that's in there. So 0:03:07.320 --> 0:03:09.440 put all of this together, and you have a situation 0:03:09.760 --> 0:03:13.240 where you have a lot of junk clogging up the 0:03:13.280 --> 0:03:16.080 airways and the lungs, making it difficult for air to 0:03:16.120 --> 0:03:19.239 move through the spaces that it normally would move. 0:03:19.160 --> 0:03:21.200 Through, meaning it's hard to breathe. 0:03:21.240 --> 0:03:23.040 It's really hard to breathe in that situation. 0:03:23.120 --> 0:03:27.079 Absolutely obviously a very bad situation. What happens, how do 0:03:27.120 --> 0:03:27.919 you treat that person? 0:03:28.680 --> 0:03:31.720 So they wind up in the hospital. Sometimes you'll see 0:03:31.720 --> 0:03:33.920 them first in the emergency room, and you know the 0:03:34.000 --> 0:03:37.080 sounds are I won't say unmistakable, but the disease is 0:03:37.120 --> 0:03:40.000 so severe, and the babies who have it, they make 0:03:40.040 --> 0:03:43.119 such awful sounds when they have these infections. And you'll 0:03:43.160 --> 0:03:45.520 see also, it's not just the sounds they make, it's 0:03:45.520 --> 0:03:48.280 the way they look. So you'll see their chests kind 0:03:48.320 --> 0:03:51.600 of cave in with every breath they're trying to take 0:03:51.640 --> 0:03:54.000 as they're sucking hard on the air around them and 0:03:54.280 --> 0:03:55.440 failing to get enough in. 0:03:55.720 --> 0:04:00.000 So, if we zoom out on a national or global scale, 0:04:00.360 --> 0:04:03.600 like what is the impact quantitatively of RSV? 0:04:04.560 --> 0:04:09.119 We see around sixty thousand hospitalizations and kids under five 0:04:09.640 --> 0:04:12.720 and around one hundred and twenty thousand hospitalizations and adults 0:04:12.760 --> 0:04:17.200 over sixty five every year, and we see anywhere between 0:04:17.200 --> 0:04:20.080 one hundred and three hundred deaths in kids and around 0:04:20.120 --> 0:04:24.600 fourteen thousand deaths in adults every year in the US alone, 0:04:24.720 --> 0:04:25.880 in the US alone. 0:04:26.000 --> 0:04:28.920 And I understand that the infections, the RSV infections, come 0:04:28.920 --> 0:04:31.640 in waves. So when there is one of these waves, 0:04:31.680 --> 0:04:32.960 what's it like in the hospital? 0:04:33.320 --> 0:04:37.600 Oh, in the hospital, it's like beds in hallways, It's 0:04:37.760 --> 0:04:41.240 like not enough nurses and doctors to take care of 0:04:41.279 --> 0:04:44.680 the number of people they're seeing. And not enough respiratory 0:04:44.720 --> 0:04:47.560 therapists to go around and get people on oxygen and 0:04:47.920 --> 0:04:49.480 get people intubated. 0:04:49.720 --> 0:04:53.159 I mean, that's it's kind of amazing, right that there 0:04:53.240 --> 0:04:56.880 is this huge problem within the hospital of so many 0:04:56.920 --> 0:04:59.640 people who basically can't breathe or need help to breathe 0:04:59.680 --> 0:05:02.479 because they're sick with RSV. I never knew that. 0:05:03.000 --> 0:05:06.279 Yeah, Oh, RSV season is something that really in any 0:05:06.360 --> 0:05:12.919 medical profession you learn to fear. You learn to fear 0:05:12.960 --> 0:05:16.200 the season because you know it's just gonna be long 0:05:16.400 --> 0:05:19.919 days and longer nights of many, many very sick people 0:05:19.920 --> 0:05:23.160 coming to the hospital. You know, tons of babies with RSV, 0:05:24.520 --> 0:05:27.479 some really really sick kids, and uh and tons of 0:05:27.520 --> 0:05:29.960 really worried parents. It's a really tough time of year. 0:05:30.320 --> 0:05:33.520 And it always felt like there was no hope, you know, 0:05:33.680 --> 0:05:37.120 for vaccinating, for creating a vaccine. 