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Works in Progress is an online magazine devoted to new and underrated ideas about economic growth, scientific progress, and technology. Subscribe to listen to the Works in Progress podcast, plus Hard Drugs by Saloni Dattani and Jacob Trefethen.
I read that if just a single
parasite makes it to the liver,
it can cause an infection. Is that true?
Yeah, that's right. And I think that's
the really tough challenge with Malaria.
The reality of this problem is the
hardness of it is set by nature,
and nature is a vicious test setter.
Adrian asked if I wanted to stay on, this
was the PhD project that he pitched to me.
I thought it sounded quite interesting to make
a new vaccine. There was a lot of iteration.
The first time I saw the particles under
electron microscope that was really exciting.
Would you participate in the challenge trial?
I would love to, but I really
hate needles. I have to lie down.
Otherwise I might faint. It's kind
of ironic for a vaccine developer.
There are people like Katharine
Collins who invent entirely new
vaccines that are now gonna be used
by millions of children. You may know
one of these people. You may become
one of these people in the future.
Malaria kills around 600,000 people a
year. Most of them are young children
in Sub-Saharan Africa. It's caused by
a parasite, not a bacterium or virus,
and it's spread by a mosquito. Until recently,
the only control measures were insecticides and a
handful of anti-malarial drugs. But in the last
few years, we finally got effective vaccines.
Two malaria vaccines have now received WHO
recommendations and are being rolled out
across Africa. And for the first time ever,
a human-infecting parasite has a vaccine.
Getting here took longer than it
should have. The first malaria
vaccine was developed and tested in the nineties,
but it's spent 23 years in clinical trials and
pilot tests before it was licensed and rolled out.
So in this episode, we're going to cover
the science of why malaria is so hard to
vaccinate against, how the vaccines
actually work, why it took so long,
what we can do to speed up the rollout
now, and what even better vaccines
are being tested now for fewer doses
and longer durability in the future.
Today's episode is special because
we're joined by Katharine Collins,
who co-invented the second malaria vaccine during
her PhD, and she can tell us what it was actually
like from the inside. Welcome to Hard Drugs,
hosted by me, Saloni Dattani, and Jacob Trefethen.
Okay, so we have some news
today, right? Because Jacob,
you have started a new job. Could you
tell us about what you're doing now?
I'm gainfully employed. I'm working at a new
foundation making grants to science still,
but from a different vantage point. It's the
OpenAI Foundation and we have been getting
started in science, so it's kind of exciting,
a little bit different than my previous job
which was at Coefficient Giving. And the
previous job was quite fun. But you'll have
to ask around what my reputation was there, for
example, Katharine, what was I like back then?
Jacob, you were the best manager I've ever had.
No no, we can't include that! No, no.
Expulsion! No, my biggest difficulty
of changing jobs is that I don't get to
work with some of the wonderful people
I worked back at Coefficient Giving with, like
Chris Somerville, Ray Kennedy, Heather Youngs,
Rafael Dib, Douglas Chukwu. Oh gosh. So
many people, Aisling Leow. And guess who?
Katharine Collins. Now the good news is
that Katharine at least is here today.
So Katharine is joining us from
Coefficient Giving as well, and is a
very special guest on today's episode because
she co-invented the second malaria vaccine.
Now we are lucky at Hard Drugs to have listeners
around the world, and that means I'm going to
start here with some insight into the British
psyche. For those listening from other places,
we have a guest on today who is an inventor and
she's also British. That means that she's very
reticent to take credit for things, even things
she invented, so it took a lot of cajoling to get
her onto this episode, though we knew if we could
pull it off that our listeners would love it.
So I am very grateful for the willingness of our
guests to be cajoled, but I should say upfront,
as part of our ability to pull it off,
that there are many other people involved
in the story of malaria vaccines and of R21 in
particular, who we won't get to have on today,
who took forward the vaccine into clinical
trials, who did all the work to make sure
it could get approved and used by kids
around the world. So that's my proviso,
that's the trade we had to make with our world
famous inventor. With that in mind, enjoy.
So I have a question for both of you,
which is, do you have a favorite parasite?
What I didn't realize until recently
was that fungi and plants can also
be parasites. And so a parasite
could be a single celled organism.
It could be an animal like a mosquito,
vampire bats, hookworms. Or it could
be fungi like the ringworm fungi. Or it could
even be a plant, like mistletoe is a parasite.
What?!
Yeah, mistletoe is a parasite.
It attaches to other trees and
extracts water and nutrients from them.
Gosh. And here I was. Okay. I think I have two
answers. You brought up hookworm. Hookworm's
one of my answers, tape worm's another one of
my answers. I mean, tape tapeworms disgusting,
obviously, but you just have to
be impressed. They get so large.
How large do they get?
Like, I don't know, probably miles long. Joking.
Wow.
They get feet long for sure. And maybe meters. I
mean, I just think that's crazy. It's obviously
gross, but luckily hookworms aren't gross
at all. All they do is hook onto the side
of your gut and suck your blood. They come
up, they sort of get up through your foot,
sneak - their whole life cycle's insane
- they eventually get down into your gut
and hook onto it and start sucking your
blood. I mean, that's pretty impressive.
Is that why they're called hookworms?
Because they hook onto your gut?
You know, I've never thought of that. And
the answer is probably yes, but I don't know.
And then are tape worms called
that because they look like tape?
No, it's actually 'cause on
the underside, they are sticky.
Oh, wow.
That's a joke. Sorry. That's
a joke. That's a joke.
Oh, you tricked me!
First trick of the episode!
Okay. My favorite parasite also, well, I'm
not impressed by this, I'm just so horrified
by it that I have decided it's also my favorite.
And it's Guinea worm, which is so horrible. And
people ingest the worm larvae when they drink
contaminated water. And the larvae get into
your stomach, they get through your gut, and
then they grow into worms that can reach up to
a meter long. And they kind of crawl through your
connective tissue and your joints, and then slowly
erupt out of your legs - usually out of the skin,
near your legs. And the emergence is also very
slow. And the way that you remove the worm is
by slowly winding the worm around a small stick,
and if you go too fast, the worm snaps and dies,
and that causes severe inflammation in your body.
That sounds like it was invented
by Jigsaw from the series Saw as
a patient to someone who was impatient or
something. Okay, well thank you for that.
Wait, wait, wait. The good news is
though, we've almost eradicated it.
Isn't that great? So it used to cause like a
million or more cases per year in the 1980s,
and it turns out just cleaning up
the water, filtering drinking water,
or telling people not to drink from
stagnant water can help prevent infections.
Do you know how near eradication we are?
I think there were 10 cases
reported in total last year.
Wow!
Wow. That's incredible.
Yeah, so from millions per year
to 10. What about you Katharine?
Yeah, mine's really boring. Mine's the malaria
parasite. I can't say anything else
after studying it for two decades.
Yeah, it would be really surprising
if you said something else.
Yeah, it would kind of be
like adultery or something.
In this episode we're going to talk a lot about
the two malaria vaccines that have been rolled
out. The first one is called RTS,S and it was
developed in the 1990s. The second was R21,
it was invented by Katharine Collins, who's
here with us today, and it was based on the
first one. So those are two names that we're
gonna refer to throughout the episode. RTS,S,
the first malaria vaccine and
R21, the second malaria vaccine.
I guess it's easy to remember because
the second one has two in it, R21,
but just in case that is confusing; those are
the two names that you've gotta remember. RTS,S,
the first malaria vaccine and R21, the second.
Maybe let's start with how you got into
malaria research in the first place.
What drew you into the field? Or how
did you get into vaccine research?
I had done my undergraduate and my master's
degree in basic research and not in global
health. I did various projects in different
disease areas, but it was really about trying
to understand the fundamentals and different
signaling pathways and things like that. So I
think one of my projects identified a protein
interacted with another protein in a pathway.
And while that was cool, and I loved science
and it's definitely where I'm supposed to be,
but it I didn't see how that was gonna have
any direct impact on health in the near term.
I actually started looking for jobs, or how
I could have an impact in global health,
or how I could transition from science into global
health work, and it wasn't really clear. And then
this job was advertised at Oxford University to
work on malaria vaccine trials. And I thought,
wow, that's global health. I should just take
that job, and or apply for that job, and that
may open doors. And so I did. And I really loved
working on malaria. It was instantly something I
was really passionate about, really motivated
to work on. It's just a fascinating parasite.
So the job was a research assistant
on malaria vaccine trials. So the
Jenner institute at Oxford, where
Adrian Hill's group that I joined,
they were testing a number of different
candidates in malaria trials. And my job
was to help coordinate those trials and to
do all the immunology in the background.
And then how did that turn
into inventing a new vaccine?
Yes. Well, after being there for about a
year, Adrian asked if I wanted to stay on,
and do a PhD. The project idea was that
Adrian had developed a vaccine that targeted
the malaria parasites, whilst they were in
the liver. It'd been shown to protect some
people against infection, but it was quite
a low level, I think it was 20% efficacy. So
the idea was to combine this liver stage
vaccine for the vaccine that could also
prevent the malaria parasites before they get
to the liver. So stop them invading the liver.
And the leading vaccine at that time targeted
the parasites before they invaded the liver,
and this was a circumsporozoite based vaccine
called RTS,S, and it was developed by GSK.
So he wanted me to work on making a newer
version, an updated version of that vaccine.
That's so cool. I feel like compared to - so
my PhD was very boring in comparison to this,
and it makes me think that there's actually -
Wait, Saloni, did you not
invent a vaccine in your PhD?
I know, I feel like people should know upfront
that some PhDs are better than others. You know,
some fields are better than others. So
who else was involved in this? Did you
have mentors, collaborators, rivals, or enemies?
I worked fairly alone in the lab. I did have
a few people that were supporting the work as
well. So my PhD supervisors were Adrian Hill
and Sarah Gilbert. There were also a couple
of postdocs and technicians and PhD students that
helped me with various parts of the project over
the years. For example, someone actually
helped me vaccinate all the mice that we
used for the preclinical experiments.
And then I did the immunology myself.
And Sarah Gilbert is the inventor of
the AstraZeneca vaccine, is that right?
That's right. Yeah.
For COVID. Got it.
Yeah.
And rivals?
Rivals, well, oh, you're asking the good
questions. I guess in the field at the time,
there were lots of people trying to
develop a malaria vaccine. I guess
there was competition between the different
groups to see who would get there first.
And whilst I was working on it,
RTS,S hadn't crossed the finish line,
but it was obviously way, way, way further
ahead in development. So the expectation
was that that vaccine would move forward and
get approved first, and then R21 may follow.
Right. And by that point, had
the RTS,S patent already expired?
Yes, actually that's right.
So if I remember correctly,
it was due to come off patent. And
interestingly, that was essentially
the starting place for learning how to
make R21. So I reviewed that patent,
I looked at how they've made RTS,S, and then
I made a plan for how to go about making R21.
Did that have enough information
for like? What was that like?
So RTS,S is actually made with a lot of a
protein on the surface of the Hep B virus.
