Inventing the second malaria vaccine with Katharine Collins

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I read that if just a single 
parasite makes it to the liver,

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it can cause an infection. Is that true?

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

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The reality of this problem is the 
hardness of it is set by nature,

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and nature is a vicious test setter.

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Adrian asked if I wanted to stay on, this 
was the PhD project that he pitched to me.

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I thought it sounded quite interesting to make 
a new vaccine. There was a lot of iteration.

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The first time I saw the particles under 
electron microscope that was really exciting.

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Would you participate in the challenge trial?

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I would love to, but I really 
hate needles. I have to lie down.

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Otherwise I might faint. It's kind 
of ironic for a vaccine developer.

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There are people like Katharine 
Collins who invent entirely new

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vaccines that are now gonna be used 
by millions of children. You may know

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one of these people. You may become 
one of these people in the future.

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Malaria kills around 600,000 people a 
year. Most of them are young children

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in Sub-Saharan Africa. It's caused by 
a parasite, not a bacterium or virus,

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and it's spread by a mosquito. Until recently, 
the only control measures were insecticides and a

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handful of anti-malarial drugs. But in the last 
few years, we finally got effective vaccines.

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Two malaria vaccines have now received WHO 
recommendations and are being rolled out

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across Africa. And for the first time ever, 
a human-infecting parasite has a vaccine.

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Getting here took longer than it 
should have. The first malaria

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vaccine was developed and tested in the nineties,

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but it's spent 23 years in clinical trials and 
pilot tests before it was licensed and rolled out.

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So in this episode, we're going to cover 
the science of why malaria is so hard to

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vaccinate against, how the vaccines 
actually work, why it took so long,

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what we can do to speed up the rollout 
now, and what even better vaccines

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are being tested now for fewer doses 
and longer durability in the future.

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Today's episode is special because 
we're joined by Katharine Collins,

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who co-invented the second malaria vaccine during 
her PhD, and she can tell us what it was actually

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like from the inside. Welcome to Hard Drugs, 
hosted by me, Saloni Dattani, and Jacob Trefethen.

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Okay, so we have some news 
today, right? Because Jacob,

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you have started a new job. Could you 
tell us about what you're doing now?

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I'm gainfully employed. I'm working at a new 
foundation making grants to science still,

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but from a different vantage point. It's the 
OpenAI Foundation and we have been getting

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started in science, so it's kind of exciting, 
a little bit different than my previous job

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which was at Coefficient Giving. And the 
previous job was quite fun. But you'll have

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to ask around what my reputation was there, for 
example, Katharine, what was I like back then?

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

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No no, we can't include that! No, no. 
Expulsion! No, my biggest difficulty

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of changing jobs is that I don't get to 
work with some of the wonderful people

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I worked back at Coefficient Giving with, like 
Chris Somerville, Ray Kennedy, Heather Youngs,

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Rafael Dib, Douglas Chukwu. Oh gosh. So 
many people, Aisling Leow. And guess who?

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Katharine Collins. Now the good news is 
that Katharine at least is here today.

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So Katharine is joining us from 
Coefficient Giving as well, and is a

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very special guest on today's episode because 
she co-invented the second malaria vaccine.

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Now we are lucky at Hard Drugs to have listeners 
around the world, and that means I'm going to

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start here with some insight into the British 
psyche. For those listening from other places,

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we have a guest on today who is an inventor and 
she's also British. That means that she's very

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reticent to take credit for things, even things 
she invented, so it took a lot of cajoling to get

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her onto this episode, though we knew if we could 
pull it off that our listeners would love it.

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So I am very grateful for the willingness of our 
guests to be cajoled, but I should say upfront,

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as part of our ability to pull it off, 
that there are many other people involved

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in the story of malaria vaccines and of R21 in 
particular, who we won't get to have on today,

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who took forward the vaccine into clinical 
trials, who did all the work to make sure

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it could get approved and used by kids 
around the world. So that's my proviso,

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that's the trade we had to make with our world 
famous inventor. With that in mind, enjoy.

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

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What I didn't realize until recently 
was that fungi and plants can also

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be parasites. And so a parasite 
could be a single celled organism.

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It could be an animal like a mosquito, 
vampire bats, hookworms. Or it could

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be fungi like the ringworm fungi. Or it could 
even be a plant, like mistletoe is a parasite.

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What?!

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Yeah, mistletoe is a parasite. 
It attaches to other trees and

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extracts water and nutrients from them.

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Gosh. And here I was. Okay. I think I have two 
answers. You brought up hookworm. Hookworm's

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one of my answers, tape worm's another one of 
my answers. I mean, tape tapeworms disgusting,

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obviously, but you just have to 
be impressed. They get so large.

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How large do they get?

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

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Wow.

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They get feet long for sure. And maybe meters. I 
mean, I just think that's crazy. It's obviously

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gross, but luckily hookworms aren't gross 
at all. All they do is hook onto the side

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of your gut and suck your blood. They come 
up, they sort of get up through your foot,

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sneak - their whole life cycle's insane 
- they eventually get down into your gut

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and hook onto it and start sucking your 
blood. I mean, that's pretty impressive.

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

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

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

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

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Oh, wow.

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That's a joke. Sorry. That's 
a joke. That's a joke.

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Oh, you tricked me!

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First trick of the episode!

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Okay. My favorite parasite also, well, I'm 
not impressed by this, I'm just so horrified

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by it that I have decided it's also my favorite. 
And it's Guinea worm, which is so horrible. And

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people ingest the worm larvae when they drink 
contaminated water. And the larvae get into

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your stomach, they get through your gut, and 
then they grow into worms that can reach up to

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a meter long. And they kind of crawl through your 
connective tissue and your joints, and then slowly

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erupt out of your legs - usually out of the skin, 
near your legs. And the emergence is also very

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slow. And the way that you remove the worm is 
by slowly winding the worm around a small stick,

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and if you go too fast, the worm snaps and dies, 
and that causes severe inflammation in your body.

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That sounds like it was invented 
by Jigsaw from the series Saw as

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a patient to someone who was impatient or 
something. Okay, well thank you for that.

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Wait, wait, wait. The good news is 
though, we've almost eradicated it.

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Isn't that great? So it used to cause like a 
million or more cases per year in the 1980s,

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and it turns out just cleaning up 
the water, filtering drinking water,

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or telling people not to drink from 
stagnant water can help prevent infections.

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Do you know how near eradication we are?

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

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Wow!

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Wow. That's incredible.

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

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Yeah, mine's really boring. Mine's the malaria

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parasite. I can't say anything else 
after studying it for two decades.

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

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

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In this episode we're going to talk a lot about 
the two malaria vaccines that have been rolled

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out. The first one is called RTS,S and it was 
developed in the 1990s. The second was R21,

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it was invented by Katharine Collins, who's 
here with us today, and it was based on the

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first one. So those are two names that we're 
gonna refer to throughout the episode. RTS,S,

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the first malaria vaccine and 
R21, the second malaria vaccine.

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I guess it's easy to remember because 
the second one has two in it, R21,

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but just in case that is confusing; those are 
the two names that you've gotta remember. RTS,S,

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the first malaria vaccine and R21, the second.

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Maybe let's start with how you got into 
malaria research in the first place.

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What drew you into the field? Or how 
did you get into vaccine research?

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I had done my undergraduate and my master's 
degree in basic research and not in global

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health. I did various projects in different 
disease areas, but it was really about trying

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to understand the fundamentals and different 
signaling pathways and things like that. So I

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think one of my projects identified a protein 
interacted with another protein in a pathway.

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And while that was cool, and I loved science 
and it's definitely where I'm supposed to be,

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but it I didn't see how that was gonna have 
any direct impact on health in the near term.

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I actually started looking for jobs, or how 
I could have an impact in global health,

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or how I could transition from science into global 
health work, and it wasn't really clear. And then

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this job was advertised at Oxford University to 
work on malaria vaccine trials. And I thought,

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wow, that's global health. I should just take 
that job, and or apply for that job, and that

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may open doors. And so I did. And I really loved 
working on malaria. It was instantly something I

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was really passionate about, really motivated 
to work on. It's just a fascinating parasite.

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So the job was a research assistant 
on malaria vaccine trials. So the

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Jenner institute at Oxford, where 
Adrian Hill's group that I joined,

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they were testing a number of different 
candidates in malaria trials. And my job

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was to help coordinate those trials and to 
do all the immunology in the background.

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

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Yes. Well, after being there for about a 
year, Adrian asked if I wanted to stay on,

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and do a PhD. The project idea was that 
Adrian had developed a vaccine that targeted

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the malaria parasites, whilst they were in 
the liver. It'd been shown to protect some

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people against infection, but it was quite 
a low level, I think it was 20% efficacy. So

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the idea was to combine this liver stage 
vaccine for the vaccine that could also

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prevent the malaria parasites before they get 
to the liver. So stop them invading the liver.

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And the leading vaccine at that time targeted 
the parasites before they invaded the liver,

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and this was a circumsporozoite based vaccine 
called RTS,S, and it was developed by GSK.

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So he wanted me to work on making a newer 
version, an updated version of that vaccine.

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That's so cool. I feel like compared to - so 
my PhD was very boring in comparison to this,

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and it makes me think that there's actually -

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

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I know, I feel like people should know upfront 
that some PhDs are better than others. You know,

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some fields are better than others. So 
who else was involved in this? Did you

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have mentors, collaborators, rivals, or enemies?

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I worked fairly alone in the lab. I did have 
a few people that were supporting the work as

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well. So my PhD supervisors were Adrian Hill 
and Sarah Gilbert. There were also a couple

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of postdocs and technicians and PhD students that 
helped me with various parts of the project over

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the years. For example, someone actually 
helped me vaccinate all the mice that we

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used for the preclinical experiments. 
And then I did the immunology myself.

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

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That's right. Yeah.

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For COVID. Got it.

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Yeah.

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And rivals?

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Rivals, well, oh, you're asking the good 
questions. I guess in the field at the time,

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there were lots of people trying to 
develop a malaria vaccine. I guess

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there was competition between the different 
groups to see who would get there first.

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And whilst I was working on it, 
RTS,S hadn't crossed the finish line,

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but it was obviously way, way, way further 
ahead in development. So the expectation

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was that that vaccine would move forward and 
get approved first, and then R21 may follow.

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

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Yes, actually that's right. 
So if I remember correctly,

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it was due to come off patent. And 
interestingly, that was essentially

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the starting place for learning how to 
make R21. So I reviewed that patent,

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I looked at how they've made RTS,S, and then 
I made a plan for how to go about making R21.

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Did that have enough information 
for like? What was that like?

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So RTS,S is actually made with a lot of a 
protein on the surface of the Hep B virus.

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This is the Hep B surface antigen and that was 
needed to make it form the virus like particle,

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but it had quite an excess of Hep B 
surface antigen. So it's actually a

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really good Hep B vaccine, and not a terribly 
good malaria vaccine. So my project was to see

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if we could remove some of that Hep B and 
actually make it a better malaria vaccine.

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And we had established a plan for how we're 
going to get there. So initially we wanted

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to just replicate the RTS,S process in the lab and 
then try a few different things to see if we could

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get the particle to form without this excess Hep 
B surface antigen. One approach was actually to

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just try and chop out some of the malaria protein 
out of the vaccine and remove some of the T-cell

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epitopes, which were in there, and a few other 
bits as well, and see if the smaller protein would

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be more able to form particles on its own. The 
other way was just to try and reduce the amount

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of extra Hep B that we were adding and see if it 
could form particles on its own that way, by using

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some of these newer yeast expression technologies 
to grow the protein and new methods to purify.

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I think RTS,S had something like a 12 step 
purification process at least in the patent, and

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that might not be what they used anymore. But I 
wasn't really interested in trying to set up this

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12 step new process in an academic lab. You know, 
I'm not a biochemist. So I essentially looked at

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their process to understand what they had done 
and why, and then developed a purification

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process using a combination of some of those 
old methods and some of the newer technologies.

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I feel like my immediate question is why 
didn't the developers of the RTS,S vaccine

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do that? Like if there were various 
steps that didn't need to be included.

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Yeah, I mean, they probably did. I mean, when 
they first patented what they were doing,

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it probably had this multi-step process. 
Maybe they had different process they were

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using lots of different methods, so 
they patented the whole process and

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I'm sure they probably optimized that as they 
scaled up and improved their manufacturing.

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I wanna just get a more of a sense of what it 
feels like to be in the lab alone, toying with

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different steps of purification, and how long were 
you - did you feel sort of lost versus actually,

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it worked pretty quickly and you got, once you 
saw in the electron microscope, you're like,

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00:17:09,600 --> 00:17:12,960
oh God, it's actually gonna work. Was that 
pretty quick or you were there for months,

199
00:17:12,960 --> 00:17:17,360
years? You're tinkering. What did 
the invention process feel like?

200
00:17:17,360 --> 00:17:21,440
Actually, I think I was interviewed 
by someone a while ago and I,

201
00:17:21,440 --> 00:17:25,360
my recollection is that it was very quick 
that I kind of give it a go and it worked.

202
00:17:25,360 --> 00:17:25,680
Wow.

203
00:17:25,680 --> 00:17:32,720
And then I thought, now I thought, is this true? 
And I went back to my lab notebooks and I had a

204
00:17:32,720 --> 00:17:37,040
look through like the electronic notebooks and I 
had a look through and it wasn't that quick. There

205
00:17:37,040 --> 00:17:44,400
was a lot of iteration, a lot of optimization 
that happened with every single stage.

206
00:17:44,400 --> 00:17:49,600
So we were using yeast to express 
the protein and grow the protein,

207
00:17:49,600 --> 00:17:53,520
and there were four different strains we were 
testing, and then for each different strain, we

208
00:17:53,520 --> 00:17:57,840
picked multiple different colonies, and I screened 
all of these different colonies first to find the

209
00:17:57,840 --> 00:18:03,520
best expressing colonies, and then I started to 
try and purify it, to purify them. And I probably

210
00:18:03,520 --> 00:18:08,880
used multiple different techniques until I got 
something that looked substantial. So it wasn't

211
00:18:08,880 --> 00:18:18,400
that quick. So I think it was a long time ago 
now, so my memory's a bit optimistic maybe?

212
00:18:19,520 --> 00:18:25,920
So am I imagining right that it's like, you 
have the instructions-ish from the patent

213
00:18:25,920 --> 00:18:31,360
and then you're trying out different options, 
like different versions of the yeast, different

214
00:18:31,360 --> 00:18:37,280
versions of the purification process, and at 
each step trying to optimize which is the best

215
00:18:37,280 --> 00:18:44,240
one to go forward with or something like that? 
Or is that not the right way to think about it?

216
00:18:44,240 --> 00:18:49,040
Yeah, that's just about right. There are a lot 
of newer technologies available for purifying

217
00:18:49,040 --> 00:18:53,120
proteins and particles, so it's kind of a 
process of looking at which steps could be

218
00:18:53,120 --> 00:18:56,480
replaced by newer technologies and going for 
something that was more modern and simpler,

219
00:18:56,480 --> 00:18:59,760
where that was possible, and where 
there wasn't a newer technology,

220
00:18:59,760 --> 00:19:02,720
we were sticking with that whole process as well.

221
00:19:02,720 --> 00:19:05,520
So you were at the Jenner 
Institute, is that right?

222
00:19:05,520 --> 00:19:06,400
That's right.

223
00:19:07,040 --> 00:19:10,240
Do they have just people working on 
many different diseases and like trying

224
00:19:10,240 --> 00:19:17,600
to develop vaccines against all of them, or 
are there some areas that they focus on? Or,

225
00:19:17,600 --> 00:19:21,760
are lots of people doing this during their PhD?

226
00:19:21,760 --> 00:19:29,200
I think developing a vaccine was rare, fairly 
novel at the time, or quite rare. So not a huge

227
00:19:29,200 --> 00:19:34,880
number of people were doing it. There were 
three PhDs I can remember that developed

228
00:19:34,880 --> 00:19:40,320
a vaccine during their PhD and I was one of 
them, but there may have been others as well.

229
00:19:40,320 --> 00:19:44,320
But in terms of the structure at the Jenner 
Institute, there were different group leaders,

230
00:19:44,320 --> 00:19:49,520
or PIs, that have their focus area, and 
the Jenner Institute was generally open

231
00:19:49,520 --> 00:19:54,640
to having new people join the institute. And 
if there was space, they did actually join

232
00:19:54,640 --> 00:20:00,160
the physical lab space as well. So we had work 
going on on multiple diseases at the same time.

233
00:20:00,160 --> 00:20:03,040
Okay. So you're, you're tinkering, 
you're tinkering, you're tinkering,

234
00:20:03,040 --> 00:20:07,760
you look under the electron microscope 
and then you test something in mice and it

235
00:20:08,320 --> 00:20:12,800
protects them from malaria. Did it feel like 
a eureka moment at any points of that step,

236
00:20:12,800 --> 00:20:19,280
or was it just iteration? Iteration, feels 
good, feels a bit better, feels a bit better?

237
00:20:19,280 --> 00:20:21,680
No, definitely a few eureka moments. I mean,

238
00:20:21,680 --> 00:20:28,480
the first time I saw the particles under the 
electron microscope, that was really exciting,

239
00:20:28,480 --> 00:20:35,040
especially when I had used the process that we 
didn't think that was possible. So by removing

240
00:20:35,040 --> 00:20:40,880
all the excess Hep B, that was really cool when 
we could see those, and they looked very similar

241
00:20:40,880 --> 00:20:45,920
to the Hep B particles. So it was it was really 
reassuring that we were doing something right.

242
00:20:45,920 --> 00:20:50,320
Then the next push was to move 
that into a preclinical study,

243
00:20:50,320 --> 00:20:53,760
to inject mice and see if we get an immune 
response, and then if we can protect the

244
00:20:53,760 --> 00:21:02,560
mice as well. And whilst I was optimizing the 
process, the yield was really, really low of

245
00:21:02,560 --> 00:21:08,240
the particles. And I tried to concentrate it 
and it wasn't easy to concentrate. So we ended

246
00:21:08,240 --> 00:21:12,960
up injecting an incredibly low dose into the 
mice and it was like, well, we might as well,

247
00:21:12,960 --> 00:21:17,840
we have the product, let's just see what it 
does. And then it protected all the mice.

248
00:21:17,840 --> 00:21:22,000
And so that was really exciting. We had 
gone for this dose that was dramatically

249
00:21:22,000 --> 00:21:27,120
lower than any other dose we normally test 
in the lab. And the vaccine I think 10 times

250
00:21:27,120 --> 00:21:31,840
lower than any other dose that had showed 
for RTS,S being tested in mice and that it

251
00:21:31,840 --> 00:21:37,040
worked. So that was really exciting. That was 
the one of the really exciting moments. Yeah.

252
00:21:37,040 --> 00:21:40,320
That's super cool because 
if you have a lower dose,

253
00:21:40,320 --> 00:21:43,520
you can vaccinate more people 
with the same amount, right?

254
00:21:43,520 --> 00:21:48,080
Yeah, exactly. And a tenfold lower dose, that's 
huge. That's not half the doubling the number

255
00:21:48,080 --> 00:21:52,800
of people. That's a dramatic increase. But 
actually at the time there wasn't a lot of

256
00:21:52,800 --> 00:21:57,200
information on how well dose in mice would 
translate to humans and if it would actually

257
00:21:57,200 --> 00:22:02,400
result in a lower dose human vaccine. We did 
later find out that it was easier to scale up.

258
00:22:03,040 --> 00:22:08,320
So, interesting how the practical constraints - 
let's say it had been effective but you would've

259
00:22:08,320 --> 00:22:13,040
needed five times more product. Is it possible 
you would've just dropped this lead and focused

260
00:22:13,040 --> 00:22:16,080
on something else 'cause you couldn't 
make enough, or what would've happened?

261
00:22:16,080 --> 00:22:20,240
No, I was really early on in the purification 
process, in optimizing that. So it was just that,

262
00:22:20,240 --> 00:22:24,560
it was just of luck. But we had 
gone in with such a low dose to

263
00:22:24,560 --> 00:22:27,760
begin with. Maybe we would never have 
got to the low dose, that lower dose,

264
00:22:27,760 --> 00:22:32,640
if we haven't had that constraint 
on the concentration of the product.

265
00:22:33,360 --> 00:22:39,440
Okay. So all of this is happening in your 
PhD, was that 2010 to 2014? Is that right?

266
00:22:39,440 --> 00:22:42,240
Yeah, well remembered!

267
00:22:42,240 --> 00:22:49,360
So we now know, with the benefit of 
hindsight, that R21 works in kids,

268
00:22:49,360 --> 00:22:58,240
in humans, and it protects babies against 
malaria. And that took time to prove out

269
00:22:58,240 --> 00:23:03,520
any clinical trials, and there was 
- to give a spoiler to the audience,

270
00:23:03,520 --> 00:23:11,360
the R21 vaccine was actually approved 
a couple years ago for wide use.

