Hard Drugs

Saloni Dattani: I read that if just a single parasite makes it to the liver, it can cause an infection. Is that true?

Katharine Collins: Yeah, that's right. And I think that's the really tough challenge with Malaria.

Jacob Trefethen: The reality of this problem is the hardness of it is set by nature, and nature is a vicious test setter.

Katharine Collins: Adrian asked if I wanted to stay on, this was the PhD project that he pitched to me. I thought it sounded quite interesting to make a new vaccine. There was a lot of iteration. The first time I saw the particles under electron microscope that was really exciting.

Saloni Dattani: Would you participate in the challenge trial?

Katharine Collins: I would love to, but I really hate needles. I have to lie down. Otherwise I might faint. It's kind of ironic for a vaccine developer.

Jacob Trefethen: There are people like Katharine Collins who invent entirely new vaccines that are now gonna be used by millions of children. You may know one of these people. You may become one of these people in the future.

Saloni Dattani: Malaria kills around 600,000 people a year. Most of them are young children in Sub-Saharan Africa. It's caused by a parasite, not a bacterium or virus, and it's spread by a mosquito. Until recently, the only control measures were insecticides and a handful of anti-malarial drugs. But in the last few years, we finally got effective vaccines.

Jacob Trefethen: Two malaria vaccines have now received WHO recommendations and are being rolled out across Africa. And for the first time ever, a human-infecting parasite has a vaccine.

Saloni Dattani: Getting here took longer than it should have. The first malaria vaccine was developed and tested in the nineties, but it's spent 23 years in clinical trials and pilot tests before it was licensed and rolled out.

Jacob Trefethen: So in this episode, we're going to cover the science of why malaria is so hard to vaccinate against, how the vaccines actually work, why it took so long, what we can do to speed up the rollout now, and what even better vaccines are being tested now for fewer doses and longer durability in the future.

Saloni Dattani: Today's episode is special because we're joined by Katharine Collins, who co-invented the second malaria vaccine during her PhD, and she can tell us what it was actually like from the inside. Welcome to Hard Drugs, hosted by me, Saloni Dattani, and Jacob Trefethen.

Okay, so we have some news today, right? Because Jacob, you have started a new job. Could you tell us about what you're doing now?

Jacob Trefethen: I'm gainfully employed. I'm working at a new foundation making grants to science still, but from a different vantage point. It's the OpenAI Foundation and we have been getting started in science, so it's kind of exciting, a little bit different than my previous job which was at Coefficient Giving. And the previous job was quite fun. But you'll have to ask around what my reputation was there, for example, Katharine, what was I like back then?

Katharine Collins: Jacob, you were the best manager I've ever had.

Jacob Trefethen: No no, we can't include that! No, no. Expulsion! No, my biggest difficulty of changing jobs is that I don't get to work with some of the wonderful people I worked back at Coefficient Giving with, like Chris Somerville, Ray Kennedy, Heather Youngs, Rafael Dib, Douglas Chukwu. Oh gosh. So many people, Aisling Leow. And guess who? Katharine Collins. Now the good news is that Katharine at least is here today.

Saloni Dattani: So Katharine is joining us from Coefficient Giving as well, and is a very special guest on today's episode because she co-invented the second malaria vaccine.

Jacob Trefethen: Now we are lucky at Hard Drugs to have listeners around the world, and that means I'm going to start here with some insight into the British psyche. For those listening from other places, we have a guest on today who is an inventor and she's also British. That means that she's very reticent to take credit for things, even things she invented, so it took a lot of cajoling to get her onto this episode, though we knew if we could pull it off that our listeners would love it.

So I am very grateful for the willingness of our guests to be cajoled, but I should say upfront, as part of our ability to pull it off, that there are many other people involved in the story of malaria vaccines and of R21 in particular, who we won't get to have on today, who took forward the vaccine into clinical trials, who did all the work to make sure it could get approved and used by kids around the world. So that's my proviso, that's the trade we had to make with our world famous inventor. With that in mind, enjoy.

Saloni Dattani: So I have a question for both of you, which is, do you have a favorite parasite?

What I didn't realize until recently was that fungi and plants can also be parasites. And so a parasite could be a single celled organism. It could be an animal like a mosquito, vampire bats, hookworms. Or it could be fungi like the ringworm fungi. Or it could even be a plant, like mistletoe is a parasite.

Jacob Trefethen: What?!

Saloni Dattani: Yeah, mistletoe is a parasite. It attaches to other trees and extracts water and nutrients from them.

Jacob Trefethen: Gosh. And here I was. Okay. I think I have two answers. You brought up hookworm. Hookworm's one of my answers, tape worm's another one of my answers. I mean, tape tapeworms disgusting, obviously, but you just have to be impressed. They get so large.

Saloni Dattani: How large do they get?

Jacob Trefethen: Like, I don't know, probably miles long. Joking.

Saloni Dattani: Wow.

Jacob Trefethen: They get feet long for sure. And maybe meters. I mean, I just think that's crazy. It's obviously gross, but luckily hookworms aren't gross at all. All they do is hook onto the side of your gut and suck your blood. They come up, they sort of get up through your foot, sneak - their whole life cycle's insane - they eventually get down into your gut and hook onto it and start sucking your blood. I mean, that's pretty impressive.

Saloni Dattani: Is that why they're called hookworms? Because they hook onto your gut?

Jacob Trefethen: You know, I've never thought of that. And the answer is probably yes, but I don't know.

Saloni Dattani: And then are tape worms called that because they look like tape?

Jacob Trefethen: No, it's actually 'cause on the underside, they are sticky.

Saloni Dattani: Oh, wow.

Jacob Trefethen: That's a joke. Sorry. That's a joke. That's a joke.

Saloni Dattani: Oh, you tricked me!

Jacob Trefethen: First trick of the episode!

Saloni Dattani: Okay. My favorite parasite also, well, I'm not impressed by this, I'm just so horrified by it that I have decided it's also my favorite. And it's Guinea worm, which is so horrible. And people ingest the worm larvae when they drink contaminated water. And the larvae get into your stomach, they get through your gut, and then they grow into worms that can reach up to a meter long. And they kind of crawl through your connective tissue and your joints, and then slowly erupt out of your legs - usually out of the skin, near your legs. And the emergence is also very slow. And the way that you remove the worm is by slowly winding the worm around a small stick, and if you go too fast, the worm snaps and dies, and that causes severe inflammation in your body.

Jacob Trefethen: That sounds like it was invented by Jigsaw from the series Saw as a patient to someone who was impatient or something. Okay, well thank you for that.

Saloni Dattani: Wait, wait, wait. The good news is though, we've almost eradicated it. Isn't that great? So it used to cause like a million or more cases per year in the 1980s, and it turns out just cleaning up the water, filtering drinking water, or telling people not to drink from stagnant water can help prevent infections.

Jacob Trefethen: Do you know how near eradication we are?

Saloni Dattani: I think there were 10 cases reported in total last year.

Jacob Trefethen: Wow!

Katharine Collins: Wow. That's incredible.

Saloni Dattani: Yeah, so from millions per year to 10. What about you Katharine?

Katharine Collins: Yeah, mine's really boring. Mine's the malaria parasite. I can't say anything else after studying it for two decades.

Saloni Dattani: Yeah, it would be really surprising if you said something else.

Jacob Trefethen: Yeah, it would kind of be like adultery or something.

Saloni Dattani: In this episode we're going to talk a lot about the two malaria vaccines that have been rolled out. The first one is called RTS,S and it was developed in the 1990s. The second was R21, it was invented by Katharine Collins, who's here with us today, and it was based on the first one. So those are two names that we're gonna refer to throughout the episode. RTS,S, the first malaria vaccine and R21, the second malaria vaccine.

I guess it's easy to remember because the second one has two in it, R21, but just in case that is confusing; those are the two names that you've gotta remember. RTS,S, the first malaria vaccine and R21, the second.

Maybe let's start with how you got into malaria research in the first place. What drew you into the field? Or how did you get into vaccine research?

Katharine Collins: I had done my undergraduate and my master's degree in basic research and not in global health. I did various projects in different disease areas, but it was really about trying to understand the fundamentals and different signaling pathways and things like that. So I think one of my projects identified a protein interacted with another protein in a pathway. And while that was cool, and I loved science and it's definitely where I'm supposed to be, but it I didn't see how that was gonna have any direct impact on health in the near term.

I actually started looking for jobs, or how I could have an impact in global health, or how I could transition from science into global health work, and it wasn't really clear. And then this job was advertised at Oxford University to work on malaria vaccine trials. And I thought, wow, that's global health. I should just take that job, and or apply for that job, and that may open doors. And so I did. And I really loved working on malaria. It was instantly something I was really passionate about, really motivated to work on. It's just a fascinating parasite.

So the job was a research assistant on malaria vaccine trials. So the Jenner institute at Oxford, where Adrian Hill's group that I joined, they were testing a number of different candidates in malaria trials. And my job was to help coordinate those trials and to do all the immunology in the background.

Saloni Dattani: And then how did that turn into inventing a new vaccine?

Katharine Collins: Yes. Well, after being there for about a year, Adrian asked if I wanted to stay on, and do a PhD. The project idea was that Adrian had developed a vaccine that targeted the malaria parasites, whilst they were in the liver. It'd been shown to protect some people against infection, but it was quite a low level, I think it was 20% efficacy. So the idea was to combine this liver stage vaccine for the vaccine that could also prevent the malaria parasites before they get to the liver. So stop them invading the liver.

And the leading vaccine at that time targeted the parasites before they invaded the liver, and this was a circumsporozoite based vaccine called RTS,S, and it was developed by GSK. So he wanted me to work on making a newer version, an updated version of that vaccine.

Saloni Dattani: That's so cool. I feel like compared to - so my PhD was very boring in comparison to this, and it makes me think that there's actually -

Jacob Trefethen: Wait, Saloni, did you not invent a vaccine in your PhD?

Saloni Dattani: I know, I feel like people should know upfront that some PhDs are better than others. You know, some fields are better than others. So who else was involved in this? Did you have mentors, collaborators, rivals, or enemies?

Katharine Collins: I worked fairly alone in the lab. I did have a few people that were supporting the work as well. So my PhD supervisors were Adrian Hill and Sarah Gilbert. There were also a couple of postdocs and technicians and PhD students that helped me with various parts of the project over the years. For example, someone actually helped me vaccinate all the mice that we used for the preclinical experiments. And then I did the immunology myself.

Saloni Dattani: And Sarah Gilbert is the inventor of the AstraZeneca vaccine, is that right?

Katharine Collins: That's right. Yeah.

Saloni Dattani: For COVID. Got it.

Katharine Collins: Yeah.

Saloni Dattani: And rivals?

Katharine Collins: Rivals, well, oh, you're asking the good questions. I guess in the field at the time, there were lots of people trying to develop a malaria vaccine. I guess there was competition between the different groups to see who would get there first. And whilst I was working on it, RTS,S hadn't crossed the finish line, but it was obviously way, way, way further ahead in development. So the expectation was that that vaccine would move forward and get approved first, and then R21 may follow.

Saloni Dattani: Right. And by that point, had the RTS,S patent already expired?

Katharine Collins: Yes, actually that's right. So if I remember correctly, it was due to come off patent. And interestingly, that was essentially the starting place for learning how to make R21. So I reviewed that patent, I looked at how they've made RTS,S, and then I made a plan for how to go about making R21.

Saloni Dattani: Did that have enough information for like? What was that like?

Katharine Collins: So RTS,S is actually made with a lot of a protein on the surface of the Hep B virus. This is the Hep B surface antigen and that was needed to make it form the virus like particle, but it had quite an excess of Hep B surface antigen. So it's actually a really good Hep B vaccine, and not a terribly good malaria vaccine. So my project was to see if we could remove some of that Hep B and actually make it a better malaria vaccine.

And we had established a plan for how we're going to get there. So initially we wanted to just replicate the RTS,S process in the lab and then try a few different things to see if we could get the particle to form without this excess Hep B surface antigen. One approach was actually to just try and chop out some of the malaria protein out of the vaccine and remove some of the T-cell epitopes, which were in there, and a few other bits as well, and see if the smaller protein would be more able to form particles on its own. The other way was just to try and reduce the amount of extra Hep B that we were adding and see if it could form particles on its own that way, by using some of these newer yeast expression technologies to grow the protein and new methods to purify.