This is the Hep B surface antigen and that was
needed to make it form the virus like particle,
but it had quite an excess of Hep B
surface antigen. So it's actually a
really good Hep B vaccine, and not a terribly
good malaria vaccine. So my project was to see
if we could remove some of that Hep B and
actually make it a better malaria vaccine.
And we had established a plan for how we're
going to get there. So initially we wanted
to just replicate the RTS,S process in the lab and
then try a few different things to see if we could
get the particle to form without this excess Hep
B surface antigen. One approach was actually to
just try and chop out some of the malaria protein
out of the vaccine and remove some of the T-cell
epitopes, which were in there, and a few other
bits as well, and see if the smaller protein would
be more able to form particles on its own. The
other way was just to try and reduce the amount
of extra Hep B that we were adding and see if it
could form particles on its own that way, by using
some of these newer yeast expression technologies
to grow the protein and new methods to purify.
I think RTS,S had something like a 12 step
purification process at least in the patent, and
that might not be what they used anymore. But I
wasn't really interested in trying to set up this
12 step new process in an academic lab. You know,
I'm not a biochemist. So I essentially looked at
their process to understand what they had done
and why, and then developed a purification
process using a combination of some of those
old methods and some of the newer technologies.
I feel like my immediate question is why
didn't the developers of the RTS,S vaccine
do that? Like if there were various
steps that didn't need to be included.
Yeah, I mean, they probably did. I mean, when
they first patented what they were doing,
it probably had this multi-step process.
Maybe they had different process they were
using lots of different methods, so
they patented the whole process and
I'm sure they probably optimized that as they
scaled up and improved their manufacturing.
I wanna just get a more of a sense of what it
feels like to be in the lab alone, toying with
different steps of purification, and how long were
you - did you feel sort of lost versus actually,
it worked pretty quickly and you got, once you
saw in the electron microscope, you're like,
oh God, it's actually gonna work. Was that
pretty quick or you were there for months,
years? You're tinkering. What did
the invention process feel like?
Actually, I think I was interviewed
by someone a while ago and I,
my recollection is that it was very quick
that I kind of give it a go and it worked.
Wow.
And then I thought, now I thought, is this true?
And I went back to my lab notebooks and I had a
look through like the electronic notebooks and I
had a look through and it wasn't that quick. There
was a lot of iteration, a lot of optimization
that happened with every single stage.
So we were using yeast to express
the protein and grow the protein,
and there were four different strains we were
testing, and then for each different strain, we
picked multiple different colonies, and I screened
all of these different colonies first to find the
best expressing colonies, and then I started to
try and purify it, to purify them. And I probably
used multiple different techniques until I got
something that looked substantial. So it wasn't
that quick. So I think it was a long time ago
now, so my memory's a bit optimistic maybe?
So am I imagining right that it's like, you
have the instructions-ish from the patent
and then you're trying out different options,
like different versions of the yeast, different
versions of the purification process, and at
each step trying to optimize which is the best
one to go forward with or something like that?
Or is that not the right way to think about it?
Yeah, that's just about right. There are a lot
of newer technologies available for purifying
proteins and particles, so it's kind of a
process of looking at which steps could be
replaced by newer technologies and going for
something that was more modern and simpler,
where that was possible, and where
there wasn't a newer technology,
we were sticking with that whole process as well.
So you were at the Jenner
Institute, is that right?
That's right.
Do they have just people working on
many different diseases and like trying
to develop vaccines against all of them, or
are there some areas that they focus on? Or,
are lots of people doing this during their PhD?
I think developing a vaccine was rare, fairly
novel at the time, or quite rare. So not a huge
number of people were doing it. There were
three PhDs I can remember that developed
a vaccine during their PhD and I was one of
them, but there may have been others as well.
But in terms of the structure at the Jenner
Institute, there were different group leaders,
or PIs, that have their focus area, and
the Jenner Institute was generally open
to having new people join the institute. And
if there was space, they did actually join
the physical lab space as well. So we had work
going on on multiple diseases at the same time.
Okay. So you're, you're tinkering,
you're tinkering, you're tinkering,
you look under the electron microscope
and then you test something in mice and it
protects them from malaria. Did it feel like
a eureka moment at any points of that step,
or was it just iteration? Iteration, feels
good, feels a bit better, feels a bit better?
No, definitely a few eureka moments. I mean,
the first time I saw the particles under the
electron microscope, that was really exciting,
especially when I had used the process that we
didn't think that was possible. So by removing
all the excess Hep B, that was really cool when
we could see those, and they looked very similar
to the Hep B particles. So it was it was really
reassuring that we were doing something right.
Then the next push was to move
that into a preclinical study,
to inject mice and see if we get an immune
response, and then if we can protect the
mice as well. And whilst I was optimizing the
process, the yield was really, really low of
the particles. And I tried to concentrate it
and it wasn't easy to concentrate. So we ended
up injecting an incredibly low dose into the
mice and it was like, well, we might as well,
we have the product, let's just see what it
does. And then it protected all the mice.
And so that was really exciting. We had
gone for this dose that was dramatically
lower than any other dose we normally test
in the lab. And the vaccine I think 10 times
lower than any other dose that had showed
for RTS,S being tested in mice and that it
worked. So that was really exciting. That was
the one of the really exciting moments. Yeah.
That's super cool because
if you have a lower dose,
you can vaccinate more people
with the same amount, right?
Yeah, exactly. And a tenfold lower dose, that's
huge. That's not half the doubling the number
of people. That's a dramatic increase. But
actually at the time there wasn't a lot of
information on how well dose in mice would
translate to humans and if it would actually
result in a lower dose human vaccine. We did
later find out that it was easier to scale up.
So, interesting how the practical constraints -
let's say it had been effective but you would've
needed five times more product. Is it possible
you would've just dropped this lead and focused
on something else 'cause you couldn't
make enough, or what would've happened?
No, I was really early on in the purification
process, in optimizing that. So it was just that,
it was just of luck. But we had
gone in with such a low dose to
begin with. Maybe we would never have
got to the low dose, that lower dose,
if we haven't had that constraint
on the concentration of the product.
Okay. So all of this is happening in your
PhD, was that 2010 to 2014? Is that right?
Yeah, well remembered!
So we now know, with the benefit of
hindsight, that R21 works in kids,
in humans, and it protects babies against
malaria. And that took time to prove out
any clinical trials, and there was
- to give a spoiler to the audience,
the R21 vaccine was actually approved
a couple years ago for wide use.
Along that journey, you finished your
PhD and you started doing other malaria
research elsewhere. Did you, when you finished
your PhD in 2014, did you have a feeling that,
oh, I just invented a vaccine that's gonna
get used by millions of people? Or did it
feel more like, okay, I've proven out that
this might work and I'm gonna pass it on,
but it's, we'll see. Yeah. What did it feel like?
I think most people in the field were quite
skeptical about R21 in the early days. They
couldn't really see the point in making
a vaccine that was so similar to RTS,S.
And the initial results, kind of backed
that up, that there was reasons for that
skepticism. It didn't look very different in
the preclinical work, in the mice studies,
there wasn't a really strong reason to
think that this was gonna save a lot
of lives, when there was already
a vaccine that was very similar.
But the dosing was very different, right?
It was, and I think this is a lesson for
vaccine developers, right? At the time,
everybody was quite negative about R21. But if you
think about things like being able to reduce dose,
making it simpler and easier to manufacture,
even small increases in immunogenicity,
if you add all of those benefits together,
you end up with a product that's easier to
deploy, a lot cheaper, and maybe easier to
manufacture. So it can really have an impact,
without just making a dramatically
better vaccine in terms of efficacy.
It's sort of scary though, 'cause I think I, as
a outsider who has never developed a vaccine,
if I had seen the results from preclinical
tests in animals and the results said, well,
we can't distinguish that this is better from
RTS,S, I probably would've killed it. And yet
now we know that it is much cheaper to produce
and it's more manufacturable and it's longer
durability. I mean, so it's sort of terrifying.
What was in the system that allowed this one to
actually go forward and now it's reaching people.
You know, is it as contingent as it sounds to me?
Yeah. You know, I think this was - all the credit
goes to Adrian Hill for pushing it forward and
really finding out what it could do in people,
right? I think so many people would've dropped
the vaccine at this point. And another difference
that we haven't mentioned so far is that R21 also
used a more scalable adjuvant, and I think that's
quite important for the supply argument as well.
An adjuvant is another ingredient in the
vaccine that strengthens its immune response?
Yeah. Yeah, absolutely.
Alright, and so these were
different between the two vaccines,
and the R21 adjuvant was cheaper
to produce and easier to scale up.
Yes, absolutely. Yeah. The adjuvant used
with the, with RTS,S is a GSK adjuvant. It's
also used in another product, and yeah, much more
difficult to scale, and much more limited supply.
I remember reading that it comes
from - that adjuvant comes from the
tree bark of a South American tree. Is that right?
Yeah. And that comes from the bark of
a Chilean - I can never get the name,
pronounce the name right, is a Quillaja
tree (Quillaja saponaria, soapbark).
Does that mean that you have to get that tree to
get the adjuvant? Is that why it's difficult to
scale up? And how come the second one is easier
to scale up if they're both from these trees?
So the supply limitation is the availability
of the trees, the raw material, and also the
purification process. So if you imagine you're
purifying all these products from the bark of
the tree, or from the tree, and if you purify and
throw away a lot - a lot of it away, it's gonna
be more expensive and harder to scale. They've
improved the ways they're producing the trees,
so supply is increasing and it's gonna
be less of a limitation moving forward.
And people are also working on
synthetic versions and special,
not sure the right word, aquaculture style
(hydroponics) growing of these, of these trees
and different methods of harvesting
from them to get the components.
Is it like someone shaving parts of
a tree off and then doing some other,
like, how does this all work?
I've never seen anybody do it that, and that's
kind of how I imagined it, taking the bark off.
But other thing I should mention is you have
to like harvest most of the tree or you have
to kill the tree and that was the problem, and
so I think they've changed the way that they
actually harvest from the tree so they can
keep growing as well in some instances. So
you don't just have to - it takes 25 years
to get the tree and then you cut it down.
So you're looking at your lab notes, Katharine?
Yeah, it's fascinating. I'm glad I kept
really good notes. It's really interesting.
Are they dated?
Yeah.
What date are you looking at?
Um, troubleshooting the purification
process, 23rd of the third, 2011.
Whoa.
Wow. What were we doing in 2011?
Yeah, 23rd of the third.
I was in school.
I was inventing vaccines, actually, Saloni.
You didn't tell me that.
Yeah, I try to keep it private.
So what happened on that day?
I tested a few different methods and then
the result: aggregation seen in sample.
Okay. Bad.
Second purification attempt: reduce aggregation.
I love it.
Do you have any, um... random comments in there?
Do people put in computerized doodles? Emoticons?
No. Definitely not, emojis
didn't exist then, Saloni!
No, but emoticons did.
LOL.