271
00:23:11,360 --> 00:23:17,360
Along that journey, you finished your 
PhD and you started doing other malaria

272
00:23:17,360 --> 00:23:24,000
research elsewhere. Did you, when you finished 
your PhD in 2014, did you have a feeling that,

273
00:23:24,000 --> 00:23:29,760
oh, I just invented a vaccine that's gonna 
get used by millions of people? Or did it

274
00:23:29,760 --> 00:23:36,160
feel more like, okay, I've proven out that 
this might work and I'm gonna pass it on,

275
00:23:36,160 --> 00:23:39,040
but it's, we'll see. Yeah. What did it feel like?

276
00:23:39,040 --> 00:23:48,000
I think most people in the field were quite 
skeptical about R21 in the early days. They

277
00:23:48,000 --> 00:23:53,680
couldn't really see the point in making 
a vaccine that was so similar to RTS,S.

278
00:23:53,680 --> 00:23:57,760
And the initial results, kind of backed 
that up, that there was reasons for that

279
00:23:57,760 --> 00:24:04,560
skepticism. It didn't look very different in 
the preclinical work, in the mice studies,

280
00:24:04,560 --> 00:24:08,400
there wasn't a really strong reason to 
think that this was gonna save a lot

281
00:24:08,400 --> 00:24:12,320
of lives, when there was already 
a vaccine that was very similar.

282
00:24:12,320 --> 00:24:15,760
But the dosing was very different, right?

283
00:24:15,760 --> 00:24:21,360
It was, and I think this is a lesson for 
vaccine developers, right? At the time,

284
00:24:21,360 --> 00:24:27,200
everybody was quite negative about R21. But if you 
think about things like being able to reduce dose,

285
00:24:27,200 --> 00:24:31,520
making it simpler and easier to manufacture, 
even small increases in immunogenicity,

286
00:24:31,520 --> 00:24:35,120
if you add all of those benefits together, 
you end up with a product that's easier to

287
00:24:35,120 --> 00:24:39,920
deploy, a lot cheaper, and maybe easier to 
manufacture. So it can really have an impact,

288
00:24:39,920 --> 00:24:44,160
without just making a dramatically 
better vaccine in terms of efficacy.

289
00:24:44,160 --> 00:24:50,160
It's sort of scary though, 'cause I think I, as 
a outsider who has never developed a vaccine,

290
00:24:50,160 --> 00:24:56,560
if I had seen the results from preclinical 
tests in animals and the results said, well,

291
00:24:56,560 --> 00:25:02,480
we can't distinguish that this is better from 
RTS,S, I probably would've killed it. And yet

292
00:25:02,480 --> 00:25:10,160
now we know that it is much cheaper to produce 
and it's more manufacturable and it's longer

293
00:25:10,160 --> 00:25:17,760
durability. I mean, so it's sort of terrifying. 
What was in the system that allowed this one to

294
00:25:17,760 --> 00:25:23,840
actually go forward and now it's reaching people. 
You know, is it as contingent as it sounds to me?

295
00:25:23,840 --> 00:25:28,080
Yeah. You know, I think this was - all the credit 
goes to Adrian Hill for pushing it forward and

296
00:25:28,080 --> 00:25:33,520
really finding out what it could do in people, 
right? I think so many people would've dropped

297
00:25:33,520 --> 00:25:39,760
the vaccine at this point. And another difference 
that we haven't mentioned so far is that R21 also

298
00:25:39,760 --> 00:25:45,440
used a more scalable adjuvant, and I think that's 
quite important for the supply argument as well.

299
00:25:45,440 --> 00:25:52,880
An adjuvant is another ingredient in the 
vaccine that strengthens its immune response?

300
00:25:52,880 --> 00:25:54,880
Yeah. Yeah, absolutely.

301
00:25:54,880 --> 00:25:58,000
Alright, and so these were 
different between the two vaccines,

302
00:25:58,000 --> 00:26:04,000
and the R21 adjuvant was cheaper 
to produce and easier to scale up.

303
00:26:04,880 --> 00:26:11,920
Yes, absolutely. Yeah. The adjuvant used 
with the, with RTS,S is a GSK adjuvant. It's

304
00:26:11,920 --> 00:26:19,600
also used in another product, and yeah, much more 
difficult to scale, and much more limited supply.

305
00:26:19,600 --> 00:26:23,680
I remember reading that it comes 
from - that adjuvant comes from the

306
00:26:23,680 --> 00:26:27,600
tree bark of a South American tree. Is that right?

307
00:26:27,600 --> 00:26:32,080
Yeah. And that comes from the bark of 
a Chilean - I can never get the name,

308
00:26:32,080 --> 00:26:34,480
pronounce the name right, is a Quillaja 
tree (Quillaja saponaria, soapbark).

309
00:26:34,480 --> 00:26:38,960
Does that mean that you have to get that tree to 
get the adjuvant? Is that why it's difficult to

310
00:26:38,960 --> 00:26:44,960
scale up? And how come the second one is easier 
to scale up if they're both from these trees?

311
00:26:44,960 --> 00:26:52,880
So the supply limitation is the availability 
of the trees, the raw material, and also the

312
00:26:52,880 --> 00:26:58,640
purification process. So if you imagine you're 
purifying all these products from the bark of

313
00:26:58,640 --> 00:27:03,520
the tree, or from the tree, and if you purify and 
throw away a lot - a lot of it away, it's gonna

314
00:27:03,520 --> 00:27:10,560
be more expensive and harder to scale. They've 
improved the ways they're producing the trees,

315
00:27:10,560 --> 00:27:13,840
so supply is increasing and it's gonna 
be less of a limitation moving forward.

316
00:27:13,840 --> 00:27:18,080
And people are also working on 
synthetic versions and special,

317
00:27:18,080 --> 00:27:22,880
not sure the right word, aquaculture style 
(hydroponics) growing of these, of these trees

318
00:27:22,880 --> 00:27:26,240
and different methods of harvesting 
from them to get the components.

319
00:27:26,240 --> 00:27:30,320
Is it like someone shaving parts of 
a tree off and then doing some other,

320
00:27:30,320 --> 00:27:33,280
like, how does this all work?

321
00:27:33,280 --> 00:27:38,560
I've never seen anybody do it that, and that's 
kind of how I imagined it, taking the bark off.

322
00:27:38,560 --> 00:27:41,680
But other thing I should mention is you have 
to like harvest most of the tree or you have

323
00:27:41,680 --> 00:27:45,440
to kill the tree and that was the problem, and 
so I think they've changed the way that they

324
00:27:45,440 --> 00:27:49,280
actually harvest from the tree so they can 
keep growing as well in some instances. So

325
00:27:49,280 --> 00:27:54,560
you don't just have to - it takes 25 years 
to get the tree and then you cut it down.

326
00:27:54,560 --> 00:27:57,040
So you're looking at your lab notes, Katharine?

327
00:27:57,040 --> 00:28:02,960
Yeah, it's fascinating. I'm glad I kept 
really good notes. It's really interesting.

328
00:28:02,960 --> 00:28:04,640
Are they dated?

329
00:28:04,640 --> 00:28:06,400
Yeah.

330
00:28:06,400 --> 00:28:08,240
What date are you looking at?

331
00:28:08,240 --> 00:28:15,120
Um, troubleshooting the purification 
process, 23rd of the third, 2011.

332
00:28:15,120 --> 00:28:15,760
Whoa.

333
00:28:15,760 --> 00:28:18,720
Wow. What were we doing in 2011?

334
00:28:18,720 --> 00:28:20,720
Yeah, 23rd of the third.

335
00:28:20,720 --> 00:28:26,400
I was in school.

336
00:28:26,400 --> 00:28:28,720
I was inventing vaccines, actually, Saloni.

337
00:28:28,720 --> 00:28:33,440
You didn't tell me that.

338
00:28:33,440 --> 00:28:35,680
Yeah, I try to keep it private.

339
00:28:36,880 --> 00:28:40,320
So what happened on that day?

340
00:28:40,320 --> 00:28:46,000
I tested a few different methods and then 
the result: aggregation seen in sample.

341
00:28:46,000 --> 00:28:48,000
Okay. Bad.

342
00:28:48,000 --> 00:28:54,480
Second purification attempt: reduce aggregation.

343
00:28:54,480 --> 00:28:55,760
I love it.

344
00:28:55,760 --> 00:29:05,120
Do you have any, um... random comments in there? 
Do people put in computerized doodles? Emoticons?

345
00:29:05,120 --> 00:29:09,520
No. Definitely not, emojis 
didn't exist then, Saloni!

346
00:29:09,520 --> 00:29:13,280
No, but emoticons did.

347
00:29:13,280 --> 00:29:15,600
LOL.

348
00:29:15,600 --> 00:29:17,360
XD

349
00:29:17,360 --> 00:29:23,360
Aggregated again, LOL. Wait,

350
00:29:23,360 --> 00:29:27,360
so how many experiments are you doing? Is 
this like every day you have new entries?

351
00:29:27,360 --> 00:29:28,240
Yeah, yeah, yeah.

352
00:29:28,240 --> 00:29:28,800
Wow.

353
00:29:28,800 --> 00:29:30,960
No, every couple of days. So I guess 
I'm gonna test this and then it

354
00:29:30,960 --> 00:29:39,840
takes a few days to test and then... 
results: aggregation seen in sample.

355
00:29:39,840 --> 00:29:53,360
ROFL. Are there images of the RTS,S or R21 under 
the microscope? Should we- we should include one.

356
00:29:53,360 --> 00:29:57,680
Well if you are up for it - us including 
some screenshots might be kind of fun for

357
00:29:57,680 --> 00:30:01,920
viewers. Oh my gosh, no. Sorry. We have 
thank goodness. We have to include this.

358
00:30:01,920 --> 00:30:02,400
Wow.

359
00:30:02,400 --> 00:30:07,520
This is so cool. Whoa. Okay, great.

360
00:30:07,520 --> 00:30:10,160
Wow. They're so cute.

361
00:30:10,160 --> 00:30:15,600
Okay, listeners, so we are looking at 
two images here. On the left it looks

362
00:30:15,600 --> 00:30:21,040
like spots on someone's skin, maybe measles. 
So talk us through the left here. Katharine,

363
00:30:21,040 --> 00:30:23,680
what are we looking at? 
Those beautiful circles. Wow.

364
00:30:23,680 --> 00:30:31,760
So those, that's a transmission electron 
micrograph of negatively stained R21 particles.

365
00:30:31,760 --> 00:30:36,800
Oh my gosh, that's so clear. They're 
so clean. They're so circular.

366
00:30:36,800 --> 00:30:40,240
They're so blobby.

367
00:30:40,240 --> 00:30:44,640
I mean, just to restate some of, and 
correct me if this is wrong, Katharine,

368
00:30:44,640 --> 00:30:53,680
but part of the reason why having these circles 
that look like viruses is so useful is that

369
00:30:53,680 --> 00:31:01,680
our immune system is really good at attacking 
circular viruses. So is that a fair statement?

370
00:31:01,680 --> 00:31:04,720
Uh, yeah. So they're easier to 
recognize by the immune response,

371
00:31:04,720 --> 00:31:08,400
definitely. That's part of the 
theory behind virus type particles.

372
00:31:08,400 --> 00:31:14,480
What reading this has just really made me realize 
how much I was reinventing the wheel. Like if this

373
00:31:14,480 --> 00:31:21,520
was anybody else making it, or company making 
it, you'd have had an expert in purification

374
00:31:21,520 --> 00:31:25,760
diving into this that would've been able 
to, I had to do all the research myself.

375
00:31:25,760 --> 00:31:27,040
Oh my gosh. Wow.

376
00:31:27,040 --> 00:31:28,080
Yeah. And figuring it out.

377
00:31:28,080 --> 00:31:29,280
That's so cool!

378
00:31:29,280 --> 00:31:32,080
Yeah, that's even cooler.

379
00:31:32,080 --> 00:31:36,560
You know I did have support. There were other 
people in the lab that I'd go to for advice,

380
00:31:36,560 --> 00:31:40,800
and I talked to Sarah and Adrian, but 
I was often figuring it out by myself,

381
00:31:40,800 --> 00:31:42,560
or at least that's how I remember it.

382
00:31:43,200 --> 00:31:52,240
It's astonishing because I tend to, sometimes 
I feel myself getting skeptical about patents

383
00:31:52,240 --> 00:31:56,880
in particular, where the trade that 
society is making with inventors is

384
00:31:56,880 --> 00:32:02,880
that if you publish in public how you 
did something, then we will give you

385
00:32:02,880 --> 00:32:06,720
exclusivity for 20 years to do whatever 
what you want. Sometimes I'm like, well,

386
00:32:06,720 --> 00:32:11,040
hold on. How much are you actually gonna be able 
to learn from reading that? They're probably

387
00:32:11,040 --> 00:32:15,680
gonna hide whatever they can and to get away 
with it. And what, how can you learn something

388
00:32:15,680 --> 00:32:19,680
from reading? You need to see someone do it, but 
you're telling me you literally read the patents

389
00:32:19,680 --> 00:32:24,960
and then you just kept plugging away until 
you've simplified and fixed all of the stuff.

390
00:32:24,960 --> 00:32:28,400
I mean, that's awesome. That's 
a one person show. And I'm like,

391
00:32:28,400 --> 00:32:32,400
wow. So knowledge in public 
is a extremely big deal.

392
00:32:32,400 --> 00:32:37,040
Yeah. I think I managed to get it to the 
point that we could make it ensure that

393
00:32:37,040 --> 00:32:42,240
it works. And then there was a huge amount of 
work that happened by others to turn it into a

394
00:32:42,240 --> 00:32:52,320
GMP grade process. And even then that was a 
simplified or a shortcut version to get to a

395
00:32:52,320 --> 00:32:56,800
GMP product that was done by the clinical 
biomanufacturing facility in Oxford. They

396
00:32:57,360 --> 00:33:02,960
did an enormous amount of work to produce the 
first batch and then Serum got involved and

397
00:33:02,960 --> 00:33:08,080
they used all of their knowledge and knowhow 
to probably dramatically change the process.

398
00:33:08,080 --> 00:33:14,160
So I wanna pause on that actually, 'cause it's my 
day job is I'm a funder and then now your day job

399
00:33:14,160 --> 00:33:17,760
is, you're a funder, Katharine. And one thing 
that comes out from this story that's really

400
00:33:17,760 --> 00:33:25,680
interesting is that a lot of universities where a 
lot of knowledge is generated and science is done,

401
00:33:25,680 --> 00:33:35,440
do not have facilities to produce the vaccines 
that you could take into humans safely,

402
00:33:35,440 --> 00:33:38,960
whereas Oxford does. Is that a fair 
statement? And do you think that

403
00:33:38,960 --> 00:33:44,480
that allows for a knowledge generation 
loop, which is unusually productive?

404
00:33:44,480 --> 00:33:48,640
Yeah, absolutely. I think that's definitely one 
of the big advantages of being in the Jenner

405
00:33:48,640 --> 00:33:53,200
Institute. Adrian had set up this clinical 
biomanufacturing facility and that meant

406
00:33:53,200 --> 00:33:58,240
he could really quickly iterate, he could design 
something in the lab with a student designing it,

407
00:33:58,240 --> 00:34:03,200
and then transfer it to the manufacturing 
facility and quickly produce a small batch.

408
00:34:03,760 --> 00:34:08,720
Does that mean we should have more 
Jenner Institutes doing other - can

409
00:34:08,720 --> 00:34:12,880
you scale that to work on more diseases 
or is it just really hard to do that?

410
00:34:12,880 --> 00:34:15,360
No, no, I think that's the way 
- people should be learning from

411
00:34:15,360 --> 00:34:18,800
that model. I think it's not cheap 
to maintain a facility like that.

412
00:34:18,800 --> 00:34:24,960
I have another question, which 
is, why is it called R21?

413
00:34:24,960 --> 00:34:27,600
Uh...

414
00:34:27,600 --> 00:34:31,280
Is that a very complicated story?

415
00:34:33,040 --> 00:34:37,120
Um.. I can't remember.

416
00:34:37,120 --> 00:34:38,720
What?!

417
00:34:38,720 --> 00:34:40,160
Wow!

418
00:34:40,160 --> 00:34:45,920
Adrian came up with a name and I think 
I remember asking him, and I think he

419
00:34:45,920 --> 00:34:56,240
said it was a 21st century version of a repeat 
region vaccine. The repeat region is the part

420
00:34:56,240 --> 00:35:02,160
of the CSP protein that's included in RTS,S and 
R21, and that's what the R stands for in RTS,S.

421
00:35:02,160 --> 00:35:05,120
Well, maybe you should ask him.

422
00:35:05,120 --> 00:35:08,640
Yes, right now.

423
00:35:08,640 --> 00:35:15,520
Alexander, why is it called penicillin? God, 
I just can't remember. I can't remember.

424
00:35:15,520 --> 00:35:17,480
I've got an answer.

425
00:35:17,480 --> 00:35:20,320
Oh, we have an answer.

426
00:35:20,320 --> 00:35:27,040
So Adrian said it's the 21st century 
presentation of the CSP repeat vaccine.

427
00:35:27,040 --> 00:35:29,840
So your earlier answer was basically correct.

428
00:35:29,840 --> 00:35:30,480
Yeah.

429
00:35:30,480 --> 00:35:36,480
That's great. It's so funny to me that 
you thought that you had made it up,

430
00:35:36,480 --> 00:35:39,120
but you actually remembered it correctly.

431
00:35:39,120 --> 00:35:46,000
I have a similar but very different story 
where I thought that my earliest memory ever

432
00:35:46,000 --> 00:35:53,040
was made up for a while and then I found 
video evidence of it being true. So my,

433
00:35:53,040 --> 00:36:00,480
so my earliest ever memory is of us, my 
family, going to the Grand Canyon and at

434
00:36:00,480 --> 00:36:06,400
the Grand Canyon I had a pink balloon and the 
only thing I remember is that I had this pink

435
00:36:06,400 --> 00:36:13,040
balloon and I dropped it down the Grand Canyon. 
And I remember mentioning this to a bunch of

436
00:36:13,040 --> 00:36:18,160
people afterwards and then eventually I was 
like, did that actually even happen at all?

437
00:36:18,160 --> 00:36:23,120
Like that just sounds like such a crazy 
story. Like why would I drop a balloon,

438
00:36:23,120 --> 00:36:29,440
that doesn't sound like me? Like I was two, but it 
still doesn't sound like me. I wouldn't do that.

439
00:36:29,440 --> 00:36:36,400
And then last year I found a video that my 
dad took of this whole trip that we took to

440
00:36:36,400 --> 00:36:43,200
the US when I was two. And in the video there's 
a segment where I'm holding the balloon, the pink

441
00:36:43,200 --> 00:36:54,000
balloon. And in the background, you can hear my 
dad telling me to drop it down the Grand Canyon.

442
00:36:54,000 --> 00:36:56,160
That is pretty much a clincher.

443
00:37:01,920 --> 00:37:07,920
I was like, wow. I finally feel so 
validated. But also it wasn't me. I didn't,

444
00:37:08,560 --> 00:37:11,360
I wouldn't, I was just listening to my dad.

445
00:37:12,240 --> 00:37:13,440
There's a lot to unpack there.

446
00:37:13,440 --> 00:37:18,880
I was like, why would I litter?

447
00:37:18,880 --> 00:37:22,480
Oh... Right?

448
00:37:23,120 --> 00:37:27,600
That's not like me at all!

449
00:37:27,600 --> 00:37:29,600
It's all adding up now.

450
00:37:29,600 --> 00:37:32,080
Before we move on to the science of malaria,

451
00:37:32,080 --> 00:37:40,160
what happened after you invented the R21 vaccine 
and what happened after you finished your PhD?

452
00:37:40,880 --> 00:37:50,000
Yeah, so after the vaccine was made, we then 
first tested it in a mouse model of malaria,

453
00:37:50,000 --> 00:37:53,840
and we showed that we could 
protect the mice against malaria,

454
00:37:53,840 --> 00:38:02,160
and this worked best when you used the right 
adjuvant. And I did a large number of studies

455
00:38:02,160 --> 00:38:07,600
in mice to really look at the dose that was 
needed, and that's really where my PhD ended.

456
00:38:07,600 --> 00:38:12,640
So once I developed the vaccine and we had shown 
that it worked in mice, Adrian was moving this

457
00:38:12,640 --> 00:38:17,120
forward into clinical trials. So I had the 
opportunity to stay at Oxford and continue

458
00:38:17,120 --> 00:38:22,160
working on the vaccine as it moved into the 
human clinical trials. But I'd finished my PhD,

459
00:38:22,160 --> 00:38:27,200
so I decided I wanted to move on and broaden 
my experience and learn some new skills.