0:05:37.120 --> 0:05:43.560 Until now, until now. The story of how we got 0:05:43.600 --> 0:05:46.880 to the RSV vaccine starts in nineteen fifty six. That 0:05:47.040 --> 0:05:49.760 was the year RSV was discovered, and as you may 0:05:49.839 --> 0:05:52.159 remember from last week's show, that was just a year 0:05:52.240 --> 0:05:55.880 after Jonas Salk's polio vaccine was approved to huge acclaim 0:05:56.360 --> 0:05:59.360 and so naturally, a group of scientists started developing an 0:05:59.480 --> 0:06:02.920 RSVV vaccine using the same technique that Saulk had used 0:06:02.920 --> 0:06:06.800 for polio. The idea was to grow the virus, kill it, 0:06:07.080 --> 0:06:10.760 and inject it into patients. By the mid nineteen sixties, 0:06:10.920 --> 0:06:13.960 scientists were ready to launch a clinical trial of their 0:06:14.000 --> 0:06:17.560 newly developed RSV vaccine, and they gave it to thirty 0:06:17.600 --> 0:06:21.520 one children in Washington, DC. I talked about this with 0:06:21.600 --> 0:06:25.800 Barney Graham. He's a virologist and he started studying RSV 0:06:26.160 --> 0:06:28.920 at the National Institutes of Health in the nineteen eighties. 0:06:29.440 --> 0:06:32.760 But that earlier work on RSV, that vaccine trial in 0:06:32.800 --> 0:06:35.919 the nineteen sixties, it had a huge effect on Barney 0:06:35.960 --> 0:06:37.360 and really on the whole field. 0:06:39.680 --> 0:06:43.640 During that winter time of sixty six sixty seven, just 0:06:43.720 --> 0:06:48.200 after Christmas, there was a big RSV outbreak that occurred, 0:06:49.160 --> 0:06:54.279 and of the thirty one children who were immunized with 0:06:54.400 --> 0:06:58.920 this vaccine, about I think twenty were infected, but of 0:06:58.960 --> 0:07:04.720 those twenty sixteen required hospitization. Two of them died. So 0:07:04.839 --> 0:07:10.920 it was a really catastrophic failure of the vaccine. 0:07:11.400 --> 0:07:13.600 Just to be clear. So that study found that the 0:07:13.680 --> 0:07:18.200 vaccine not only did it not protect children, it actually 0:07:19.560 --> 0:07:20.400 made them sicker. 0:07:20.760 --> 0:07:24.480 Yes, my first twenty years of research were really focused 0:07:24.520 --> 0:07:28.240 almost entirely on trying to understand this problem so we 0:07:28.280 --> 0:07:31.880 could get back to RSV vaccine development. 0:07:32.480 --> 0:07:35.000 So what happened with that nineteen sixties vaccine trail? Why 0:07:35.040 --> 0:07:35.559 did it fail? 0:07:36.160 --> 0:07:39.440 So the vaccine that was made in the nineteen sixties, 0:07:40.120 --> 0:07:44.080 the way that the vaccine was prepared changed the proteins 0:07:44.120 --> 0:07:48.040 in a way that when that was used to immunize, 0:07:48.200 --> 0:07:52.320 it created antibodies that could bind the virus but did 0:07:52.360 --> 0:07:55.720 not block the virus or didn't prevent virus infection. And 0:07:55.800 --> 0:07:59.280 so having a lot of antibody and a lot of 0:07:59.360 --> 0:08:03.760 virus to get together without preventing infection can sometimes lead 0:08:04.200 --> 0:08:05.560 to problems. 0:08:05.680 --> 0:08:08.400 And in this instance, it did lead to problems. 