XD
Aggregated again, LOL. Wait,
so how many experiments are you doing? Is
this like every day you have new entries?
Yeah, yeah, yeah.
Wow.
No, every couple of days. So I guess
I'm gonna test this and then it
takes a few days to test and then...
results: aggregation seen in sample.
ROFL. Are there images of the RTS,S or R21 under
the microscope? Should we- we should include one.
Well if you are up for it - us including
some screenshots might be kind of fun for
viewers. Oh my gosh, no. Sorry. We have
thank goodness. We have to include this.
Wow.
This is so cool. Whoa. Okay, great.
Wow. They're so cute.
Okay, listeners, so we are looking at
two images here. On the left it looks
like spots on someone's skin, maybe measles.
So talk us through the left here. Katharine,
what are we looking at?
Those beautiful circles. Wow.
So those, that's a transmission electron
micrograph of negatively stained R21 particles.
Oh my gosh, that's so clear. They're
so clean. They're so circular.
They're so blobby.
I mean, just to restate some of, and
correct me if this is wrong, Katharine,
but part of the reason why having these circles
that look like viruses is so useful is that
our immune system is really good at attacking
circular viruses. So is that a fair statement?
Uh, yeah. So they're easier to
recognize by the immune response,
definitely. That's part of the
theory behind virus type particles.
What reading this has just really made me realize
how much I was reinventing the wheel. Like if this
was anybody else making it, or company making
it, you'd have had an expert in purification
diving into this that would've been able
to, I had to do all the research myself.
Oh my gosh. Wow.
Yeah. And figuring it out.
That's so cool!
Yeah, that's even cooler.
You know I did have support. There were other
people in the lab that I'd go to for advice,
and I talked to Sarah and Adrian, but
I was often figuring it out by myself,
or at least that's how I remember it.
It's astonishing because I tend to, sometimes
I feel myself getting skeptical about patents
in particular, where the trade that
society is making with inventors is
that if you publish in public how you
did something, then we will give you
exclusivity for 20 years to do whatever
what you want. Sometimes I'm like, well,
hold on. How much are you actually gonna be able
to learn from reading that? They're probably
gonna hide whatever they can and to get away
with it. And what, how can you learn something
from reading? You need to see someone do it, but
you're telling me you literally read the patents
and then you just kept plugging away until
you've simplified and fixed all of the stuff.
I mean, that's awesome. That's
a one person show. And I'm like,
wow. So knowledge in public
is a extremely big deal.
Yeah. I think I managed to get it to the
point that we could make it ensure that
it works. And then there was a huge amount of
work that happened by others to turn it into a
GMP grade process. And even then that was a
simplified or a shortcut version to get to a
GMP product that was done by the clinical
biomanufacturing facility in Oxford. They
did an enormous amount of work to produce the
first batch and then Serum got involved and
they used all of their knowledge and knowhow
to probably dramatically change the process.
So I wanna pause on that actually, 'cause it's my
day job is I'm a funder and then now your day job
is, you're a funder, Katharine. And one thing
that comes out from this story that's really
interesting is that a lot of universities where a
lot of knowledge is generated and science is done,
do not have facilities to produce the vaccines
that you could take into humans safely,
whereas Oxford does. Is that a fair
statement? And do you think that
that allows for a knowledge generation
loop, which is unusually productive?
Yeah, absolutely. I think that's definitely one
of the big advantages of being in the Jenner
Institute. Adrian had set up this clinical
biomanufacturing facility and that meant
he could really quickly iterate, he could design
something in the lab with a student designing it,
and then transfer it to the manufacturing
facility and quickly produce a small batch.
Does that mean we should have more
Jenner Institutes doing other - can
you scale that to work on more diseases
or is it just really hard to do that?
No, no, I think that's the way
- people should be learning from
that model. I think it's not cheap
to maintain a facility like that.
I have another question, which
is, why is it called R21?
Uh...
Is that a very complicated story?
Um.. I can't remember.
What?!
Wow!
Adrian came up with a name and I think
I remember asking him, and I think he
said it was a 21st century version of a repeat
region vaccine. The repeat region is the part
of the CSP protein that's included in RTS,S and
R21, and that's what the R stands for in RTS,S.
Well, maybe you should ask him.
Yes, right now.
Alexander, why is it called penicillin? God,
I just can't remember. I can't remember.
I've got an answer.
Oh, we have an answer.
So Adrian said it's the 21st century
presentation of the CSP repeat vaccine.
So your earlier answer was basically correct.
Yeah.
That's great. It's so funny to me that
you thought that you had made it up,
but you actually remembered it correctly.
I have a similar but very different story
where I thought that my earliest memory ever
was made up for a while and then I found
video evidence of it being true. So my,
so my earliest ever memory is of us, my
family, going to the Grand Canyon and at
the Grand Canyon I had a pink balloon and the
only thing I remember is that I had this pink
balloon and I dropped it down the Grand Canyon.
And I remember mentioning this to a bunch of
people afterwards and then eventually I was
like, did that actually even happen at all?
Like that just sounds like such a crazy
story. Like why would I drop a balloon,
that doesn't sound like me? Like I was two, but it
still doesn't sound like me. I wouldn't do that.
And then last year I found a video that my
dad took of this whole trip that we took to
the US when I was two. And in the video there's
a segment where I'm holding the balloon, the pink
balloon. And in the background, you can hear my
dad telling me to drop it down the Grand Canyon.
That is pretty much a clincher.
I was like, wow. I finally feel so
validated. But also it wasn't me. I didn't,
I wouldn't, I was just listening to my dad.
There's a lot to unpack there.
I was like, why would I litter?
Oh... Right?
That's not like me at all!
It's all adding up now.
Before we move on to the science of malaria,
what happened after you invented the R21 vaccine
and what happened after you finished your PhD?
Yeah, so after the vaccine was made, we then
first tested it in a mouse model of malaria,
and we showed that we could
protect the mice against malaria,
and this worked best when you used the right
adjuvant. And I did a large number of studies
in mice to really look at the dose that was
needed, and that's really where my PhD ended.
So once I developed the vaccine and we had shown
that it worked in mice, Adrian was moving this
forward into clinical trials. So I had the
opportunity to stay at Oxford and continue
working on the vaccine as it moved into the
human clinical trials. But I'd finished my PhD,
so I decided I wanted to move on and broaden
my experience and learn some new skills.
I moved to work with James McCarthy in Brisbane
and he had set up a model where you could infect
people with malaria - this was a challenge trial
- and evaluate the efficacy of drugs. And so
I was working there on those studies and also
developed a new challenge model as well. I then
moved on to work in - on projects in the field,
understanding malaria transmission more fully,
and looking at interventions to
interrupt malaria transmission.
That work was mainly based in Burkina Faso and
it was based out of a lab in the Netherlands.
Hmm. And then how did you get
from there to Coefficient?
Jacob hired me.
Oh, wow!
No, I mean, it's an interesting story.
I wasn't particularly looking to leave
academia. I was loving the work I was doing,
but obviously Coefficient Giving, or Open
Philanthropy at the time, is a really exciting
funding organization that's quite innovative.
And what happened to the vaccine after that?
So Adrian then took the vaccine forward into
clinical trials and there were lots of other
people involved in the development of the
vaccine. All the investigators in Africa,
the clinical investigators in Oxford, and
also the Serum Institute who licensed the
vaccine from Adrian and from Oxford,
and worked with the team there to carry
out the phase three trials and then
obviously develop the final product.
I think it's sort of underappreciated just
how many people work on these, like actually
getting the testing and scaling up to people.
It takes so many people and it makes me think
also that it's not just about funding, it's also
the number of people working on things like this.
Yeah, I mean, absolutely. I think this large
number of people it takes is really important
for me. I just played a very small role at
the beginning and there's such an enormous
number of people that made this vaccine get to the
finish line and have the impact it's gonna have.
I think it's time to get into the science of
malaria. But before we move on, I'll just,
my reflection on this segment, is there gonna
be a lot of people listening who - basically
science nerds - who sometimes it may feel like
the big things left to do in science while they're
all behind us. That's why Saloni and Jacob talk
about Gaston Ramon. You know, we've already had
all these antibiotics invented. Oh, well and so,
wouldn't it have been cool to live back then and.
I think that's entirely the wrong orientation.
You know, there are people like Katharine Collins,
who in 2010 to 2014, invent entirely new
vaccines that are now gonna be used by millions
of children. And yet, and she is right here. We
got to talk to her right now. And you can too!
You can work on important problems and there
are many people who can benefit! And it's just,
it's almost scary how sensitive to
particular scientists at particular
times a lot of this stuff is,
and it's very inspiring too.
So, Katharine, thank you so much for joining us.
Great to be here.
All right, so how come it took so
long to develop a malaria vaccine?
And why are malaria vaccines so much harder to
develop than vaccines against other diseases?
Malaria is caused by a parasite, which is
quite different to a bacteria or a virus,
it's a lot more complex. And the malaria
parasite actually moves- it has a really
complicated lifecycle, and it moves
through at least three different stages.
So it's first injected into the body by the
mosquito, and then travels from your skin into the
liver. It develops in the liver for about seven
days and then bursts out into your red blood cells
in your bloodstream and it invades your red blood
cells. The symptoms are caused by the parasites
invading your red blood cells and then destroying
them, and then it does this many times. Each cycle
it produces many more parasites and so it invades
many more red blood cells and that's what causes
the anemia. And then the parasites within the
red blood cell, those infected red blood cells,
can adhere to different tissues and that can
cause problems for different organs as well.
I read that if just a single
parasite makes it to the liver,
it can cause an infection. Is that true?
Yeah, that's right. And that, I think that's the
really tough challenge with malaria, but you know,
you can get hundreds or thousands of sporozoites
from one bite. But I think you - we don't think
it's many thousands, and you could have some
immunity that gets rid of a lot of those,
but just one has to get through the defenses, and
that gets into the liver, and then in the liver
they actually replicate so that it doesn't stay as
one parasite. It turns into many, many merozoites,
and they then burst out of the liver cell and
start invading blood cells. By the time you
get to the blood, you've got many parasites again,
and very quickly, they replicate and produce more.
That makes me think, both of the
vaccines are - the efficacy is much
lower than many other vaccines.
But if I think about it this way,
that they're trying to prevent even just
one parasite from getting to the liver,
then from that perspective, it sounds like they're
actually really effective at doing that, at least.
Yeah. Yeah, it's a very high bar. Exactly. Yeah.
Well, that's terrifying. Just one parasite.
So all of that makes it much harder than,
let's say, measles or flu,
which are caused by viruses
and where the vaccines are produced
by killing or attenuating the virus.
So there are many reasons that it's difficult
to make a vaccine against malaria parasites.
First is this really complex life cycle
and then also the malaria parasite has
been around since Egyptian times. So it's
evolved to evolve with the human immune
system for a really long time, it's learnt
how to evade our immune responses really
well. So every time our immune system is
managed to attack the malaria parasite,
or find a good way to get rid of it, it's then
evolved another mechanism to keep surviving.