460
00:38:27,200 --> 00:38:32,560
I moved to work with James McCarthy in Brisbane 
and he had set up a model where you could infect

461
00:38:32,560 --> 00:38:39,200
people with malaria - this was a challenge trial 
- and evaluate the efficacy of drugs. And so

462
00:38:39,200 --> 00:38:46,880
I was working there on those studies and also 
developed a new challenge model as well. I then

463
00:38:46,880 --> 00:38:53,200
moved on to work in - on projects in the field, 
understanding malaria transmission more fully,

464
00:38:53,200 --> 00:38:56,560
and looking at interventions to 
interrupt malaria transmission.

465
00:38:56,560 --> 00:39:02,800
That work was mainly based in Burkina Faso and 
it was based out of a lab in the Netherlands.

466
00:39:03,440 --> 00:39:06,960
Hmm. And then how did you get 
from there to Coefficient?

467
00:39:06,960 --> 00:39:08,800
Jacob hired me.

468
00:39:08,800 --> 00:39:10,960
Oh, wow!

469
00:39:10,960 --> 00:39:13,760
No, I mean, it's an interesting story. 
I wasn't particularly looking to leave

470
00:39:13,760 --> 00:39:18,640
academia. I was loving the work I was doing, 
but obviously Coefficient Giving, or Open

471
00:39:18,640 --> 00:39:25,840
Philanthropy at the time, is a really exciting 
funding organization that's quite innovative.

472
00:39:25,840 --> 00:39:28,480
And what happened to the vaccine after that?

473
00:39:28,480 --> 00:39:32,960
So Adrian then took the vaccine forward into 
clinical trials and there were lots of other

474
00:39:32,960 --> 00:39:37,040
people involved in the development of the 
vaccine. All the investigators in Africa,

475
00:39:37,040 --> 00:39:42,320
the clinical investigators in Oxford, and 
also the Serum Institute who licensed the

476
00:39:42,320 --> 00:39:48,560
vaccine from Adrian and from Oxford, 
and worked with the team there to carry

477
00:39:48,560 --> 00:39:53,680
out the phase three trials and then 
obviously develop the final product.

478
00:39:53,680 --> 00:39:59,760
I think it's sort of underappreciated just 
how many people work on these, like actually

479
00:39:59,760 --> 00:40:05,520
getting the testing and scaling up to people. 
It takes so many people and it makes me think

480
00:40:05,520 --> 00:40:11,760
also that it's not just about funding, it's also 
the number of people working on things like this.

481
00:40:11,760 --> 00:40:15,280
Yeah, I mean, absolutely. I think this large 
number of people it takes is really important

482
00:40:15,280 --> 00:40:19,600
for me. I just played a very small role at 
the beginning and there's such an enormous

483
00:40:19,600 --> 00:40:25,440
number of people that made this vaccine get to the 
finish line and have the impact it's gonna have.

484
00:40:25,440 --> 00:40:30,480
I think it's time to get into the science of 
malaria. But before we move on, I'll just,

485
00:40:30,480 --> 00:40:37,120
my reflection on this segment, is there gonna 
be a lot of people listening who - basically

486
00:40:37,120 --> 00:40:44,160
science nerds - who sometimes it may feel like 
the big things left to do in science while they're

487
00:40:44,160 --> 00:40:49,040
all behind us. That's why Saloni and Jacob talk 
about Gaston Ramon. You know, we've already had

488
00:40:49,040 --> 00:40:56,080
all these antibiotics invented. Oh, well and so, 
wouldn't it have been cool to live back then and.

489
00:40:56,080 --> 00:41:00,400
I think that's entirely the wrong orientation. 
You know, there are people like Katharine Collins,

490
00:41:00,400 --> 00:41:05,920
who in 2010 to 2014, invent entirely new 
vaccines that are now gonna be used by millions

491
00:41:05,920 --> 00:41:14,400
of children. And yet, and she is right here. We 
got to talk to her right now. And you can too!

492
00:41:14,400 --> 00:41:20,480
You can work on important problems and there 
are many people who can benefit! And it's just,

493
00:41:20,480 --> 00:41:25,280
it's almost scary how sensitive to 
particular scientists at particular

494
00:41:25,280 --> 00:41:28,880
times a lot of this stuff is, 
and it's very inspiring too.

495
00:41:28,880 --> 00:41:32,560
So, Katharine, thank you so much for joining us.

496
00:41:32,560 --> 00:41:36,160
Great to be here.

497
00:41:39,120 --> 00:41:43,040
All right, so how come it took so 
long to develop a malaria vaccine?

498
00:41:43,040 --> 00:41:49,760
And why are malaria vaccines so much harder to 
develop than vaccines against other diseases?

499
00:41:49,760 --> 00:41:53,360
Malaria is caused by a parasite, which is 
quite different to a bacteria or a virus,

500
00:41:53,360 --> 00:41:57,280
it's a lot more complex. And the malaria 
parasite actually moves- it has a really

501
00:41:57,280 --> 00:42:00,560
complicated lifecycle, and it moves 
through at least three different stages.

502
00:42:00,560 --> 00:42:05,440
So it's first injected into the body by the 
mosquito, and then travels from your skin into the

503
00:42:05,440 --> 00:42:10,560
liver. It develops in the liver for about seven 
days and then bursts out into your red blood cells

504
00:42:10,560 --> 00:42:17,120
in your bloodstream and it invades your red blood 
cells. The symptoms are caused by the parasites

505
00:42:17,120 --> 00:42:22,800
invading your red blood cells and then destroying 
them, and then it does this many times. Each cycle

506
00:42:22,800 --> 00:42:27,040
it produces many more parasites and so it invades 
many more red blood cells and that's what causes

507
00:42:27,040 --> 00:42:34,880
the anemia. And then the parasites within the 
red blood cell, those infected red blood cells,

508
00:42:34,880 --> 00:42:39,040
can adhere to different tissues and that can 
cause problems for different organs as well.

509
00:42:39,040 --> 00:42:44,000
I read that if just a single 
parasite makes it to the liver,

510
00:42:44,000 --> 00:42:46,240
it can cause an infection. Is that true?

511
00:42:46,240 --> 00:42:50,640
Yeah, that's right. And that, I think that's the 
really tough challenge with malaria, but you know,

512
00:42:50,640 --> 00:42:57,280
you can get hundreds or thousands of sporozoites 
from one bite. But I think you - we don't think

513
00:42:57,280 --> 00:43:02,560
it's many thousands, and you could have some 
immunity that gets rid of a lot of those,

514
00:43:02,560 --> 00:43:07,520
but just one has to get through the defenses, and 
that gets into the liver, and then in the liver

515
00:43:07,520 --> 00:43:13,440
they actually replicate so that it doesn't stay as 
one parasite. It turns into many, many merozoites,

516
00:43:13,440 --> 00:43:17,440
and they then burst out of the liver cell and 
start invading blood cells. By the time you

517
00:43:17,440 --> 00:43:23,600
get to the blood, you've got many parasites again, 
and very quickly, they replicate and produce more.

518
00:43:23,600 --> 00:43:30,080
That makes me think, both of the 
vaccines are - the efficacy is much

519
00:43:30,080 --> 00:43:33,840
lower than many other vaccines. 
But if I think about it this way,

520
00:43:33,840 --> 00:43:39,440
that they're trying to prevent even just 
one parasite from getting to the liver,

521
00:43:39,440 --> 00:43:45,120
then from that perspective, it sounds like they're 
actually really effective at doing that, at least.

522
00:43:45,120 --> 00:43:48,320
Yeah. Yeah, it's a very high bar. Exactly. Yeah.

523
00:43:48,320 --> 00:43:57,440
Well, that's terrifying. Just one parasite. 
So all of that makes it much harder than,

524
00:43:57,440 --> 00:44:01,680
let's say, measles or flu, 
which are caused by viruses

525
00:44:01,680 --> 00:44:10,000
and where the vaccines are produced 
by killing or attenuating the virus.

526
00:44:10,000 --> 00:44:16,080
So there are many reasons that it's difficult 
to make a vaccine against malaria parasites.

527
00:44:16,080 --> 00:44:21,360
First is this really complex life cycle 
and then also the malaria parasite has

528
00:44:21,360 --> 00:44:25,360
been around since Egyptian times. So it's 
evolved to evolve with the human immune

529
00:44:25,360 --> 00:44:30,160
system for a really long time, it's learnt 
how to evade our immune responses really

530
00:44:30,160 --> 00:44:34,400
well. So every time our immune system is 
managed to attack the malaria parasite,

531
00:44:34,400 --> 00:44:40,080
or find a good way to get rid of it, it's then 
evolved another mechanism to keep surviving.

532
00:44:40,080 --> 00:44:43,840
There are lots and lots of redundant 
proteins in the parasites. So you think

533
00:44:43,840 --> 00:44:46,560
you can block something that's important 
and then it just switches on a different

534
00:44:46,560 --> 00:44:51,680
protein instead and uses that. That's been 
one of the reasons it's been quite tricky.

535
00:44:51,680 --> 00:44:56,960
So the malaria parasite has a very 
complicated lifecycle. Does it,

536
00:44:56,960 --> 00:45:03,120
when it goes through these different stages, 
does it also change shape? What actually happens?

537
00:45:03,120 --> 00:45:09,760
Yeah, it looks completely different at each stage. 
It starts with what we call a sporozoite that

538
00:45:09,760 --> 00:45:13,920
looks like a little eyelash when you look 
under the microscope, it's a curve shape.

539
00:45:13,920 --> 00:45:19,200
Then when it invades the red blood cell, it's 
called a merozoite; it's like a round, almost

540
00:45:19,200 --> 00:45:25,520
cone shape. But not only does it look different, 
but it has different proteins on the surface. So

541
00:45:25,520 --> 00:45:30,160
a vaccine that works against one stage isn't 
necessarily gonna work against another stage.

542
00:45:30,160 --> 00:45:34,160
Right. And that's one thing that's 
hard about developing a vaccine. Like,

543
00:45:34,160 --> 00:45:37,840
how do you pick which protein 
to use in the vaccine?

544
00:45:37,840 --> 00:45:42,320
Yeah, absolutely. Yeah. You know, the approach 
is normally to look for a protein that's really

545
00:45:42,320 --> 00:45:47,600
important. So you find out something that's 
probably something that's involved for an invasion

546
00:45:47,600 --> 00:45:53,040
or adhesion. So people would look at knocking 
out different proteins and seeing whether they're

547
00:45:53,040 --> 00:45:57,520
critical for development. If you find something 
that's essential, then that's also gonna be a

548
00:45:57,520 --> 00:46:03,760
good target. And the other way is that people 
look for what's most abundant on the parasite,

549
00:46:04,480 --> 00:46:10,400
or the pathogen in general, but that can often be 
a decoy. That's an interesting one. Like sometimes

550
00:46:10,400 --> 00:46:15,360
the things that were abundant on the surface 
are there to misdirect the immune response.

551
00:46:15,360 --> 00:46:19,680
Okay. So you're taking these samples 
from mice and you're learning a lot,

552
00:46:19,680 --> 00:46:27,920
it sounds like, from mice. So firstly, 
thank you to our mouse brethren. And Saloni,

553
00:46:27,920 --> 00:46:34,320
I know that you have written a lot about, 
in one of my favorite pieces that I read

554
00:46:34,320 --> 00:46:39,680
two years ago was about the invention of the 
malaria vaccine. And you wrote about how mice

555
00:46:39,680 --> 00:46:46,720
were originally domesticated in some sense, to 
be models for malaria. So how did that work?

556
00:46:46,720 --> 00:46:56,640
It starts out before mice, I think there were 
some animal models in the late 19th century,

557
00:46:56,640 --> 00:47:04,480
the first animal models for malaria were birds. 
And the way that scientists proved that malaria

558
00:47:04,480 --> 00:47:12,720
was spread by mosquitoes, was by using sparrows 
and infecting them with the blood of an infected

559
00:47:12,720 --> 00:47:19,680
human, and seeing whether it would transmit. 
And I think it seemed like there were some,

560
00:47:19,680 --> 00:47:23,680
there were a bunch of different birds that 
could get infected by malaria, but they just

561
00:47:23,680 --> 00:47:29,200
didn't translate that well to what would happen 
in humans? So people tried developing drugs,

562
00:47:29,200 --> 00:47:36,000
like testing new drugs, in bird malaria, and they 
seemed to work there, but in humans they didn't;

563
00:47:36,000 --> 00:47:40,880
they caused various side effects. And so 
they were trying to find different models.

564
00:47:40,880 --> 00:47:47,120
There are also two other types of 
models used in between. One was monkeys;

565
00:47:47,120 --> 00:47:53,600
monkeys are really expensive and difficult 
to work with. And then the other was humans,

566
00:47:53,600 --> 00:48:02,800
right? Because in the 1920s, if I remember 
right, humans were used as a model to study

567
00:48:02,800 --> 00:48:09,840
malaria because people with syphilis could 
be treated by infecting them with malaria,

568
00:48:09,840 --> 00:48:16,720
because the bacteria doesn't survive after 
the fevers that are caused by malaria.

569
00:48:16,720 --> 00:48:23,680
It's a bit like solving your aching thumb 
by chopping it off to me, but, okay.

570
00:48:23,680 --> 00:48:26,640
Would you rather get syphilis or malaria?

571
00:48:26,640 --> 00:48:35,840
Ah, the eternal question. And my answer is 
I'm glad that we're in the 21st century.

572
00:48:35,840 --> 00:48:39,840
Syphilis seems like it was 
really scary before antibiotics.

573
00:48:39,840 --> 00:48:40,720
Yeah.

574
00:48:40,720 --> 00:48:43,280
Especially if you got neurosyphilis.

575
00:48:43,280 --> 00:48:48,560
Yeah. The bacteria would worm its way up into 
your brain and stick around for years or decades.

576
00:48:48,560 --> 00:48:52,960
I've been to a medical museum in 
London called the Hunterian Museum,

577
00:48:52,960 --> 00:48:59,440
and they have exhibits of people 
who had syphilis at the time,

578
00:48:59,440 --> 00:49:05,760
and their skulls are filled with holes 
from the infection. It's very scary.

579
00:49:05,760 --> 00:49:09,760
Well, that's a wonderful tangent, 
but I was wondering about,

580
00:49:09,760 --> 00:49:12,240
I was wondering if we could talk more about mice.

581
00:49:12,240 --> 00:49:20,080
Right. Okay, so mice, so we have the bird models 
that aren't great. You have the monkey models that

582
00:49:20,080 --> 00:49:28,080
are really expensive, and the human models, which 
once you could treat syphilis with antibiotics,

583
00:49:28,080 --> 00:49:35,200
there was no longer an audience of people 
who were interested in being infected with

584
00:49:35,200 --> 00:49:41,680
malaria deliberately. So the next 
question was, let's try to find a

585
00:49:41,680 --> 00:49:47,200
different animal model. Let's try to find 
a rodent that can be infected by malaria.

586
00:49:47,200 --> 00:49:54,800
And I think it took quite a while to find any 
rodents that were infected by malaria. There

587
00:49:54,800 --> 00:50:02,000
were two researchers that finally figured it out. 
I think they were two Belgian researchers who

588
00:50:02,000 --> 00:50:10,480
were in the Congo, and they were doing tests 
to see which animals mosquitoes had bitten,

589
00:50:10,480 --> 00:50:18,160
and that ruled out various animals nearby and 
it didn't rule out rodents. So they thought

590
00:50:18,160 --> 00:50:23,280
maybe there's something here, and they continued 
trying to look for rodents that were infected by

591
00:50:23,280 --> 00:50:29,920
malaria. And eventually they found a thicket rat 
(Grammomys dolichurus) that was infected with it.

592
00:50:29,920 --> 00:50:37,840
This thicket rat was infected by a different 
strain of malaria called Plasmodium berghei,

593
00:50:37,840 --> 00:50:45,120
and that seems to be much more - like that's just 
much easier to work with. I think at first, they

594
00:50:45,120 --> 00:50:53,520
also, they couldn't replicate the whole lifecycle 
of the parasite in those thicket rats, because

595
00:50:53,520 --> 00:50:59,360
there were certain stages of the parasite's 
lifecycle that needed a cooler temperature.

596
00:50:59,360 --> 00:51:06,000
So when I was reading about this, it seemed like 
it took 16 years for them to work that out. It was

597
00:51:06,000 --> 00:51:15,120
several things. So the original research was just 
post World War II and then in the 1950s, various

598
00:51:15,120 --> 00:51:23,040
countries did large-scale malaria elimination 
programs and cut down on malaria research.

599
00:51:23,040 --> 00:51:28,080
And so all the people who were working on that 
stopped working on, or many of them did, stopped

600
00:51:28,080 --> 00:51:35,920
working on it, and then only then got interested 
again in it during the Vietnam War. So I think it

601
00:51:35,920 --> 00:51:46,400
was like partly that and partly just, historical 
contingency of which parasite they discovered. And

602
00:51:46,400 --> 00:51:53,520
did they look at their own lab notes from 16 years 
ago to see what the temperatures were in that

603
00:51:53,520 --> 00:52:01,840
forest where they found the first malaria infected 
rats. Goes to show how important lab notes are.

604
00:52:01,840 --> 00:52:04,080
Sounds like mice can tell you something, and took

605
00:52:04,080 --> 00:52:09,760
a long time to get to a model that worked in 
the lab. But they can't tell you everything,

606
00:52:09,760 --> 00:52:13,840
'cause mice aren't humans, and 
they might mislead you sometimes.

607
00:52:13,840 --> 00:52:16,720
A mouse has never told me anything.

608
00:52:16,720 --> 00:52:22,320
Speak for yourself. Well, I mean, 
that brings me onto a question I have,

609
00:52:22,320 --> 00:52:26,720
which is: are mice enough? 
If not, what's the next step?

610
00:52:26,720 --> 00:52:32,880
Well, so you could use non-human primates, but 
they aren't the perfect model for malaria. There's

611
00:52:32,880 --> 00:52:38,160
only one that gets infected, that could 
be affected with human malaria parasites,

612
00:52:38,160 --> 00:52:42,480
and so none of the models are perfect. So people 
don't often do a lot of non-human primate work,

613
00:52:42,480 --> 00:52:48,240
but they can be used to answer specific questions. 
So then your next model is obviously humans.

614
00:52:48,240 --> 00:52:49,920
Mm-hmm.

615
00:52:49,920 --> 00:52:54,000
And that makes sense because if you 
want to make a vaccine for humans,

616
00:52:54,000 --> 00:52:58,320
you probably wanna test it on humans.

617
00:52:58,320 --> 00:53:03,040
Okay. So we're segueing to humans. How did that 
begin? What were the first experiments in humans?

618
00:53:03,040 --> 00:53:09,280
So the first ones were the ones that were 
treatments for syphilis in the 1910s to

619
00:53:09,280 --> 00:53:16,400
forties. And then when penicillin was developed, 
it wasn't necessary anymore. But then, after that,

620
00:53:16,400 --> 00:53:24,960
there were various experiments in prisoners in 
different parts of the US, I think. And what was

621
00:53:24,960 --> 00:53:30,160
interesting to me when I was reading about this 
was that - so the prisoners were volunteering for

622
00:53:30,160 --> 00:53:35,520
these experiments, but some of the prisoners were 
not just subjects in the experiments. Some of them

623
00:53:35,520 --> 00:53:41,920
were actually technicians and researchers, 
who helped in the experiments as well.

624
00:53:41,920 --> 00:53:49,600
And one of the most famous ones is Nathan 
Leopold. Do you know, do you recognize that name?

625
00:53:49,600 --> 00:53:51,200
Not me.

626
00:53:51,200 --> 00:53:59,120
So he was a - I know this because of a film that 
was inspired by his life. He was a murderer who

627
00:53:59,120 --> 00:54:07,120
murdered a friend, I think, a classmate of his. 
So with a friend of his, they both kidnapped and

628
00:54:07,120 --> 00:54:11,280
murdered one of their classmates while they 
were students at the University of Chicago.

629
00:54:11,920 --> 00:54:16,320
And while they were serving their sentences,

630
00:54:16,320 --> 00:54:23,760
Nathan Leopold, one of them, enrolled in one of 
the malaria research studies. And after that,

631
00:54:23,760 --> 00:54:31,360
he then became a technician, he started doing - 
like he was actually operating research as well.

632
00:54:31,360 --> 00:54:38,480
And the reason that I know this is because that 
story inspired the Alfred Hitchcock film Rope,

633
00:54:38,480 --> 00:54:40,160
if you've seen that. Have you seen that?

634
00:54:40,160 --> 00:54:41,760
I have not seen that.