0:08:08.560 --> 0:08:11.760 Yes, it did lead to problems. And then what was 0:08:11.840 --> 0:08:17.160 needed to make that vaccine work is having proteins that 0:08:17.280 --> 0:08:21.520 could make better antibody responses and not so many ineffective 0:08:21.520 --> 0:08:22.720 antibody responses. 0:08:24.840 --> 0:08:28.400 When Barney says proteins there, he's talking in particular about 0:08:28.400 --> 0:08:31.400 this one protein that sits on the outer surface of 0:08:31.440 --> 0:08:35.720 the virus. That protein is important because our immune system 0:08:36.040 --> 0:08:40.000 recognizes that protein and then creates matching antibodies to destroy 0:08:40.040 --> 0:08:43.679 the virus. The proteins called the F protein or the 0:08:43.800 --> 0:08:48.240 F glycoprotein. F stands for fusion because it's the protein 0:08:48.320 --> 0:08:50.880 that the virus uses to fuse with the cell in 0:08:50.920 --> 0:08:54.360 the human body, and Barney and his colleagues knew they 0:08:54.440 --> 0:08:57.000 needed to crack the code of that F protein. 0:08:58.640 --> 0:09:02.600 What I knew about the F protein on RSV was 0:09:02.600 --> 0:09:05.720 that it was a blob on a western blot that 0:09:05.960 --> 0:09:09.760 just looked like a black ink spot, and you could 0:09:09.840 --> 0:09:14.120 tell what size it was, but you couldn't really see it. 0:09:14.200 --> 0:09:18.200 You couldn't really understand how it was folded and how 0:09:18.240 --> 0:09:22.160 it worked. If you want to make a vaccine, you 0:09:22.320 --> 0:09:25.640 really need to see the protein and how it interacts 0:09:25.640 --> 0:09:29.280 with the antibodies and the exact surface contours and the 0:09:29.360 --> 0:09:32.720 exact shape of that protein. So if you want to 0:09:32.720 --> 0:09:35.439 get a virus infection started, you have to figure out 0:09:35.440 --> 0:09:37.679 a way to get the virus, you know, inside the 0:09:37.880 --> 0:09:40.600 human cell in order for the virus to start growing. 0:09:41.640 --> 0:09:43.800 And the way the virus does that it has this 0:09:44.880 --> 0:09:49.040 interesting protein on its surface that is able to transform. 0:09:49.120 --> 0:09:53.800 It is able to unravel, reach out, grab the host 0:09:53.920 --> 0:09:58.960 cell or target cell membrane and pull the membranes back together, 0:09:59.200 --> 0:10:05.320 so the host cell and the virus membrane fuse. They merged, 0:10:06.320 --> 0:10:09.679 then the virus genome can enter the cell and start 0:10:09.720 --> 0:10:11.000 the replication process. 0:10:11.080 --> 0:10:14.160 I mean, that's the crucial bad thing that happens, right, 0:10:14.240 --> 0:10:15.760 That's the thing we don't want to happen. 0:10:15.880 --> 0:10:18.720 If you want to stop a virus infection, if you 0:10:18.800 --> 0:10:23.600 can stop that F protein from rearranging or from attaching, 0:10:23.840 --> 0:10:28.480 then you've got a good way of stopping the virus infection. 0:10:29.600 --> 0:10:34.679 What did scientists not know about that F protein. 0:10:35.040 --> 0:10:37.960 Well, the main thing we didn't know is why it 0:10:38.040 --> 0:10:40.560 had not worked as a vaccine. 0:10:41.200 --> 0:10:43.880 And what did you want to learn about the F 0:10:43.960 --> 0:10:46.040 protein to try and solve that problem. 