There are lots and lots of redundant
proteins in the parasites. So you think
you can block something that's important
and then it just switches on a different
protein instead and uses that. That's been
one of the reasons it's been quite tricky.
So the malaria parasite has a very
complicated lifecycle. Does it,
when it goes through these different stages,
does it also change shape? What actually happens?
Yeah, it looks completely different at each stage.
It starts with what we call a sporozoite that
looks like a little eyelash when you look
under the microscope, it's a curve shape.
Then when it invades the red blood cell, it's
called a merozoite; it's like a round, almost
cone shape. But not only does it look different,
but it has different proteins on the surface. So
a vaccine that works against one stage isn't
necessarily gonna work against another stage.
Right. And that's one thing that's
hard about developing a vaccine. Like,
how do you pick which protein
to use in the vaccine?
Yeah, absolutely. Yeah. You know, the approach
is normally to look for a protein that's really
important. So you find out something that's
probably something that's involved for an invasion
or adhesion. So people would look at knocking
out different proteins and seeing whether they're
critical for development. If you find something
that's essential, then that's also gonna be a
good target. And the other way is that people
look for what's most abundant on the parasite,
or the pathogen in general, but that can often be
a decoy. That's an interesting one. Like sometimes
the things that were abundant on the surface
are there to misdirect the immune response.
Okay. So you're taking these samples
from mice and you're learning a lot,
it sounds like, from mice. So firstly,
thank you to our mouse brethren. And Saloni,
I know that you have written a lot about,
in one of my favorite pieces that I read
two years ago was about the invention of the
malaria vaccine. And you wrote about how mice
were originally domesticated in some sense, to
be models for malaria. So how did that work?
It starts out before mice, I think there were
some animal models in the late 19th century,
the first animal models for malaria were birds.
And the way that scientists proved that malaria
was spread by mosquitoes, was by using sparrows
and infecting them with the blood of an infected
human, and seeing whether it would transmit.
And I think it seemed like there were some,
there were a bunch of different birds that
could get infected by malaria, but they just
didn't translate that well to what would happen
in humans? So people tried developing drugs,
like testing new drugs, in bird malaria, and they
seemed to work there, but in humans they didn't;
they caused various side effects. And so
they were trying to find different models.
There are also two other types of
models used in between. One was monkeys;
monkeys are really expensive and difficult
to work with. And then the other was humans,
right? Because in the 1920s, if I remember
right, humans were used as a model to study
malaria because people with syphilis could
be treated by infecting them with malaria,
because the bacteria doesn't survive after
the fevers that are caused by malaria.
It's a bit like solving your aching thumb
by chopping it off to me, but, okay.
Would you rather get syphilis or malaria?
Ah, the eternal question. And my answer is
I'm glad that we're in the 21st century.
Syphilis seems like it was
really scary before antibiotics.
Yeah.
Especially if you got neurosyphilis.
Yeah. The bacteria would worm its way up into
your brain and stick around for years or decades.
I've been to a medical museum in
London called the Hunterian Museum,
and they have exhibits of people
who had syphilis at the time,
and their skulls are filled with holes
from the infection. It's very scary.
Well, that's a wonderful tangent,
but I was wondering about,
I was wondering if we could talk more about mice.
Right. Okay, so mice, so we have the bird models
that aren't great. You have the monkey models that
are really expensive, and the human models, which
once you could treat syphilis with antibiotics,
there was no longer an audience of people
who were interested in being infected with
malaria deliberately. So the next
question was, let's try to find a
different animal model. Let's try to find
a rodent that can be infected by malaria.
And I think it took quite a while to find any
rodents that were infected by malaria. There
were two researchers that finally figured it out.
I think they were two Belgian researchers who
were in the Congo, and they were doing tests
to see which animals mosquitoes had bitten,
and that ruled out various animals nearby and
it didn't rule out rodents. So they thought
maybe there's something here, and they continued
trying to look for rodents that were infected by
malaria. And eventually they found a thicket rat
(Grammomys dolichurus) that was infected with it.
This thicket rat was infected by a different
strain of malaria called Plasmodium berghei,
and that seems to be much more - like that's just
much easier to work with. I think at first, they
also, they couldn't replicate the whole lifecycle
of the parasite in those thicket rats, because
there were certain stages of the parasite's
lifecycle that needed a cooler temperature.
So when I was reading about this, it seemed like
it took 16 years for them to work that out. It was
several things. So the original research was just
post World War II and then in the 1950s, various
countries did large-scale malaria elimination
programs and cut down on malaria research.
And so all the people who were working on that
stopped working on, or many of them did, stopped
working on it, and then only then got interested
again in it during the Vietnam War. So I think it
was like partly that and partly just, historical
contingency of which parasite they discovered. And
did they look at their own lab notes from 16 years
ago to see what the temperatures were in that
forest where they found the first malaria infected
rats. Goes to show how important lab notes are.
Sounds like mice can tell you something, and took
a long time to get to a model that worked in
the lab. But they can't tell you everything,
'cause mice aren't humans, and
they might mislead you sometimes.
A mouse has never told me anything.
Speak for yourself. Well, I mean,
that brings me onto a question I have,
which is: are mice enough?
If not, what's the next step?
Well, so you could use non-human primates, but
they aren't the perfect model for malaria. There's
only one that gets infected, that could
be affected with human malaria parasites,
and so none of the models are perfect. So people
don't often do a lot of non-human primate work,
but they can be used to answer specific questions.
So then your next model is obviously humans.
Mm-hmm.
And that makes sense because if you
want to make a vaccine for humans,
you probably wanna test it on humans.
Okay. So we're segueing to humans. How did that
begin? What were the first experiments in humans?
So the first ones were the ones that were
treatments for syphilis in the 1910s to
forties. And then when penicillin was developed,
it wasn't necessary anymore. But then, after that,
there were various experiments in prisoners in
different parts of the US, I think. And what was
interesting to me when I was reading about this
was that - so the prisoners were volunteering for
these experiments, but some of the prisoners were
not just subjects in the experiments. Some of them
were actually technicians and researchers,
who helped in the experiments as well.
And one of the most famous ones is Nathan
Leopold. Do you know, do you recognize that name?
Not me.
So he was a - I know this because of a film that
was inspired by his life. He was a murderer who
murdered a friend, I think, a classmate of his.
So with a friend of his, they both kidnapped and
murdered one of their classmates while they
were students at the University of Chicago.
And while they were serving their sentences,
Nathan Leopold, one of them, enrolled in one of
the malaria research studies. And after that,
he then became a technician, he started doing -
like he was actually operating research as well.
And the reason that I know this is because that
story inspired the Alfred Hitchcock film Rope,
if you've seen that. Have you seen that?
I have not seen that.
It's a very good movie where, I mean, it's the
same-ish story. They've kind of changed what
actually happened. But in the film, these two
students decide to kidnap and kill one of their
classmates for fun, essentially. And then they
store him in a, what is it called? Like a box in
their apartment. And they then host a party just
hours after this murder, to basically show the
fact that they could get away with it. And the
whole film was taken in 10 shots, like 10 long
segments that are just stitched together. And it's
an incredible film. Like very, very well made.
Wow. Okay, so...
So how does this relate to malaria?
Many prisoners would've been part
of this malaria research in the mid
20th century, and they contributed
to our understanding of various parts
of the transmission process, I think.
And since then, we've continued studying malaria
in humans in a type of study called a challenge
trial, where you deliberately infect volunteers
with mosquitoes with malaria. So I think in the
past it was many mosquitoes per person and
now it's just five bites. Is that right?
Yeah. I guess there was work to improve and
standardize the modern challenge trials.
That's where they landed on five mosquito bites
that could reproducible infect the volunteers.
So what happens in one of these experiments
do you sit with. Do you put your hand into
a jar that's filled with mosquitoes
or what? What's the what's it like?
No, the process is quite dull, actually. I guess
you normally have to travel to somewhere where
there's a facility. And because these sort
of things do contain mosquitoes infected with
malaria, they're usually under high containment,
so then the volunteers need to pass into a
contained containment area, and then a cup is
often passed through a window into that room
and they have a cup - it's like a coffee cup -
and it has gauze on the top and the mosquitoes
will be inside. The lid will all be taped shut
so they can't escape, and then you place your arm
on top of the cup and allow the five mosquitoes
to bite you and say, a few minutes for feeding.
And then they'll have a look and see how
many of those mosquitoes have fed on you.
So what they do is they take the cup
of mosquitoes, they then look at them,
each mosquito individually under the microscope.
You can see whether it's blood fed, because it's
got blood in its abdomen, in its belly. Then if
it's got blood in the belly, then look at the
salivary glands and check that it had sporozoites
in the salivary glands. And so you're looking,
five mosquitoes in that cup that fed. But so
they count up how many did feed, then they'll
put more mosquitoes in a cup. So if you only
need one more infected bite, they'll put one more
mosquito in, and then you can be bitten by that
mosquito. If that one doesn't bite you, then they
take that one out, put another one in
until you've had five infected bites.
Oh, I see. That's probably the most
disgusting coffee cup I've heard of.
Not so tasty. These, these days, are the
people who are putting their arms out,
are they mostly undergrads somewhere
or, yeah, what, who are the volunteers?
I think it depends where you do the trials. I
think in Oxford it's typically lots of students,
but other people as well. But you, the students
are often quite willing to get involved.
Legends.
I saw a picture where it wasn't a coffee
cup, but it was a cup noodle box container.
Yeah or soup. And they're often called, used as
soup cups. They're like, or ice cream containers,
they're that kind of large, larger size that
would be used. That's usually used to hold
a lot more mosquitoes. It would've
been a different study, probably.
Oh, I see.
So you, in those challenge models, you
are giving some of the students or other
volunteers injections of vaccine, some of
them placebo, and then they're getting bitten.
Exactly. That's right. Yeah.
Okay. And then what do you, how do you figure out
the truth afterwards? You're just
seeing which one of them faint, or?
Once you've been challenged, you start following
them up a couple of days later. So the parasites
will be in the liver for seven days. You
don't have to monitor them too carefully
in the beginning, but you still monitor them and
check the parasites haven't got into the liver,
into the blood from the liver. And
then you are monitoring quite closely
from liver emergence. So once the parasites are
entering the blood or you're expecting them to,
you can see them once or twice a day,
up to twice a day, take their blood.
You can look under the microscope for
the parasites, see if they've got the
parasites in their blood, and you can
also do molecular diagnostics as well,
like PCR to look - it's a much more
sensitive method. So you can detect
the parasites in the blood before they will
make the people sick. And so you can treat
them quite quickly and then you'll know which
volunteers have been protected and which haven't.
That's very cool. And then now there are
methods that are beyond mosquito bites.
People directly inject volunteers
with the parasite, is that right?
Yeah, there's a couple of models. So
the other models you would inject either
cryopreserved sporozoites, that's that
first stage that goes into the liver.