I think RTS,S had something like a 12 step purification process at least in the patent, and that might not be what they used anymore. But I wasn't really interested in trying to set up this 12 step new process in an academic lab. You know, I'm not a biochemist. So I essentially looked at their process to understand what they had done and why, and then developed a purification process using a combination of some of those old methods and some of the newer technologies.

Saloni Dattani: I feel like my immediate question is why didn't the developers of the RTS,S vaccine do that? Like if there were various steps that didn't need to be included.

Katharine Collins: Yeah, I mean, they probably did. I mean, when they first patented what they were doing, it probably had this multi-step process. Maybe they had different process they were using lots of different methods, so they patented the whole process and I'm sure they probably optimized that as they scaled up and improved their manufacturing.

Jacob Trefethen: I wanna just get a more of a sense of what it feels like to be in the lab alone, toying with different steps of purification, and how long were you - did you feel sort of lost versus actually, it worked pretty quickly and you got, once you saw in the electron microscope, you're like, oh God, it's actually gonna work. Was that pretty quick or you were there for months, years? You're tinkering. What did the invention process feel like?

Katharine Collins: Actually, I think I was interviewed by someone a while ago and I, my recollection is that it was very quick that I kind of give it a go and it worked.

Saloni Dattani: Wow.

Katharine Collins: And then I thought, now I thought, is this true? And I went back to my lab notebooks and I had a look through like the electronic notebooks and I had a look through and it wasn't that quick. There was a lot of iteration, a lot of optimization that happened with every single stage.

So we were using yeast to express the protein and grow the protein, and there were four different strains we were testing, and then for each different strain, we picked multiple different colonies, and I screened all of these different colonies first to find the best expressing colonies, and then I started to try and purify it, to purify them. And I probably used multiple different techniques until I got something that looked substantial. So it wasn't that quick. So I think it was a long time ago now, so my memory's a bit optimistic maybe?

Saloni Dattani: So am I imagining right that it's like, you have the instructions-ish from the patent and then you're trying out different options, like different versions of the yeast, different versions of the purification process, and at each step trying to optimize which is the best one to go forward with or something like that? Or is that not the right way to think about it?

Katharine Collins: Yeah, that's just about right. There are a lot of newer technologies available for purifying proteins and particles, so it's kind of a process of looking at which steps could be replaced by newer technologies and going for something that was more modern and simpler, where that was possible, and where there wasn't a newer technology, we were sticking with that whole process as well.

Saloni Dattani: So you were at the Jenner Institute, is that right?

Katharine Collins: That's right.

Saloni Dattani: Do they have just people working on many different diseases and like trying to develop vaccines against all of them, or are there some areas that they focus on? Or, are lots of people doing this during their PhD?

Katharine Collins: I think developing a vaccine was rare, fairly novel at the time, or quite rare. So not a huge number of people were doing it. There were three PhDs I can remember that developed a vaccine during their PhD and I was one of them, but there may have been others as well.

But in terms of the structure at the Jenner Institute, there were different group leaders, or PIs, that have their focus area, and the Jenner Institute was generally open to having new people join the institute. And if there was space, they did actually join the physical lab space as well. So we had work going on on multiple diseases at the same time.

Jacob Trefethen: Okay. So you're, you're tinkering, you're tinkering, you're tinkering, you look under the electron microscope and then you test something in mice and it protects them from malaria. Did it feel like a eureka moment at any points of that step, or was it just iteration? Iteration, feels good, feels a bit better, feels a bit better?

Katharine Collins: No, definitely a few eureka moments. I mean, the first time I saw the particles under the electron microscope, that was really exciting, especially when I had used the process that we didn't think that was possible. So by removing all the excess Hep B, that was really cool when we could see those, and they looked very similar to the Hep B particles. So it was it was really reassuring that we were doing something right.

Then the next push was to move that into a preclinical study, to inject mice and see if we get an immune response, and then if we can protect the mice as well. And whilst I was optimizing the process, the yield was really, really low of the particles. And I tried to concentrate it and it wasn't easy to concentrate. So we ended up injecting an incredibly low dose into the mice and it was like, well, we might as well, we have the product, let's just see what it does. And then it protected all the mice.

And so that was really exciting. We had gone for this dose that was dramatically lower than any other dose we normally test in the lab. And the vaccine I think 10 times lower than any other dose that had showed for RTS,S being tested in mice and that it worked. So that was really exciting. That was the one of the really exciting moments. Yeah.

Saloni Dattani: That's super cool because if you have a lower dose, you can vaccinate more people with the same amount, right?

Katharine Collins: Yeah, exactly. And a tenfold lower dose, that's huge. That's not half the doubling the number of people. That's a dramatic increase. But actually at the time there wasn't a lot of information on how well dose in mice would translate to humans and if it would actually result in a lower dose human vaccine. We did later find out that it was easier to scale up.

Jacob Trefethen: So, interesting how the practical constraints - let's say it had been effective but you would've needed five times more product. Is it possible you would've just dropped this lead and focused on something else 'cause you couldn't make enough, or what would've happened?

Katharine Collins: No, I was really early on in the purification process, in optimizing that. So it was just that, it was just of luck. But we had gone in with such a low dose to begin with. Maybe we would never have got to the low dose, that lower dose, if we haven't had that constraint on the concentration of the product.

Jacob Trefethen: Okay. So all of this is happening in your PhD, was that 2010 to 2014? Is that right?

Katharine Collins: Yeah, well remembered!

Jacob Trefethen: So we now know, with the benefit of hindsight, that R21 works in kids, in humans, and it protects babies against malaria. And that took time to prove out any clinical trials, and there was - to give a spoiler to the audience, the R21 vaccine was actually approved a couple years ago for wide use.

Along that journey, you finished your PhD and you started doing other malaria research elsewhere. Did you, when you finished your PhD in 2014, did you have a feeling that, oh, I just invented a vaccine that's gonna get used by millions of people? Or did it feel more like, okay, I've proven out that this might work and I'm gonna pass it on, but it's, we'll see. Yeah. What did it feel like?

Katharine Collins: I think most people in the field were quite skeptical about R21 in the early days. They couldn't really see the point in making a vaccine that was so similar to RTS,S. And the initial results, kind of backed that up, that there was reasons for that skepticism. It didn't look very different in the preclinical work, in the mice studies, there wasn't a really strong reason to think that this was gonna save a lot of lives, when there was already a vaccine that was very similar.

Saloni Dattani: But the dosing was very different, right?

Katharine Collins: It was, and I think this is a lesson for vaccine developers, right? At the time, everybody was quite negative about R21. But if you think about things like being able to reduce dose, making it simpler and easier to manufacture, even small increases in immunogenicity, if you add all of those benefits together, you end up with a product that's easier to deploy, a lot cheaper, and maybe easier to manufacture. So it can really have an impact, without just making a dramatically better vaccine in terms of efficacy.

Jacob Trefethen: It's sort of scary though, 'cause I think I, as a outsider who has never developed a vaccine, if I had seen the results from preclinical tests in animals and the results said, well, we can't distinguish that this is better from RTS,S, I probably would've killed it. And yet now we know that it is much cheaper to produce and it's more manufacturable and it's longer durability. I mean, so it's sort of terrifying. What was in the system that allowed this one to actually go forward and now it's reaching people. You know, is it as contingent as it sounds to me?

Katharine Collins: Yeah. You know, I think this was - all the credit goes to Adrian Hill for pushing it forward and really finding out what it could do in people, right? I think so many people would've dropped the vaccine at this point. And another difference that we haven't mentioned so far is that R21 also used a more scalable adjuvant, and I think that's quite important for the supply argument as well.

Saloni Dattani: An adjuvant is another ingredient in the vaccine that strengthens its immune response?

Katharine Collins: Yeah. Yeah, absolutely.

Saloni Dattani: Alright, and so these were different between the two vaccines, and the R21 adjuvant was cheaper to produce and easier to scale up.

Katharine Collins: Yes, absolutely. Yeah. The adjuvant used with the, with RTS,S is a GSK adjuvant. It's also used in another product, and yeah, much more difficult to scale, and much more limited supply.

Saloni Dattani: I remember reading that it comes from - that adjuvant comes from the tree bark of a South American tree. Is that right?

Katharine Collins: Yeah. And that comes from the bark of a Chilean - I can never get the name, pronounce the name right, is a Quillaja tree (Quillaja saponaria, soapbark).

Saloni Dattani: Does that mean that you have to get that tree to get the adjuvant? Is that why it's difficult to scale up? And how come the second one is easier to scale up if they're both from these trees?

Katharine Collins: So the supply limitation is the availability of the trees, the raw material, and also the purification process. So if you imagine you're purifying all these products from the bark of the tree, or from the tree, and if you purify and throw away a lot - a lot of it away, it's gonna be more expensive and harder to scale. They've improved the ways they're producing the trees, so supply is increasing and it's gonna be less of a limitation moving forward. And people are also working on synthetic versions and special, not sure the right word, aquaculture style (hydroponics) growing of these, of these trees and different methods of harvesting from them to get the components.

Saloni Dattani: Is it like someone shaving parts of a tree off and then doing some other, like, how does this all work?

Katharine Collins: I've never seen anybody do it that, and that's kind of how I imagined it, taking the bark off. But other thing I should mention is you have to like harvest most of the tree or you have to kill the tree and that was the problem, and so I think they've changed the way that they actually harvest from the tree so they can keep growing as well in some instances. So you don't just have to - it takes 25 years to get the tree and then you cut it down.

Jacob Trefethen: So you're looking at your lab notes, Katharine?

Katharine Collins: Yeah, it's fascinating. I'm glad I kept really good notes. It's really interesting.

Jacob Trefethen: Are they dated?

Katharine Collins: Yeah.

Jacob Trefethen: What date are you looking at?

Katharine Collins: Um, troubleshooting the purification process, 23rd of the third, 2011.

Jacob Trefethen: Whoa.

Saloni Dattani: Wow. What were we doing in 2011?

Jacob Trefethen: Yeah, 23rd of the third.

Saloni Dattani: I was in school.

Jacob Trefethen: I was inventing vaccines, actually, Saloni.

Saloni Dattani: You didn't tell me that.

Jacob Trefethen: Yeah, I try to keep it private.

Saloni Dattani: So what happened on that day?

Katharine Collins: I tested a few different methods and then the result: aggregation seen in sample.

Jacob Trefethen: Okay. Bad.

Katharine Collins: Second purification attempt: reduce aggregation.

Jacob Trefethen: I love it.

Saloni Dattani: Do you have any, um... random comments in there? Do people put in computerized doodles? Emoticons?

Katharine Collins: No. Definitely not, emojis didn't exist then, Saloni!

Saloni Dattani: No, but emoticons did.

Katharine Collins: LOL.

Saloni Dattani: XD

Jacob Trefethen: Aggregated again, LOL. Wait, so how many experiments are you doing? Is this like every day you have new entries?

Katharine Collins: Yeah, yeah, yeah.

Jacob Trefethen: Wow.

Katharine Collins: No, every couple of days. So I guess I'm gonna test this and then it takes a few days to test and then... results: aggregation seen in sample.

Saloni Dattani: ROFL. Are there images of the RTS,S or R21 under the microscope? Should we- we should include one.

Jacob Trefethen: Well if you are up for it - us including some screenshots might be kind of fun for viewers. Oh my gosh, no. Sorry. We have thank goodness. We have to include this.

Saloni Dattani: Wow.

Jacob Trefethen: This is so cool. Whoa. Okay, great.

Saloni Dattani: Wow. They're so cute.

Jacob Trefethen: Okay, listeners, so we are looking at two images here. On the left it looks like spots on someone's skin, maybe measles. So talk us through the left here. Katharine, what are we looking at? Those beautiful circles. Wow.

Katharine Collins: So those, that's a transmission electron micrograph of negatively stained R21 particles.

Jacob Trefethen: Oh my gosh, that's so clear. They're so clean. They're so circular.

Saloni Dattani: They're so blobby.

Jacob Trefethen: I mean, just to restate some of, and correct me if this is wrong, Katharine, but part of the reason why having these circles that look like viruses is so useful is that our immune system is really good at attacking circular viruses. So is that a fair statement?

Katharine Collins: Uh, yeah. So they're easier to recognize by the immune response, definitely. That's part of the theory behind virus type particles.

What reading this has just really made me realize how much I was reinventing the wheel. Like if this was anybody else making it, or company making it, you'd have had an expert in purification diving into this that would've been able to, I had to do all the research myself.