0:10:46.480 --> 0:10:49.240 Well, we really wanted to know what the F protein 0:10:49.320 --> 0:10:53.440 looked like in its original state. We wanted to know 0:10:54.040 --> 0:10:58.160 where the antibodies could bind F protein and how what 0:10:58.400 --> 0:11:02.160 was the mechanism for neutral the virus. And to understand 0:11:02.240 --> 0:11:04.920 those things, we needed to know more about the structure 0:11:04.920 --> 0:11:08.679 off not just in its final rearranged state, but in 0:11:08.720 --> 0:11:09.760 its original state. 0:11:11.679 --> 0:11:15.240 Barney's making a really key point right here that F 0:11:15.320 --> 0:11:18.800 protein on the surface of rsv it exists in two 0:11:18.880 --> 0:11:21.800 different shapes. It has one shape when the virus is 0:11:21.840 --> 0:11:24.080 floating around in the body searching for a cell to 0:11:24.160 --> 0:11:27.640 fuse with. Then when the virus fuses with the cell, 0:11:27.800 --> 0:11:31.440 the F protein changes shape. So what our immune system 0:11:31.480 --> 0:11:34.840 needs are antibodies to that F protein when it's in 0:11:34.880 --> 0:11:38.079 its prefusion state, before it's fused with the cell in 0:11:38.120 --> 0:11:41.000 our body. But when Barney and his colleagues were studying 0:11:41.040 --> 0:11:44.200 the virus, they always saw the protein in the other shape, 0:11:44.320 --> 0:11:47.200 in the post fusion shape. That problem went all the 0:11:47.200 --> 0:11:50.160 way back to that failed vaccine in the nineteen sixties, 0:11:50.480 --> 0:11:52.440 and it was a problem Barney was still trying to 0:11:52.440 --> 0:11:55.520 solve in two thousand and eight. That's when Barney had 0:11:55.559 --> 0:11:58.680 a chance meeting with the scientist who would finally solve 0:11:58.760 --> 0:12:01.520 the puzzle that r s V researchers had been working 0:12:01.520 --> 0:12:04.040 on for decades. Well, hear that part of the story 0:12:04.240 --> 0:12:15.120 in just a minute. While Barney Graham was working way 0:12:15.240 --> 0:12:17.240 trying to solve the puzzle of how to create a 0:12:17.280 --> 0:12:20.800 vaccine for RSV, he met a guy named Jason McClellan, 0:12:21.040 --> 0:12:23.800 who at the time was a research fellow who worked 0:12:23.840 --> 0:12:27.720 just down the hall. I recently talked with Jason McClellan 0:12:27.840 --> 0:12:29.520 and we started with the work he was doing when 0:12:29.520 --> 0:12:32.240 he met Barney. While Barney had been studying the proteins 0:12:32.240 --> 0:12:35.560 on the outside of RSV, Jason was studying the proteins 0:12:35.559 --> 0:12:39.160 on the outside of a different virus, HIV. This was 0:12:39.200 --> 0:12:41.280 back in two thousand and eight, and at the time 0:12:41.400 --> 0:12:43.600 Jason told me he was working in a field called 0:12:43.720 --> 0:12:45.520 structure based vaccine design. 0:12:46.760 --> 0:12:49.640 It's really a trying to turn vaccine development into a 0:12:49.760 --> 0:12:54.200 very rational engineering approach that's guided by the human immune system. 