You can inject those intravenously, you
can ship those anywhere in the world to
do that type of study. The other model
is injecting blood stage parasites. So
both of these are greats and they
can answer different questions.
And these two vaccines, the RTS,S and
R21, are for the first stage. So you'd
want to be able to test it against the
natural infection with the mosquito bite.
Yeah, definitely.
Saloni, I've got a question for you.
Oh, what's the question?
Would you have volunteered for one
of these human challenge trials?
I was thinking about this back when you asked
who was volunteering in the studies because as
I have described in the first episode we did,
I once volunteered for an HIV vaccine trial,
phase one trial. And I enjoyed
it and I think I probably would.
I think the difficulty is that back when
I did that, I was a student and I was very
bored and I didn't have anything to do in my
free time anyway and I didn't have a social
life. And now I have a lot of stuff going on
in my life, like I just have a lot of work.
By the way... congratulations.
Thank you.
Me, I'm still alone, but I'll get there.
But I was thinking like, there are lots
of different types of diseases that you
might do a challenge trial for, right?
Like you could do one for rhinovirus or
like flu or cholera or I don't know,
what else is there - Shigella maybe,
or something like that. And all of these
sound very unappetizing to me. Like,
I wouldn't wanna do a challenge trial for any
of those. Like the flu, the respiratory ones,
I'm like, that's just boring and someone else
is gonna do them anyway. Probably the, that's -
Amazing. I'm not gonna do that one.
It's boring. I want something harder!
Right. And then the other,
like cholera and shigella,
I mean, diarrhea... I don't want, that
sounds horrible. And also I feel like
I'm quite small and if I lose too much
weight, there'll be none of me left,
and so I can't do that one. So what I would
do is a more dangerous pathogen, I think.
Okay, nice. Is malaria dangerous enough for you?
That would make it worth it. I think so, yeah.
Okay. Even though malaria -
Even though it's treatable and stuff.
It's treatable. Yeah. I mean, just in case
listeners are thinking about it themselves
and concerned; in the diarrhea ones, they
do treat you. They don't just leave you,
they give you antibiotics. But yeah,
those in order to get more of a signal,
they don't treat you in, within an
hour, they'll probably you within 12
hours or something. So it's a - it's not, you
gotta go through some pain to get the gain.
Well, I read that with the cholera vaccine
challenge trials some people... actually,
you know what? I'm not gonna finish that sentence.
Oh -
It was about how much diarrhea
they had. And you know what? I
don't actually wanna give people that image.
That's.. you know what, Saloni?
I think they've got it now.
So my question for malaria, Katharine, how
sick do you get? Do you get sick at all or
do you get treated as soon as there's any risk
of sickness or? What if you're in, what happens?
I guess the idea is that they treat you before
you develop any real symptoms. So you probably
start to feel a bit fluey. You may get a headache,
but because they're monitoring your parasitemia
so closely, the plan is to treat you before
you get any really uncomfortable symptoms. By
the time you get treatment, you could have
some symptoms. I think people do typically
get symptoms. They feel rough for a day or
two, but that's hopefully the extent of it.
I think that's kind of cool. Yeah, I
would do it. I mean, I haven't done it,
so you always have to take with a grain of
salt, whatever I say now. The issue, yeah,
I tried to volunteer for a trial recently and
ended up getting swamped in the logistics. So
your point Saloni, that it's harder once you
have a job? I've had that experience too.
It also depends where you live, whether there are
trials around you that are convenient that you can
participate in. So it comes down to those aspects
as much as anything. But malaria sounds kind of
fun. If you get, the drugs are great. You get,
if you get feel a little bit sick, that will make
me feel like I've done something for humanity and
then I get treated, I'm up for that. Sounds good.
And also you get to live in a cool
quarantine hotel for a bit. No?
No, because -
No?
It's safe to walk outside. In England, right?
There's no, there's no mosquitoes that bite you.
So you are infected and then they're just like,
go on with your life. Yeah. And
you just feel sick at home instead?
Yeah. They give you a little card to
put in your wallet, which tells people
what you have and what you need to be
treated with in case something happens.
Oh, really?
Okay. I'm not volunteering for this thing.
Emergencies, like if you ended up in hospital
from a car crash or something, they would know
that they should probably give you
antimalarials now. The study's over.
No, I thought, I thought you'd be in
a little quarantine hotel. I thought
it was like a mini vacation but you're sick.
No, I think maybe they do it differently
in different places. So it depends maybe
what type of trial you are in. So for the drug
trials with malaria, because they actually let
you develop parasitemia to a certain level,
then they treat you. And then they want to
measure the clearance rate of the parasites.
So they want to sample you quite quickly and
frequently after treatment. So for those, they
do often do inpatient for your convenience,
then they let you go once you are treated,
so it could be just a couple of days.
I think I'm thinking of the respiratory
virus challenge trials where, because
you could transmit it to someone
else, they keep you in a facility.
Diarrhea as well, for the shigella one they
keep you in. Yeah. I realized Katharine in
that description though, one of the other
reasons why people might not want to do it,
which is you're getting pinpricked constantly
'cause people are taking a lot of blood samples.
So that's if you wanna get over needle
phobia via exposure therapy, go for it!
I feel like the way to - Exposure
therapy is supposed to give you
like a mild version where it's like,
oh, nothing actually happens when you
get injections. This seems like
it would actually scare you more!
Well, I did exposure therapy and nearly died.
Would you participate in the challenge trial?
I would love to, but I really hate needles.
Oh, there we go! There we go!
It's kind of ironic for a vaccine developer.
That's so funny.
I'm terrified of getting vaccines. When
I have, when I go to get a vaccine,
I have to lie down to have a vaccine, I
have to lie down with the blood taken,
as otherwise I might faint. I think I have
fainted in the past, that's the problem.
Oh, wow.
And so, as you mentioned we take blood in these
challenge trials, 10 to 15 times depending on
when you get malaria. So I just couldn't,
I couldn't cope with that. Unfortunately.
We must know our limits. Okay. So how come
that's not enough? Or is it enough? So
let's say you've taken a malaria vaccine through
human challenge trials. You ready to license it,
roll it out across different countries or
not? I know the answer, but I'm curious.
Well, obviously no, I guess that's not the target
population. So you still need to find out if your
vaccine's gonna work in the people that it's
intended for, which would be children in Africa.
Well, we have some vaccines
that are approved just from
challenge trials. Right? Like the typhoid vaccine.
Yeah, that's right. Yeah, I think when the
trial isn't feasible to be done in the target
population, there's good arguments to try and
get that efficacy signal from a challenge trial,
and then they still need to get
your safety data from the target
population that you're gonna
use the vaccine in as well.
Okay. So we've talked about the second
malaria vaccine, and we are talking about
the animal models and the human challenge
models for vaccines in general. Saloni,
since you've written about the history of malaria,
I'd love to hear, if you're willing, what was
the first malaria vaccine development timeline
like? What were the steps there? What happened?
I love how we've gone through this backwards, like
we're doing the Star Wars prequels or something.
But more entertaining.
Well, I guess it's a long story. So I think I
probably wanna start with a quick summary of
the whole development. I first got interested in
this topic when I was reading about the news of
the malaria vaccine being rolled out in 2021,
and I wanted to write a blog post about it.
So I was starting to write this blog post, and one
of the first things that I learned was that it was
actually developed in the '90s. And it really
kind of shocked me and I was just thinking:
what went wrong? Like, what happened? Why
was it, why it didn't only get released now,
if it was developed so long ago? And
a lot of my interest just stemmed from
that curiosity and frustration, with
how things could have taken so long.
The short version is that I think a lot of it
is because of a lack of funding, infrastructure,
and in some cases, also the regulatory changes
and standards that there were. But I think the
broader version is really, you know, this malaria
vaccine essentially came out of research from the
US Army. In the 1950s, almost every country
was affected by malaria, and they used, there
were large scale malaria eradication programs in
the 1950s, mostly using insecticides like DDT.
And those were very effective, like a lot of high
income countries eliminated malaria in the
1950s with DDT and other control efforts.
And funding also declined, so there was no more
reason for a lot of high income countries to do
research on malaria, and a lot of the researchers
who were previously doing it became operators and
managers of this eradication program. So funding
for research and development massively contracted,
and that kind of stayed that way until really
the 1960s, when the Vietnam War was happening,
and the US Army was then once again facing
malaria in Southeast Asia. But by then it was
kind of drug resistant malaria. So there was
once again, this need for research trying to
develop new drugs that were effective against drug
resistant malaria, but also potentially vaccines.
And so some researchers started working on
this program to try to develop a malaria
vaccine. And their names were Ruth Nussenzweig,
Jerome Vanderberg and some of their colleagues.
And what they did was, they first tried to
build a proof of concept of the vaccine,
so let's see if you can protect mice by
infecting them first with a killed version
of the parasite. If you protect them with this
killed version of the parasite, will they then
be protected from another infection? And what
they found was that yes, you could do that.
And, this eventually much later led to a different
type of vaccine, which we might come back to later
on, but it's not really scalable. So the other
option is let's try to develop a subunit vaccine.
From our previous episode on a history of vaccines
and Hepatitis B, basically the idea here is that,
instead of using the whole organism, the whole
parasite as a vaccine, let's try to find a few
components, or maybe the one component, that
is enough to stimulate an immune response.
And so that's what they tried to find and
they sort of looked at these mice that they
were protecting with this killed parasite and saw:
what are they generating antibodies against? What
is their immune response reacting against?
And they found that that clustered around a
protein called the circumsporozoite protein.
That protein, it turned out, was gonna be a
very good candidate for a vaccine. That was
gonna be the main component of the vaccine.
So the initial attempts were to use that protein
as the vaccine. If you remember back from our
protein subunit vaccines episode, the Hepatitis
B one, often just using a single protein in a
vaccine is not very effective. And the reason for
that is that, often when you have a whole pathogen
being a vaccine, or when you're exposed to a
whole pathogen, there are many things about that
pathogen that can stimulate your immune response.
Whereas when it's just one protein from that,
that's often not enough for your immune system
to recognize that this is something that we need
to react to. There are obviously lots of nuances
there, but that's kind of the simplified version.
So this initial vaccine, just using that
one circumsporozoite, or CSP, protein,
was not very effective. They only managed to
protect one volunteer out of six in their first
study. The way that you improve that, is often
by adding an adjuvant. So an adjuvant boosts the
immune response in some way, and so that's kind of
what they tried. They tried different adjuvants,
they tried different formulations, and
eventually they created this formulation.
And I forget what each of the letters
stands for. And this, the formulation
was the RTS,S vaccine. And so Katharine,
what does, what is this formulation made of?
So the formulation is made of parts of the
malaria parasite and the Hep B virus. So
the R stands for the repeat region, which is
from the CS protein in the malaria parasite.
The T is for the T cell epitopes
that are from the same protein,
and the S is from the Hep B surface antigen,
and this is fused to that malaria protein.
Then there's the excess Hep B surface antigen
I mentioned before that was needed for this to
form a virus-like particle, and that's
the extra S so that makes the RTS,S.