635
00:54:41,760 --> 00:54:48,800
It's a very good movie where, I mean, it's the 
same-ish story. They've kind of changed what

636
00:54:48,800 --> 00:54:56,320
actually happened. But in the film, these two 
students decide to kidnap and kill one of their

637
00:54:56,320 --> 00:55:05,680
classmates for fun, essentially. And then they 
store him in a, what is it called? Like a box in

638
00:55:05,680 --> 00:55:14,560
their apartment. And they then host a party just 
hours after this murder, to basically show the

639
00:55:14,560 --> 00:55:21,040
fact that they could get away with it. And the 
whole film was taken in 10 shots, like 10 long

640
00:55:21,040 --> 00:55:27,200
segments that are just stitched together. And it's 
an incredible film. Like very, very well made.

641
00:55:27,200 --> 00:55:30,400
Wow. Okay, so...

642
00:55:30,400 --> 00:55:38,480
So how does this relate to malaria? 
Many prisoners would've been part

643
00:55:38,480 --> 00:55:46,000
of this malaria research in the mid 
20th century, and they contributed

644
00:55:46,000 --> 00:55:51,840
to our understanding of various parts 
of the transmission process, I think.

645
00:55:51,840 --> 00:55:57,360
And since then, we've continued studying malaria 
in humans in a type of study called a challenge

646
00:55:57,360 --> 00:56:04,800
trial, where you deliberately infect volunteers 
with mosquitoes with malaria. So I think in the

647
00:56:04,800 --> 00:56:12,560
past it was many mosquitoes per person and 
now it's just five bites. Is that right?

648
00:56:12,560 --> 00:56:20,560
Yeah. I guess there was work to improve and 
standardize the modern challenge trials.

649
00:56:20,560 --> 00:56:26,640
That's where they landed on five mosquito bites 
that could reproducible infect the volunteers.

650
00:56:26,640 --> 00:56:32,240
So what happens in one of these experiments 
do you sit with. Do you put your hand into

651
00:56:32,240 --> 00:56:36,960
a jar that's filled with mosquitoes 
or what? What's the what's it like?

652
00:56:36,960 --> 00:56:42,480
No, the process is quite dull, actually. I guess 
you normally have to travel to somewhere where

653
00:56:42,480 --> 00:56:47,600
there's a facility. And because these sort 
of things do contain mosquitoes infected with

654
00:56:47,600 --> 00:56:52,560
malaria, they're usually under high containment, 
so then the volunteers need to pass into a

655
00:56:52,560 --> 00:56:58,480
contained containment area, and then a cup is 
often passed through a window into that room

656
00:56:58,480 --> 00:57:04,000
and they have a cup - it's like a coffee cup - 
and it has gauze on the top and the mosquitoes

657
00:57:04,000 --> 00:57:09,840
will be inside. The lid will all be taped shut 
so they can't escape, and then you place your arm

658
00:57:09,840 --> 00:57:15,920
on top of the cup and allow the five mosquitoes 
to bite you and say, a few minutes for feeding.

659
00:57:15,920 --> 00:57:19,320
And then they'll have a look and see how 
many of those mosquitoes have fed on you.

660
00:57:19,320 --> 00:57:20,191
So what they do is they take the cup 
of mosquitoes, they then look at them,

661
00:57:20,191 --> 00:57:22,703
each mosquito individually under the microscope. 
You can see whether it's blood fed, because it's

662
00:57:22,703 --> 00:57:23,105
got blood in its abdomen, in its belly. Then if 
it's got blood in the belly, then look at the

663
00:57:23,105 --> 00:57:23,202
salivary glands and check that it had sporozoites 
in the salivary glands. And so you're looking,

664
00:57:23,202 --> 00:57:23,893
five mosquitoes in that cup that fed. But so 
they count up how many did feed, then they'll

665
00:57:27,413 --> 00:57:29,360
put more mosquitoes in a cup. So if you only 
need one more infected bite, they'll put one more

666
00:57:29,360 --> 00:57:30,480
mosquito in, and then you can be bitten by that 
mosquito. If that one doesn't bite you, then they

667
00:57:30,480 --> 00:57:31,680
take that one out, put another one in 
until you've had five infected bites.

668
00:57:31,680 --> 00:57:39,360
Oh, I see. That's probably the most 
disgusting coffee cup I've heard of.

669
00:57:39,360 --> 00:57:44,160
Not so tasty. These, these days, are the 
people who are putting their arms out,

670
00:57:44,160 --> 00:57:47,840
are they mostly undergrads somewhere 
or, yeah, what, who are the volunteers?

671
00:57:47,840 --> 00:57:52,720
I think it depends where you do the trials. I 
think in Oxford it's typically lots of students,

672
00:57:52,720 --> 00:58:00,880
but other people as well. But you, the students 
are often quite willing to get involved.

673
00:58:00,880 --> 00:58:02,880
Legends.

674
00:58:02,880 --> 00:58:09,920
I saw a picture where it wasn't a coffee 
cup, but it was a cup noodle box container.

675
00:58:09,920 --> 00:58:14,480
Yeah or soup. And they're often called, used as 
soup cups. They're like, or ice cream containers,

676
00:58:14,480 --> 00:58:18,480
they're that kind of large, larger size that 
would be used. That's usually used to hold

677
00:58:18,480 --> 00:58:21,440
a lot more mosquitoes. It would've 
been a different study, probably.

678
00:58:21,440 --> 00:58:22,480
Oh, I see.

679
00:58:23,040 --> 00:58:28,400
So you, in those challenge models, you 
are giving some of the students or other

680
00:58:28,400 --> 00:58:33,760
volunteers injections of vaccine, some of 
them placebo, and then they're getting bitten.

681
00:58:33,760 --> 00:58:35,440
Exactly. That's right. Yeah.

682
00:58:35,440 --> 00:58:38,240
Okay. And then what do you, how do you figure out

683
00:58:38,240 --> 00:58:41,440
the truth afterwards? You're just 
seeing which one of them faint, or?

684
00:58:41,440 --> 00:58:49,600
Once you've been challenged, you start following 
them up a couple of days later. So the parasites

685
00:58:49,600 --> 00:58:52,880
will be in the liver for seven days. You 
don't have to monitor them too carefully

686
00:58:52,880 --> 00:58:58,000
in the beginning, but you still monitor them and 
check the parasites haven't got into the liver,

687
00:58:58,000 --> 00:59:03,280
into the blood from the liver. And 
then you are monitoring quite closely

688
00:59:03,280 --> 00:59:08,320
from liver emergence. So once the parasites are 
entering the blood or you're expecting them to,

689
00:59:08,320 --> 00:59:11,840
you can see them once or twice a day, 
up to twice a day, take their blood.

690
00:59:11,840 --> 00:59:14,400
You can look under the microscope for 
the parasites, see if they've got the

691
00:59:15,120 --> 00:59:19,600
parasites in their blood, and you can 
also do molecular diagnostics as well,

692
00:59:19,600 --> 00:59:24,240
like PCR to look - it's a much more 
sensitive method. So you can detect

693
00:59:24,240 --> 00:59:28,560
the parasites in the blood before they will 
make the people sick. And so you can treat

694
00:59:28,560 --> 00:59:34,640
them quite quickly and then you'll know which 
volunteers have been protected and which haven't.

695
00:59:34,640 --> 00:59:41,520
That's very cool. And then now there are 
methods that are beyond mosquito bites.

696
00:59:41,520 --> 00:59:47,760
People directly inject volunteers 
with the parasite, is that right?

697
00:59:47,760 --> 00:59:52,080
Yeah, there's a couple of models. So 
the other models you would inject either

698
00:59:52,080 --> 00:59:56,320
cryopreserved sporozoites, that's that 
first stage that goes into the liver.

699
00:59:56,320 --> 01:00:00,880
You can inject those intravenously, you 
can ship those anywhere in the world to

700
01:00:00,880 --> 01:00:05,600
do that type of study. The other model 
is injecting blood stage parasites. So

701
01:00:05,600 --> 01:00:08,640
both of these are greats and they 
can answer different questions.

702
01:00:08,640 --> 01:00:16,080
And these two vaccines, the RTS,S and 
R21, are for the first stage. So you'd

703
01:00:16,080 --> 01:00:21,040
want to be able to test it against the 
natural infection with the mosquito bite.

704
01:00:21,040 --> 01:00:22,000
Yeah, definitely.

705
01:00:22,000 --> 01:00:23,840
Saloni, I've got a question for you.

706
01:00:23,840 --> 01:00:26,000
Oh, what's the question?

707
01:00:26,000 --> 01:00:29,280
Would you have volunteered for one 
of these human challenge trials?

708
01:00:29,280 --> 01:00:35,840
I was thinking about this back when you asked 
who was volunteering in the studies because as

709
01:00:35,840 --> 01:00:42,400
I have described in the first episode we did, 
I once volunteered for an HIV vaccine trial,

710
01:00:42,400 --> 01:00:48,480
phase one trial. And I enjoyed 
it and I think I probably would.

711
01:00:48,480 --> 01:00:52,960
I think the difficulty is that back when 
I did that, I was a student and I was very

712
01:00:52,960 --> 01:00:57,360
bored and I didn't have anything to do in my 
free time anyway and I didn't have a social

713
01:00:57,360 --> 01:01:03,520
life. And now I have a lot of stuff going on 
in my life, like I just have a lot of work.

714
01:01:03,520 --> 01:01:08,000
By the way... congratulations.

715
01:01:08,000 --> 01:01:08,880
Thank you.

716
01:01:09,440 --> 01:01:13,280
Me, I'm still alone, but I'll get there.

717
01:01:13,280 --> 01:01:19,200
But I was thinking like, there are lots 
of different types of diseases that you

718
01:01:19,200 --> 01:01:23,040
might do a challenge trial for, right? 
Like you could do one for rhinovirus or

719
01:01:23,040 --> 01:01:29,040
like flu or cholera or I don't know, 
what else is there - Shigella maybe,

720
01:01:29,040 --> 01:01:34,080
or something like that. And all of these 
sound very unappetizing to me. Like,

721
01:01:34,080 --> 01:01:39,200
I wouldn't wanna do a challenge trial for any 
of those. Like the flu, the respiratory ones,

722
01:01:39,200 --> 01:01:45,808
I'm like, that's just boring and someone else 
is gonna do them anyway. Probably the, that's -

723
01:01:45,808 --> 01:01:50,080
Amazing. I'm not gonna do that one. 
It's boring. I want something harder!

724
01:01:50,080 --> 01:01:53,920
Right. And then the other, 
like cholera and shigella,

725
01:01:53,920 --> 01:02:01,120
I mean, diarrhea... I don't want, that 
sounds horrible. And also I feel like

726
01:02:01,120 --> 01:02:06,560
I'm quite small and if I lose too much 
weight, there'll be none of me left,

727
01:02:06,560 --> 01:02:13,760
and so I can't do that one. So what I would 
do is a more dangerous pathogen, I think.

728
01:02:13,760 --> 01:02:16,301
Okay, nice. Is malaria dangerous enough for you?

729
01:02:16,301 --> 01:02:18,240
That would make it worth it. I think so, yeah.

730
01:02:18,240 --> 01:02:19,600
Okay. Even though malaria -

731
01:02:19,600 --> 01:02:20,880
Even though it's treatable and stuff.

732
01:02:20,880 --> 01:02:26,480
It's treatable. Yeah. I mean, just in case 
listeners are thinking about it themselves

733
01:02:26,480 --> 01:02:31,440
and concerned; in the diarrhea ones, they 
do treat you. They don't just leave you,

734
01:02:31,440 --> 01:02:36,880
they give you antibiotics. But yeah, 
those in order to get more of a signal,

735
01:02:36,880 --> 01:02:40,960
they don't treat you in, within an 
hour, they'll probably you within 12

736
01:02:40,960 --> 01:02:46,000
hours or something. So it's a - it's not, you 
gotta go through some pain to get the gain.

737
01:02:46,000 --> 01:02:52,720
Well, I read that with the cholera vaccine 
challenge trials some people... actually,

738
01:02:52,720 --> 01:02:54,800
you know what? I'm not gonna finish that sentence.

739
01:02:54,800 --> 01:02:56,280
Oh -

740
01:02:58,400 --> 01:03:01,200
It was about how much diarrhea 
they had. And you know what? I

741
01:03:01,200 --> 01:03:03,600
don't actually wanna give people that image.

742
01:03:03,600 --> 01:03:09,440
That's.. you know what, Saloni? 
I think they've got it now.

743
01:03:09,440 --> 01:03:14,240
So my question for malaria, Katharine, how 
sick do you get? Do you get sick at all or

744
01:03:14,240 --> 01:03:19,600
do you get treated as soon as there's any risk 
of sickness or? What if you're in, what happens?

745
01:03:20,400 --> 01:03:25,280
I guess the idea is that they treat you before 
you develop any real symptoms. So you probably

746
01:03:25,280 --> 01:03:30,880
start to feel a bit fluey. You may get a headache, 
but because they're monitoring your parasitemia

747
01:03:30,880 --> 01:03:36,240
so closely, the plan is to treat you before 
you get any really uncomfortable symptoms. By

748
01:03:36,240 --> 01:03:41,040
the time you get treatment, you could have 
some symptoms. I think people do typically

749
01:03:41,040 --> 01:03:47,360
get symptoms. They feel rough for a day or 
two, but that's hopefully the extent of it.

750
01:03:47,360 --> 01:03:50,240
I think that's kind of cool. Yeah, I 
would do it. I mean, I haven't done it,

751
01:03:50,240 --> 01:03:54,560
so you always have to take with a grain of 
salt, whatever I say now. The issue, yeah,

752
01:03:54,560 --> 01:04:00,880
I tried to volunteer for a trial recently and 
ended up getting swamped in the logistics. So

753
01:04:00,880 --> 01:04:06,160
your point Saloni, that it's harder once you 
have a job? I've had that experience too.

754
01:04:06,160 --> 01:04:13,360
It also depends where you live, whether there are 
trials around you that are convenient that you can

755
01:04:13,360 --> 01:04:20,480
participate in. So it comes down to those aspects 
as much as anything. But malaria sounds kind of

756
01:04:20,480 --> 01:04:24,320
fun. If you get, the drugs are great. You get, 
if you get feel a little bit sick, that will make

757
01:04:24,320 --> 01:04:29,680
me feel like I've done something for humanity and 
then I get treated, I'm up for that. Sounds good.

758
01:04:29,680 --> 01:04:34,800
And also you get to live in a cool 
quarantine hotel for a bit. No?

759
01:04:34,800 --> 01:04:35,917
No, because -

760
01:04:35,917 --> 01:04:35,920
No?

761
01:04:35,920 --> 01:04:40,320
It's safe to walk outside. In England, right? 
There's no, there's no mosquitoes that bite you.

762
01:04:41,760 --> 01:04:44,960
So you are infected and then they're just like,

763
01:04:44,960 --> 01:04:50,000
go on with your life. Yeah. And 
you just feel sick at home instead?

764
01:04:50,000 --> 01:04:53,520
Yeah. They give you a little card to 
put in your wallet, which tells people

765
01:04:53,520 --> 01:04:56,320
what you have and what you need to be 
treated with in case something happens.

766
01:04:56,320 --> 01:04:56,960
Oh, really?

767
01:04:56,960 --> 01:05:01,440
Okay. I'm not volunteering for this thing.

768
01:05:01,440 --> 01:05:05,440
Emergencies, like if you ended up in hospital 
from a car crash or something, they would know

769
01:05:05,440 --> 01:05:08,720
that they should probably give you 
antimalarials now. The study's over.

770
01:05:08,720 --> 01:05:12,240
No, I thought, I thought you'd be in 
a little quarantine hotel. I thought

771
01:05:12,240 --> 01:05:15,840
it was like a mini vacation but you're sick.

772
01:05:15,840 --> 01:05:20,720
No, I think maybe they do it differently 
in different places. So it depends maybe

773
01:05:20,720 --> 01:05:26,720
what type of trial you are in. So for the drug 
trials with malaria, because they actually let

774
01:05:26,720 --> 01:05:32,000
you develop parasitemia to a certain level, 
then they treat you. And then they want to

775
01:05:32,000 --> 01:05:37,440
measure the clearance rate of the parasites. 
So they want to sample you quite quickly and

776
01:05:37,440 --> 01:05:43,200
frequently after treatment. So for those, they 
do often do inpatient for your convenience,

777
01:05:43,200 --> 01:05:48,000
then they let you go once you are treated, 
so it could be just a couple of days.

778
01:05:48,000 --> 01:05:53,040
I think I'm thinking of the respiratory 
virus challenge trials where, because

779
01:05:53,040 --> 01:05:56,560
you could transmit it to someone 
else, they keep you in a facility.

780
01:05:56,560 --> 01:06:01,920
Diarrhea as well, for the shigella one they 
keep you in. Yeah. I realized Katharine in

781
01:06:01,920 --> 01:06:06,640
that description though, one of the other 
reasons why people might not want to do it,

782
01:06:06,640 --> 01:06:12,000
which is you're getting pinpricked constantly 
'cause people are taking a lot of blood samples.

783
01:06:12,000 --> 01:06:19,680
So that's if you wanna get over needle 
phobia via exposure therapy, go for it!

784
01:06:23,760 --> 01:06:29,920
I feel like the way to - Exposure 
therapy is supposed to give you

785
01:06:29,920 --> 01:06:33,200
like a mild version where it's like, 
oh, nothing actually happens when you

786
01:06:33,200 --> 01:06:39,040
get injections. This seems like 
it would actually scare you more!

787
01:06:39,040 --> 01:06:47,120
Well, I did exposure therapy and nearly died.

788
01:06:47,120 --> 01:06:49,440
Would you participate in the challenge trial?

789
01:06:50,080 --> 01:06:54,000
I would love to, but I really hate needles.

790
01:06:54,000 --> 01:06:56,240
Oh, there we go! There we go!

791
01:06:56,240 --> 01:06:59,840
It's kind of ironic for a vaccine developer.

792
01:06:59,840 --> 01:07:02,000
That's so funny.

793
01:07:05,200 --> 01:07:08,320
I'm terrified of getting vaccines. When 
I have, when I go to get a vaccine,

794
01:07:08,320 --> 01:07:12,720
I have to lie down to have a vaccine, I 
have to lie down with the blood taken,

795
01:07:12,720 --> 01:07:16,720
as otherwise I might faint. I think I have 
fainted in the past, that's the problem.

796
01:07:16,720 --> 01:07:17,280
Oh, wow.

797
01:07:18,000 --> 01:07:24,560
And so, as you mentioned we take blood in these 
challenge trials, 10 to 15 times depending on

798
01:07:24,560 --> 01:07:30,960
when you get malaria. So I just couldn't, 
I couldn't cope with that. Unfortunately.

799
01:07:30,960 --> 01:07:35,680
We must know our limits. Okay. So how come 
that's not enough? Or is it enough? So

800
01:07:35,680 --> 01:07:40,160
let's say you've taken a malaria vaccine through 
human challenge trials. You ready to license it,

801
01:07:40,160 --> 01:07:45,040
roll it out across different countries or 
not? I know the answer, but I'm curious.

802
01:07:45,040 --> 01:07:50,000
Well, obviously no, I guess that's not the target 
population. So you still need to find out if your

803
01:07:50,000 --> 01:07:55,280
vaccine's gonna work in the people that it's 
intended for, which would be children in Africa.

804
01:07:55,280 --> 01:07:57,920
Well, we have some vaccines 
that are approved just from

805
01:07:57,920 --> 01:08:01,040
challenge trials. Right? Like the typhoid vaccine.

806
01:08:01,040 --> 01:08:06,240
Yeah, that's right. Yeah, I think when the 
trial isn't feasible to be done in the target

807
01:08:06,240 --> 01:08:11,680
population, there's good arguments to try and 
get that efficacy signal from a challenge trial,

808
01:08:11,680 --> 01:08:15,520
and then they still need to get 
your safety data from the target

809
01:08:15,520 --> 01:08:18,320
population that you're gonna 
use the vaccine in as well.

810
01:08:18,320 --> 01:08:22,800
Okay. So we've talked about the second 
malaria vaccine, and we are talking about

811
01:08:22,800 --> 01:08:28,880
the animal models and the human challenge 
models for vaccines in general. Saloni,

812
01:08:28,880 --> 01:08:35,360
since you've written about the history of malaria, 
I'd love to hear, if you're willing, what was

813
01:08:35,360 --> 01:08:41,200
the first malaria vaccine development timeline 
like? What were the steps there? What happened?

814
01:08:41,200 --> 01:08:47,920
I love how we've gone through this backwards, like 
we're doing the Star Wars prequels or something.

815
01:08:47,920 --> 01:08:50,160
But more entertaining.