Jacob Trefethen: Oh my gosh. Wow.

Katharine Collins: Yeah. And figuring it out.

Jacob Trefethen: That's so cool!

Saloni Dattani: Yeah, that's even cooler.

Katharine Collins: You know I did have support. There were other people in the lab that I'd go to for advice, and I talked to Sarah and Adrian, but I was often figuring it out by myself, or at least that's how I remember it.

Jacob Trefethen: It's astonishing because I tend to, sometimes I feel myself getting skeptical about patents in particular, where the trade that society is making with inventors is that if you publish in public how you did something, then we will give you exclusivity for 20 years to do whatever what you want. Sometimes I'm like, well, hold on. How much are you actually gonna be able to learn from reading that? They're probably gonna hide whatever they can and to get away with it. And what, how can you learn something from reading? You need to see someone do it, but you're telling me you literally read the patents and then you just kept plugging away until you've simplified and fixed all of the stuff.

I mean, that's awesome. That's a one person show. And I'm like, wow. So knowledge in public is a extremely big deal.

Katharine Collins: Yeah. I think I managed to get it to the point that we could make it ensure that it works. And then there was a huge amount of work that happened by others to turn it into a GMP grade process. And even then that was a simplified or a shortcut version to get to a GMP product that was done by the clinical biomanufacturing facility in Oxford. They did an enormous amount of work to produce the first batch and then Serum got involved and they used all of their knowledge and knowhow to probably dramatically change the process.

Jacob Trefethen: So I wanna pause on that actually, 'cause it's my day job is I'm a funder and then now your day job is, you're a funder, Katharine. And one thing that comes out from this story that's really interesting is that a lot of universities where a lot of knowledge is generated and science is done, do not have facilities to produce the vaccines that you could take into humans safely, whereas Oxford does. Is that a fair statement? And do you think that that allows for a knowledge generation loop, which is unusually productive?

Katharine Collins: Yeah, absolutely. I think that's definitely one of the big advantages of being in the Jenner Institute. Adrian had set up this clinical biomanufacturing facility and that meant he could really quickly iterate, he could design something in the lab with a student designing it, and then transfer it to the manufacturing facility and quickly produce a small batch.

Saloni Dattani: Does that mean we should have more Jenner Institutes doing other - can you scale that to work on more diseases or is it just really hard to do that?

Katharine Collins: No, no, I think that's the way - people should be learning from that model. I think it's not cheap to maintain a facility like that.

Saloni Dattani: I have another question, which is, why is it called R21?

Katharine Collins: Uh...

Saloni Dattani: Is that a very complicated story?

Katharine Collins: Um.. I can't remember.

Jacob Trefethen: What?!

Saloni Dattani: Wow!

Katharine Collins: Adrian came up with a name and I think I remember asking him, and I think he said it was a 21st century version of a repeat region vaccine. The repeat region is the part of the CSP protein that's included in RTS,S and R21, and that's what the R stands for in RTS,S.

Saloni Dattani: Well, maybe you should ask him.

Katharine Collins: Yes, right now.

Jacob Trefethen: Alexander, why is it called penicillin? God, I just can't remember. I can't remember.

Katharine Collins: I've got an answer.

Jacob Trefethen: Oh, we have an answer.

Katharine Collins: So Adrian said it's the 21st century presentation of the CSP repeat vaccine.

Saloni Dattani: So your earlier answer was basically correct.

Katharine Collins: Yeah.

Saloni Dattani: That's great. It's so funny to me that you thought that you had made it up, but you actually remembered it correctly.

I have a similar but very different story where I thought that my earliest memory ever was made up for a while and then I found video evidence of it being true. So my, so my earliest ever memory is of us, my family, going to the Grand Canyon and at the Grand Canyon I had a pink balloon and the only thing I remember is that I had this pink balloon and I dropped it down the Grand Canyon. And I remember mentioning this to a bunch of people afterwards and then eventually I was like, did that actually even happen at all? Like that just sounds like such a crazy story. Like why would I drop a balloon, that doesn't sound like me? Like I was two, but it still doesn't sound like me. I wouldn't do that.

And then last year I found a video that my dad took of this whole trip that we took to the US when I was two. And in the video there's a segment where I'm holding the balloon, the pink balloon. And in the background, you can hear my dad telling me to drop it down the Grand Canyon.

Jacob Trefethen: That is pretty much a clincher.

Saloni Dattani: I was like, wow. I finally feel so validated. But also it wasn't me. I didn't, I wouldn't, I was just listening to my dad.

Jacob Trefethen: There's a lot to unpack there.

Saloni Dattani: I was like, why would I litter?

Jacob Trefethen: Oh... Right?

Saloni Dattani: That's not like me at all!

Jacob Trefethen: It's all adding up now.

Saloni Dattani: Before we move on to the science of malaria, what happened after you invented the R21 vaccine and what happened after you finished your PhD?

Katharine Collins: Yeah, so after the vaccine was made, we then first tested it in a mouse model of malaria, and we showed that we could protect the mice against malaria, and this worked best when you used the right adjuvant. And I did a large number of studies in mice to really look at the dose that was needed, and that's really where my PhD ended.

So once I developed the vaccine and we had shown that it worked in mice, Adrian was moving this forward into clinical trials. So I had the opportunity to stay at Oxford and continue working on the vaccine as it moved into the human clinical trials. But I'd finished my PhD, so I decided I wanted to move on and broaden my experience and learn some new skills.

I moved to work with James McCarthy in Brisbane and he had set up a model where you could infect people with malaria - this was a challenge trial - and evaluate the efficacy of drugs. And so I was working there on those studies and also developed a new challenge model as well. I then moved on to work in - on projects in the field, understanding malaria transmission more fully, and looking at interventions to interrupt malaria transmission. That work was mainly based in Burkina Faso and it was based out of a lab in the Netherlands.

Saloni Dattani: Hmm. And then how did you get from there to Coefficient?

Katharine Collins: Jacob hired me.

Saloni Dattani: Oh, wow!

Katharine Collins: No, I mean, it's an interesting story. I wasn't particularly looking to leave academia. I was loving the work I was doing, but obviously Coefficient Giving, or Open Philanthropy at the time, is a really exciting funding organization that's quite innovative.

Saloni Dattani: And what happened to the vaccine after that?

Katharine Collins: So Adrian then took the vaccine forward into clinical trials and there were lots of other people involved in the development of the vaccine. All the investigators in Africa, the clinical investigators in Oxford, and also the Serum Institute who licensed the vaccine from Adrian and from Oxford, and worked with the team there to carry out the phase three trials and then obviously develop the final product.

Saloni Dattani: I think it's sort of underappreciated just how many people work on these, like actually getting the testing and scaling up to people. It takes so many people and it makes me think also that it's not just about funding, it's also the number of people working on things like this.

Katharine Collins: Yeah, I mean, absolutely. I think this large number of people it takes is really important for me. I just played a very small role at the beginning and there's such an enormous number of people that made this vaccine get to the finish line and have the impact it's gonna have.

Jacob Trefethen: I think it's time to get into the science of malaria. But before we move on, I'll just, my reflection on this segment, is there gonna be a lot of people listening who - basically science nerds - who sometimes it may feel like the big things left to do in science while they're all behind us. That's why Saloni and Jacob talk about Gaston Ramon. You know, we've already had all these antibiotics invented. Oh, well and so, wouldn't it have been cool to live back then and.

I think that's entirely the wrong orientation. You know, there are people like Katharine Collins, who in 2010 to 2014, invent entirely new vaccines that are now gonna be used by millions of children. And yet, and she is right here. We got to talk to her right now. And you can too! You can work on important problems and there are many people who can benefit! And it's just, it's almost scary how sensitive to particular scientists at particular times a lot of this stuff is, and it's very inspiring too.

So, Katharine, thank you so much for joining us.

Katharine Collins: Great to be here.

Saloni Dattani: All right, so how come it took so long to develop a malaria vaccine? And why are malaria vaccines so much harder to develop than vaccines against other diseases?

Katharine Collins: Malaria is caused by a parasite, which is quite different to a bacteria or a virus, it's a lot more complex. And the malaria parasite actually moves- it has a really complicated lifecycle, and it moves through at least three different stages.

So it's first injected into the body by the mosquito, and then travels from your skin into the liver. It develops in the liver for about seven days and then bursts out into your red blood cells in your bloodstream and it invades your red blood cells. The symptoms are caused by the parasites invading your red blood cells and then destroying them, and then it does this many times. Each cycle it produces many more parasites and so it invades many more red blood cells and that's what causes the anemia. And then the parasites within the red blood cell, those infected red blood cells, can adhere to different tissues and that can cause problems for different organs as well.

Saloni Dattani: I read that if just a single parasite makes it to the liver, it can cause an infection. Is that true?

Katharine Collins: Yeah, that's right. And that, I think that's the really tough challenge with malaria, but you know, you can get hundreds or thousands of sporozoites from one bite. But I think you - we don't think it's many thousands, and you could have some immunity that gets rid of a lot of those, but just one has to get through the defenses, and that gets into the liver, and then in the liver they actually replicate so that it doesn't stay as one parasite. It turns into many, many merozoites, and they then burst out of the liver cell and start invading blood cells. By the time you get to the blood, you've got many parasites again, and very quickly, they replicate and produce more.

Saloni Dattani: That makes me think, both of the vaccines are - the efficacy is much lower than many other vaccines. But if I think about it this way, that they're trying to prevent even just one parasite from getting to the liver, then from that perspective, it sounds like they're actually really effective at doing that, at least.

Katharine Collins: Yeah. Yeah, it's a very high bar. Exactly. Yeah.

Saloni Dattani: Well, that's terrifying. Just one parasite. So all of that makes it much harder than, let's say, measles or flu, which are caused by viruses and where the vaccines are produced by killing or attenuating the virus.

Katharine Collins: So there are many reasons that it's difficult to make a vaccine against malaria parasites. First is this really complex life cycle and then also the malaria parasite has been around since Egyptian times. So it's evolved to evolve with the human immune system for a really long time, it's learnt how to evade our immune responses really well. So every time our immune system is managed to attack the malaria parasite, or find a good way to get rid of it, it's then evolved another mechanism to keep surviving.

There are lots and lots of redundant proteins in the parasites. So you think you can block something that's important and then it just switches on a different protein instead and uses that. That's been one of the reasons it's been quite tricky.

Saloni Dattani: So the malaria parasite has a very complicated lifecycle. Does it, when it goes through these different stages, does it also change shape? What actually happens?

Katharine Collins: Yeah, it looks completely different at each stage. It starts with what we call a sporozoite that looks like a little eyelash when you look under the microscope, it's a curve shape. Then when it invades the red blood cell, it's called a merozoite; it's like a round, almost cone shape. But not only does it look different, but it has different proteins on the surface. So a vaccine that works against one stage isn't necessarily gonna work against another stage.

Saloni Dattani: Right. And that's one thing that's hard about developing a vaccine. Like, how do you pick which protein to use in the vaccine?

Katharine Collins: Yeah, absolutely. Yeah. You know, the approach is normally to look for a protein that's really important. So you find out something that's probably something that's involved for an invasion or adhesion. So people would look at knocking out different proteins and seeing whether they're critical for development. If you find something that's essential, then that's also gonna be a good target. And the other way is that people look for what's most abundant on the parasite, or the pathogen in general, but that can often be a decoy. That's an interesting one. Like sometimes the things that were abundant on the surface are there to misdirect the immune response.

Jacob Trefethen: Okay. So you're taking these samples from mice and you're learning a lot, it sounds like, from mice. So firstly, thank you to our mouse brethren. And Saloni, I know that you have written a lot about, in one of my favorite pieces that I read two years ago was about the invention of the malaria vaccine. And you wrote about how mice were originally domesticated in some sense, to be models for malaria. So how did that work?

Saloni Dattani: It starts out before mice, I think there were some animal models in the late 19th century, the first animal models for malaria were birds. And the way that scientists proved that malaria was spread by mosquitoes, was by using sparrows and infecting them with the blood of an infected human, and seeing whether it would transmit. And I think it seemed like there were some, there were a bunch of different birds that could get infected by malaria, but they just didn't translate that well to what would happen in humans? So people tried developing drugs, like testing new drugs, in bird malaria, and they seemed to work there, but in humans they didn't; they caused various side effects. And so they were trying to find different models.