Unfortunately, by the '90s, there was no
longer interest in funding it from Vietnam War
era army research anymore, and they couldn't
scale up and continue that research. So they
only found this adjuvant, that they ended
up using, in the nineties. So at that point,
we have a possibly more effective vaccine
and they did another challenge trial to
see how effective that would be.
This time it was more effective,
it was six out of seven people in the challenge
trial that were protected from further infections.
And again, this, a seven person study
sounds extremely small and it is,
but that was one - this is a preliminary, pilot
type of study, so this isn't really the real deal,
but it is still much better than
any other study had shown so far.
So this was a much more promising
candidate for further research.
So what they did next was to do a field trial with
many more participants. So they ran a field trial
in The Gambia with 300 men, they vaccinated
them with this candidate and with a placebo,
and they looked at their rates of malaria
infection afterwards. And in the group
that received the vaccine, they had a 34%
lower rate of malaria infections over the
next four months. So that was the first
field trial, and that was done in 1998.
And okay, this field trial looks not amazingly
effective, but still effective in a way that
no other vaccine candidate had been up to
that point. And so the next step was really,
let's try to get this into real, clinical trials
in the population that needs these vaccine,
which are children. So they started with trials
in older children, who were 6 to 11 years old,
and then younger children, who were 1 to 4
years old, and then finally infants. This
idea is called age deescalation. Basically you're
testing it first in children who are least likely
to be affected by potential side effects, and
then the infant group who are more vulnerable.
You sort of wanna make sure that it works first in
adults, and then in children, and then in infants.
But this process took a long time and they
struggled to find funding at every stage
of the process from what I read, and also needed
to themselves set up clinical trial sites across
Africa. Often there were just not clinics
with the expertise to run clinical trials,
or the equipment to do testing and things
like that, and the researchers themselves
had to fund some of that work, so it was a
very long process. And then it eventually
finished in 2015, the phase three trials
ended at that point. That is, I think,
much longer than the research process
that we often have for vaccines today.
Though, luckily, I'm sure that
meant it got approved in 2015.
No!
No. What happened then?
What happened then? Well, in 2015, the phase
three results came in and the European Medicines
Agency said, this looks safe and effective, but
the World Health Organization didn't recommend
it for a large scale rollout. They asked for
more pilot studies before they would do that.
And one of the reasons for that was that there
were some, in post hoc analyses of the data,
they found higher rates of meningitis in
older children and higher rates of death
in girls at two of the trial sites. And the World
Health Organization, if I understand correctly,
didn't think that they were - those signs
were causally related to the vaccine,
but they wanted it to be ruled out,
and so they asked for pilot studies.
The pilot studies took around four years to
find funding for, and to get staffing for,
and they finally launched in 2019. And then
another two years into the pilot studies,
there was enough data for the Data Safety
Monitoring Board to look at the data, find no
increased risk of these side effects, and then
finally clear the vaccine for the World Health
Organization's endorsement in October, 2021. So
that is 23 years after the first field trials.
The safety was one of the reasons,
but that wasn't the only reason,
right? They, there was a lack of
confidence in how effective the
vaccine was. So it wasn't the risk, it was
about the risk benefit analysis. You know,
it was only 36% effective in those phase
three trials, and there was the safety signal.
The RTS,S vaccine was going up for EMA and WHO
review in 2014, 2015. That was just about when
you were finishing your PhD, working on the R21
vaccine. Katharine, so what was the feeling like
in the malaria research community at that time?
Did people have conflicting and different views,
and there was a lot of debate? Was there
consensus and surprise? What, what was it like?
I think everybody was really hopeful that the
vaccine would get approved. I think there was
definitely mixed opinions in the field
about whether a vaccine that showed such
low efficacy in the phase three trial should
be rolled out and would actually be effective.
So I think what was really important and really
key was the cost effectiveness modeling that was
done with the data. And I think that was quite
pivotal. And in that it really showed that
even a poorly effective vaccine or suboptimal
vaccine, most vaccines that have been used in
children at the time had really high levels of
efficacy, like 80, 90%. So it was a completely
uncharted territory. But the modeling showed that
even with this low level of efficacy, because
there's so much malaria, it could have quite
dramatic impact and it would be cost effective.
I think that was a bit of a surprise to everybody.
We've been aiming for this really high bar,
and then all of a sudden there was this
realization actually a quite a suboptimal
tool could make a big difference. I think
that was quite unfortunate and quite pivotal.
So what did it feel like when the WHO verdict
came in that more studies were needed?
I think it was really disappointing. I think
it's a difficult decision that they had to
make. This is really uncharted territory; a
vaccine with really poor efficacy and this
safety signal. So it's a tough call for
them to make, but I think people at the
time and now still think there could have been
a better way to resolve the safety signal issue.
And had they prepared better for understanding
the public health impact of a vaccine that has
this level of efficacy, maybe that messaging
could have been different when they were
trying to make the recommendations, if they
understood the potential value more fully,
maybe that would've have shifted the approach
away from a pilot implementation program that
took six years to conclude versus doing
a much more rapid safety assessment.
I guess I also, I feel like it's a little
bit surprising just because even the first
field trials in 1997 and 1998 also showed
fairly low efficacy, but they continued
working on it and people probably should
have been prepared by that point that,
hey, this even though this isn't a very highly
effective vaccine, it probably will save a lot
of lives. And so it's surprising that that wasn't
enough to not require another study after that.
Yeah, I think you're right, and what I've
said just now is my recollection of the
events at the time. This is a while ago and
I wasn't deeply involved in the process,
so perhaps there was more preparation than
that I was aware of, but it feels like that
was the missing piece that people didn't
truly, at least the people I was talking to,
didn't truly appreciate the potential impact,
global health impact, of this tool at the time.
And there were other consequences as
well to delaying the rollout. So you'll
see GSK would be hoping that at the end of
their phase three trial, they can scale up
manufacture and start delivering the vaccine.
They probably had a factory that was making it,
but now there was gonna be this huge delay.
What were they gonna do with the facilities
that were producing the vaccine? And then what
was that gonna mean for vaccine supply later
on? All these knock on effects as well that in
hindsight it's easy to think differently about
what we could have done differently. But I'm not
sure it was so easy at the time, to be honest.
It's also just like to state the
obvious, so strange and messed up
that the way that things currently work is
that to get a scalable regulatory opinion,
you end up relying on the EU and the WHO when,
you know, over time we have to get to a world
where kids in Ghana rely on regulators in Ghana,
not these kind of more distant bodies. 'Cause
you could totally imagine, as happened with
the next vaccine, R21, that some nations want
to go ahead with vaccination campaigns,
even if the WHO doesn't agree and they
absolutely should. So that's another part
of this story that's a bit heart wrenching.
I feel like there's also a part of this
that's like what safety standards we're
used to here might be different. Like the
cost benefit just might be very different
and the willingness to take vaccine at
an earlier stage might be different.
But I think there's also another thing that
kind of drew out the process, which was a
lack of funding and a lack of infrastructure
for clinical trials at the time. So especially
in the early 2000s, there were very few trial
sites in Africa where you could actually try to
do research on the malaria vaccine at all. And
it was only in the 2000s when malaria funding
actually grew from various organizations like
the President's Malaria Initiative in the US,
and Unitaid and the PATH's Malaria Vaccine
Initiative that was funded by the Gates
Foundation and the Global Fund. And all of
these appeared only in the mid-, early-2000s.
Until then, it would've been really difficult,
I think, to get enough funding to set up these
trial sites and to actually do the research. To
me, when I think about it seems like mostly a
failure of infrastructure and funding. And
there are also these regulatory concerns,
but if we'd had that sooner, we would've been
able to test many other vaccines as well.
Yeah, I agree with that. I think that's
a really important point. I think,
we take it for granted now that
actually these clinical trial
facilities are so well established, and
the investigators there are so competent,
that they can run their own trials, lead
their own work. That wasn't the case.
I remember the stories of the people
leading the RTS,S work doing the draw
of the sites that existed at the time,
and injecting cash into a lot of these
sites to bring them up to the standards that
would be needed for their product development
needs. So I think a lot of that work
done by GSK has really benefited the rest
of the malaria community and other
development of other vaccines as well.
Okay. So there's infrastructure, which is
key, and also funding, as you mentioned,
Saloni. So let's say that there had been a
big burst of funding back then that was even
bigger than we saw. How would that have
happened? Were there people proposing it?
There were people proposing it, but they
were proposing a different type of funding.
Much of the funding that we're talking
about is sort of directed at specific
groups to do the research, or to set up
the trial sites, and things like that.
But in 2004, some economists, Michael Kremer
and Rachel Glennerster proposed an Advanced
Market Commitment, which is a different type
of funding model to try to spur innovation
and change the commercial incentives for
vaccine development. So the general idea,
of why did we need philanthropy and like foreign
aid and all of these global health programs,
is that there isn't otherwise a commercial
incentive to develop vaccines where it's very
small. The reason for that is that the people who
are most affected by malaria are very poor and you
can't really sell vaccines at a high price
because they wouldn't be able to afford it.
So here the idea is, what if we could change those
commercial incentives? And the Advanced Market
Commitment is a way of doing that. So instead of
directing funding at specific research groups,
it's actually a pool of funding that is only
available to researchers or to manufacturers
if they develop a successful vaccine in
trials and they reach certain criteria.
So Rachel Glennerster and Michael
Kremer proposed this Advanced Market
Commitment where they said we should have a
commitment for around $3.2 billion in total,
where you would pay per person who was
vaccinated, for the first 200 million people,
and you would pay about $13 per person. What this
does is it actually incentivizes companies to
develop a vaccine and take it to the finish
line. Both invent-, both developing it and
then also scaling it up because they're only
gonna get that payout per person they immunize.
So I think that is a really cool model that
spurs commercial development and it's very
different from the type of funding that was
actually done. But the problem was that that
idea didn't actually get taken up. And there
were various reasons for that. One was that
at the time people thought the malaria vaccine
was just too technically difficult. It was too
far away to be reality. So they didn't want to
use this new funding model that was proposed,
for something that might not ever happen, and
they thought that you, we have to have a lot
more basic R&D before we'd have a product that
could reach that standard. That also just made it
more politically risky. People were like, well,
we want something that will definitely or has a
much higher chance of success. We want a proof
of concept that this funding model could work.
And the other problem is that it's hard, in
a commitment like that, which is essentially
this legal document that funders, in this
case they would be countries - governments,
or philanthropists agreeing to pay out a
vaccine that meets these standards. It's
hard to decide what those standards are and what
kinds of products would fit those criteria if you
don't have a malaria vaccine yet, and you don't
have like things that are late in the pipeline.