816
01:08:52,160 --> 01:08:57,680
Well, I guess it's a long story. So I think I 
probably wanna start with a quick summary of

817
01:08:57,680 --> 01:09:04,400
the whole development. I first got interested in 
this topic when I was reading about the news of

818
01:09:04,400 --> 01:09:13,760
the malaria vaccine being rolled out in 2021, 
and I wanted to write a blog post about it.

819
01:09:14,880 --> 01:09:20,320
So I was starting to write this blog post, and one 
of the first things that I learned was that it was

820
01:09:20,320 --> 01:09:26,480
actually developed in the '90s. And it really 
kind of shocked me and I was just thinking:

821
01:09:26,480 --> 01:09:32,480
what went wrong? Like, what happened? Why 
was it, why it didn't only get released now,

822
01:09:32,480 --> 01:09:38,880
if it was developed so long ago? And 
a lot of my interest just stemmed from

823
01:09:38,880 --> 01:09:46,160
that curiosity and frustration, with 
how things could have taken so long.

824
01:09:46,160 --> 01:09:53,280
The short version is that I think a lot of it 
is because of a lack of funding, infrastructure,

825
01:09:53,280 --> 01:10:02,640
and in some cases, also the regulatory changes 
and standards that there were. But I think the

826
01:10:02,640 --> 01:10:12,240
broader version is really, you know, this malaria 
vaccine essentially came out of research from the

827
01:10:12,240 --> 01:10:23,520
US Army. In the 1950s, almost every country 
was affected by malaria, and they used, there

828
01:10:23,520 --> 01:10:30,400
were large scale malaria eradication programs in 
the 1950s, mostly using insecticides like DDT.

829
01:10:31,840 --> 01:10:34,576
And those were very effective, like a lot of high

830
01:10:34,576 --> 01:10:42,320
income countries eliminated malaria in the 
1950s with DDT and other control efforts.

831
01:10:42,320 --> 01:10:48,480
And funding also declined, so there was no more 
reason for a lot of high income countries to do

832
01:10:48,480 --> 01:10:55,360
research on malaria, and a lot of the researchers 
who were previously doing it became operators and

833
01:10:55,360 --> 01:11:03,440
managers of this eradication program. So funding 
for research and development massively contracted,

834
01:11:03,440 --> 01:11:12,400
and that kind of stayed that way until really 
the 1960s, when the Vietnam War was happening,

835
01:11:12,400 --> 01:11:18,400
and the US Army was then once again facing 
malaria in Southeast Asia. But by then it was

836
01:11:18,400 --> 01:11:23,440
kind of drug resistant malaria. So there was 
once again, this need for research trying to

837
01:11:23,440 --> 01:11:30,000
develop new drugs that were effective against drug 
resistant malaria, but also potentially vaccines.

838
01:11:30,000 --> 01:11:36,960
And so some researchers started working on 
this program to try to develop a malaria

839
01:11:36,960 --> 01:11:44,240
vaccine. And their names were Ruth Nussenzweig, 
Jerome Vanderberg and some of their colleagues.

840
01:11:44,240 --> 01:11:49,040
And what they did was, they first tried to 
build a proof of concept of the vaccine,

841
01:11:49,040 --> 01:11:57,600
so let's see if you can protect mice by 
infecting them first with a killed version

842
01:11:57,600 --> 01:12:03,360
of the parasite. If you protect them with this 
killed version of the parasite, will they then

843
01:12:03,360 --> 01:12:08,160
be protected from another infection? And what 
they found was that yes, you could do that.

844
01:12:08,160 --> 01:12:14,560
And, this eventually much later led to a different 
type of vaccine, which we might come back to later

845
01:12:14,560 --> 01:12:23,920
on, but it's not really scalable. So the other 
option is let's try to develop a subunit vaccine.

846
01:12:24,640 --> 01:12:32,000
From our previous episode on a history of vaccines 
and Hepatitis B, basically the idea here is that,

847
01:12:32,000 --> 01:12:38,080
instead of using the whole organism, the whole 
parasite as a vaccine, let's try to find a few

848
01:12:38,080 --> 01:12:43,280
components, or maybe the one component, that 
is enough to stimulate an immune response.

849
01:12:43,280 --> 01:12:50,160
And so that's what they tried to find and 
they sort of looked at these mice that they

850
01:12:50,160 --> 01:12:56,800
were protecting with this killed parasite and saw: 
what are they generating antibodies against? What

851
01:12:56,800 --> 01:13:03,040
is their immune response reacting against? 
And they found that that clustered around a

852
01:13:03,040 --> 01:13:10,320
protein called the circumsporozoite protein. 
That protein, it turned out, was gonna be a

853
01:13:10,320 --> 01:13:17,440
very good candidate for a vaccine. That was 
gonna be the main component of the vaccine.

854
01:13:17,440 --> 01:13:25,040
So the initial attempts were to use that protein 
as the vaccine. If you remember back from our

855
01:13:25,040 --> 01:13:32,320
protein subunit vaccines episode, the Hepatitis 
B one, often just using a single protein in a

856
01:13:32,320 --> 01:13:38,560
vaccine is not very effective. And the reason for 
that is that, often when you have a whole pathogen

857
01:13:38,560 --> 01:13:42,400
being a vaccine, or when you're exposed to a 
whole pathogen, there are many things about that

858
01:13:42,400 --> 01:13:48,560
pathogen that can stimulate your immune response. 
Whereas when it's just one protein from that,

859
01:13:48,560 --> 01:13:54,080
that's often not enough for your immune system 
to recognize that this is something that we need

860
01:13:54,080 --> 01:14:00,000
to react to. There are obviously lots of nuances 
there, but that's kind of the simplified version.

861
01:14:00,000 --> 01:14:06,320
So this initial vaccine, just using that 
one circumsporozoite, or CSP, protein,

862
01:14:06,320 --> 01:14:13,200
was not very effective. They only managed to 
protect one volunteer out of six in their first

863
01:14:13,200 --> 01:14:21,760
study. The way that you improve that, is often 
by adding an adjuvant. So an adjuvant boosts the

864
01:14:21,760 --> 01:14:27,920
immune response in some way, and so that's kind of 
what they tried. They tried different adjuvants,

865
01:14:27,920 --> 01:14:34,160
they tried different formulations, and 
eventually they created this formulation.

866
01:14:34,160 --> 01:14:38,560
And I forget what each of the letters 
stands for. And this, the formulation

867
01:14:38,560 --> 01:14:45,040
was the RTS,S vaccine. And so Katharine, 
what does, what is this formulation made of?

868
01:14:45,040 --> 01:14:49,920
So the formulation is made of parts of the 
malaria parasite and the Hep B virus. So

869
01:14:49,920 --> 01:14:55,360
the R stands for the repeat region, which is 
from the CS protein in the malaria parasite.

870
01:14:55,360 --> 01:14:59,120
The T is for the T cell epitopes 
that are from the same protein,

871
01:14:59,120 --> 01:15:05,600
and the S is from the Hep B surface antigen, 
and this is fused to that malaria protein.

872
01:15:05,600 --> 01:15:10,560
Then there's the excess Hep B surface antigen 
I mentioned before that was needed for this to

873
01:15:10,560 --> 01:15:15,120
form a virus-like particle, and that's 
the extra S so that makes the RTS,S.

874
01:15:17,040 --> 01:15:24,000
Unfortunately, by the '90s, there was no 
longer interest in funding it from Vietnam War

875
01:15:24,000 --> 01:15:31,840
era army research anymore, and they couldn't 
scale up and continue that research. So they

876
01:15:31,840 --> 01:15:38,880
only found this adjuvant, that they ended 
up using, in the nineties. So at that point,

877
01:15:38,880 --> 01:15:45,440
we have a possibly more effective vaccine 
and they did another challenge trial to

878
01:15:45,440 --> 01:15:49,520
see how effective that would be. 
This time it was more effective,

879
01:15:49,520 --> 01:15:56,320
it was six out of seven people in the challenge 
trial that were protected from further infections.

880
01:15:56,320 --> 01:16:02,000
And again, this, a seven person study 
sounds extremely small and it is,

881
01:16:02,000 --> 01:16:11,920
but that was one - this is a preliminary, pilot 
type of study, so this isn't really the real deal,

882
01:16:11,920 --> 01:16:17,520
but it is still much better than 
any other study had shown so far.

883
01:16:17,520 --> 01:16:22,160
So this was a much more promising 
candidate for further research.

884
01:16:22,160 --> 01:16:29,120
So what they did next was to do a field trial with 
many more participants. So they ran a field trial

885
01:16:29,120 --> 01:16:36,080
in The Gambia with 300 men, they vaccinated 
them with this candidate and with a placebo,

886
01:16:36,080 --> 01:16:41,360
and they looked at their rates of malaria 
infection afterwards. And in the group

887
01:16:41,360 --> 01:16:48,400
that received the vaccine, they had a 34% 
lower rate of malaria infections over the

888
01:16:48,400 --> 01:16:55,360
next four months. So that was the first 
field trial, and that was done in 1998.

889
01:16:55,360 --> 01:17:04,080
And okay, this field trial looks not amazingly 
effective, but still effective in a way that

890
01:17:04,080 --> 01:17:09,680
no other vaccine candidate had been up to 
that point. And so the next step was really,

891
01:17:09,680 --> 01:17:16,640
let's try to get this into real, clinical trials 
in the population that needs these vaccine,

892
01:17:16,640 --> 01:17:23,040
which are children. So they started with trials 
in older children, who were 6 to 11 years old,

893
01:17:23,040 --> 01:17:28,240
and then younger children, who were 1 to 4 
years old, and then finally infants. This

894
01:17:28,240 --> 01:17:36,160
idea is called age deescalation. Basically you're 
testing it first in children who are least likely

895
01:17:36,160 --> 01:17:42,640
to be affected by potential side effects, and 
then the infant group who are more vulnerable.

896
01:17:42,640 --> 01:17:51,200
You sort of wanna make sure that it works first in 
adults, and then in children, and then in infants.

897
01:17:51,200 --> 01:17:58,880
But this process took a long time and they 
struggled to find funding at every stage

898
01:17:58,880 --> 01:18:07,680
of the process from what I read, and also needed 
to themselves set up clinical trial sites across

899
01:18:07,680 --> 01:18:15,120
Africa. Often there were just not clinics 
with the expertise to run clinical trials,

900
01:18:15,120 --> 01:18:21,120
or the equipment to do testing and things 
like that, and the researchers themselves

901
01:18:21,120 --> 01:18:26,720
had to fund some of that work, so it was a 
very long process. And then it eventually

902
01:18:26,720 --> 01:18:34,160
finished in 2015, the phase three trials 
ended at that point. That is, I think,

903
01:18:34,160 --> 01:18:39,600
much longer than the research process 
that we often have for vaccines today.

904
01:18:39,600 --> 01:18:44,080
Though, luckily, I'm sure that 
meant it got approved in 2015.

905
01:18:44,080 --> 01:18:45,280
No!

906
01:18:45,280 --> 01:18:49,280
No. What happened then?

907
01:18:49,280 --> 01:18:57,440
What happened then? Well, in 2015, the phase 
three results came in and the European Medicines

908
01:18:57,440 --> 01:19:05,680
Agency said, this looks safe and effective, but 
the World Health Organization didn't recommend

909
01:19:05,680 --> 01:19:14,320
it for a large scale rollout. They asked for 
more pilot studies before they would do that.

910
01:19:14,320 --> 01:19:20,880
And one of the reasons for that was that there 
were some, in post hoc analyses of the data,

911
01:19:20,880 --> 01:19:26,720
they found higher rates of meningitis in 
older children and higher rates of death

912
01:19:26,720 --> 01:19:35,760
in girls at two of the trial sites. And the World 
Health Organization, if I understand correctly,

913
01:19:35,760 --> 01:19:40,320
didn't think that they were - those signs 
were causally related to the vaccine,

914
01:19:40,320 --> 01:19:45,520
but they wanted it to be ruled out, 
and so they asked for pilot studies.

915
01:19:45,520 --> 01:19:51,280
The pilot studies took around four years to 
find funding for, and to get staffing for,

916
01:19:51,280 --> 01:19:58,160
and they finally launched in 2019. And then 
another two years into the pilot studies,

917
01:19:58,160 --> 01:20:05,840
there was enough data for the Data Safety 
Monitoring Board to look at the data, find no

918
01:20:05,840 --> 01:20:12,640
increased risk of these side effects, and then 
finally clear the vaccine for the World Health

919
01:20:12,640 --> 01:20:22,640
Organization's endorsement in October, 2021. So 
that is 23 years after the first field trials.

920
01:20:22,640 --> 01:20:25,680
The safety was one of the reasons, 
but that wasn't the only reason,

921
01:20:25,680 --> 01:20:30,560
right? They, there was a lack of 
confidence in how effective the

922
01:20:30,560 --> 01:20:37,680
vaccine was. So it wasn't the risk, it was 
about the risk benefit analysis. You know,

923
01:20:37,680 --> 01:20:43,280
it was only 36% effective in those phase 
three trials, and there was the safety signal.

924
01:20:43,280 --> 01:20:50,080
The RTS,S vaccine was going up for EMA and WHO 
review in 2014, 2015. That was just about when

925
01:20:50,080 --> 01:20:56,240
you were finishing your PhD, working on the R21 
vaccine. Katharine, so what was the feeling like

926
01:20:56,240 --> 01:21:02,400
in the malaria research community at that time? 
Did people have conflicting and different views,

927
01:21:02,400 --> 01:21:08,000
and there was a lot of debate? Was there 
consensus and surprise? What, what was it like?

928
01:21:08,000 --> 01:21:11,920
I think everybody was really hopeful that the 
vaccine would get approved. I think there was

929
01:21:11,920 --> 01:21:16,720
definitely mixed opinions in the field 
about whether a vaccine that showed such

930
01:21:16,720 --> 01:21:21,440
low efficacy in the phase three trial should 
be rolled out and would actually be effective.

931
01:21:21,440 --> 01:21:26,320
So I think what was really important and really 
key was the cost effectiveness modeling that was

932
01:21:26,320 --> 01:21:30,720
done with the data. And I think that was quite 
pivotal. And in that it really showed that

933
01:21:30,720 --> 01:21:37,040
even a poorly effective vaccine or suboptimal 
vaccine, most vaccines that have been used in

934
01:21:37,040 --> 01:21:42,480
children at the time had really high levels of 
efficacy, like 80, 90%. So it was a completely

935
01:21:42,480 --> 01:21:47,200
uncharted territory. But the modeling showed that 
even with this low level of efficacy, because

936
01:21:47,200 --> 01:21:51,680
there's so much malaria, it could have quite 
dramatic impact and it would be cost effective.

937
01:21:51,680 --> 01:21:56,640
I think that was a bit of a surprise to everybody. 
We've been aiming for this really high bar,

938
01:21:56,640 --> 01:22:00,560
and then all of a sudden there was this 
realization actually a quite a suboptimal

939
01:22:00,560 --> 01:22:05,680
tool could make a big difference. I think 
that was quite unfortunate and quite pivotal.

940
01:22:05,680 --> 01:22:12,080
So what did it feel like when the WHO verdict 
came in that more studies were needed?

941
01:22:12,080 --> 01:22:17,440
I think it was really disappointing. I think 
it's a difficult decision that they had to

942
01:22:17,440 --> 01:22:21,520
make. This is really uncharted territory; a 
vaccine with really poor efficacy and this

943
01:22:21,520 --> 01:22:27,680
safety signal. So it's a tough call for 
them to make, but I think people at the

944
01:22:27,680 --> 01:22:32,800
time and now still think there could have been 
a better way to resolve the safety signal issue.

945
01:22:32,800 --> 01:22:40,400
And had they prepared better for understanding 
the public health impact of a vaccine that has

946
01:22:40,400 --> 01:22:44,000
this level of efficacy, maybe that messaging 
could have been different when they were

947
01:22:44,000 --> 01:22:48,720
trying to make the recommendations, if they 
understood the potential value more fully,

948
01:22:49,840 --> 01:22:57,600
maybe that would've have shifted the approach 
away from a pilot implementation program that

949
01:22:57,600 --> 01:23:04,560
took six years to conclude versus doing 
a much more rapid safety assessment.

950
01:23:04,560 --> 01:23:10,800
I guess I also, I feel like it's a little 
bit surprising just because even the first

951
01:23:10,800 --> 01:23:16,960
field trials in 1997 and 1998 also showed 
fairly low efficacy, but they continued

952
01:23:16,960 --> 01:23:21,520
working on it and people probably should 
have been prepared by that point that,

953
01:23:21,520 --> 01:23:26,960
hey, this even though this isn't a very highly 
effective vaccine, it probably will save a lot

954
01:23:26,960 --> 01:23:38,000
of lives. And so it's surprising that that wasn't 
enough to not require another study after that.

955
01:23:38,000 --> 01:23:42,160
Yeah, I think you're right, and what I've 
said just now is my recollection of the

956
01:23:42,160 --> 01:23:47,120
events at the time. This is a while ago and 
I wasn't deeply involved in the process,

957
01:23:47,120 --> 01:23:52,000
so perhaps there was more preparation than 
that I was aware of, but it feels like that

958
01:23:52,000 --> 01:23:55,840
was the missing piece that people didn't 
truly, at least the people I was talking to,

959
01:23:55,840 --> 01:24:02,640
didn't truly appreciate the potential impact, 
global health impact, of this tool at the time.

960
01:24:02,640 --> 01:24:07,040
And there were other consequences as 
well to delaying the rollout. So you'll

961
01:24:07,040 --> 01:24:11,760
see GSK would be hoping that at the end of 
their phase three trial, they can scale up

962
01:24:11,760 --> 01:24:15,840
manufacture and start delivering the vaccine. 
They probably had a factory that was making it,

963
01:24:15,840 --> 01:24:19,040
but now there was gonna be this huge delay. 
What were they gonna do with the facilities

964
01:24:19,040 --> 01:24:22,960
that were producing the vaccine? And then what 
was that gonna mean for vaccine supply later

965
01:24:22,960 --> 01:24:30,000
on? All these knock on effects as well that in 
hindsight it's easy to think differently about

966
01:24:30,000 --> 01:24:34,080
what we could have done differently. But I'm not 
sure it was so easy at the time, to be honest.

967
01:24:34,080 --> 01:24:40,880
It's also just like to state the 
obvious, so strange and messed up

968
01:24:40,880 --> 01:24:48,640
that the way that things currently work is 
that to get a scalable regulatory opinion,

969
01:24:48,640 --> 01:24:56,640
you end up relying on the EU and the WHO when, 
you know, over time we have to get to a world

970
01:24:56,640 --> 01:25:03,840
where kids in Ghana rely on regulators in Ghana, 
not these kind of more distant bodies. 'Cause

971
01:25:03,840 --> 01:25:10,240
you could totally imagine, as happened with 
the next vaccine, R21, that some nations want

972
01:25:10,240 --> 01:25:16,320
to go ahead with vaccination campaigns, 
even if the WHO doesn't agree and they

973
01:25:16,320 --> 01:25:21,840
absolutely should. So that's another part 
of this story that's a bit heart wrenching.

974
01:25:21,840 --> 01:25:27,280
I feel like there's also a part of this 
that's like what safety standards we're

975
01:25:27,280 --> 01:25:34,000
used to here might be different. Like the 
cost benefit just might be very different

976
01:25:34,000 --> 01:25:39,760
and the willingness to take vaccine at 
an earlier stage might be different.

977
01:25:39,760 --> 01:25:44,640
But I think there's also another thing that 
kind of drew out the process, which was a

978
01:25:44,640 --> 01:25:51,440
lack of funding and a lack of infrastructure 
for clinical trials at the time. So especially

979
01:25:51,440 --> 01:25:58,400
in the early 2000s, there were very few trial 
sites in Africa where you could actually try to

980
01:25:58,400 --> 01:26:06,240
do research on the malaria vaccine at all. And 
it was only in the 2000s when malaria funding

981
01:26:06,240 --> 01:26:13,520
actually grew from various organizations like 
the President's Malaria Initiative in the US,

982
01:26:13,520 --> 01:26:21,680
and Unitaid and the PATH's Malaria Vaccine 
Initiative that was funded by the Gates

983
01:26:21,680 --> 01:26:30,080
Foundation and the Global Fund. And all of 
these appeared only in the mid-, early-2000s.

984
01:26:30,080 --> 01:26:35,600
Until then, it would've been really difficult, 
I think, to get enough funding to set up these

985
01:26:35,600 --> 01:26:44,240
trial sites and to actually do the research. To 
me, when I think about it seems like mostly a

986
01:26:44,240 --> 01:26:52,240
failure of infrastructure and funding. And 
there are also these regulatory concerns,

987
01:26:52,240 --> 01:26:59,680
but if we'd had that sooner, we would've been 
able to test many other vaccines as well.