There are also two other types of models used in between. One was monkeys; monkeys are really expensive and difficult to work with. And then the other was humans, right? Because in the 1920s, if I remember right, humans were used as a model to study malaria because people with syphilis could be treated by infecting them with malaria, because the bacteria doesn't survive after the fevers that are caused by malaria.

Jacob Trefethen: It's a bit like solving your aching thumb by chopping it off to me, but, okay.

Saloni Dattani: Would you rather get syphilis or malaria?

Jacob Trefethen: Ah, the eternal question. And my answer is I'm glad that we're in the 21st century.

Saloni Dattani: Syphilis seems like it was really scary before antibiotics.

Jacob Trefethen: Yeah.

Saloni Dattani: Especially if you got neurosyphilis.

Jacob Trefethen: Yeah. The bacteria would worm its way up into your brain and stick around for years or decades.

Saloni Dattani: I've been to a medical museum in London called the Hunterian Museum, and they have exhibits of people who had syphilis at the time, and their skulls are filled with holes from the infection. It's very scary.

Jacob Trefethen: Well, that's a wonderful tangent, but I was wondering about, I was wondering if we could talk more about mice.

Saloni Dattani: Right. Okay, so mice, so we have the bird models that aren't great. You have the monkey models that are really expensive, and the human models, which once you could treat syphilis with antibiotics, there was no longer an audience of people who were interested in being infected with malaria deliberately. So the next question was, let's try to find a different animal model. Let's try to find a rodent that can be infected by malaria.

And I think it took quite a while to find any rodents that were infected by malaria. There were two researchers that finally figured it out. I think they were two Belgian researchers who were in the Congo, and they were doing tests to see which animals mosquitoes had bitten, and that ruled out various animals nearby and it didn't rule out rodents. So they thought maybe there's something here, and they continued trying to look for rodents that were infected by malaria. And eventually they found a thicket rat (Grammomys dolichurus) that was infected with it.

This thicket rat was infected by a different strain of malaria called Plasmodium berghei, and that seems to be much more - like that's just much easier to work with. I think at first, they also, they couldn't replicate the whole lifecycle of the parasite in those thicket rats, because there were certain stages of the parasite's lifecycle that needed a cooler temperature.

So when I was reading about this, it seemed like it took 16 years for them to work that out. It was several things. So the original research was just post World War II and then in the 1950s, various countries did large-scale malaria elimination programs and cut down on malaria research. And so all the people who were working on that stopped working on, or many of them did, stopped working on it, and then only then got interested again in it during the Vietnam War. So I think it was like partly that and partly just, historical contingency of which parasite they discovered. And did they look at their own lab notes from 16 years ago to see what the temperatures were in that forest where they found the first malaria infected rats. Goes to show how important lab notes are.

Jacob Trefethen: Sounds like mice can tell you something, and took a long time to get to a model that worked in the lab. But they can't tell you everything, 'cause mice aren't humans, and they might mislead you sometimes.

Saloni Dattani: A mouse has never told me anything.

Jacob Trefethen: Speak for yourself. Well, I mean, that brings me onto a question I have, which is: are mice enough? If not, what's the next step?

Katharine Collins: Well, so you could use non-human primates, but they aren't the perfect model for malaria. There's only one that gets infected, that could be affected with human malaria parasites, and so none of the models are perfect. So people don't often do a lot of non-human primate work, but they can be used to answer specific questions. So then your next model is obviously humans.

Jacob Trefethen: Mm-hmm.

Saloni Dattani: And that makes sense because if you want to make a vaccine for humans, you probably wanna test it on humans.

Jacob Trefethen: Okay. So we're segueing to humans. How did that begin? What were the first experiments in humans?

Saloni Dattani: So the first ones were the ones that were treatments for syphilis in the 1910s to forties. And then when penicillin was developed, it wasn't necessary anymore. But then, after that, there were various experiments in prisoners in different parts of the US, I think. And what was interesting to me when I was reading about this was that - so the prisoners were volunteering for these experiments, but some of the prisoners were not just subjects in the experiments. Some of them were actually technicians and researchers, who helped in the experiments as well.

And one of the most famous ones is Nathan Leopold. Do you know, do you recognize that name?

Jacob Trefethen: Not me.

Saloni Dattani: So he was a - I know this because of a film that was inspired by his life. He was a murderer who murdered a friend, I think, a classmate of his. So with a friend of his, they both kidnapped and murdered one of their classmates while they were students at the University of Chicago. And while they were serving their sentences, Nathan Leopold, one of them, enrolled in one of the malaria research studies. And after that, he then became a technician, he started doing - like he was actually operating research as well.

And the reason that I know this is because that story inspired the Alfred Hitchcock film Rope, if you've seen that. Have you seen that?

Jacob Trefethen: I have not seen that.

Saloni Dattani: It's a very good movie where, I mean, it's the same-ish story. They've kind of changed what actually happened. But in the film, these two students decide to kidnap and kill one of their classmates for fun, essentially. And then they store him in a, what is it called? Like a box in their apartment. And they then host a party just hours after this murder, to basically show the fact that they could get away with it. And the whole film was taken in 10 shots, like 10 long segments that are just stitched together. And it's an incredible film. Like very, very well made.

Jacob Trefethen: Wow. Okay, so...

Saloni Dattani: So how does this relate to malaria? Many prisoners would've been part of this malaria research in the mid 20th century, and they contributed to our understanding of various parts of the transmission process, I think.

And since then, we've continued studying malaria in humans in a type of study called a challenge trial, where you deliberately infect volunteers with mosquitoes with malaria. So I think in the past it was many mosquitoes per person and now it's just five bites. Is that right?

Katharine Collins: Yeah. I guess there was work to improve and standardize the modern challenge trials. That's where they landed on five mosquito bites that could reproducible infect the volunteers.

Saloni Dattani: So what happens in one of these experiments do you sit with. Do you put your hand into a jar that's filled with mosquitoes or what? What's the what's it like?

Katharine Collins: No, the process is quite dull, actually. I guess you normally have to travel to somewhere where there's a facility. And because these sort of things do contain mosquitoes infected with malaria, they're usually under high containment, so then the volunteers need to pass into a contained containment area, and then a cup is often passed through a window into that room and they have a cup - it's like a coffee cup - and it has gauze on the top and the mosquitoes will be inside. The lid will all be taped shut so they can't escape, and then you place your arm on top of the cup and allow the five mosquitoes to bite you and say, a few minutes for feeding. And then they'll have a look and see how many of those mosquitoes have fed on you.

So what they do is they take the cup of mosquitoes, they then look at them, each mosquito individually under the microscope. You can see whether it's blood fed, because it's got blood in its abdomen, in its belly. Then if it's got blood in the belly, then look at the salivary glands and check that it had sporozoites in the salivary glands. And so you're looking, five mosquitoes in that cup that fed. But so they count up how many did feed, then they'll put more mosquitoes in a cup. So if you only need one more infected bite, they'll put one more mosquito in, and then you can be bitten by that mosquito. If that one doesn't bite you, then they take that one out, put another one in until you've had five infected bites.

Saloni Dattani: Oh, I see. That's probably the most disgusting coffee cup I've heard of.

Jacob Trefethen: Not so tasty. These, these days, are the people who are putting their arms out, are they mostly undergrads somewhere or, yeah, what, who are the volunteers?

Katharine Collins: I think it depends where you do the trials. I think in Oxford it's typically lots of students, but other people as well. But you, the students are often quite willing to get involved.

Jacob Trefethen: Legends.

Saloni Dattani: I saw a picture where it wasn't a coffee cup, but it was a cup noodle box container.

Katharine Collins: Yeah or soup. And they're often called, used as soup cups. They're like, or ice cream containers, they're that kind of large, larger size that would be used. That's usually used to hold a lot more mosquitoes. It would've been a different study, probably.

Saloni Dattani: Oh, I see.

Jacob Trefethen: So you, in those challenge models, you are giving some of the students or other volunteers injections of vaccine, some of them placebo, and then they're getting bitten.

Katharine Collins: Exactly. That's right. Yeah.

Jacob Trefethen: Okay. And then what do you, how do you figure out the truth afterwards? You're just seeing which one of them faint, or?

Katharine Collins: Once you've been challenged, you start following them up a couple of days later. So the parasites will be in the liver for seven days. You don't have to monitor them too carefully in the beginning, but you still monitor them and check the parasites haven't got into the liver, into the blood from the liver. And then you are monitoring quite closely from liver emergence. So once the parasites are entering the blood or you're expecting them to, you can see them once or twice a day, up to twice a day, take their blood.

You can look under the microscope for the parasites, see if they've got the parasites in their blood, and you can also do molecular diagnostics as well, like PCR to look - it's a much more sensitive method. So you can detect the parasites in the blood before they will make the people sick. And so you can treat them quite quickly and then you'll know which volunteers have been protected and which haven't.

Saloni Dattani: That's very cool. And then now there are methods that are beyond mosquito bites. People directly inject volunteers with the parasite, is that right?

Katharine Collins: Yeah, there's a couple of models. So the other models you would inject either cryopreserved sporozoites, that's that first stage that goes into the liver. You can inject those intravenously, you can ship those anywhere in the world to do that type of study. The other model is injecting blood stage parasites. So both of these are greats and they can answer different questions.

Saloni Dattani: And these two vaccines, the RTS,S and R21, are for the first stage. So you'd want to be able to test it against the natural infection with the mosquito bite.

Katharine Collins: Yeah, definitely.

Jacob Trefethen: Saloni, I've got a question for you.

Saloni Dattani: Oh, what's the question?

Jacob Trefethen: Would you have volunteered for one of these human challenge trials?

Saloni Dattani: I was thinking about this back when you asked who was volunteering in the studies because as I have described in the first episode we did, I once volunteered for an HIV vaccine trial, phase one trial. And I enjoyed it and I think I probably would.

I think the difficulty is that back when I did that, I was a student and I was very bored and I didn't have anything to do in my free time anyway and I didn't have a social life. And now I have a lot of stuff going on in my life, like I just have a lot of work.

Jacob Trefethen: By the way... congratulations.

Saloni Dattani: Thank you.

Jacob Trefethen: Me, I'm still alone, but I'll get there.

Saloni Dattani: But I was thinking like, there are lots of different types of diseases that you might do a challenge trial for, right? Like you could do one for rhinovirus or like flu or cholera or I don't know, what else is there - Shigella maybe, or something like that. And all of these sound very unappetizing to me. Like, I wouldn't wanna do a challenge trial for any of those. Like the flu, the respiratory ones, I'm like, that's just boring and someone else is gonna do them anyway. Probably the, that's -

Jacob Trefethen: Amazing. I'm not gonna do that one. It's boring. I want something harder!

Saloni Dattani: Right. And then the other, like cholera and shigella, I mean, diarrhea... I don't want, that sounds horrible. And also I feel like I'm quite small and if I lose too much weight, there'll be none of me left, and so I can't do that one. So what I would do is a more dangerous pathogen, I think.

Jacob Trefethen: Okay, nice. Is malaria dangerous enough for you?

Saloni Dattani: That would make it worth it. I think so, yeah.

Jacob Trefethen: Okay. Even though malaria -

Saloni Dattani: Even though it's treatable and stuff.

Jacob Trefethen: It's treatable. Yeah. I mean, just in case listeners are thinking about it themselves and concerned; in the diarrhea ones, they do treat you. They don't just leave you, they give you antibiotics. But yeah, those in order to get more of a signal, they don't treat you in, within an hour, they'll probably you within 12 hours or something. So it's a - it's not, you gotta go through some pain to get the gain.

Saloni Dattani: Well, I read that with the cholera vaccine challenge trials some people... actually, you know what? I'm not gonna finish that sentence.

Jacob Trefethen: Oh -

Saloni Dattani: It was about how much diarrhea they had. And you know what? I don't actually wanna give people that image.

Jacob Trefethen: That's.. you know what, Saloni? I think they've got it now.

So my question for malaria, Katharine, how sick do you get? Do you get sick at all or do you get treated as soon as there's any risk of sickness or? What if you're in, what happens?

Katharine Collins: I guess the idea is that they treat you before you develop any real symptoms. So you probably start to feel a bit fluey. You may get a headache, but because they're monitoring your parasitemia so closely, the plan is to treat you before you get any really uncomfortable symptoms. By the time you get treatment, you could have some symptoms. I think people do typically get symptoms. They feel rough for a day or two, but that's hopefully the extent of it.