0:12:54.840 --> 0:12:57.400 That word engineering is good, right, You're like actually trying 0:12:57.440 --> 0:13:01.000 to build a thing in a certain shape exactly when 0:13:01.040 --> 0:13:04.040 you so you joined this lab working on this idea 0:13:04.480 --> 0:13:08.160 structure based vaccine design for HIV. There's this idea, Oh, 0:13:08.200 --> 0:13:10.800 we have these new tools, we could we could build 0:13:10.880 --> 0:13:17.120 vaccines in this new, potentially better way. Had anybody done 0:13:17.160 --> 0:13:17.520 it yet? 0:13:18.760 --> 0:13:22.680 No. That's really some of the pioneering efforts for structure 0:13:22.720 --> 0:13:27.880 based vaccine design and its application to HIV, And it 0:13:27.960 --> 0:13:32.640 quickly became a parent that we're developing really cool approaches, 0:13:33.040 --> 0:13:35.320 but many of them aren't working, and it's unclear whether 0:13:35.360 --> 0:13:38.480 the approaches aren't good or the virus is just so 0:13:38.600 --> 0:13:42.280 difficult to make a vaccine for why don't we sort 0:13:42.280 --> 0:13:44.680 of apply this to maybe a more tractable virus so 0:13:44.679 --> 0:13:49.080 we could test some of these techniques. And I was 0:13:49.120 --> 0:13:50.920 on a different floor from the rest of the lab. 0:13:50.960 --> 0:13:54.000 I was actually in Barney Graham's floor, and Barney heard 0:13:54.040 --> 0:13:56.680 of this and he was like, you know, RSV would 0:13:56.679 --> 0:13:59.640 be perfect for applications of structure based vaccine design. So 0:14:00.480 --> 0:14:02.440 for the next yeah, the rest of my time next 0:14:02.440 --> 0:14:04.680 five years or so, I sort of split half my 0:14:04.720 --> 0:14:07.960 time working on HIV and half my time working on RSB. 0:14:08.559 --> 0:14:10.640 So this is a good guy for you to meet 0:14:10.720 --> 0:14:13.320 at this moment. This is a good happy meeting in 0:14:13.320 --> 0:14:14.520 this science. 0:14:14.160 --> 0:14:18.040 Scenario, it's very fertuitous happy meeting. It was like December 0:14:18.040 --> 0:14:20.280 two thousand and eight, when we had sort of formalized 0:14:20.280 --> 0:14:23.680 the plan. We decided to start working on RSV in 0:14:23.720 --> 0:14:24.800 structure based design. 0:14:25.240 --> 0:14:27.440 At this moment, when you decide to do this, what's 0:14:27.480 --> 0:14:28.680 the key thing you don't know? 0:14:30.240 --> 0:14:34.160 So we know that the F protein exists in two confirmations. 0:14:33.720 --> 0:14:35.040 Too, Does that mean two shapes? 0:14:35.480 --> 0:14:38.160 Two shapes? Yeah, So they had been so it had 0:14:38.200 --> 0:14:42.160 been imaged by electron microscopy, and it was clear that 0:14:42.240 --> 0:14:45.080 one form looked like these elongated golf teas and the 0:14:45.160 --> 0:14:48.720 other was sort of more oval, lollipop shaped with like 0:14:48.720 --> 0:14:51.760 a little stock. And so it had become appreciated that 0:14:52.000 --> 0:14:55.480 one of them was the prefusion confirmation, okay, and then 0:14:55.720 --> 0:14:57.480 the other one is postfusion. 0:14:57.640 --> 0:15:00.840 And so it's basically, before it's attached to this this 0:15:00.920 --> 0:15:03.160 protein has one shape and after it's attached to the shell, 0:15:03.200 --> 0:15:04.000 it has another shape. 0:15:04.160 --> 0:15:10.040 Yeah, we were unable to make the prefusion state as 0:15:10.040 --> 0:15:13.960 a purified protein. So if you just purify f it 0:15:14.040 --> 0:15:16.840 sort of snaps into the postfusion state, which is the 0:15:16.880 --> 0:15:21.040 lowest energy, most stable state, and people had immunized with that, 0:15:21.440 --> 0:15:23.920 but it was insufficient to make a vaccine. 0:15:23.960 --> 0:15:27.120 Well, and that makes sense at some level, right, because 0:15:27.600 --> 0:15:31.560 what you actually want to immunize against is the prefusion shape. 0:15:31.640 --> 0:15:31.760 Right. 