So instead of doing an Advanced Market Commitment
for malaria, there was a different Advanced Market
Commitment that was actually implemented, and that
was for the pneumococcal vaccine. And so in 2009,
various countries and the Gates Foundation came
together to fund an Advanced Market Commitment to
develop a new pneumococcal vaccine that would
target the strains that were common in Africa
and South Asia. Those strains were not included in
the previous pneumococcal vaccines, but there was
already a proof of concept that we have this, we
have these other pneumococcal vaccines, it should
be fairly easy to turn to make new ones against
these strains. And it worked. So there were three
companies, I think, that quickly developed these
pneumococcal vaccines, took them through phase
three trials and then manufactured them in
bulk to get that payout from the commitment.
I personally think it feels like
a very big missed opportunity to
use it for malaria as well. But many
people disagreed with that at the time.
Okay. Katharine, you were around. Do
you think it would've worked back then?
I'm not sure. I think the
limitations were scientific,
biological, we had the
problems with the adjuvants,
we had lack of trial infrastructure. I'm not
sure it would've made things go much faster.
Well, it's hard to say as well, because this
was proposed in 2004. And so at that point,
the RTS,S vaccine already existed and it already
had like an efficacy of 30 something percent. And
so if you were at the time, and you were trying
to put this commitment together and you said,
we'll fund a vaccine that reaches these
standards, probably you would, the standards
that you would ask a vaccine to be developed
for would be higher than the 30% I think.
So I think in that sense it would've been
hard. What's interesting though is that
there was another paper in 2005 where
they tried to model this explicitly,
so trying to model the cost-effectiveness under
different estimates of the efficacy. Like if
it was 30%, how would it be cost effective? If
it was 60%, et cetera? And this was a paper by
also Rachel Glennerster, Michael Kremer,
many other economists, Heidi Williams,
and they found basically that it was, it
would still be cost effective to fund an
Advanced Market Commitment for a malaria
vaccine, even if the efficacy was only 30%.
So I think to some degree there had been a bunch
of thinking on this, but at the same time, I don't
think we know what the counterfactual is because
I don't think that other, there are enough other
commercial companies that are developing malaria
vaccines now that we can compare this to. Like
the thing that is effective about the Advanced
Market Commitment is that it gets people to enter
the market that wouldn't otherwise. And so it's
hard to know how that could have gone, I think.
I think that's the bit that I agree with
that there weren't other people that
were that far advanced in their vaccine. The
only thing that has worked to date is a CSP
based vaccine. There were people working on other
types of vaccines at the time. But it's not sure,
because it's not clear any of those would've made
it either, or looked promising enough to advance.
So that's a pull funding mechanism incentive
to get to the finish line. Katharine,
did it feel like more grant money, and more
universities, and more companies wherever,
would have made the difference if there
was a hundred million more every year
going into malaria vaccines? Or
did it feel like the science and
the infrastructure - you can't rush that, and
you actually just have to do it step by step?
That's a very good question and,
actually I, maybe I'm gonna change
my opinion slightly and that there were
other, with more funding available,
there were other people doing great science at
the time. So Simon Draper at the University of
Oxford has developed a blood stage vaccine with
RH5, and that work was happening at the same
time on the lab bench next to me, when I was
doing R21. But that was seriously underfunded,
so there was - people had to prioritize what
they were gonna support with their funding,
there was limited funding. So the focus went on
to CSP based vaccines and that's what the Gates
Foundation funded the RTS,S vaccine through MVI
and the Gates Foundation didn't fund blood stage.
There was only one funder at the time that was
supporting that work, or one main funder, and that
was USAID (United States Agency for International
Development). Had there been more money, that work
could have been accelerated. And you know, that's
shown now in a phase two trial that it gives good
levels of efficacy, not as high as R21 and RTS,S,
but there's potential to combine that with R21.
So that work could have been accelerated a lot
quicker, had there been more funding around.
So just playing that out. So that,
that result you just referenced,
that was from about a year ago, was it? That
was pretty recent. Right? Yeah. And so if that
funding had happened a decade earlier, could
that result have come about a decade earlier,
do you think? Or is - that's
just a funding question really.
Yeah, I think the product was the one
they were working on in the beginning.
No!!
Depressing.
Wow. That is incredibly depressing.
I know, but I think credit has to go to Simon
Draper and the funders that supported him and
Lorraine Soisson at USAID, they kept that
work going with quite limited budgets,
and they've made it to the finish
line, well, not to the finish line,
but to the clinical trials
now, and the efficacy trials.
Wow, geez.
Thank you Simon. Thank you Lorraine, for
believing against consensus and keeping it going.
I have a question related to this because
both these are different stages of the
vaccine and so I'm wondering if you had a
vaccine that combines the vaccines against
both of these different stages, would you
expect that to have a higher efficacy,
and have people tried to do things like that?
Yeah, I think that was the original approach
from Adrian, when I was making R21. He also
had a liver stage vaccine. The other vaccine he
had developed was the ME-TRAP vaccine (Multiple
Epitope–Thrombospondin-Related Adhesion Protein),
and that targeted the infected hepatocytes.
His theory was that if you could reduce the
number of sporozoites that get to the liver,
then the liver stage vaccine would have an easier
time finding and clearing out those liver cells.
And that was valua - that was tested and it didn't
work, so that was a great theory that didn't work.
Now people are looking at combining the CSP based
vaccines with the blood stage vaccines that Simon
Draper's developed and others. There are lots of
other people working on blood stage vaccines now
as well. But the preclinical models are really
difficult to evaluate all stages of the parasites
in the same model and the combination of those
vaccines. So we really have to get into humans,
and that's the work that Simon and Angela
and his team are working on at the moment.
Wow. And so that was also - could that
have also been sped up by 10 years?
Yeah, that vaccine that they're now putting
into clinical trials with R21 was being
developed at the same time as I was developing
R21. So I know that could have gone quicker.
This is crazy.
It wasn't exactly hard to spot, it was right next
to you on the lab next to you. I'm gonna cry.
Geez.
I mean, so as someone who works in philanthropic
funding, I think the main lesson here is just
that funding in global health R&D is
so tight that you have to make these
prioritization decisions that are vicious and
impossible. So we just - I mean, a more sane
society would have more long-term government and
philanthropic funding that was less correlated,
more decision makers, more money total,
so that you could get more shots on goal.
So I think, for anyone listening who
is wondering what the solution is,
I think that's the most obvious general solution
staring us in the face, and so I don't wanna hide
it. There's obviously all these specifics
we can get into that are more technical,
but that one is just - is obvious. So
we just have to say it out loud. Sorry!
Geez.
No, I agree with that. I don't disagree with
the decisions that were made about what you
had to prioritize at the time. I think
they were tough decisions that people had
to make. That had there been more money,
we could have moved things a lot faster.
I feel like what's even more depressing
about this is that... Despite all of that,
malaria is still one of the more well-funded
diseases in global health world, and there
are various others that are large burdens
and get tiny fractions of the funding.
I am wondering if we could just talk about the
two vaccines already approved next to each other,
and then what's coming next after these two? What
needs to be done next in the invention pipeline?
So RTS,S versus R21. I will tee this off by saying
I don't know that there's - there are different
comparisons you could make, but one fact just to
state upfront is that neither has faced a rollout
where tens of millions of children have received
the vaccine, so perhaps the biggest problem is
simply that there is not enough reach of either
of them, let alone comparing between the two.
That said, what do we know
about the data that has come in,
about how they look? So there's
more data coming in every year,
but what do we know so far about efficacy,
about safety, and other factors? Katharine?
The headline efficacy figures from the phase
three trials look quite different for the two
vaccines. So RTS,S, we mentioned it was something
like 36% an efficacy overall. And actually for
the population that was used for the phase
three trials for R21, that was most similar,
the efficacy I think was 57% overall. And then for
R21, the phase three result was something around
75%. I can't remember the same, the exact numbers,
so this looks like R21 may be a lot better.
But there's some nuance and detail
about how these trials were conducted,
and where they were conducted, and when they were
conducted, that means we can't - we probably can't
directly compare these trial results. So I don't
think you can claim that R21 definitely has a
higher level of efficacy. There were different
things happening at the time; different other
malaria interventions that were being used,
like bed nets, or seasonal chemo-prevention
drugs that were given to children every year,
so those results aren't directly comparable.
So I think we have to try not to make that
comparison unless we run a head-to-head trial.
What I think is interesting about the R21 data
that's starting to emerge is that it does - it
may be more durable than RTS,S. So the decline of
protection seems to be slightly slower. So it may,
even if the efficacy isn't much different,
that peak protection they gets the,
it may last a little bit longer, so
that could make quite a big difference.
I see. So, but in both cases, your first shot,
you'll probably get it at five months old. Is
that about right? And then you might get another,
the ideal is you get one at five, one
at six, one at seven months. And you're
saying that the immune response from R21 is
lasting for longer after those first shots?
That's right. That's actually a fourth
dose that's given around 18 months.
I think my takeaway from the difference
between the two is mostly the manufacturing
and the cost. Is that also how you see
it? And are there any other differences?
Why is there such a huge difference
in the cost of both of these? And is
that because of the dosing that
we talked about at the start?
I guess, the other big difference is of
the scalability of the vaccines. R21,
it seems to be easier and cheaper to produce
and that may be in part due to the lower dose
and maybe also new technologies that have been
used to produce the vaccine itself - so newer
yeast expression systems and things like that. And
also, the adjuvant that's added to the vaccine.
As we mentioned earlier, that the adjuvant
was really important for the RTS,S vaccine.
We found the same with R21, only when we used
a certain adjuvant did we see protection. And
that the adjuvant that's been chosen for R21
was Matrix-M and that doesn't have the same
supply limitations as AS01, and it's slightly
cheaper as well. So that makes it more scalable.
Yeah, I mean it's funny, it's not the property
you'd think about first – scalability,
and how that might have implications for cost
and price. But last price that I saw for RTS,S
was about €9 a dose and there are four doses. And
then the last price I saw for R21 was the original
price was 3.90 and it maybe has come down to
$3? So we're, we're talking about a 3X, say,
difference, which may not sound like much, but
is decisive in a lot of these cost-effectiveness
calculations because global health funding,
there's just not so much of it going around.
So when you think of cost-effectiveness, it's
not just how effective are these vaccines,
it's how much it cost to actually deliver
them to the kids who need them. So anything
you can do to bring the numbers down
is, it could change the equation.
Yeah. And just going back to the delivery schedule
you mentioned earlier Jacob, which is giving doses
of the vaccine at five, six, and seven months.
And then there's this booster dose or final dose
that's given around a year later, and none of
these time points are actually aligned with
the schedule for other infant vaccines. So what
this means in reality is that children and their
parents and caregivers have to travel for each
of these visits at another time. And what we're
finding is that people are not showing up for all
of their doses of vaccine, and so if they're not
getting the full course, it's gonna reduce
the effectiveness of both of these vaccines.
Right. If you have to travel three months
in a row, but you are busy taking care of
your other kids or you're at work, or, I
mean, it's, you can see how you might miss
a dose. And then if that happens, then
whatever we saw in the clinical trial
may not reflect the reality of what kids are
getting protected, so more work to do there.
Okay. So those are two
vaccines and they're imperfect,
but they are helpful for kids. Do you
think they're good enough, Katharine?