Jacob Trefethen: I think that's kind of cool. Yeah, I would do it. I mean, I haven't done it, so you always have to take with a grain of salt, whatever I say now. The issue, yeah, I tried to volunteer for a trial recently and ended up getting swamped in the logistics. So your point Saloni, that it's harder once you have a job? I've had that experience too.

It also depends where you live, whether there are trials around you that are convenient that you can participate in. So it comes down to those aspects as much as anything. But malaria sounds kind of fun. If you get, the drugs are great. You get, if you get feel a little bit sick, that will make me feel like I've done something for humanity and then I get treated, I'm up for that. Sounds good.

Saloni Dattani: And also you get to live in a cool quarantine hotel for a bit. No?

Jacob Trefethen: No, because -

Saloni Dattani: No?

Jacob Trefethen: It's safe to walk outside. In England, right? There's no, there's no mosquitoes that bite you.

Saloni Dattani: So you are infected and then they're just like, go on with your life. Yeah. And you just feel sick at home instead?

Katharine Collins: Yeah. They give you a little card to put in your wallet, which tells people what you have and what you need to be treated with in case something happens.

Jacob Trefethen: Oh, really?

Saloni Dattani: Okay. I'm not volunteering for this thing.

Katharine Collins: Emergencies, like if you ended up in hospital from a car crash or something, they would know that they should probably give you antimalarials now. The study's over.

Saloni Dattani: No, I thought, I thought you'd be in a little quarantine hotel. I thought it was like a mini vacation but you're sick.

Katharine Collins: No, I think maybe they do it differently in different places. So it depends maybe what type of trial you are in. So for the drug trials with malaria, because they actually let you develop parasitemia to a certain level, then they treat you. And then they want to measure the clearance rate of the parasites. So they want to sample you quite quickly and frequently after treatment. So for those, they do often do inpatient for your convenience, then they let you go once you are treated, so it could be just a couple of days.

Saloni Dattani: I think I'm thinking of the respiratory virus challenge trials where, because you could transmit it to someone else, they keep you in a facility.

Jacob Trefethen: Diarrhea as well, for the shigella one they keep you in. Yeah. I realized Katharine in that description though, one of the other reasons why people might not want to do it, which is you're getting pinpricked constantly 'cause people are taking a lot of blood samples. So that's if you wanna get over needle phobia via exposure therapy, go for it!

Saloni Dattani: I feel like the way to - Exposure therapy is supposed to give you like a mild version where it's like, oh, nothing actually happens when you get injections. This seems like it would actually scare you more!

Jacob Trefethen: Well, I did exposure therapy and nearly died.

Saloni Dattani: Would you participate in the challenge trial?

Katharine Collins: I would love to, but I really hate needles.

Jacob Trefethen: Oh, there we go! There we go!

Katharine Collins: It's kind of ironic for a vaccine developer.

Jacob Trefethen: That's so funny.

Katharine Collins: I'm terrified of getting vaccines. When I have, when I go to get a vaccine, I have to lie down to have a vaccine, I have to lie down with the blood taken, as otherwise I might faint. I think I have fainted in the past, that's the problem.

Jacob Trefethen: Oh, wow.

Katharine Collins: And so, as you mentioned we take blood in these challenge trials, 10 to 15 times depending on when you get malaria. So I just couldn't, I couldn't cope with that. Unfortunately.

Jacob Trefethen: We must know our limits. Okay. So how come that's not enough? Or is it enough? So let's say you've taken a malaria vaccine through human challenge trials. You ready to license it, roll it out across different countries or not? I know the answer, but I'm curious.

Katharine Collins: Well, obviously no, I guess that's not the target population. So you still need to find out if your vaccine's gonna work in the people that it's intended for, which would be children in Africa.

Saloni Dattani: Well, we have some vaccines that are approved just from challenge trials. Right? Like the typhoid vaccine.

Katharine Collins: Yeah, that's right. Yeah, I think when the trial isn't feasible to be done in the target population, there's good arguments to try and get that efficacy signal from a challenge trial, and then they still need to get your safety data from the target population that you're gonna use the vaccine in as well.

Jacob Trefethen: Okay. So we've talked about the second malaria vaccine, and we are talking about the animal models and the human challenge models for vaccines in general. Saloni, since you've written about the history of malaria, I'd love to hear, if you're willing, what was the first malaria vaccine development timeline like? What were the steps there? What happened?

Saloni Dattani: I love how we've gone through this backwards, like we're doing the Star Wars prequels or something.

Jacob Trefethen: But more entertaining.

Saloni Dattani: Well, I guess it's a long story. So I think I probably wanna start with a quick summary of the whole development. I first got interested in this topic when I was reading about the news of the malaria vaccine being rolled out in 2021, and I wanted to write a blog post about it. So I was starting to write this blog post, and one of the first things that I learned was that it was actually developed in the '90s. And it really kind of shocked me and I was just thinking: what went wrong? Like, what happened? Why was it, why it didn't only get released now, if it was developed so long ago? And a lot of my interest just stemmed from that curiosity and frustration, with how things could have taken so long.

The short version is that I think a lot of it is because of a lack of funding, infrastructure, and in some cases, also the regulatory changes and standards that there were. But I think the broader version is really, you know, this malaria vaccine essentially came out of research from the US Army. In the 1950s, almost every country was affected by malaria, and they used, there were large scale malaria eradication programs in the 1950s, mostly using insecticides like DDT. And those were very effective, like a lot of high income countries eliminated malaria in the 1950s with DDT and other control efforts.

And funding also declined, so there was no more reason for a lot of high income countries to do research on malaria, and a lot of the researchers who were previously doing it became operators and managers of this eradication program. So funding for research and development massively contracted, and that kind of stayed that way until really the 1960s, when the Vietnam War was happening, and the US Army was then once again facing malaria in Southeast Asia. But by then it was kind of drug resistant malaria. So there was once again, this need for research trying to develop new drugs that were effective against drug resistant malaria, but also potentially vaccines.

And so some researchers started working on this program to try to develop a malaria vaccine. And their names were Ruth Nussenzweig, Jerome Vanderberg and some of their colleagues. And what they did was, they first tried to build a proof of concept of the vaccine, so let's see if you can protect mice by infecting them first with a killed version of the parasite. If you protect them with this killed version of the parasite, will they then be protected from another infection? And what they found was that yes, you could do that.

And, this eventually much later led to a different type of vaccine, which we might come back to later on, but it's not really scalable. So the other option is let's try to develop a subunit vaccine. From our previous episode on a history of vaccines and Hepatitis B, basically the idea here is that, instead of using the whole organism, the whole parasite as a vaccine, let's try to find a few components, or maybe the one component, that is enough to stimulate an immune response. And so that's what they tried to find and they sort of looked at these mice that they were protecting with this killed parasite and saw: what are they generating antibodies against? What is their immune response reacting against? And they found that that clustered around a protein called the circumsporozoite protein. That protein, it turned out, was gonna be a very good candidate for a vaccine. That was gonna be the main component of the vaccine.

So the initial attempts were to use that protein as the vaccine. If you remember back from our protein subunit vaccines episode, the Hepatitis B one, often just using a single protein in a vaccine is not very effective. And the reason for that is that, often when you have a whole pathogen being a vaccine, or when you're exposed to a whole pathogen, there are many things about that pathogen that can stimulate your immune response. Whereas when it's just one protein from that, that's often not enough for your immune system to recognize that this is something that we need to react to. There are obviously lots of nuances there, but that's kind of the simplified version.

So this initial vaccine, just using that one circumsporozoite, or CSP, protein, was not very effective. They only managed to protect one volunteer out of six in their first study. The way that you improve that, is often by adding an adjuvant. So an adjuvant boosts the immune response in some way, and so that's kind of what they tried. They tried different adjuvants, they tried different formulations, and eventually they created this formulation. And I forget what each of the letters stands for. And this, the formulation was the RTS,S vaccine. And so Katharine, what does, what is this formulation made of?

Katharine Collins: So the formulation is made of parts of the malaria parasite and the Hep B virus. So the R stands for the repeat region, which is from the CS protein in the malaria parasite. The T is for the T cell epitopes that are from the same protein, and the S is from the Hep B surface antigen, and this is fused to that malaria protein. Then there's the excess Hep B surface antigen I mentioned before that was needed for this to form a virus-like particle, and that's the extra S so that makes the RTS,S.

Saloni Dattani: Unfortunately, by the '90s, there was no longer interest in funding it from Vietnam War era army research anymore, and they couldn't scale up and continue that research. So they only found this adjuvant, that they ended up using, in the nineties. So at that point, we have a possibly more effective vaccine and they did another challenge trial to see how effective that would be. This time it was more effective, it was six out of seven people in the challenge trial that were protected from further infections.

And again, this, a seven person study sounds extremely small and it is, but that was one - this is a preliminary, pilot type of study, so this isn't really the real deal, but it is still much better than any other study had shown so far. So this was a much more promising candidate for further research.

So what they did next was to do a field trial with many more participants. So they ran a field trial in The Gambia with 300 men, they vaccinated them with this candidate and with a placebo, and they looked at their rates of malaria infection afterwards. And in the group that received the vaccine, they had a 34% lower rate of malaria infections over the next four months. So that was the first field trial, and that was done in 1998.

And okay, this field trial looks not amazingly effective, but still effective in a way that no other vaccine candidate had been up to that point. And so the next step was really, let's try to get this into real, clinical trials in the population that needs these vaccine, which are children. So they started with trials in older children, who were 6 to 11 years old, and then younger children, who were 1 to 4 years old, and then finally infants. This idea is called age deescalation. Basically you're testing it first in children who are least likely to be affected by potential side effects, and then the infant group who are more vulnerable. You sort of wanna make sure that it works first in adults, and then in children, and then in infants.

But this process took a long time and they struggled to find funding at every stage of the process from what I read, and also needed to themselves set up clinical trial sites across Africa. Often there were just not clinics with the expertise to run clinical trials, or the equipment to do testing and things like that, and the researchers themselves had to fund some of that work, so it was a very long process. And then it eventually finished in 2015, the phase three trials ended at that point. That is, I think, much longer than the research process that we often have for vaccines today.

Jacob Trefethen: Though, luckily, I'm sure that meant it got approved in 2015.

Saloni Dattani: No!

Jacob Trefethen: No. What happened then?

Saloni Dattani: What happened then? Well, in 2015, the phase three results came in and the European Medicines Agency said, this looks safe and effective, but the World Health Organization didn't recommend it for a large scale rollout. They asked for more pilot studies before they would do that.

And one of the reasons for that was that there were some, in post hoc analyses of the data, they found higher rates of meningitis in older children and higher rates of death in girls at two of the trial sites. And the World Health Organization, if I understand correctly, didn't think that they were - those signs were causally related to the vaccine, but they wanted it to be ruled out, and so they asked for pilot studies.

The pilot studies took around four years to find funding for, and to get staffing for, and they finally launched in 2019. And then another two years into the pilot studies, there was enough data for the Data Safety Monitoring Board to look at the data, find no increased risk of these side effects, and then finally clear the vaccine for the World Health Organization's endorsement in October, 2021. So that is 23 years after the first field trials.

Katharine Collins: The safety was one of the reasons, but that wasn't the only reason, right? They, there was a lack of confidence in how effective the vaccine was. So it wasn't the risk, it was about the risk benefit analysis. You know, it was only 36% effective in those phase three trials, and there was the safety signal.

Jacob Trefethen: The RTS,S vaccine was going up for EMA and WHO review in 2014, 2015. That was just about when you were finishing your PhD, working on the R21 vaccine. Katharine, so what was the feeling like in the malaria research community at that time? Did people have conflicting and different views, and there was a lot of debate? Was there consensus and surprise? What, what was it like?

Katharine Collins: I think everybody was really hopeful that the vaccine would get approved. I think there was definitely mixed opinions in the field about whether a vaccine that showed such low efficacy in the phase three trial should be rolled out and would actually be effective.

So I think what was really important and really key was the cost effectiveness modeling that was done with the data. And I think that was quite pivotal. And in that it really showed that even a poorly effective vaccine or suboptimal vaccine, most vaccines that have been used in children at the time had really high levels of efficacy, like 80, 90%. So it was a completely uncharted territory. But the modeling showed that even with this low level of efficacy, because there's so much malaria, it could have quite dramatic impact and it would be cost effective.