0:15:31.800 --> 0:15:34.720 The virus is floating around in our respiratory tract and 0:15:35.040 --> 0:15:37.240 it's before it attaches to the cells, it's in the 0:15:37.280 --> 0:15:38.480 prefusion shape. 0:15:38.520 --> 0:15:38.680 Right. 0:15:38.680 --> 0:15:40.760 What we really want is for our body to have 0:15:40.800 --> 0:15:43.360 on the bodies to attack that. So if you're using 0:15:43.360 --> 0:15:46.160 the postfusion state, it's intuitive that like that's not going 0:15:46.240 --> 0:15:47.320 to work as well. 0:15:47.120 --> 0:15:51.080 Right, Exactly, Our colleague Jose Malero in Spain. What he 0:15:51.200 --> 0:15:54.800 showed was that most of the neutralizing antibodies did not 0:15:54.920 --> 0:15:59.800 bind postfusion, suggesting that the majority of the antibodies humans 0:15:59.800 --> 0:16:04.120 may in response to an RSV infection do not target posts. 0:16:04.280 --> 0:16:06.920 And we have the problem that it's hard to isolate 0:16:06.960 --> 0:16:09.200 pre we don't know exactly what it looks like, like, 0:16:09.240 --> 0:16:11.080 this is the this is the problem, right. 0:16:11.040 --> 0:16:15.640 Yeah, So we assumed that from Hose's data that there 0:16:15.640 --> 0:16:20.040 are antibodies that bind only to prefusion. So we thought 0:16:20.080 --> 0:16:25.040 that if we could isolate some antibodies like this, we 0:16:25.080 --> 0:16:27.840 could make F protein in the presence of these antibodies, 0:16:28.360 --> 0:16:33.600 and when F transiently adopts prefusion, the antibody binds and 0:16:33.640 --> 0:16:37.119 locks it, and then we'd be able to purify that complex. 0:16:37.520 --> 0:16:42.000 That's very clever. So you're using the body's own response 0:16:42.120 --> 0:16:46.240 to the prefusion protein, the antibodies to basically make a 0:16:46.280 --> 0:16:51.920 trap for the prefusion protein. Exactly In the lab, Jason 0:16:52.000 --> 0:16:55.000 runs an experiment to do just this. He takes an 0:16:55.200 --> 0:16:59.120 F protein in that prefusion shape, that lollipop shape, and 0:16:59.160 --> 0:17:02.720 then he binds the protein to an antibody, and once 0:17:02.760 --> 0:17:05.920 the F protein is bound to the antibody. The protein 0:17:06.080 --> 0:17:09.520 cannot change its shape. So now Jason has the F 0:17:09.560 --> 0:17:12.800 protein locked in place in the right shape, and he 0:17:12.880 --> 0:17:16.440 needs to see exactly what it looks like. To do that, 0:17:16.760 --> 0:17:20.400 he uses a technique called xtray crystallography, which lets him 0:17:20.440 --> 0:17:23.639 see the shape of the protein in incredible detail. He 0:17:23.680 --> 0:17:28.000 can see the atomic level structure of this prefusion F protein, 0:17:28.560 --> 0:17:31.680 and Jason knew this was a very big deal. 0:17:33.440 --> 0:17:37.800 It was going to allow us to make prefusion. 0:17:37.280 --> 0:17:39.520 F okay to use as a vaccine. 0:17:39.680 --> 0:17:40.000 Aha. 0:17:40.400 --> 0:17:43.560 Right, So you can make the exact thing as it 0:17:43.600 --> 0:17:48.200 exists on the surface of an RSV cell and put 0:17:48.240 --> 0:17:52.159 it into people's bodies in some fashion, and you'll have 0:17:52.240 --> 0:17:55.359 the perfect protein. You'll have the exact shape of the protein, 0:17:55.400 --> 0:17:59.440 and the body will make these great antibodies and that 0:17:59.480 --> 0:18:02.439 body don't get sick with RSV if everything goes according 0:18:02.480 --> 0:18:03.720 to plan exactly right. 