988
01:26:59,680 --> 01:27:02,400
Yeah, I agree with that. I think that's 
a really important point. I think,

989
01:27:02,400 --> 01:27:05,360
we take it for granted now that 
actually these clinical trial

990
01:27:05,360 --> 01:27:11,280
facilities are so well established, and 
the investigators there are so competent,

991
01:27:11,280 --> 01:27:15,520
that they can run their own trials, lead 
their own work. That wasn't the case.

992
01:27:15,520 --> 01:27:20,480
I remember the stories of the people 
leading the RTS,S work doing the draw

993
01:27:20,480 --> 01:27:24,720
of the sites that existed at the time, 
and injecting cash into a lot of these

994
01:27:24,720 --> 01:27:29,360
sites to bring them up to the standards that 
would be needed for their product development

995
01:27:30,080 --> 01:27:36,320
needs. So I think a lot of that work 
done by GSK has really benefited the rest

996
01:27:36,320 --> 01:27:40,880
of the malaria community and other 
development of other vaccines as well.

997
01:27:40,880 --> 01:27:44,640
Okay. So there's infrastructure, which is 
key, and also funding, as you mentioned,

998
01:27:44,640 --> 01:27:49,440
Saloni. So let's say that there had been a 
big burst of funding back then that was even

999
01:27:49,440 --> 01:27:55,200
bigger than we saw. How would that have 
happened? Were there people proposing it?

1000
01:27:55,200 --> 01:27:58,880
There were people proposing it, but they 
were proposing a different type of funding.

1001
01:27:59,520 --> 01:28:04,320
Much of the funding that we're talking 
about is sort of directed at specific

1002
01:28:04,320 --> 01:28:09,760
groups to do the research, or to set up 
the trial sites, and things like that.

1003
01:28:09,760 --> 01:28:17,120
But in 2004, some economists, Michael Kremer 
and Rachel Glennerster proposed an Advanced

1004
01:28:17,120 --> 01:28:23,440
Market Commitment, which is a different type 
of funding model to try to spur innovation

1005
01:28:23,440 --> 01:28:28,480
and change the commercial incentives for 
vaccine development. So the general idea,

1006
01:28:28,480 --> 01:28:34,560
of why did we need philanthropy and like foreign 
aid and all of these global health programs,

1007
01:28:34,560 --> 01:28:39,760
is that there isn't otherwise a commercial 
incentive to develop vaccines where it's very

1008
01:28:39,760 --> 01:28:46,800
small. The reason for that is that the people who 
are most affected by malaria are very poor and you

1009
01:28:46,800 --> 01:28:52,240
can't really sell vaccines at a high price 
because they wouldn't be able to afford it.

1010
01:28:53,040 --> 01:28:59,360
So here the idea is, what if we could change those 
commercial incentives? And the Advanced Market

1011
01:28:59,360 --> 01:29:06,240
Commitment is a way of doing that. So instead of 
directing funding at specific research groups,

1012
01:29:06,240 --> 01:29:13,120
it's actually a pool of funding that is only 
available to researchers or to manufacturers

1013
01:29:13,120 --> 01:29:18,640
if they develop a successful vaccine in 
trials and they reach certain criteria.

1014
01:29:19,200 --> 01:29:23,200
So Rachel Glennerster and Michael 
Kremer proposed this Advanced Market

1015
01:29:23,200 --> 01:29:31,040
Commitment where they said we should have a 
commitment for around $3.2 billion in total,

1016
01:29:31,040 --> 01:29:37,360
where you would pay per person who was 
vaccinated, for the first 200 million people,

1017
01:29:37,360 --> 01:29:45,760
and you would pay about $13 per person. What this 
does is it actually incentivizes companies to

1018
01:29:45,760 --> 01:29:51,920
develop a vaccine and take it to the finish 
line. Both invent-, both developing it and

1019
01:29:51,920 --> 01:29:57,120
then also scaling it up because they're only 
gonna get that payout per person they immunize.

1020
01:29:57,120 --> 01:30:03,360
So I think that is a really cool model that 
spurs commercial development and it's very

1021
01:30:03,360 --> 01:30:09,280
different from the type of funding that was 
actually done. But the problem was that that

1022
01:30:09,280 --> 01:30:15,760
idea didn't actually get taken up. And there 
were various reasons for that. One was that

1023
01:30:15,760 --> 01:30:22,400
at the time people thought the malaria vaccine 
was just too technically difficult. It was too

1024
01:30:22,400 --> 01:30:28,480
far away to be reality. So they didn't want to 
use this new funding model that was proposed,

1025
01:30:28,480 --> 01:30:33,680
for something that might not ever happen, and 
they thought that you, we have to have a lot

1026
01:30:33,680 --> 01:30:40,960
more basic R&D before we'd have a product that 
could reach that standard. That also just made it

1027
01:30:40,960 --> 01:30:46,960
more politically risky. People were like, well, 
we want something that will definitely or has a

1028
01:30:46,960 --> 01:30:52,880
much higher chance of success. We want a proof 
of concept that this funding model could work.

1029
01:30:52,880 --> 01:30:59,280
And the other problem is that it's hard, in 
a commitment like that, which is essentially

1030
01:30:59,280 --> 01:31:04,720
this legal document that funders, in this 
case they would be countries - governments,

1031
01:31:04,720 --> 01:31:10,080
or philanthropists agreeing to pay out a 
vaccine that meets these standards. It's

1032
01:31:10,080 --> 01:31:16,880
hard to decide what those standards are and what 
kinds of products would fit those criteria if you

1033
01:31:16,880 --> 01:31:21,840
don't have a malaria vaccine yet, and you don't 
have like things that are late in the pipeline.

1034
01:31:21,840 --> 01:31:29,280
So instead of doing an Advanced Market Commitment 
for malaria, there was a different Advanced Market

1035
01:31:29,280 --> 01:31:37,680
Commitment that was actually implemented, and that 
was for the pneumococcal vaccine. And so in 2009,

1036
01:31:37,680 --> 01:31:43,760
various countries and the Gates Foundation came 
together to fund an Advanced Market Commitment to

1037
01:31:43,760 --> 01:31:49,440
develop a new pneumococcal vaccine that would 
target the strains that were common in Africa

1038
01:31:49,440 --> 01:31:55,920
and South Asia. Those strains were not included in 
the previous pneumococcal vaccines, but there was

1039
01:31:55,920 --> 01:32:00,720
already a proof of concept that we have this, we 
have these other pneumococcal vaccines, it should

1040
01:32:00,720 --> 01:32:08,640
be fairly easy to turn to make new ones against 
these strains. And it worked. So there were three

1041
01:32:08,640 --> 01:32:15,120
companies, I think, that quickly developed these 
pneumococcal vaccines, took them through phase

1042
01:32:15,120 --> 01:32:21,840
three trials and then manufactured them in 
bulk to get that payout from the commitment.

1043
01:32:22,720 --> 01:32:30,320
I personally think it feels like 
a very big missed opportunity to

1044
01:32:30,320 --> 01:32:35,760
use it for malaria as well. But many 
people disagreed with that at the time.

1045
01:32:35,760 --> 01:32:39,200
Okay. Katharine, you were around. Do 
you think it would've worked back then?

1046
01:32:39,200 --> 01:32:42,960
I'm not sure. I think the 
limitations were scientific,

1047
01:32:42,960 --> 01:32:44,880
biological, we had the 
problems with the adjuvants,

1048
01:32:44,880 --> 01:32:50,880
we had lack of trial infrastructure. I'm not 
sure it would've made things go much faster.

1049
01:32:50,880 --> 01:32:56,960
Well, it's hard to say as well, because this 
was proposed in 2004. And so at that point,

1050
01:32:56,960 --> 01:33:03,920
the RTS,S vaccine already existed and it already 
had like an efficacy of 30 something percent. And

1051
01:33:03,920 --> 01:33:09,040
so if you were at the time, and you were trying 
to put this commitment together and you said,

1052
01:33:09,040 --> 01:33:14,720
we'll fund a vaccine that reaches these 
standards, probably you would, the standards

1053
01:33:14,720 --> 01:33:20,160
that you would ask a vaccine to be developed 
for would be higher than the 30% I think.

1054
01:33:20,160 --> 01:33:25,920
So I think in that sense it would've been 
hard. What's interesting though is that

1055
01:33:25,920 --> 01:33:31,440
there was another paper in 2005 where 
they tried to model this explicitly,

1056
01:33:31,440 --> 01:33:37,120
so trying to model the cost-effectiveness under 
different estimates of the efficacy. Like if

1057
01:33:37,120 --> 01:33:45,040
it was 30%, how would it be cost effective? If 
it was 60%, et cetera? And this was a paper by

1058
01:33:45,040 --> 01:33:50,240
also Rachel Glennerster, Michael Kremer, 
many other economists, Heidi Williams,

1059
01:33:50,240 --> 01:33:55,680
and they found basically that it was, it 
would still be cost effective to fund an

1060
01:33:55,680 --> 01:34:01,520
Advanced Market Commitment for a malaria 
vaccine, even if the efficacy was only 30%.

1061
01:34:01,520 --> 01:34:10,000
So I think to some degree there had been a bunch 
of thinking on this, but at the same time, I don't

1062
01:34:10,000 --> 01:34:15,760
think we know what the counterfactual is because 
I don't think that other, there are enough other

1063
01:34:15,760 --> 01:34:23,840
commercial companies that are developing malaria 
vaccines now that we can compare this to. Like

1064
01:34:24,880 --> 01:34:30,800
the thing that is effective about the Advanced 
Market Commitment is that it gets people to enter

1065
01:34:30,800 --> 01:34:37,120
the market that wouldn't otherwise. And so it's 
hard to know how that could have gone, I think.

1066
01:34:37,120 --> 01:34:43,520
I think that's the bit that I agree with 
that there weren't other people that

1067
01:34:43,520 --> 01:34:48,400
were that far advanced in their vaccine. The 
only thing that has worked to date is a CSP

1068
01:34:48,400 --> 01:34:54,320
based vaccine. There were people working on other 
types of vaccines at the time. But it's not sure,

1069
01:34:54,320 --> 01:35:00,640
because it's not clear any of those would've made 
it either, or looked promising enough to advance.

1070
01:35:00,640 --> 01:35:06,080
So that's a pull funding mechanism incentive 
to get to the finish line. Katharine,

1071
01:35:06,080 --> 01:35:12,640
did it feel like more grant money, and more 
universities, and more companies wherever,

1072
01:35:12,640 --> 01:35:16,480
would have made the difference if there 
was a hundred million more every year

1073
01:35:16,480 --> 01:35:20,480
going into malaria vaccines? Or 
did it feel like the science and

1074
01:35:20,480 --> 01:35:26,720
the infrastructure - you can't rush that, and 
you actually just have to do it step by step?

1075
01:35:26,720 --> 01:35:29,840
That's a very good question and, 
actually I, maybe I'm gonna change

1076
01:35:29,840 --> 01:35:34,160
my opinion slightly and that there were 
other, with more funding available,

1077
01:35:34,160 --> 01:35:39,280
there were other people doing great science at 
the time. So Simon Draper at the University of

1078
01:35:39,280 --> 01:35:45,040
Oxford has developed a blood stage vaccine with 
RH5, and that work was happening at the same

1079
01:35:45,040 --> 01:35:52,000
time on the lab bench next to me, when I was 
doing R21. But that was seriously underfunded,

1080
01:35:52,000 --> 01:35:55,600
so there was - people had to prioritize what 
they were gonna support with their funding,

1081
01:35:55,600 --> 01:36:03,040
there was limited funding. So the focus went on 
to CSP based vaccines and that's what the Gates

1082
01:36:03,040 --> 01:36:10,640
Foundation funded the RTS,S vaccine through MVI 
and the Gates Foundation didn't fund blood stage.

1083
01:36:10,640 --> 01:36:14,640
There was only one funder at the time that was 
supporting that work, or one main funder, and that

1084
01:36:14,640 --> 01:36:18,480
was USAID (United States Agency for International 
Development). Had there been more money, that work

1085
01:36:18,480 --> 01:36:24,320
could have been accelerated. And you know, that's 
shown now in a phase two trial that it gives good

1086
01:36:24,320 --> 01:36:33,760
levels of efficacy, not as high as R21 and RTS,S, 
but there's potential to combine that with R21.

1087
01:36:33,760 --> 01:36:37,680
So that work could have been accelerated a lot 
quicker, had there been more funding around.

1088
01:36:37,680 --> 01:36:41,200
So just playing that out. So that, 
that result you just referenced,

1089
01:36:41,200 --> 01:36:46,160
that was from about a year ago, was it? That 
was pretty recent. Right? Yeah. And so if that

1090
01:36:46,160 --> 01:36:51,440
funding had happened a decade earlier, could 
that result have come about a decade earlier,

1091
01:36:51,440 --> 01:36:55,200
do you think? Or is - that's 
just a funding question really.

1092
01:36:55,200 --> 01:37:01,745
Yeah, I think the product was the one 
they were working on in the beginning.

1093
01:37:01,745 --> 01:37:01,760
No!!
Depressing.

1094
01:37:01,760 --> 01:37:05,120
Wow. That is incredibly depressing.

1095
01:37:05,120 --> 01:37:12,080
I know, but I think credit has to go to Simon 
Draper and the funders that supported him and

1096
01:37:12,080 --> 01:37:17,200
Lorraine Soisson at USAID, they kept that 
work going with quite limited budgets,

1097
01:37:17,200 --> 01:37:20,400
and they've made it to the finish 
line, well, not to the finish line,

1098
01:37:20,400 --> 01:37:24,390
but to the clinical trials 
now, and the efficacy trials.

1099
01:37:24,390 --> 01:37:24,400
Wow, geez.

1100
01:37:24,400 --> 01:37:30,160
Thank you Simon. Thank you Lorraine, for 
believing against consensus and keeping it going.

1101
01:37:30,160 --> 01:37:35,200
I have a question related to this because 
both these are different stages of the

1102
01:37:35,200 --> 01:37:41,680
vaccine and so I'm wondering if you had a 
vaccine that combines the vaccines against

1103
01:37:41,680 --> 01:37:45,920
both of these different stages, would you 
expect that to have a higher efficacy,

1104
01:37:45,920 --> 01:37:50,000
and have people tried to do things like that?

1105
01:37:50,000 --> 01:37:55,200
Yeah, I think that was the original approach 
from Adrian, when I was making R21. He also

1106
01:37:55,200 --> 01:38:00,268
had a liver stage vaccine. The other vaccine he 
had developed was the ME-TRAP vaccine (Multiple

1107
01:38:00,268 --> 01:38:04,080
Epitope–Thrombospondin-Related Adhesion Protein), 
and that targeted the infected hepatocytes.

1108
01:38:04,080 --> 01:38:08,160
His theory was that if you could reduce the 
number of sporozoites that get to the liver,

1109
01:38:08,160 --> 01:38:13,680
then the liver stage vaccine would have an easier 
time finding and clearing out those liver cells.

1110
01:38:13,680 --> 01:38:21,280
And that was valua - that was tested and it didn't 
work, so that was a great theory that didn't work.

1111
01:38:21,280 --> 01:38:26,960
Now people are looking at combining the CSP based 
vaccines with the blood stage vaccines that Simon

1112
01:38:26,960 --> 01:38:30,320
Draper's developed and others. There are lots of 
other people working on blood stage vaccines now

1113
01:38:30,320 --> 01:38:36,880
as well. But the preclinical models are really 
difficult to evaluate all stages of the parasites

1114
01:38:36,880 --> 01:38:42,240
in the same model and the combination of those 
vaccines. So we really have to get into humans,

1115
01:38:42,240 --> 01:38:46,960
and that's the work that Simon and Angela 
and his team are working on at the moment.

1116
01:38:46,960 --> 01:38:51,920
Wow. And so that was also - could that 
have also been sped up by 10 years?

1117
01:38:51,920 --> 01:38:56,320
Yeah, that vaccine that they're now putting 
into clinical trials with R21 was being

1118
01:38:56,320 --> 01:39:01,440
developed at the same time as I was developing 
R21. So I know that could have gone quicker.

1119
01:39:01,440 --> 01:39:03,200
This is crazy.

1120
01:39:03,200 --> 01:39:11,920
It wasn't exactly hard to spot, it was right next 
to you on the lab next to you. I'm gonna cry.

1121
01:39:11,920 --> 01:39:12,720
Geez.

1122
01:39:12,720 --> 01:39:19,040
I mean, so as someone who works in philanthropic 
funding, I think the main lesson here is just

1123
01:39:19,920 --> 01:39:25,920
that funding in global health R&D is 
so tight that you have to make these

1124
01:39:25,920 --> 01:39:34,800
prioritization decisions that are vicious and 
impossible. So we just - I mean, a more sane

1125
01:39:34,800 --> 01:39:42,160
society would have more long-term government and 
philanthropic funding that was less correlated,

1126
01:39:42,160 --> 01:39:47,200
more decision makers, more money total, 
so that you could get more shots on goal.

1127
01:39:47,200 --> 01:39:54,320
So I think, for anyone listening who 
is wondering what the solution is,

1128
01:39:54,320 --> 01:39:59,440
I think that's the most obvious general solution 
staring us in the face, and so I don't wanna hide

1129
01:39:59,440 --> 01:40:03,360
it. There's obviously all these specifics 
we can get into that are more technical,

1130
01:40:03,360 --> 01:40:11,200
but that one is just - is obvious. So 
we just have to say it out loud. Sorry!

1131
01:40:11,200 --> 01:40:12,800
Geez.

1132
01:40:12,800 --> 01:40:16,640
No, I agree with that. I don't disagree with 
the decisions that were made about what you

1133
01:40:16,640 --> 01:40:20,000
had to prioritize at the time. I think 
they were tough decisions that people had

1134
01:40:20,000 --> 01:40:24,720
to make. That had there been more money, 
we could have moved things a lot faster.

1135
01:40:25,280 --> 01:40:31,760
I feel like what's even more depressing 
about this is that... Despite all of that,

1136
01:40:31,760 --> 01:40:37,280
malaria is still one of the more well-funded 
diseases in global health world, and there

1137
01:40:37,280 --> 01:40:43,440
are various others that are large burdens 
and get tiny fractions of the funding.

1138
01:40:43,440 --> 01:40:48,720
I am wondering if we could just talk about the 
two vaccines already approved next to each other,

1139
01:40:48,720 --> 01:40:54,240
and then what's coming next after these two? What 
needs to be done next in the invention pipeline?

1140
01:40:54,240 --> 01:41:03,840
So RTS,S versus R21. I will tee this off by saying 
I don't know that there's - there are different

1141
01:41:03,840 --> 01:41:10,960
comparisons you could make, but one fact just to 
state upfront is that neither has faced a rollout

1142
01:41:10,960 --> 01:41:16,080
where tens of millions of children have received 
the vaccine, so perhaps the biggest problem is

1143
01:41:16,080 --> 01:41:23,680
simply that there is not enough reach of either 
of them, let alone comparing between the two.

1144
01:41:23,680 --> 01:41:27,760
That said, what do we know 
about the data that has come in,

1145
01:41:27,760 --> 01:41:31,760
about how they look? So there's 
more data coming in every year,

1146
01:41:31,760 --> 01:41:39,440
but what do we know so far about efficacy, 
about safety, and other factors? Katharine?

1147
01:41:39,440 --> 01:41:43,600
The headline efficacy figures from the phase 
three trials look quite different for the two

1148
01:41:43,600 --> 01:41:51,040
vaccines. So RTS,S, we mentioned it was something 
like 36% an efficacy overall. And actually for

1149
01:41:51,040 --> 01:41:57,360
the population that was used for the phase 
three trials for R21, that was most similar,

1150
01:41:57,360 --> 01:42:05,040
the efficacy I think was 57% overall. And then for 
R21, the phase three result was something around

1151
01:42:05,040 --> 01:42:13,120
75%. I can't remember the same, the exact numbers, 
so this looks like R21 may be a lot better.

1152
01:42:13,120 --> 01:42:17,040
But there's some nuance and detail 
about how these trials were conducted,

1153
01:42:17,040 --> 01:42:21,520
and where they were conducted, and when they were 
conducted, that means we can't - we probably can't

1154
01:42:21,520 --> 01:42:27,440
directly compare these trial results. So I don't 
think you can claim that R21 definitely has a

1155
01:42:27,440 --> 01:42:32,800
higher level of efficacy. There were different 
things happening at the time; different other

1156
01:42:32,800 --> 01:42:38,400
malaria interventions that were being used, 
like bed nets, or seasonal chemo-prevention

1157
01:42:38,400 --> 01:42:43,600
drugs that were given to children every year, 
so those results aren't directly comparable.

1158
01:42:43,600 --> 01:42:49,120
So I think we have to try not to make that 
comparison unless we run a head-to-head trial.