I think that was a bit of a surprise to everybody. We've been aiming for this really high bar, and then all of a sudden there was this realization actually a quite a suboptimal tool could make a big difference. I think that was quite unfortunate and quite pivotal.

Jacob Trefethen: So what did it feel like when the WHO verdict came in that more studies were needed?

Katharine Collins: I think it was really disappointing. I think it's a difficult decision that they had to make. This is really uncharted territory; a vaccine with really poor efficacy and this safety signal. So it's a tough call for them to make, but I think people at the time and now still think there could have been a better way to resolve the safety signal issue.

And had they prepared better for understanding the public health impact of a vaccine that has this level of efficacy, maybe that messaging could have been different when they were trying to make the recommendations, if they understood the potential value more fully, maybe that would've have shifted the approach away from a pilot implementation program that took six years to conclude versus doing a much more rapid safety assessment.

Saloni Dattani: I guess I also, I feel like it's a little bit surprising just because even the first field trials in 1997 and 1998 also showed fairly low efficacy, but they continued working on it and people probably should have been prepared by that point that, hey, this even though this isn't a very highly effective vaccine, it probably will save a lot of lives. And so it's surprising that that wasn't enough to not require another study after that.

Katharine Collins: Yeah, I think you're right, and what I've said just now is my recollection of the events at the time. This is a while ago and I wasn't deeply involved in the process, so perhaps there was more preparation than that I was aware of, but it feels like that was the missing piece that people didn't truly, at least the people I was talking to, didn't truly appreciate the potential impact, global health impact, of this tool at the time.

And there were other consequences as well to delaying the rollout. So you'll see GSK would be hoping that at the end of their phase three trial, they can scale up manufacture and start delivering the vaccine. They probably had a factory that was making it, but now there was gonna be this huge delay. What were they gonna do with the facilities that were producing the vaccine? And then what was that gonna mean for vaccine supply later on? All these knock on effects as well that in hindsight it's easy to think differently about what we could have done differently. But I'm not sure it was so easy at the time, to be honest.

Jacob Trefethen: It's also just like to state the obvious, so strange and messed up that the way that things currently work is that to get a scalable regulatory opinion, you end up relying on the EU and the WHO when, you know, over time we have to get to a world where kids in Ghana rely on regulators in Ghana, not these kind of more distant bodies. 'Cause you could totally imagine, as happened with the next vaccine, R21, that some nations want to go ahead with vaccination campaigns, even if the WHO doesn't agree and they absolutely should. So that's another part of this story that's a bit heart wrenching.

Saloni Dattani: I feel like there's also a part of this that's like what safety standards we're used to here might be different. Like the cost benefit just might be very different and the willingness to take vaccine at an earlier stage might be different.

But I think there's also another thing that kind of drew out the process, which was a lack of funding and a lack of infrastructure for clinical trials at the time. So especially in the early 2000s, there were very few trial sites in Africa where you could actually try to do research on the malaria vaccine at all. And it was only in the 2000s when malaria funding actually grew from various organizations like the President's Malaria Initiative in the US, and Unitaid and the PATH's Malaria Vaccine Initiative that was funded by the Gates Foundation and the Global Fund. And all of these appeared only in the mid-, early-2000s.

Until then, it would've been really difficult, I think, to get enough funding to set up these trial sites and to actually do the research. To me, when I think about it seems like mostly a failure of infrastructure and funding. And there are also these regulatory concerns, but if we'd had that sooner, we would've been able to test many other vaccines as well.

Katharine Collins: Yeah, I agree with that. I think that's a really important point. I think, we take it for granted now that actually these clinical trial facilities are so well established, and the investigators there are so competent, that they can run their own trials, lead their own work. That wasn't the case.

I remember the stories of the people leading the RTS,S work doing the draw of the sites that existed at the time, and injecting cash into a lot of these sites to bring them up to the standards that would be needed for their product development needs. So I think a lot of that work done by GSK has really benefited the rest of the malaria community and other development of other vaccines as well.

Jacob Trefethen: Okay. So there's infrastructure, which is key, and also funding, as you mentioned, Saloni. So let's say that there had been a big burst of funding back then that was even bigger than we saw. How would that have happened? Were there people proposing it?

Saloni Dattani: There were people proposing it, but they were proposing a different type of funding. Much of the funding that we're talking about is sort of directed at specific groups to do the research, or to set up the trial sites, and things like that.

But in 2004, some economists, Michael Kremer and Rachel Glennerster proposed an Advanced Market Commitment, which is a different type of funding model to try to spur innovation and change the commercial incentives for vaccine development. So the general idea, of why did we need philanthropy and like foreign aid and all of these global health programs, is that there isn't otherwise a commercial incentive to develop vaccines where it's very small. The reason for that is that the people who are most affected by malaria are very poor and you can't really sell vaccines at a high price because they wouldn't be able to afford it.

So here the idea is, what if we could change those commercial incentives? And the Advanced Market Commitment is a way of doing that. So instead of directing funding at specific research groups, it's actually a pool of funding that is only available to researchers or to manufacturers if they develop a successful vaccine in trials and they reach certain criteria. So Rachel Glennerster and Michael Kremer proposed this Advanced Market Commitment where they said we should have a commitment for around $3.2 billion in total, where you would pay per person who was vaccinated, for the first 200 million people, and you would pay about $13 per person. What this does is it actually incentivizes companies to develop a vaccine and take it to the finish line. Both invent-, both developing it and then also scaling it up because they're only gonna get that payout per person they immunize.

So I think that is a really cool model that spurs commercial development and it's very different from the type of funding that was actually done. But the problem was that that idea didn't actually get taken up. And there were various reasons for that. One was that at the time people thought the malaria vaccine was just too technically difficult. It was too far away to be reality. So they didn't want to use this new funding model that was proposed, for something that might not ever happen, and they thought that you, we have to have a lot more basic R&D before we'd have a product that could reach that standard. That also just made it more politically risky. People were like, well, we want something that will definitely or has a much higher chance of success. We want a proof of concept that this funding model could work.

And the other problem is that it's hard, in a commitment like that, which is essentially this legal document that funders, in this case they would be countries - governments, or philanthropists agreeing to pay out a vaccine that meets these standards. It's hard to decide what those standards are and what kinds of products would fit those criteria if you don't have a malaria vaccine yet, and you don't have like things that are late in the pipeline.

So instead of doing an Advanced Market Commitment for malaria, there was a different Advanced Market Commitment that was actually implemented, and that was for the pneumococcal vaccine. And so in 2009, various countries and the Gates Foundation came together to fund an Advanced Market Commitment to develop a new pneumococcal vaccine that would target the strains that were common in Africa and South Asia. Those strains were not included in the previous pneumococcal vaccines, but there was already a proof of concept that we have this, we have these other pneumococcal vaccines, it should be fairly easy to turn to make new ones against these strains. And it worked. So there were three companies, I think, that quickly developed these pneumococcal vaccines, took them through phase three trials and then manufactured them in bulk to get that payout from the commitment.

I personally think it feels like a very big missed opportunity to use it for malaria as well. But many people disagreed with that at the time.

Jacob Trefethen: Okay. Katharine, you were around. Do you think it would've worked back then?

Katharine Collins: I'm not sure. I think the limitations were scientific, biological, we had the problems with the adjuvants, we had lack of trial infrastructure. I'm not sure it would've made things go much faster.

Saloni Dattani: Well, it's hard to say as well, because this was proposed in 2004. And so at that point, the RTS,S vaccine already existed and it already had like an efficacy of 30 something percent. And so if you were at the time, and you were trying to put this commitment together and you said, we'll fund a vaccine that reaches these standards, probably you would, the standards that you would ask a vaccine to be developed for would be higher than the 30% I think.

So I think in that sense it would've been hard. What's interesting though is that there was another paper in 2005 where they tried to model this explicitly, so trying to model the cost-effectiveness under different estimates of the efficacy. Like if it was 30%, how would it be cost effective? If it was 60%, et cetera? And this was a paper by also Rachel Glennerster, Michael Kremer, many other economists, Heidi Williams, and they found basically that it was, it would still be cost effective to fund an Advanced Market Commitment for a malaria vaccine, even if the efficacy was only 30%.

So I think to some degree there had been a bunch of thinking on this, but at the same time, I don't think we know what the counterfactual is because I don't think that other, there are enough other commercial companies that are developing malaria vaccines now that we can compare this to. Like the thing that is effective about the Advanced Market Commitment is that it gets people to enter the market that wouldn't otherwise. And so it's hard to know how that could have gone, I think.

Katharine Collins: I think that's the bit that I agree with that there weren't other people that were that far advanced in their vaccine. The only thing that has worked to date is a CSP based vaccine. There were people working on other types of vaccines at the time. But it's not sure, because it's not clear any of those would've made it either, or looked promising enough to advance.

Jacob Trefethen: So that's a pull funding mechanism incentive to get to the finish line. Katharine, did it feel like more grant money, and more universities, and more companies wherever, would have made the difference if there was a hundred million more every year going into malaria vaccines? Or did it feel like the science and the infrastructure - you can't rush that, and you actually just have to do it step by step?

Katharine Collins: That's a very good question and, actually I, maybe I'm gonna change my opinion slightly and that there were other, with more funding available, there were other people doing great science at the time. So Simon Draper at the University of Oxford has developed a blood stage vaccine with RH5, and that work was happening at the same time on the lab bench next to me, when I was doing R21. But that was seriously underfunded, so there was - people had to prioritize what they were gonna support with their funding, there was limited funding. So the focus went on to CSP based vaccines and that's what the Gates Foundation funded the RTS,S vaccine through MVI and the Gates Foundation didn't fund blood stage.

There was only one funder at the time that was supporting that work, or one main funder, and that was USAID (United States Agency for International Development). Had there been more money, that work could have been accelerated. And you know, that's shown now in a phase two trial that it gives good levels of efficacy, not as high as R21 and RTS,S, but there's potential to combine that with R21. So that work could have been accelerated a lot quicker, had there been more funding around.

Jacob Trefethen: So just playing that out. So that, that result you just referenced, that was from about a year ago, was it? That was pretty recent. Right? Yeah. And so if that funding had happened a decade earlier, could that result have come about a decade earlier, do you think? Or is - that's just a funding question really.

Katharine Collins: Yeah, I think the product was the one they were working on in the beginning.

Jacob Trefethen: No!!

Katharine Collins: Depressing.

Saloni Dattani: Wow. That is incredibly depressing.

Katharine Collins: I know, but I think credit has to go to Simon Draper and the funders that supported him and Lorraine Soisson at USAID, they kept that work going with quite limited budgets, and they've made it to the finish line, well, not to the finish line, but to the clinical trials now, and the efficacy trials.

Saloni Dattani: Wow, geez.

Jacob Trefethen: Thank you Simon. Thank you Lorraine, for believing against consensus and keeping it going.

Saloni Dattani: I have a question related to this because both these are different stages of the vaccine and so I'm wondering if you had a vaccine that combines the vaccines against both of these different stages, would you expect that to have a higher efficacy, and have people tried to do things like that?

Katharine Collins: Yeah, I think that was the original approach from Adrian, when I was making R21. He also had a liver stage vaccine. The other vaccine he had developed was the ME-TRAP vaccine (Multiple Epitope–Thrombospondin-Related Adhesion Protein), and that targeted the infected hepatocytes. His theory was that if you could reduce the number of sporozoites that get to the liver, then the liver stage vaccine would have an easier time finding and clearing out those liver cells. And that was valua - that was tested and it didn't work, so that was a great theory that didn't work.

Now people are looking at combining the CSP based vaccines with the blood stage vaccines that Simon Draper's developed and others. There are lots of other people working on blood stage vaccines now as well. But the preclinical models are really difficult to evaluate all stages of the parasites in the same model and the combination of those vaccines. So we really have to get into humans, and that's the work that Simon and Angela and his team are working on at the moment.

Saloni Dattani: Wow. And so that was also - could that have also been sped up by 10 years?

Katharine Collins: Yeah, that vaccine that they're now putting into clinical trials with R21 was being developed at the same time as I was developing R21. So I know that could have gone quicker.

Saloni Dattani: This is crazy.

Jacob Trefethen: It wasn't exactly hard to spot, it was right next to you on the lab next to you. I'm gonna cry.

Saloni Dattani: Geez.