0:18:03.760 --> 0:18:06.239 It's like, I don't know, we're sculptors, and now we 0:18:06.280 --> 0:18:08.240 have the model of what we need to make the 0:18:08.280 --> 0:18:11.440 sculpture of and it allows us to make ideal mimics 0:18:11.680 --> 0:18:14.080 of these proteins found on the surface of the virus. 0:18:14.280 --> 0:18:18.560 Amazing. So at this at this moment, do you feel 0:18:18.560 --> 0:18:25.480 like you've got it, Like you feel like you yet Yeah, okay, 0:18:25.800 --> 0:18:27.960 what has to happen when we're very excited? 0:18:27.960 --> 0:18:30.879 We have pre F, but we we have not been 0:18:30.920 --> 0:18:33.720 able to produce it in the absence of those antibodies 0:18:33.760 --> 0:18:36.800 the camp it okay, right, So that's the key. We 0:18:36.880 --> 0:18:40.280 have to modify the F protein such that when we 0:18:40.440 --> 0:18:44.359 express it in cells in the absence of antibodies, it 0:18:44.480 --> 0:18:48.159 folds into PREF, stays in pre F, and allows us 0:18:48.200 --> 0:18:49.000 to immunize with it. 0:18:49.600 --> 0:18:52.119 So you have to kind of build a version of 0:18:52.160 --> 0:18:56.840 it from scratch. Now that'll work in this very particular 0:18:56.880 --> 0:18:59.159 way that it has to work for you're going to 0:18:59.200 --> 0:19:00.440 make a vaccine, right. 0:19:00.640 --> 0:19:05.720 I designed several substitutions that ended up working. Four of 0:19:05.760 --> 0:19:10.800 them in combination allowed the prefusion F protein to be 0:19:11.160 --> 0:19:12.439 expressed and purified. 0:19:12.560 --> 0:19:16.160 And this is more sculpting, right, literally like filling holes 0:19:16.200 --> 0:19:18.640 in the shape of the protein, right, Yeah. 0:19:18.480 --> 0:19:20.800 Because the structure tells us, oh, there's some pockets and 0:19:20.800 --> 0:19:24.280 cavities here that are causing instability, so why don't we 0:19:24.359 --> 0:19:24.880 fill them? 0:19:25.560 --> 0:19:28.800 You're really building this physical thing in a particular way. 0:19:29.000 --> 0:19:32.080 Yeah, yeah, very specifically. So we have we have like 0:19:32.119 --> 0:19:36.200 almost an atomic level mimic. And then the next step 0:19:36.359 --> 0:19:39.040 was to make those proteins and provide them to Barney 0:19:39.040 --> 0:19:42.920 Graham's lab. And so Barney then immunized mice and then 0:19:43.000 --> 0:19:45.439 blood was drawn from the mice and they'd performed the 0:19:45.520 --> 0:19:49.800 neutralization essays. And then that was the exciting day. That's 0:19:49.840 --> 0:19:53.600 when because Barney told me it's he couldn't believe it. It 0:19:53.640 --> 0:19:57.000 was the highest neutralizing antibody tighters he had ever seen 0:19:57.240 --> 0:19:59.360 in his decades of working on RSV. 0:20:00.160 --> 0:20:05.600 Meaning the best, right, yeah, it listened, the strongest response. Yeah. 0:20:05.600 --> 0:20:07.960 And so at that point we're like, we got it, 0:20:08.119 --> 0:20:10.720 Like this, this is exactly what we were looking for, 0:20:11.200 --> 0:20:14.760 this proof of concept for structure based vaccine design. 0:20:15.680 --> 0:20:23.720 So now in twenty twenty three, these RSV vaccines based 0:20:23.760 --> 0:20:27.080 on your research are are coming out. They're a thing 0:20:27.080 --> 0:20:30.719 in the world, and millions of people presumably are getting 0:20:30.720 --> 0:20:33.520 this vaccine, are about to get this vaccine. I mean, 0:20:33.520 --> 0:20:36.160 what's that like for you? That's amazing. 