1159
01:42:49,120 --> 01:42:53,760
What I think is interesting about the R21 data 
that's starting to emerge is that it does - it

1160
01:42:53,760 --> 01:43:02,800
may be more durable than RTS,S. So the decline of 
protection seems to be slightly slower. So it may,

1161
01:43:02,800 --> 01:43:07,280
even if the efficacy isn't much different, 
that peak protection they gets the,

1162
01:43:07,280 --> 01:43:10,880
it may last a little bit longer, so 
that could make quite a big difference.

1163
01:43:10,880 --> 01:43:14,880
I see. So, but in both cases, your first shot,

1164
01:43:14,880 --> 01:43:19,280
you'll probably get it at five months old. Is 
that about right? And then you might get another,

1165
01:43:19,280 --> 01:43:24,000
the ideal is you get one at five, one 
at six, one at seven months. And you're

1166
01:43:24,000 --> 01:43:31,680
saying that the immune response from R21 is 
lasting for longer after those first shots?

1167
01:43:31,680 --> 01:43:36,480
That's right. That's actually a fourth 
dose that's given around 18 months.

1168
01:43:36,480 --> 01:43:43,760
I think my takeaway from the difference 
between the two is mostly the manufacturing

1169
01:43:43,760 --> 01:43:49,920
and the cost. Is that also how you see 
it? And are there any other differences?

1170
01:43:49,920 --> 01:43:55,520
Why is there such a huge difference 
in the cost of both of these? And is

1171
01:43:55,520 --> 01:43:59,120
that because of the dosing that 
we talked about at the start?

1172
01:43:59,120 --> 01:44:05,920
I guess, the other big difference is of 
the scalability of the vaccines. R21,

1173
01:44:06,880 --> 01:44:12,240
it seems to be easier and cheaper to produce 
and that may be in part due to the lower dose

1174
01:44:12,240 --> 01:44:18,320
and maybe also new technologies that have been 
used to produce the vaccine itself - so newer

1175
01:44:18,320 --> 01:44:25,520
yeast expression systems and things like that. And 
also, the adjuvant that's added to the vaccine.

1176
01:44:25,520 --> 01:44:30,800
As we mentioned earlier, that the adjuvant 
was really important for the RTS,S vaccine.

1177
01:44:30,800 --> 01:44:37,680
We found the same with R21, only when we used 
a certain adjuvant did we see protection. And

1178
01:44:37,680 --> 01:44:42,080
that the adjuvant that's been chosen for R21 
was Matrix-M and that doesn't have the same

1179
01:44:42,080 --> 01:44:50,000
supply limitations as AS01, and it's slightly 
cheaper as well. So that makes it more scalable.

1180
01:44:50,000 --> 01:44:54,960
Yeah, I mean it's funny, it's not the property 
you'd think about first – scalability,

1181
01:44:54,960 --> 01:45:02,160
and how that might have implications for cost 
and price. But last price that I saw for RTS,S

1182
01:45:02,160 --> 01:45:10,960
was about €9 a dose and there are four doses. And 
then the last price I saw for R21 was the original

1183
01:45:10,960 --> 01:45:17,840
price was 3.90 and it maybe has come down to 
$3? So we're, we're talking about a 3X, say,

1184
01:45:17,840 --> 01:45:24,960
difference, which may not sound like much, but 
is decisive in a lot of these cost-effectiveness

1185
01:45:24,960 --> 01:45:30,000
calculations because global health funding, 
there's just not so much of it going around.

1186
01:45:30,000 --> 01:45:36,160
So when you think of cost-effectiveness, it's 
not just how effective are these vaccines,

1187
01:45:36,160 --> 01:45:40,240
it's how much it cost to actually deliver 
them to the kids who need them. So anything

1188
01:45:40,240 --> 01:45:44,480
you can do to bring the numbers down 
is, it could change the equation.

1189
01:45:44,480 --> 01:45:49,920
Yeah. And just going back to the delivery schedule 
you mentioned earlier Jacob, which is giving doses

1190
01:45:49,920 --> 01:45:54,720
of the vaccine at five, six, and seven months. 
And then there's this booster dose or final dose

1191
01:45:54,720 --> 01:45:58,720
that's given around a year later, and none of 
these time points are actually aligned with

1192
01:45:58,720 --> 01:46:04,320
the schedule for other infant vaccines. So what 
this means in reality is that children and their

1193
01:46:04,320 --> 01:46:10,960
parents and caregivers have to travel for each 
of these visits at another time. And what we're

1194
01:46:10,960 --> 01:46:15,920
finding is that people are not showing up for all 
of their doses of vaccine, and so if they're not

1195
01:46:15,920 --> 01:46:20,640
getting the full course, it's gonna reduce 
the effectiveness of both of these vaccines.

1196
01:46:20,640 --> 01:46:26,320
Right. If you have to travel three months 
in a row, but you are busy taking care of

1197
01:46:26,320 --> 01:46:29,920
your other kids or you're at work, or, I 
mean, it's, you can see how you might miss

1198
01:46:29,920 --> 01:46:34,160
a dose. And then if that happens, then 
whatever we saw in the clinical trial

1199
01:46:34,160 --> 01:46:40,640
may not reflect the reality of what kids are 
getting protected, so more work to do there.

1200
01:46:40,640 --> 01:46:46,720
Okay. So those are two 
vaccines and they're imperfect,

1201
01:46:46,720 --> 01:46:53,120
but they are helpful for kids. Do you 
think they're good enough, Katharine?

1202
01:46:53,120 --> 01:46:58,480
If we did this again today, 
could we make better vaccines?

1203
01:46:58,480 --> 01:47:03,600
Uh, yeah, I think well, oh gosh. 
Wow. That's a tough one. I think...

1204
01:47:03,600 --> 01:47:09,600
I mean, scientifically, not in terms of the 
funding or trials or anything like that.

1205
01:47:09,600 --> 01:47:16,240
Yeah, I think we have better techniques 
and technologies for developing

1206
01:47:16,240 --> 01:47:22,160
vaccines. Structured-guided design, reverse 
vaccinology, computational protein design,

1207
01:47:22,160 --> 01:47:27,040
things that you've talked about in your 
previous podcast episodes, where we really

1208
01:47:27,040 --> 01:47:32,960
try and understand more specifically what type 
of immune response you want to generate. So you

1209
01:47:32,960 --> 01:47:36,880
can take the whole protein that you think is 
important, and show that to the immune system,

1210
01:47:36,880 --> 01:47:41,440
but it might generate a mixture of 
helpful responses and unhelpful responses.

1211
01:47:41,440 --> 01:47:47,280
So using these more sophisticated techniques, 
we can try and understand which parts are really

1212
01:47:47,280 --> 01:47:52,240
helpful, and design the proteins or the 
antigens to really elicit those responses

1213
01:47:52,240 --> 01:47:57,680
more carefully and more specifically. So using 
those techniques, people are already doing this.

1214
01:47:57,680 --> 01:48:02,080
They're working on trying to make better 
CSP vaccines, better blood stage vaccines,

1215
01:48:02,080 --> 01:48:05,760
and also vaccines that target the 
transmission blocking stage as well.

1216
01:48:05,760 --> 01:48:08,560
But why were you hesitant before?

1217
01:48:08,560 --> 01:48:13,680
It's not clear that any of those will actually 
be any better. So I think there was a really

1218
01:48:13,680 --> 01:48:18,400
interesting paper published by the Protein Design 
Institute by Neil King, someone that we support

1219
01:48:18,400 --> 01:48:24,960
and think is an incredible institute for using 
computational design to really improve vaccine

1220
01:48:24,960 --> 01:48:31,520
antigens. And they tried to make better versions 
of R21, and I can't remember what the paper showed

1221
01:48:31,520 --> 01:48:37,360
exactly now, but there were many candidates 
they assessed and they used this incredible

1222
01:48:37,360 --> 01:48:41,600
methodology to try and improve the vaccines, but 
none of them looked substantially better than R21.

1223
01:48:42,880 --> 01:48:48,320
What do you think of the whole sporozoite 
vaccines where scientists were just

1224
01:48:48,320 --> 01:48:51,600
irradiating the whole parasite at the 
early stage and injecting that as a

1225
01:48:51,600 --> 01:48:54,320
whole? I think they were doing that 
in the '70s, and that seems like in

1226
01:48:54,320 --> 01:48:58,320
that research it was pretty effective and 
some people are continuing to work on it.

1227
01:48:58,320 --> 01:49:02,640
Yeah, absolutely. I think those are some 
of the first data that really stimulated

1228
01:49:02,640 --> 01:49:06,560
the vaccine development community. They 
showed really early on, decades ago,

1229
01:49:06,560 --> 01:49:12,000
that you could protect people by using these 
irradiated sporozoites, and that work continued.

1230
01:49:12,000 --> 01:49:18,720
So a company called Sanaria, with Steve Hoffman 
and others, developed the PfSPZ vaccine,

1231
01:49:18,720 --> 01:49:23,840
and this worked really well with 
three doses in people in the US,

1232
01:49:23,840 --> 01:49:27,760
so people who had no experience with 
malaria infections before. But when they

1233
01:49:27,760 --> 01:49:32,480
ultimately got this into children in Africa 
who had had malaria infections in the past,

1234
01:49:32,480 --> 01:49:37,600
the vaccines didn't work very well, so that 
hasn't moved forward for that population.

1235
01:49:37,600 --> 01:49:40,480
There's actually been some really 
interesting work more recently that

1236
01:49:40,480 --> 01:49:44,880
they've used genetically attenuated parasites. 
So instead of irradiating the parasites and

1237
01:49:44,880 --> 01:49:50,400
then using them, they've made them so that 
they can't survive beyond the liver stage,

1238
01:49:50,400 --> 01:49:55,280
but importantly, if these parasites 
live to the end of the liver stage,

1239
01:49:55,280 --> 01:49:59,920
then they're really protective. And there 
was a recent study where they showed that a

1240
01:49:59,920 --> 01:50:05,440
single dose of this vaccine provided really high 
levels of protection in their challenge trial.

1241
01:50:05,440 --> 01:50:08,880
But again, this was in people that 
haven't been exposed to malaria before,

1242
01:50:08,880 --> 01:50:11,360
so while this looks really exciting at the moment,

1243
01:50:11,360 --> 01:50:15,280
it still needs to be tested in the field, 
in people who have been exposed to malaria,

1244
01:50:15,280 --> 01:50:19,360
and then ultimately in children as well. But 
it's really exciting. It's pretty game changing

1245
01:50:19,360 --> 01:50:25,680
if you can get a single dose vaccine to protect 
against malaria; we've never seen that before.

1246
01:50:25,680 --> 01:50:30,320
But the challenge with these parasites is that 
they need to be stored in liquid nitrogen,

1247
01:50:30,320 --> 01:50:35,680
so you can't just kill them like we have done 
in the past with other whole pathogen vaccines.

1248
01:50:35,680 --> 01:50:39,840
They need to be viable, they need to be able to 
survive in the liver, and that's gonna be quite

1249
01:50:39,840 --> 01:50:44,080
challenging for delivery in Africa, because there 
aren't liquid nitrogen facilities everywhere.

1250
01:50:44,080 --> 01:50:45,680
Why does it have to be so cold?

1251
01:50:46,240 --> 01:50:48,874
That's the way of putting them in stasis.

1252
01:50:48,874 --> 01:50:50,080
Is it just preserving them?

1253
01:50:50,080 --> 01:50:54,320
Preserving them, yeah. So that they 
can be woken up. They've either got

1254
01:50:54,320 --> 01:50:59,920
to be kept alive until you inject them, 
or you can try and cryo-preserve them in

1255
01:50:59,920 --> 01:51:03,600
a way that they could be thawed, 
and then they'd still be viable.

1256
01:51:03,600 --> 01:51:07,920
What if someone found a different way 
to preserve them for a long time? Are

1257
01:51:07,920 --> 01:51:13,760
there other options? Can you 
like freeze frame a vaccine?

1258
01:51:13,760 --> 01:51:19,360
No. The - no?

1259
01:51:19,360 --> 01:51:25,600
I have no idea. I feel, well, I've 
been watching a lot of Pokémon and

1260
01:51:25,600 --> 01:51:32,560
Team Rocket has all of these crazy 
tools and equipment to do things.

1261
01:51:32,560 --> 01:51:34,080
We can learn from them.

1262
01:51:34,080 --> 01:51:40,160
I feel like they would have a laser beam 
that could just freeze someone in place.

1263
01:51:40,160 --> 01:51:41,440
That would be cool, yeah.

1264
01:51:41,440 --> 01:51:48,880
Let's take a note. Let, let's look into that, 
I think that could be pretty interesting.

1265
01:51:48,880 --> 01:51:53,200
I know a funder that's just started there.

1266
01:51:53,200 --> 01:51:56,960
Yeah. Yeah. Let me just, actually I've 
already got too much in my laser beam column,

1267
01:51:56,960 --> 01:51:59,920
someone else is gonna have fund that one. But...

1268
01:51:59,920 --> 01:52:03,360
Also this laser beam thing 
that could freeze - could be

1269
01:52:03,360 --> 01:52:06,560
used much more widely than just malaria research.

1270
01:52:06,560 --> 01:52:11,280
You could zap people miles away. It's interesting

1271
01:52:11,280 --> 01:52:15,920
I don't hear people talking about this 
more given how important it could be.

1272
01:52:15,920 --> 01:52:16,400
Yeah!

1273
01:52:16,400 --> 01:52:22,880
Now on our current technologies, boring, so 
it sounds like - my sort of takeaways from

1274
01:52:22,880 --> 01:52:27,760
this section are that when people talk about 
vaccines, the thing you always hear about is

1275
01:52:27,760 --> 01:52:34,160
efficacy. COVID vaccine is 90% efficacious, blah, 
blah, blah, blah, blah. But that is one number.

1276
01:52:34,160 --> 01:52:40,560
Firstly, that number does not bake 
in to the public narrative, duration.

1277
01:52:40,560 --> 01:52:46,400
It does not matter if something is 90% 
efficacious and lasts for three months,

1278
01:52:46,400 --> 01:52:52,960
if it then decays. Secondly, it doesn't bake in 
cost. What's the manufacturability of this? How

1279
01:52:52,960 --> 01:52:58,720
widespread is it gonna be in a global health 
context? But then in addition, it doesn't bake

1280
01:52:58,720 --> 01:53:07,520
in how many doses do you need? And, in a context 
where people might not be - they're juggling a

1281
01:53:07,520 --> 01:53:12,640
lot, may not come back for a second, third, or 
fourth dose; getting down from four to three,

1282
01:53:12,640 --> 01:53:16,960
three to two or two to one is just an 
incredibly big deal, not for scientists,

1283
01:53:16,960 --> 01:53:20,400
but for people in the real world who're 
actually gonna be taking these vaccines.

1284
01:53:20,400 --> 01:53:23,360
So Katharine, is that a fair summary?

1285
01:53:23,360 --> 01:53:25,120
Yeah, absolutely. Spot on.

1286
01:53:25,120 --> 01:53:31,520
It reminds me of, you know the HPV vaccine, 
where it was originally a three dose vaccine,

1287
01:53:31,520 --> 01:53:37,200
and then it turned out that actually one 
dose was really effective. But it took a

1288
01:53:37,200 --> 01:53:41,840
really long time for them to change the 
recommendation on how many doses people

1289
01:53:41,840 --> 01:53:46,960
needed. And now that they have that new 
recommendation that you only need one dose,

1290
01:53:46,960 --> 01:53:49,760
you can actually scale it up 
much more widely than before.

1291
01:53:50,320 --> 01:53:55,520
So, Katharine, if you had to make a 
guess, I'm gonna put you on the spot:

1292
01:53:55,520 --> 01:54:07,440
in 10 years will we have an approved vaccine 
in use, which is, say, two doses for kids?

1293
01:54:07,440 --> 01:54:11,920
10 years, I think, two doses is too 
high a bar. I think we can get to three.

1294
01:54:11,920 --> 01:54:12,960
Mm.

1295
01:54:12,960 --> 01:54:18,800
I think we can get to a more durable and a 
more protective vaccine with three doses.

1296
01:54:20,160 --> 01:54:24,240
What's the - what are the 
barriers to making it happen?

1297
01:54:24,240 --> 01:54:29,040
I don't know. Maybe I wanna change 
my answer there. I think 10 years,

1298
01:54:29,040 --> 01:54:33,280
I would put it 60% chance we can get to two doses.

1299
01:54:33,280 --> 01:54:37,989
Okay. But it's all to play for, you're 
saying it really could go either way.

1300
01:54:37,989 --> 01:54:41,440
Yeah, it's not a done deal. I think 
60% chance we can get to two doses,

1301
01:54:41,440 --> 01:54:44,800
like 90% chance we're gonna have a better vaccine.

1302
01:54:44,800 --> 01:54:45,280
Okay.

1303
01:54:45,280 --> 01:54:51,040
Three doses, 90%. That's too high, 80%.

1304
01:54:51,040 --> 01:54:55,600
Okay. So you're saying we've 
got to plug away and get to

1305
01:54:55,600 --> 01:54:59,280
a better vaccine than even the one you invented.

1306
01:54:59,280 --> 01:55:07,520
Definitely! R21 is suboptimal. It can have 
impact like we've discussed, but it's not a

1307
01:55:07,520 --> 01:55:13,400
game changing vaccine. The delivery challenges, 
the durability - that all needs to be solved.

1308
01:55:13,400 --> 01:55:14,480
Hmm.

1309
01:55:14,480 --> 01:55:19,840
Okay. So challenge number one then. So you're 
saying there's a good chance if we really push

1310
01:55:19,840 --> 01:55:24,640
for it, we can get to a better vaccine. Maybe 
it's three doses, maybe it's longer duration,

1311
01:55:24,640 --> 01:55:31,680
and then - but we have to also be aiming at the 
same time for even further improvement for kids,

1312
01:55:31,680 --> 01:55:35,280
and that's hopefully getting to perhaps two doses,

1313
01:55:35,280 --> 01:55:39,600
perhaps, you know, transmission 
blocking, that kind of thing.

1314
01:55:39,600 --> 01:55:40,960
Yeah, absolutely.

1315
01:55:40,960 --> 01:55:46,400
So it's all to play for. Okay. Saloni, how 
are you feeling at the end of this section?

1316
01:55:46,400 --> 01:55:48,800
This makes me sad.

1317
01:55:50,000 --> 01:55:56,720
I feel like it's so sad that one, our technology 
has improved so much, but it doesn't seem to have

1318
01:55:56,720 --> 01:56:02,000
made that much of a difference in terms of 
the efficacy – except for this one vaccine,

1319
01:56:02,000 --> 01:56:09,280
which is really hard to scale up because you 
need to cryo-preserve the sporozoite stage,

1320
01:56:09,280 --> 01:56:17,760
which means that it sort of rules it out being 
used widely. And the third thing, is that there

1321
01:56:17,760 --> 01:56:23,920
were like various vaccines that are in late stages 
of trials right now that could have been in late

1322
01:56:23,920 --> 01:56:31,520
stages 10 years ago. It's just the combination of 
all of that is just incredibly depressing to me.

1323
01:56:31,520 --> 01:56:35,680
Yeah. Well, can I try and cheer you up?

1324
01:56:35,680 --> 01:56:36,720
Yes.

1325
01:56:38,400 --> 01:56:45,280
Just to reorient to how many lives a vaccine 
can save. That is even imperfect. You know,

1326
01:56:45,280 --> 01:56:54,080
if R21 or RTS,S - I mean R21 seems more likely 
now - could scale up to more children who need it,

1327
01:56:54,080 --> 01:56:59,280
tens of thousands of children's lives would be 
saved already. And then Katharine is telling

1328
01:56:59,280 --> 01:57:04,400
us that within 10 years, we have a good shot 
at an improved vaccine that's even better,

1329
01:57:04,400 --> 01:57:07,040
so that is gonna matter to a lot of children.

1330
01:57:07,040 --> 01:57:13,840
And science, the reality of this problem 
is the hardness of it is set by nature,

1331
01:57:13,840 --> 01:57:21,120
and nature is a vicious, vicious, test setter 
sometimes. The fact we've got this far, I mean,

1332
01:57:21,120 --> 01:57:26,640
that is pretty impressive and we have a ways to 
go, but there's a line of sight to improvement,

1333
01:57:26,640 --> 01:57:32,480
even if not to the absolute a hundred 
percent blocking one dose thing.

1334
01:57:32,480 --> 01:57:37,920
I mean, I'm happy for the children 
who are getting these vaccines,

1335
01:57:37,920 --> 01:57:43,440
but it's just that counterfactual. It's 
just very hard to get out of your head.

1336
01:57:43,440 --> 01:57:50,720
Yeah. Yeah. So, Katharine, as you look 
to the next 10 years, how do you feel?