Jacob Trefethen: I mean, so as someone who works in philanthropic funding, I think the main lesson here is just that funding in global health R&D is so tight that you have to make these prioritization decisions that are vicious and impossible. So we just - I mean, a more sane society would have more long-term government and philanthropic funding that was less correlated, more decision makers, more money total, so that you could get more shots on goal.

So I think, for anyone listening who is wondering what the solution is, I think that's the most obvious general solution staring us in the face, and so I don't wanna hide it. There's obviously all these specifics we can get into that are more technical, but that one is just - is obvious. So we just have to say it out loud. Sorry!

Saloni Dattani: Geez.

Katharine Collins: No, I agree with that. I don't disagree with the decisions that were made about what you had to prioritize at the time. I think they were tough decisions that people had to make. That had there been more money, we could have moved things a lot faster.

Saloni Dattani: I feel like what's even more depressing about this is that... Despite all of that, malaria is still one of the more well-funded diseases in global health world, and there are various others that are large burdens and get tiny fractions of the funding.

Jacob Trefethen: I am wondering if we could just talk about the two vaccines already approved next to each other, and then what's coming next after these two? What needs to be done next in the invention pipeline?

So RTS,S versus R21. I will tee this off by saying I don't know that there's - there are different comparisons you could make, but one fact just to state upfront is that neither has faced a rollout where tens of millions of children have received the vaccine, so perhaps the biggest problem is simply that there is not enough reach of either of them, let alone comparing between the two.

That said, what do we know about the data that has come in, about how they look? So there's more data coming in every year, but what do we know so far about efficacy, about safety, and other factors? Katharine?

Katharine Collins: The headline efficacy figures from the phase three trials look quite different for the two vaccines. So RTS,S, we mentioned it was something like 36% an efficacy overall. And actually for the population that was used for the phase three trials for R21, that was most similar, the efficacy I think was 57% overall. And then for R21, the phase three result was something around 75%. I can't remember the same, the exact numbers, so this looks like R21 may be a lot better.

But there's some nuance and detail about how these trials were conducted, and where they were conducted, and when they were conducted, that means we can't - we probably can't directly compare these trial results. So I don't think you can claim that R21 definitely has a higher level of efficacy. There were different things happening at the time; different other malaria interventions that were being used, like bed nets, or seasonal chemo-prevention drugs that were given to children every year, so those results aren't directly comparable. So I think we have to try not to make that comparison unless we run a head-to-head trial.

What I think is interesting about the R21 data that's starting to emerge is that it does - it may be more durable than RTS,S. So the decline of protection seems to be slightly slower. So it may, even if the efficacy isn't much different, that peak protection they gets the, it may last a little bit longer, so that could make quite a big difference.

Jacob Trefethen: I see. So, but in both cases, your first shot, you'll probably get it at five months old. Is that about right? And then you might get another, the ideal is you get one at five, one at six, one at seven months. And you're saying that the immune response from R21 is lasting for longer after those first shots?

Katharine Collins: That's right. That's actually a fourth dose that's given around 18 months.

Saloni Dattani: I think my takeaway from the difference between the two is mostly the manufacturing and the cost. Is that also how you see it? And are there any other differences? Why is there such a huge difference in the cost of both of these? And is that because of the dosing that we talked about at the start?

Katharine Collins: I guess, the other big difference is of the scalability of the vaccines. R21, it seems to be easier and cheaper to produce and that may be in part due to the lower dose and maybe also new technologies that have been used to produce the vaccine itself - so newer yeast expression systems and things like that. And also, the adjuvant that's added to the vaccine.

As we mentioned earlier, that the adjuvant was really important for the RTS,S vaccine. We found the same with R21, only when we used a certain adjuvant did we see protection. And that the adjuvant that's been chosen for R21 was Matrix-M and that doesn't have the same supply limitations as AS01, and it's slightly cheaper as well. So that makes it more scalable.

Jacob Trefethen: Yeah, I mean it's funny, it's not the property you'd think about first – scalability, and how that might have implications for cost and price. But last price that I saw for RTS,S was about €9 a dose and there are four doses. And then the last price I saw for R21 was the original price was 3.90 and it maybe has come down to $3? So we're, we're talking about a 3X, say, difference, which may not sound like much, but is decisive in a lot of these cost-effectiveness calculations because global health funding, there's just not so much of it going around. So when you think of cost-effectiveness, it's not just how effective are these vaccines, it's how much it cost to actually deliver them to the kids who need them. So anything you can do to bring the numbers down is, it could change the equation.

Katharine Collins: Yeah. And just going back to the delivery schedule you mentioned earlier Jacob, which is giving doses of the vaccine at five, six, and seven months. And then there's this booster dose or final dose that's given around a year later, and none of these time points are actually aligned with the schedule for other infant vaccines. So what this means in reality is that children and their parents and caregivers have to travel for each of these visits at another time. And what we're finding is that people are not showing up for all of their doses of vaccine, and so if they're not getting the full course, it's gonna reduce the effectiveness of both of these vaccines.

Jacob Trefethen: Right. If you have to travel three months in a row, but you are busy taking care of your other kids or you're at work, or, I mean, it's, you can see how you might miss a dose. And then if that happens, then whatever we saw in the clinical trial may not reflect the reality of what kids are getting protected, so more work to do there.

Okay. So those are two vaccines and they're imperfect, but they are helpful for kids. Do you think they're good enough, Katharine?

Saloni Dattani: If we did this again today, could we make better vaccines?

Katharine Collins: Uh, yeah, I think well, oh gosh. Wow. That's a tough one. I think...

Saloni Dattani: I mean, scientifically, not in terms of the funding or trials or anything like that.

Katharine Collins: Yeah, I think we have better techniques and technologies for developing vaccines. Structured-guided design, reverse vaccinology, computational protein design, things that you've talked about in your previous podcast episodes, where we really try and understand more specifically what type of immune response you want to generate. So you can take the whole protein that you think is important, and show that to the immune system, but it might generate a mixture of helpful responses and unhelpful responses.

So using these more sophisticated techniques, we can try and understand which parts are really helpful, and design the proteins or the antigens to really elicit those responses more carefully and more specifically. So using those techniques, people are already doing this. They're working on trying to make better CSP vaccines, better blood stage vaccines, and also vaccines that target the transmission blocking stage as well.

Saloni Dattani: But why were you hesitant before?

Katharine Collins: It's not clear that any of those will actually be any better. So I think there was a really interesting paper published by the Protein Design Institute by Neil King, someone that we support and think is an incredible institute for using computational design to really improve vaccine antigens. And they tried to make better versions of R21, and I can't remember what the paper showed exactly now, but there were many candidates they assessed and they used this incredible methodology to try and improve the vaccines, but none of them looked substantially better than R21.

Saloni Dattani: What do you think of the whole sporozoite vaccines where scientists were just irradiating the whole parasite at the early stage and injecting that as a whole? I think they were doing that in the '70s, and that seems like in that research it was pretty effective and some people are continuing to work on it.

Katharine Collins: Yeah, absolutely. I think those are some of the first data that really stimulated the vaccine development community. They showed really early on, decades ago, that you could protect people by using these irradiated sporozoites, and that work continued.

So a company called Sanaria, with Steve Hoffman and others, developed the PfSPZ vaccine, and this worked really well with three doses in people in the US, so people who had no experience with malaria infections before. But when they ultimately got this into children in Africa who had had malaria infections in the past, the vaccines didn't work very well, so that hasn't moved forward for that population.

There's actually been some really interesting work more recently that they've used genetically attenuated parasites. So instead of irradiating the parasites and then using them, they've made them so that they can't survive beyond the liver stage, but importantly, if these parasites live to the end of the liver stage, then they're really protective. And there was a recent study where they showed that a single dose of this vaccine provided really high levels of protection in their challenge trial.

But again, this was in people that haven't been exposed to malaria before, so while this looks really exciting at the moment, it still needs to be tested in the field, in people who have been exposed to malaria, and then ultimately in children as well. But it's really exciting. It's pretty game changing if you can get a single dose vaccine to protect against malaria; we've never seen that before.

But the challenge with these parasites is that they need to be stored in liquid nitrogen, so you can't just kill them like we have done in the past with other whole pathogen vaccines. They need to be viable, they need to be able to survive in the liver, and that's gonna be quite challenging for delivery in Africa, because there aren't liquid nitrogen facilities everywhere.

Saloni Dattani: Why does it have to be so cold?

Katharine Collins: That's the way of putting them in stasis.

Saloni Dattani: Is it just preserving them?

Katharine Collins: Preserving them, yeah. So that they can be woken up. They've either got to be kept alive until you inject them, or you can try and cryo-preserve them in a way that they could be thawed, and then they'd still be viable.

Saloni Dattani: What if someone found a different way to preserve them for a long time? Are there other options? Can you like freeze frame a vaccine?

Katharine Collins: No. The - no?

Saloni Dattani: I have no idea. I feel, well, I've been watching a lot of Pokémon and Team Rocket has all of these crazy tools and equipment to do things.

Jacob Trefethen: We can learn from them.

Saloni Dattani: I feel like they would have a laser beam that could just freeze someone in place.

Katharine Collins: That would be cool, yeah.

Jacob Trefethen: Let's take a note. Let, let's look into that, I think that could be pretty interesting.

Katharine Collins: I know a funder that's just started there.

Jacob Trefethen: Yeah. Yeah. Let me just, actually I've already got too much in my laser beam column, someone else is gonna have fund that one. But...

Saloni Dattani: Also this laser beam thing that could freeze - could be used much more widely than just malaria research.

Jacob Trefethen: You could zap people miles away. It's interesting I don't hear people talking about this more given how important it could be.

Saloni Dattani: Yeah!

Jacob Trefethen: Now on our current technologies, boring, so it sounds like - my sort of takeaways from this section are that when people talk about vaccines, the thing you always hear about is efficacy. COVID vaccine is 90% efficacious, blah, blah, blah, blah, blah. But that is one number.

Firstly, that number does not bake in to the public narrative, duration. It does not matter if something is 90% efficacious and lasts for three months, if it then decays. Secondly, it doesn't bake in cost. What's the manufacturability of this? How widespread is it gonna be in a global health context? But then in addition, it doesn't bake in how many doses do you need? And, in a context where people might not be - they're juggling a lot, may not come back for a second, third, or fourth dose; getting down from four to three, three to two or two to one is just an incredibly big deal, not for scientists, but for people in the real world who're actually gonna be taking these vaccines.

So Katharine, is that a fair summary?

Katharine Collins: Yeah, absolutely. Spot on.

Saloni Dattani: It reminds me of, you know the HPV vaccine, where it was originally a three dose vaccine, and then it turned out that actually one dose was really effective. But it took a really long time for them to change the recommendation on how many doses people needed. And now that they have that new recommendation that you only need one dose, you can actually scale it up much more widely than before.

Jacob Trefethen: So, Katharine, if you had to make a guess, I'm gonna put you on the spot: in 10 years will we have an approved vaccine in use, which is, say, two doses for kids?

Katharine Collins: 10 years, I think, two doses is too high a bar. I think we can get to three.

Jacob Trefethen: Mm.

Katharine Collins: I think we can get to a more durable and a more protective vaccine with three doses.

Saloni Dattani: What's the - what are the barriers to making it happen?

Katharine Collins: I don't know. Maybe I wanna change my answer there. I think 10 years, I would put it 60% chance we can get to two doses.

Jacob Trefethen: Okay. But it's all to play for, you're saying it really could go either way.

Katharine Collins: Yeah, it's not a done deal. I think 60% chance we can get to two doses, like 90% chance we're gonna have a better vaccine.

Jacob Trefethen: Okay.

Katharine Collins: Three doses, 90%. That's too high, 80%.

Jacob Trefethen: Okay. So you're saying we've got to plug away and get to a better vaccine than even the one you invented.

Katharine Collins: Definitely! R21 is suboptimal. It can have impact like we've discussed, but it's not a game changing vaccine. The delivery challenges, the durability - that all needs to be solved.

Saloni Dattani: Hmm.

Jacob Trefethen: Okay. So challenge number one then. So you're saying there's a good chance if we really push for it, we can get to a better vaccine. Maybe it's three doses, maybe it's longer duration, and then - but we have to also be aiming at the same time for even further improvement for kids, and that's hopefully getting to perhaps two doses, perhaps, you know, transmission blocking, that kind of thing.

Katharine Collins: Yeah, absolutely.