0:20:38.359 --> 0:20:41.520 That always wanted to try to have some impact improve 0:20:41.560 --> 0:20:43.960 people's lives, and you know, you know, it's sort of 0:20:44.000 --> 0:20:46.720 a long shot to actually help make a vaccine, just 0:20:46.760 --> 0:20:50.919 given how few vaccines get approved but to actually do 0:20:51.000 --> 0:20:53.159 it is I mean, it's credible. It's everything you can 0:20:53.240 --> 0:20:53.640 hope for. 0:20:55.359 --> 0:20:58.240 There is one more piece of the Jason and Barney 0:20:58.280 --> 0:21:03.120 story that's worth telling before we go. In twenty twelve, 0:21:03.200 --> 0:21:06.080 there was an outbreak of a new disease in Saudi Arabia. 0:21:06.480 --> 0:21:09.320 The disease was caused by a coronavirus, and it was 0:21:09.359 --> 0:21:14.200 given the name MERZ for Middle Eastern Respiratory syndrome. Jason 0:21:14.240 --> 0:21:17.480 and Barney went to work on that coronavirus. Using the 0:21:17.600 --> 0:21:21.440 engineering and structural biology techniques they'd honed in their work 0:21:21.480 --> 0:21:25.639 on RSV. They developed an incredibly detailed picture of the 0:21:25.680 --> 0:21:29.840 prefusion spike protein. They did that sculpting works to create 0:21:29.880 --> 0:21:33.960 a stable version of that protein, and they did preliminary 0:21:34.000 --> 0:21:39.199 work toward developing a vaccine. Then, in twenty nineteen, another 0:21:39.280 --> 0:21:43.680 new coronavirus emerged, the virus that causes COVID. This time, 0:21:43.960 --> 0:21:46.720 Jason and Barney were ready. The work they had done 0:21:46.720 --> 0:21:50.359 first on RSV then on MERZ meant that just a 0:21:50.400 --> 0:21:53.720 few weeks after that new virus was discovered, they were 0:21:53.760 --> 0:21:57.040 able to create a stabilized version of that key spike 0:21:57.080 --> 0:22:00.439 protein in just the right shape that work played a 0:22:00.480 --> 0:22:04.440 major role in designing the COVID nineteen vaccines. The protein 0:22:04.480 --> 0:22:06.600 they created was one of the key reasons it was 0:22:06.680 --> 0:22:12.840 possible for the vaccines to be developed so quickly. Thanks 0:22:12.840 --> 0:22:16.760 to my guests today Karen Lanman, Arnie Graham, and Jason McClellan. 0:22:17.840 --> 0:22:21.280 Next week on Incubation, the story of the Common Cold Unit, 0:22:21.600 --> 0:22:25.480 a place where tens of thousands of people went voluntarily 0:22:25.600 --> 0:22:30.640 for decades to catch a cold. You know, Britain post war. 0:22:31.359 --> 0:22:33.679 Chimpanzees are not easy to come by to do this 0:22:33.760 --> 0:22:37.160 type of research, So what's definitely the next best thing 0:22:37.320 --> 0:22:43.240 are human volunteers, so human guinea pigs. Incubation is a 0:22:43.240 --> 0:22:47.040 co production of Pushkin Industries and Ruby Studio at iHeartMedia. 0:22:47.359 --> 0:22:50.720 It's produced by Gabriel Hunter Chang, Ariela Markowitz and Amy 0:22:50.800 --> 0:22:55.440 Gaines McQuaid. Our editors are Julia Barton and Karen Schakerjie 0:22:55.480 --> 0:22:59.119 Mastering by Anne Pope, fact checking by Joseph Fridman. Our 0:22:59.160 --> 0:23:03.520 executive producers are Katherine Girardeau and Matt Romano. I'm Jacob Goldstein. 0:23:03.720 --> 0:23:04.479 Thanks for listening.