1337
01:57:50,720 --> 01:57:56,560
I'm optimistic. I think we can do better. I think 
we've got great people doing incredible work,

1338
01:57:56,560 --> 01:58:02,960
great new tools and more people thinking 
about the problem end to end. So more

1339
01:58:02,960 --> 01:58:07,840
people thinking more about more than just 
efficacy, with all the other criteria you

1340
01:58:07,840 --> 01:58:11,760
raised that we should be considering. 
More developers are now aware of all

1341
01:58:11,760 --> 01:58:20,080
of those things to consider in the development 
pathway, and so I think there's a lot of hope.

1342
01:58:20,080 --> 01:58:26,080
There's also the current rollout, 
right? That we could scale up.

1343
01:58:26,080 --> 01:58:29,360
Yeah, I think that's a tough one. I think 
it's a really difficult funding environment,

1344
01:58:29,360 --> 01:58:33,920
so we don't have enough donor support to provide

1345
01:58:33,920 --> 01:58:37,680
R21 and RTS,S or the countries that 
would like it, that would need it,

1346
01:58:37,680 --> 01:58:45,760
and are requesting from Gavi. So if we had more 
support coming from the different donor countries.

1347
01:58:45,760 --> 01:58:49,520
The UK's cutting back, US cutting 
back, Japan's cutting back.

1348
01:58:49,520 --> 01:58:56,720
Germany as well. What I read from a report, 
talking about the situation at the time,

1349
01:58:56,720 --> 01:59:02,080
two years ago, was back then, both of 
the vaccines had been pre-qualified

1350
01:59:02,080 --> 01:59:10,000
from by the World Health Organization 
and they were being rolled out and they

1351
01:59:10,000 --> 01:59:17,760
estimated that it would take another 
12 years after that for all children

1352
01:59:17,760 --> 01:59:23,200
under three in the countries with high 
malaria prevalence to be vaccinated.

1353
01:59:23,200 --> 01:59:31,280
And another 2.5 million children were expected to 
die being unvaccinated from malaria, and the main

1354
01:59:31,280 --> 01:59:38,720
constraints to increasing the number of children 
who were vaccinated fast was a lack of funding.

1355
01:59:38,720 --> 01:59:44,240
And I remember reading this and finding 
it surprising in one sense that this was

1356
01:59:44,240 --> 01:59:49,680
the only constraint. But also, I think, 
after everything that we talked about,

1357
01:59:49,680 --> 01:59:56,880
thinking that it was actually not that surprising 
and just very depressing. But the fact that if you

1358
01:59:56,880 --> 02:00:04,800
had a few more billion dollars of funding 
for Gavi, which supports vaccination in

1359
02:00:04,800 --> 02:00:11,280
countries around the world, you could vaccinate 
enough children to save another 300,000 lives.

1360
02:00:11,280 --> 02:00:16,240
The other thing that was interesting to 
me about this was that one of the reasons

1361
02:00:16,240 --> 02:00:21,360
that there was this funding constraint 
was that one of the countries with the

1362
02:00:21,360 --> 02:00:30,400
highest burdens of malaria was Nigeria. And 
Nigeria had just increased its GDP enough

1363
02:00:30,400 --> 02:00:36,400
to be placed in a higher threshold, of a 
higher income country, according to Gavi,

1364
02:00:36,400 --> 02:00:44,400
and that meant that they were no longer eligible 
for financial support to purchase these vaccines,

1365
02:00:44,400 --> 02:00:48,880
and that meant that a lot of children would 
go unvaccinated, and that the cost was just

1366
02:00:48,880 --> 02:01:02,640
so much higher after just passing this threshold. 
It seemed very bad to me that that was the case.

1367
02:01:02,640 --> 02:01:07,200
But there is some good news, which is 
that there was another deal where the

1368
02:01:07,200 --> 02:01:14,720
price of R21 was reduced from $4 to $3 per dose,

1369
02:01:14,720 --> 02:01:21,760
and that would save around $90 million and 
help vaccinate another 7 million children.

1370
02:01:21,760 --> 02:01:27,200
So all in all, what do you each wish 
that donors and funders and other

1371
02:01:27,200 --> 02:01:32,560
decision makers understood about vaccine 
development that they're getting wrong?

1372
02:01:32,560 --> 02:01:40,320
I mean, I think it's one of these situations where 
actually throwing money at the problem would make

1373
02:01:40,320 --> 02:01:48,640
a difference. And that is something that people 
might find surprising in other fields, but here,

1374
02:01:48,640 --> 02:01:53,680
funding Gavi would actually go a pretty long 
way. Or funding the other types of malaria

1375
02:01:53,680 --> 02:01:58,800
vaccine research would go a long way. I 
think that's quite surprising to people.

1376
02:01:58,800 --> 02:02:06,320
I think we should really be learning from 
our experience with RTS,S and R21. And the

1377
02:02:06,320 --> 02:02:12,080
biggest problem, with both those vaccines, is 
getting all of the doses into the children,

1378
02:02:12,080 --> 02:02:17,600
that they need. So thinking more carefully about 
how you develop a product that's deliverable,

1379
02:02:17,600 --> 02:02:24,240
earlier on in development, could have 
such a dramatic impact on the impact the

1380
02:02:24,240 --> 02:02:31,920
vaccine can actually have. And I don't 
think the researchers doing the work,

1381
02:02:31,920 --> 02:02:37,920
the ones running the very first trials in 
humans, are thinking about that enough.

1382
02:02:37,920 --> 02:02:45,120
Right? It's less pizzaz-y, but actually 
testing different delivery schedules in

1383
02:02:45,120 --> 02:02:48,240
the clinical trials can have these incredible

1384
02:02:48,240 --> 02:02:52,640
downstream effects of what gets 
recommended for millions of kids.

1385
02:02:53,280 --> 02:02:57,120
And maybe it's not fair to put that all on 
the researchers and the developers actually, I

1386
02:02:57,120 --> 02:03:02,080
think. They're asking for funding to do the work. 
Funding's tight and limited, funders will give you

1387
02:03:02,080 --> 02:03:08,480
the bare minimum, to do the bare minimum. So you 
can only test one schedule, and so you have to go

1388
02:03:08,480 --> 02:03:13,360
with what you have the data on already, or what 
already looks promising instead of exploring what

1389
02:03:13,360 --> 02:03:21,200
the other options could be. To me, that's also 
on the funders to really understand that as well.

1390
02:03:21,200 --> 02:03:27,200
I think another thing is - that people 
may not know is just how important it is

1391
02:03:27,200 --> 02:03:33,680
to have clinical trial infrastructure, to have 
better ways of running trials more efficiently,

1392
02:03:33,680 --> 02:03:39,840
but also just more sites, more people doing 
these tests, being able to test multiple

1393
02:03:39,840 --> 02:03:44,000
vaccines and not having the situation 
where people have to prioritize funding

1394
02:03:44,000 --> 02:03:49,040
for one vaccine over the other, at the 
expense of testing the others as well.

1395
02:03:49,680 --> 02:03:54,320
But I think there's also another part to 
the story as well in that, with malaria,

1396
02:03:54,320 --> 02:04:00,160
everybody knows about malaria. The burden's really 
well known. So as soon as a malaria vaccine was

1397
02:04:00,160 --> 02:04:05,120
developed, countries were asking for it. They 
knew they had a problem, they wanted the vaccine

1398
02:04:05,120 --> 02:04:09,920
and they're pushing to roll it out to protect 
people, so those vaccines can have an impact.

1399
02:04:09,920 --> 02:04:13,040
But there are other vaccines that we've 
tried to develop in the past where we

1400
02:04:13,040 --> 02:04:17,280
didn't have good data on the burden in all 
the countries that possibly needed it. And so

1401
02:04:17,280 --> 02:04:21,760
I think the Hib vaccine was a good example. 
It was developed, it was ready to be used,

1402
02:04:21,760 --> 02:04:26,080
but countries didn't know they had a problem. 
So it was this huge delay in rollout. There's

1403
02:04:26,080 --> 02:04:29,280
so much more that needs to be done when 
you're thinking about developing a vaccine,

1404
02:04:29,280 --> 02:04:33,840
beyond just developing the product, 
thinking about how it's gonna reach people,

1405
02:04:33,840 --> 02:04:43,040
and how people are gonna understand whether 
they need the vaccine, what the demand is.

1406
02:04:43,040 --> 02:04:49,280
That was quite an episode. That is our first 
episode where we had a expert interviewee with

1407
02:04:49,280 --> 02:04:55,360
us the entire time. Thank you so much, Katharine. 
And now it's time to conclude with what some

1408
02:04:55,360 --> 02:05:00,640
of the things, what are some of the things we 
learned or that stuck out to us from this episode?

1409
02:05:00,640 --> 02:05:06,800
And I'm gonna start. Number one, how much 
you can learn from patents. It turns out

1410
02:05:06,800 --> 02:05:10,560
that there are people who read them and then 
they tweak them, and then they change them,

1411
02:05:10,560 --> 02:05:18,000
and then they make new inventions. I mean, that 
really gave me hope for public knowledge again.

1412
02:05:18,000 --> 02:05:20,800
That was really cool to hear about.

1413
02:05:20,800 --> 02:05:23,600
Saloni, what did you, what stuck with you?

1414
02:05:23,600 --> 02:05:29,120
So I had a bunch of thoughts. The first 
one, which I was thinking about before

1415
02:05:29,120 --> 02:05:34,480
we started recording was that, and 
this is a very unpopular opinion,

1416
02:05:34,480 --> 02:05:40,400
but some PhDs are just better than others 
and some fields are better than others too.

1417
02:05:41,440 --> 02:05:46,560
I know it's controversial, but I think more 
students should go into infectious diseases,

1418
02:05:46,560 --> 02:05:52,960
and should go into vaccine development. 
And I have many thoughts about which fields

1419
02:05:52,960 --> 02:06:02,640
should move into those, but I won't name them 
- they'll probably, they'll know who they are.

1420
02:06:02,640 --> 02:06:07,760
The other was that I thought it was really 
interesting to hear about the Jenner Institute,

1421
02:06:07,760 --> 02:06:14,160
and how it was set up in such a way that there 
was a manufacturing facility that researchers

1422
02:06:14,160 --> 02:06:20,480
could work with, and they could learn from 
that stage of the process in manufacturing.

1423
02:06:20,480 --> 02:06:26,640
And I thought maybe more institutes should 
be set up like this, where you can see the

1424
02:06:26,640 --> 02:06:32,480
both the basic research and the translation and 
the manufacturing happening in the same place,

1425
02:06:32,480 --> 02:06:38,960
and learn from these different stages. That I 
thought was a really cool thing to learn about.

1426
02:06:38,960 --> 02:06:44,880
The other that stuck with me throughout this 
episode was that malaria is very complicated,

1427
02:06:44,880 --> 02:06:49,360
especially compared to the other pathogens 
that we've talked about in previous episodes.

1428
02:06:49,360 --> 02:06:54,400
It has many different stages of its 
lifecycle, it changes shape. It's harder

1429
02:06:54,400 --> 02:07:00,800
to develop vaccines for malaria than for many 
other diseases. And there were various parts

1430
02:07:00,800 --> 02:07:07,120
of that process that were just very tricky 
to do scientifically. It was hard to find

1431
02:07:07,120 --> 02:07:12,560
good animal models that helped replicate 
what the disease would be like in humans.

1432
02:07:12,560 --> 02:07:21,600
The next was that a lot of the research funding 
for malaria was affected by priorities that

1433
02:07:21,600 --> 02:07:29,120
high income countries had. So in the 1950s 
during the global Malaria eradication program,

1434
02:07:29,120 --> 02:07:35,520
the funding for research dried up and a lot of 
researchers were made program operators in the

1435
02:07:35,520 --> 02:07:44,800
eradication program, and that stalled research 
until the Vietnam War, where the US Army troops

1436
02:07:44,800 --> 02:07:52,720
were facing potentially drug resistant malaria, 
and there was now a renewed need for research

1437
02:07:52,720 --> 02:07:59,520
into new malaria drugs, but also malaria 
vaccines. And that is where the RTS,S vaccine

1438
02:07:59,520 --> 02:08:06,560
originally came from, was research from people 
who were working on that during the Vietnam War.

1439
02:08:06,560 --> 02:08:12,640
So that stood out to me as well, that we sort 
of think of research happening in the lab,

1440
02:08:12,640 --> 02:08:17,680
but it's really actually influenced by 
all of these much broader considerations,

1441
02:08:17,680 --> 02:08:24,320
and the historical context, and things like that, 
that I think people don't appreciate enough.

1442
02:08:24,320 --> 02:08:29,200
So the first one for me is 
probably the cost, scalability,

1443
02:08:29,200 --> 02:08:33,440
and deliverability are actually really 
important. People should think about them

1444
02:08:33,440 --> 02:08:38,880
earlier in the process. I think it's clear 
from the R21 and RTS,S experiences that the

1445
02:08:38,880 --> 02:08:43,440
vaccines could have much greater impact 
if those things were considered earlier.

1446
02:08:43,440 --> 02:08:50,240
I also thought that just within that 
process, it's not just the broader concerns,

1447
02:08:50,240 --> 02:08:56,000
but at every stage of vaccine development, these 
things are really important. Like how you develop

1448
02:08:56,000 --> 02:09:02,000
the adjuvants and how expensive those are, or 
how that affects the efficacy of the vaccines,

1449
02:09:02,000 --> 02:09:08,560
and how accessible they might be later on as well. 
And then things like, how does the dosing of the

1450
02:09:08,560 --> 02:09:17,520
vaccine that's being developed affect how easy 
it is to scale it up, across countries, or across

1451
02:09:17,520 --> 02:09:24,640
millions of children, I think is something that 
people underappreciate. And then similarly, the

1452
02:09:24,640 --> 02:09:30,800
vaccination schedules - the fact that the malaria 
vaccine is taken at different ages than other

1453
02:09:30,800 --> 02:09:37,840
childhood vaccines, and how that affects uptake 
of the vaccines, is something that was new to me.

1454
02:09:37,840 --> 02:09:45,840
And just this idea of making things more efficient 
at all of these stages could be really important.

1455
02:09:45,840 --> 02:09:53,280
I've been reading the book The Origins of 
Efficiency by Brian Potter, and one of the key

1456
02:09:53,280 --> 02:10:00,800
things that stood out to me from that book was 
just how much progress we've made in medicine,

1457
02:10:00,800 --> 02:10:06,480
but also engineering, and all parts of life 
were from improving the efficiency of things

1458
02:10:06,480 --> 02:10:12,720
that people have already discovered, and that 
that stage can often make the difference between

1459
02:10:12,720 --> 02:10:17,600
something that is possible versus something 
that's actually used by millions of people,

1460
02:10:17,600 --> 02:10:21,920
and I think that's actually 
a huge part of the picture.

1461
02:10:21,920 --> 02:10:27,520
The other thing that I have always been 
thinking about is just how different things

1462
02:10:27,520 --> 02:10:31,600
could have been. Like what others, what other 
alternative universe we could have lived in,

1463
02:10:31,600 --> 02:10:37,520
if things were different. And the key 
things that I think about here are:

1464
02:10:37,520 --> 02:10:41,920
one, how things would be different if 
there was more funding. And second,

1465
02:10:41,920 --> 02:10:46,720
how different things would be if there was better 
infrastructure for running clinical trials.

1466
02:10:46,720 --> 02:10:52,800
And we talked about a bunch of examples of how 
that could have been different. So one, that

1467
02:10:52,800 --> 02:10:59,040
probably would've sped up the developments of the 
RTS,S vaccine, the first malaria vaccine. Having

1468
02:10:59,040 --> 02:11:06,320
the clinical trials sites set up earlier, that 
would've made a difference. Having more funding,

1469
02:11:06,320 --> 02:11:11,840
that would've made a difference. But then we also 
talked about other vaccine candidates for malaria,

1470
02:11:11,840 --> 02:11:19,200
and how more funding for that research could 
have changed the picture and sped up the trials

1471
02:11:19,200 --> 02:11:24,160
for those vaccines. And then finally, the 
rollout of the malaria vaccines that have

1472
02:11:24,160 --> 02:11:30,000
already been approved could be sped up with more 
funding. And that funding was the constraint,

1473
02:11:30,000 --> 02:11:34,960
and still is the constraint, to 
getting that out to more children.

1474
02:11:34,960 --> 02:11:40,960
And I think that often people think of 
this as purely a scientific problem,

1475
02:11:40,960 --> 02:11:46,240
but I think that's not the case, and 
that in many situations when we're

1476
02:11:46,240 --> 02:11:51,840
talking about diseases that affect people and 
poor countries, often commercial incentives,

1477
02:11:51,840 --> 02:11:59,200
and funding, and the historical context and all 
of these things actually have a very big impact.

1478
02:11:59,200 --> 02:12:04,160
I think it's really easy to look back and think 
about how things could have been done differently

1479
02:12:04,160 --> 02:12:09,040
with hindsight. But it's really important 
to remember that these were really uncharted

1480
02:12:09,040 --> 02:12:13,840
times for this type of vaccine, and it's really 
quite amazing what was achieved over the time.

1481
02:12:13,840 --> 02:12:19,840
Obviously, we all wish things could have been done 
faster and can keep going faster in the future,

1482
02:12:19,840 --> 02:12:26,000
but it is quite remarkable what was achieved. But 
I think it's important that we do look back. I

1483
02:12:26,000 --> 02:12:31,440
think we should all be looking at the experiences 
of the past and learning from them so we can

1484
02:12:31,440 --> 02:12:35,760
improve what we're doing as we're developing 
future vaccines; learn from those mistakes.

1485
02:12:36,720 --> 02:12:40,640
And you know, now as a funder, I'm trying 
to take a lot of those lessons and those

1486
02:12:40,640 --> 02:12:45,665
experiences and apply them to the development of 
next gen malaria vaccines and Strep A (Group A

1487
02:12:45,665 --> 02:12:50,560
Streptococcus) vaccines and any other products 
we end up working on at Coefficient Giving.

1488
02:12:50,560 --> 02:12:57,360
What you just mentioned, made me realize that the 
alternative universe that we could have lived in:

1489
02:12:57,360 --> 02:13:02,800
it could have been faster, but it also could have 
been slower, and I hadn't thought about that.

1490
02:13:02,800 --> 02:13:10,000
I think my main takeaway from looking 
backwards into the past today is about

1491
02:13:10,000 --> 02:13:14,800
the present and about the future. 
And it's that we live at a time of

1492
02:13:14,800 --> 02:13:23,680
scientific wonder. We - people who invented 
world-changing technology are among us today.

1493
02:13:23,680 --> 02:13:30,320
Invention is often a process of building on other 
people's work, tinkering, tinkering in the lab,

1494
02:13:30,320 --> 02:13:36,400
and taking care of those lab notebooks, looking 
in an electron microscope, trying an experiment,

1495
02:13:36,400 --> 02:13:41,760
changing what you started with, trying another 
experiment. And these people are heroes.

1496
02:13:41,760 --> 02:13:46,880
They're real people. Sometimes you can 
even get them to come on your podcast,

1497
02:13:46,880 --> 02:13:53,760
thank you very much, Katharine. And to anyone 
listening, you may know one of these people,

1498
02:13:53,760 --> 02:13:59,680
and society may not recognize it yet, and they're 
still inventing and they're still trying stuff.

1499
02:13:59,680 --> 02:14:05,760
You may become one of these people in the 
future. And when it comes to science, we are

1500
02:14:05,760 --> 02:14:11,360
all in this together. We're trying to figure 
out what is true and what we should do next.

1501
02:14:11,360 --> 02:14:15,760
So I just wanna end by saying, 
Katharine, thank you very much.

1502
02:14:15,760 --> 02:14:22,800
This was very enjoyable and I'm very 
excited about everything that comes next.

1503
02:14:22,800 --> 02:14:25,920
Thank you. It's been great 
to be here. Great to chat.

1504
02:14:25,920 --> 02:14:31,920
If you enjoyed this episode, you should rate us 
on Spotify or Apple or wherever you listen to this

1505
02:14:31,920 --> 02:14:39,520
and share it with everyone you know, including any 
parasites that you are currently infected with.

1506
02:14:39,520 --> 02:14:44,160
Maybe they are heroes too, you never know, 
they could contribute in their own way.

1507
02:14:44,720 --> 02:14:50,560
Please share this one in particular with 
anyone who's considering starting a PhD.

1508
02:14:50,560 --> 02:14:53,520
Yes!

1509
02:14:53,520 --> 02:14:56,240
Great. See you next time everyone!

1510
02:14:56,240 --> 02:14:57,440
Bye!

1511
02:14:57,440 --> 02:14:58,400
Bye!

1512
02:14:58,400 --> 02:15:03,680
Bye!