Jacob Trefethen: So it's all to play for. Okay. Saloni, how are you feeling at the end of this section?

Saloni Dattani: This makes me sad. I feel like it's so sad that one, our technology has improved so much, but it doesn't seem to have made that much of a difference in terms of the efficacy – except for this one vaccine, which is really hard to scale up because you need to cryo-preserve the sporozoite stage, which means that it sort of rules it out being used widely. And the third thing, is that there were like various vaccines that are in late stages of trials right now that could have been in late stages 10 years ago. It's just the combination of all of that is just incredibly depressing to me.

Jacob Trefethen: Yeah. Well, can I try and cheer you up?

Saloni Dattani: Yes.

Jacob Trefethen: Just to reorient to how many lives a vaccine can save. That is even imperfect. You know, if R21 or RTS,S - I mean R21 seems more likely now - could scale up to more children who need it, tens of thousands of children's lives would be saved already. And then Katharine is telling us that within 10 years, we have a good shot at an improved vaccine that's even better, so that is gonna matter to a lot of children.

And science, the reality of this problem is the hardness of it is set by nature, and nature is a vicious, vicious, test setter sometimes. The fact we've got this far, I mean, that is pretty impressive and we have a ways to go, but there's a line of sight to improvement, even if not to the absolute a hundred percent blocking one dose thing.

Saloni Dattani: I mean, I'm happy for the children who are getting these vaccines, but it's just that counterfactual. It's just very hard to get out of your head.

Jacob Trefethen: Yeah. Yeah. So, Katharine, as you look to the next 10 years, how do you feel?

Katharine Collins: I'm optimistic. I think we can do better. I think we've got great people doing incredible work, great new tools and more people thinking about the problem end to end. So more people thinking more about more than just efficacy, with all the other criteria you raised that we should be considering. More developers are now aware of all of those things to consider in the development pathway, and so I think there's a lot of hope.

Saloni Dattani: There's also the current rollout, right? That we could scale up.

Katharine Collins: Yeah, I think that's a tough one. I think it's a really difficult funding environment, so we don't have enough donor support to provide R21 and RTS,S or the countries that would like it, that would need it, and are requesting from Gavi. So if we had more support coming from the different donor countries.

Jacob Trefethen: The UK's cutting back, US cutting back, Japan's cutting back.

Saloni Dattani: Germany as well. What I read from a report, talking about the situation at the time, two years ago, was back then, both of the vaccines had been pre-qualified from by the World Health Organization and they were being rolled out and they estimated that it would take another 12 years after that for all children under three in the countries with high malaria prevalence to be vaccinated. And another 2.5 million children were expected to die being unvaccinated from malaria, and the main constraints to increasing the number of children who were vaccinated fast was a lack of funding.

And I remember reading this and finding it surprising in one sense that this was the only constraint. But also, I think, after everything that we talked about, thinking that it was actually not that surprising and just very depressing. But the fact that if you had a few more billion dollars of funding for Gavi, which supports vaccination in countries around the world, you could vaccinate enough children to save another 300,000 lives.

The other thing that was interesting to me about this was that one of the reasons that there was this funding constraint was that one of the countries with the highest burdens of malaria was Nigeria. And Nigeria had just increased its GDP enough to be placed in a higher threshold, of a higher income country, according to Gavi, and that meant that they were no longer eligible for financial support to purchase these vaccines, and that meant that a lot of children would go unvaccinated, and that the cost was just so much higher after just passing this threshold. It seemed very bad to me that that was the case.

But there is some good news, which is that there was another deal where the price of R21 was reduced from $4 to $3 per dose, and that would save around $90 million and help vaccinate another 7 million children.

Jacob Trefethen: So all in all, what do you each wish that donors and funders and other decision makers understood about vaccine development that they're getting wrong?

Saloni Dattani: I mean, I think it's one of these situations where actually throwing money at the problem would make a difference. And that is something that people might find surprising in other fields, but here, funding Gavi would actually go a pretty long way. Or funding the other types of malaria vaccine research would go a long way. I think that's quite surprising to people.

Katharine Collins: I think we should really be learning from our experience with RTS,S and R21. And the biggest problem, with both those vaccines, is getting all of the doses into the children, that they need. So thinking more carefully about how you develop a product that's deliverable, earlier on in development, could have such a dramatic impact on the impact the vaccine can actually have. And I don't think the researchers doing the work, the ones running the very first trials in humans, are thinking about that enough.

Jacob Trefethen: Right? It's less pizzaz-y, but actually testing different delivery schedules in the clinical trials can have these incredible downstream effects of what gets recommended for millions of kids.

Katharine Collins: And maybe it's not fair to put that all on the researchers and the developers actually, I think. They're asking for funding to do the work. Funding's tight and limited, funders will give you the bare minimum, to do the bare minimum. So you can only test one schedule, and so you have to go with what you have the data on already, or what already looks promising instead of exploring what the other options could be. To me, that's also on the funders to really understand that as well.

Saloni Dattani: I think another thing is - that people may not know is just how important it is to have clinical trial infrastructure, to have better ways of running trials more efficiently, but also just more sites, more people doing these tests, being able to test multiple vaccines and not having the situation where people have to prioritize funding for one vaccine over the other, at the expense of testing the others as well.

Katharine Collins: But I think there's also another part to the story as well in that, with malaria, everybody knows about malaria. The burden's really well known. So as soon as a malaria vaccine was developed, countries were asking for it. They knew they had a problem, they wanted the vaccine and they're pushing to roll it out to protect people, so those vaccines can have an impact.

But there are other vaccines that we've tried to develop in the past where we didn't have good data on the burden in all the countries that possibly needed it. And so I think the Hib vaccine was a good example. It was developed, it was ready to be used, but countries didn't know they had a problem. So it was this huge delay in rollout. There's so much more that needs to be done when you're thinking about developing a vaccine, beyond just developing the product, thinking about how it's gonna reach people, and how people are gonna understand whether they need the vaccine, what the demand is.

Jacob Trefethen: That was quite an episode. That is our first episode where we had a expert interviewee with us the entire time. Thank you so much, Katharine. And now it's time to conclude with what some of the things, what are some of the things we learned or that stuck out to us from this episode?

And I'm gonna start. Number one, how much you can learn from patents. It turns out that there are people who read them and then they tweak them, and then they change them, and then they make new inventions. I mean, that really gave me hope for public knowledge again.

Saloni Dattani: That was really cool to hear about.

Jacob Trefethen: Saloni, what did you, what stuck with you?

Saloni Dattani: So I had a bunch of thoughts. The first one, which I was thinking about before we started recording was that, and this is a very unpopular opinion, but some PhDs are just better than others and some fields are better than others too. I know it's controversial, but I think more students should go into infectious diseases, and should go into vaccine development. And I have many thoughts about which fields should move into those, but I won't name them - they'll probably, they'll know who they are.

The other was that I thought it was really interesting to hear about the Jenner Institute, and how it was set up in such a way that there was a manufacturing facility that researchers could work with, and they could learn from that stage of the process in manufacturing. And I thought maybe more institutes should be set up like this, where you can see the both the basic research and the translation and the manufacturing happening in the same place, and learn from these different stages. That I thought was a really cool thing to learn about.

The other that stuck with me throughout this episode was that malaria is very complicated, especially compared to the other pathogens that we've talked about in previous episodes. It has many different stages of its lifecycle, it changes shape. It's harder to develop vaccines for malaria than for many other diseases. And there were various parts of that process that were just very tricky to do scientifically. It was hard to find good animal models that helped replicate what the disease would be like in humans.

The next was that a lot of the research funding for malaria was affected by priorities that high income countries had. So in the 1950s during the global Malaria eradication program, the funding for research dried up and a lot of researchers were made program operators in the eradication program, and that stalled research until the Vietnam War, where the US Army troops were facing potentially drug resistant malaria, and there was now a renewed need for research into new malaria drugs, but also malaria vaccines. And that is where the RTS,S vaccine originally came from, was research from people who were working on that during the Vietnam War. So that stood out to me as well, that we sort of think of research happening in the lab, but it's really actually influenced by all of these much broader considerations, and the historical context, and things like that, that I think people don't appreciate enough.

Katharine Collins: So the first one for me is probably the cost, scalability, and deliverability are actually really important. People should think about them earlier in the process. I think it's clear from the R21 and RTS,S experiences that the vaccines could have much greater impact if those things were considered earlier.

Saloni Dattani: I also thought that just within that process, it's not just the broader concerns, but at every stage of vaccine development, these things are really important. Like how you develop the adjuvants and how expensive those are, or how that affects the efficacy of the vaccines, and how accessible they might be later on as well. And then things like, how does the dosing of the vaccine that's being developed affect how easy it is to scale it up, across countries, or across millions of children, I think is something that people underappreciate. And then similarly, the vaccination schedules - the fact that the malaria vaccine is taken at different ages than other childhood vaccines, and how that affects uptake of the vaccines, is something that was new to me. And just this idea of making things more efficient at all of these stages could be really important.

I've been reading the book The Origins of Efficiency by Brian Potter, and one of the key things that stood out to me from that book was just how much progress we've made in medicine, but also engineering, and all parts of life were from improving the efficiency of things that people have already discovered, and that that stage can often make the difference between something that is possible versus something that's actually used by millions of people, and I think that's actually a huge part of the picture.

The other thing that I have always been thinking about is just how different things could have been. Like what others, what other alternative universe we could have lived in, if things were different. And the key things that I think about here are: one, how things would be different if there was more funding. And second, how different things would be if there was better infrastructure for running clinical trials.

And we talked about a bunch of examples of how that could have been different. So one, that probably would've sped up the developments of the RTS,S vaccine, the first malaria vaccine. Having the clinical trials sites set up earlier, that would've made a difference. Having more funding, that would've made a difference. But then we also talked about other vaccine candidates for malaria, and how more funding for that research could have changed the picture and sped up the trials for those vaccines. And then finally, the rollout of the malaria vaccines that have already been approved could be sped up with more funding. And that funding was the constraint, and still is the constraint, to getting that out to more children.

And I think that often people think of this as purely a scientific problem, but I think that's not the case, and that in many situations when we're talking about diseases that affect people and poor countries, often commercial incentives, and funding, and the historical context and all of these things actually have a very big impact.

Katharine Collins: I think it's really easy to look back and think about how things could have been done differently with hindsight. But it's really important to remember that these were really uncharted times for this type of vaccine, and it's really quite amazing what was achieved over the time. Obviously, we all wish things could have been done faster and can keep going faster in the future, but it is quite remarkable what was achieved. But I think it's important that we do look back. I think we should all be looking at the experiences of the past and learning from them so we can improve what we're doing as we're developing future vaccines; learn from those mistakes.

And you know, now as a funder, I'm trying to take a lot of those lessons and those experiences and apply them to the development of next gen malaria vaccines and Strep A (Group A Streptococcus) vaccines and any other products we end up working on at Coefficient Giving.

Saloni Dattani: What you just mentioned, made me realize that the alternative universe that we could have lived in: it could have been faster, but it also could have been slower, and I hadn't thought about that.

Jacob Trefethen: I think my main takeaway from looking backwards into the past today is about the present and about the future. And it's that we live at a time of scientific wonder. We - people who invented world-changing technology are among us today. Invention is often a process of building on other people's work, tinkering, tinkering in the lab, and taking care of those lab notebooks, looking in an electron microscope, trying an experiment, changing what you started with, trying another experiment. And these people are heroes.

They're real people. Sometimes you can even get them to come on your podcast, thank you very much, Katharine. And to anyone listening, you may know one of these people, and society may not recognize it yet, and they're still inventing and they're still trying stuff. You may become one of these people in the future. And when it comes to science, we are all in this together. We're trying to figure out what is true and what we should do next.

So I just wanna end by saying, Katharine, thank you very much. This was very enjoyable and I'm very excited about everything that comes next.

Katharine Collins: Thank you. It's been great to be here. Great to chat.

Saloni Dattani: If you enjoyed this episode, you should rate us on Spotify or Apple or wherever you listen to this and share it with everyone you know, including any parasites that you are currently infected with.

Jacob Trefethen: Maybe they are heroes too, you never know, they could contribute in their own way. Please share this one in particular with anyone who's considering starting a PhD.

Saloni Dattani: Yes!

Jacob Trefethen: Great. See you next time everyone!

Saloni Dattani: Bye!

Jacob Trefethen: Bye!

Katharine Collins: Bye!