If we did this again today,
could we make better vaccines?
Uh, yeah, I think well, oh gosh.
Wow. That's a tough one. I think...
I mean, scientifically, not in terms of the
funding or trials or anything like that.
Yeah, I think we have better techniques
and technologies for developing
vaccines. Structured-guided design, reverse
vaccinology, computational protein design,
things that you've talked about in your
previous podcast episodes, where we really
try and understand more specifically what type
of immune response you want to generate. So you
can take the whole protein that you think is
important, and show that to the immune system,
but it might generate a mixture of
helpful responses and unhelpful responses.
So using these more sophisticated techniques,
we can try and understand which parts are really
helpful, and design the proteins or the
antigens to really elicit those responses
more carefully and more specifically. So using
those techniques, people are already doing this.
They're working on trying to make better
CSP vaccines, better blood stage vaccines,
and also vaccines that target the
transmission blocking stage as well.
But why were you hesitant before?
It's not clear that any of those will actually
be any better. So I think there was a really
interesting paper published by the Protein Design
Institute by Neil King, someone that we support
and think is an incredible institute for using
computational design to really improve vaccine
antigens. And they tried to make better versions
of R21, and I can't remember what the paper showed
exactly now, but there were many candidates
they assessed and they used this incredible
methodology to try and improve the vaccines, but
none of them looked substantially better than R21.
What do you think of the whole sporozoite
vaccines where scientists were just
irradiating the whole parasite at the
early stage and injecting that as a
whole? I think they were doing that
in the '70s, and that seems like in
that research it was pretty effective and
some people are continuing to work on it.
Yeah, absolutely. I think those are some
of the first data that really stimulated
the vaccine development community. They
showed really early on, decades ago,
that you could protect people by using these
irradiated sporozoites, and that work continued.
So a company called Sanaria, with Steve Hoffman
and others, developed the PfSPZ vaccine,
and this worked really well with
three doses in people in the US,
so people who had no experience with
malaria infections before. But when they
ultimately got this into children in Africa
who had had malaria infections in the past,
the vaccines didn't work very well, so that
hasn't moved forward for that population.
There's actually been some really
interesting work more recently that
they've used genetically attenuated parasites.
So instead of irradiating the parasites and
then using them, they've made them so that
they can't survive beyond the liver stage,
but importantly, if these parasites
live to the end of the liver stage,
then they're really protective. And there
was a recent study where they showed that a
single dose of this vaccine provided really high
levels of protection in their challenge trial.
But again, this was in people that
haven't been exposed to malaria before,
so while this looks really exciting at the moment,
it still needs to be tested in the field,
in people who have been exposed to malaria,
and then ultimately in children as well. But
it's really exciting. It's pretty game changing
if you can get a single dose vaccine to protect
against malaria; we've never seen that before.
But the challenge with these parasites is that
they need to be stored in liquid nitrogen,
so you can't just kill them like we have done
in the past with other whole pathogen vaccines.
They need to be viable, they need to be able to
survive in the liver, and that's gonna be quite
challenging for delivery in Africa, because there
aren't liquid nitrogen facilities everywhere.
Why does it have to be so cold?
That's the way of putting them in stasis.
Is it just preserving them?
Preserving them, yeah. So that they
can be woken up. They've either got
to be kept alive until you inject them,
or you can try and cryo-preserve them in
a way that they could be thawed,
and then they'd still be viable.
What if someone found a different way
to preserve them for a long time? Are
there other options? Can you
like freeze frame a vaccine?
No. The - no?
I have no idea. I feel, well, I've
been watching a lot of Pokémon and
Team Rocket has all of these crazy
tools and equipment to do things.
We can learn from them.
I feel like they would have a laser beam
that could just freeze someone in place.
That would be cool, yeah.
Let's take a note. Let, let's look into that,
I think that could be pretty interesting.
I know a funder that's just started there.
Yeah. Yeah. Let me just, actually I've
already got too much in my laser beam column,
someone else is gonna have fund that one. But...
Also this laser beam thing
that could freeze - could be
used much more widely than just malaria research.
You could zap people miles away. It's interesting
I don't hear people talking about this
more given how important it could be.
Yeah!
Now on our current technologies, boring, so
it sounds like - my sort of takeaways from
this section are that when people talk about
vaccines, the thing you always hear about is
efficacy. COVID vaccine is 90% efficacious, blah,
blah, blah, blah, blah. But that is one number.
Firstly, that number does not bake
in to the public narrative, duration.
It does not matter if something is 90%
efficacious and lasts for three months,
if it then decays. Secondly, it doesn't bake in
cost. What's the manufacturability of this? How
widespread is it gonna be in a global health
context? But then in addition, it doesn't bake
in how many doses do you need? And, in a context
where people might not be - they're juggling a
lot, may not come back for a second, third, or
fourth dose; getting down from four to three,
three to two or two to one is just an
incredibly big deal, not for scientists,
but for people in the real world who're
actually gonna be taking these vaccines.
So Katharine, is that a fair summary?
Yeah, absolutely. Spot on.
It reminds me of, you know the HPV vaccine,
where it was originally a three dose vaccine,
and then it turned out that actually one
dose was really effective. But it took a
really long time for them to change the
recommendation on how many doses people
needed. And now that they have that new
recommendation that you only need one dose,
you can actually scale it up
much more widely than before.
So, Katharine, if you had to make a
guess, I'm gonna put you on the spot:
in 10 years will we have an approved vaccine
in use, which is, say, two doses for kids?
10 years, I think, two doses is too
high a bar. I think we can get to three.
Mm.
I think we can get to a more durable and a
more protective vaccine with three doses.
What's the - what are the
barriers to making it happen?
I don't know. Maybe I wanna change
my answer there. I think 10 years,
I would put it 60% chance we can get to two doses.
Okay. But it's all to play for, you're
saying it really could go either way.
Yeah, it's not a done deal. I think
60% chance we can get to two doses,
like 90% chance we're gonna have a better vaccine.
Okay.
Three doses, 90%. That's too high, 80%.
Okay. So you're saying we've
got to plug away and get to
a better vaccine than even the one you invented.
Definitely! R21 is suboptimal. It can have
impact like we've discussed, but it's not a
game changing vaccine. The delivery challenges,
the durability - that all needs to be solved.
Hmm.
Okay. So challenge number one then. So you're
saying there's a good chance if we really push
for it, we can get to a better vaccine. Maybe
it's three doses, maybe it's longer duration,
and then - but we have to also be aiming at the
same time for even further improvement for kids,
and that's hopefully getting to perhaps two doses,
perhaps, you know, transmission
blocking, that kind of thing.
Yeah, absolutely.
So it's all to play for. Okay. Saloni, how
are you feeling at the end of this section?
This makes me sad.
I feel like it's so sad that one, our technology
has improved so much, but it doesn't seem to have
made that much of a difference in terms of
the efficacy – except for this one vaccine,
which is really hard to scale up because you
need to cryo-preserve the sporozoite stage,
which means that it sort of rules it out being
used widely. And the third thing, is that there
were like various vaccines that are in late stages
of trials right now that could have been in late
stages 10 years ago. It's just the combination of
all of that is just incredibly depressing to me.
Yeah. Well, can I try and cheer you up?
Yes.
Just to reorient to how many lives a vaccine
can save. That is even imperfect. You know,
if R21 or RTS,S - I mean R21 seems more likely
now - could scale up to more children who need it,
tens of thousands of children's lives would be
saved already. And then Katharine is telling
us that within 10 years, we have a good shot
at an improved vaccine that's even better,
so that is gonna matter to a lot of children.
And science, the reality of this problem
is the hardness of it is set by nature,
and nature is a vicious, vicious, test setter
sometimes. The fact we've got this far, I mean,
that is pretty impressive and we have a ways to
go, but there's a line of sight to improvement,
even if not to the absolute a hundred
percent blocking one dose thing.
I mean, I'm happy for the children
who are getting these vaccines,
but it's just that counterfactual. It's
just very hard to get out of your head.
Yeah. Yeah. So, Katharine, as you look
to the next 10 years, how do you feel?
I'm optimistic. I think we can do better. I think
we've got great people doing incredible work,
great new tools and more people thinking
about the problem end to end. So more
people thinking more about more than just
efficacy, with all the other criteria you
raised that we should be considering.
More developers are now aware of all
of those things to consider in the development
pathway, and so I think there's a lot of hope.
There's also the current rollout,
right? That we could scale up.
Yeah, I think that's a tough one. I think
it's a really difficult funding environment,
so we don't have enough donor support to provide
R21 and RTS,S or the countries that
would like it, that would need it,
and are requesting from Gavi. So if we had more
support coming from the different donor countries.
The UK's cutting back, US cutting
back, Japan's cutting back.
Germany as well. What I read from a report,
talking about the situation at the time,
two years ago, was back then, both of
the vaccines had been pre-qualified
from by the World Health Organization
and they were being rolled out and they
estimated that it would take another
12 years after that for all children
under three in the countries with high
malaria prevalence to be vaccinated.
And another 2.5 million children were expected to
die being unvaccinated from malaria, and the main
constraints to increasing the number of children
who were vaccinated fast was a lack of funding.
And I remember reading this and finding
it surprising in one sense that this was
the only constraint. But also, I think,
after everything that we talked about,
thinking that it was actually not that surprising
and just very depressing. But the fact that if you
had a few more billion dollars of funding
for Gavi, which supports vaccination in
countries around the world, you could vaccinate
enough children to save another 300,000 lives.
The other thing that was interesting to
me about this was that one of the reasons
that there was this funding constraint
was that one of the countries with the
highest burdens of malaria was Nigeria. And
Nigeria had just increased its GDP enough
to be placed in a higher threshold, of a
higher income country, according to Gavi,
and that meant that they were no longer eligible
for financial support to purchase these vaccines,
and that meant that a lot of children would
go unvaccinated, and that the cost was just
so much higher after just passing this threshold.
It seemed very bad to me that that was the case.
But there is some good news, which is
that there was another deal where the
price of R21 was reduced from $4 to $3 per dose,
and that would save around $90 million and
help vaccinate another 7 million children.
So all in all, what do you each wish
that donors and funders and other
decision makers understood about vaccine
development that they're getting wrong?
I mean, I think it's one of these situations where
actually throwing money at the problem would make
a difference. And that is something that people
might find surprising in other fields, but here,
funding Gavi would actually go a pretty long
way. Or funding the other types of malaria
vaccine research would go a long way. I
think that's quite surprising to people.
I think we should really be learning from
our experience with RTS,S and R21. And the
biggest problem, with both those vaccines, is
getting all of the doses into the children,
that they need. So thinking more carefully about
how you develop a product that's deliverable,
earlier on in development, could have
such a dramatic impact on the impact the
vaccine can actually have. And I don't
think the researchers doing the work,
the ones running the very first trials in
humans, are thinking about that enough.
Right? It's less pizzaz-y, but actually
testing different delivery schedules in
the clinical trials can have these incredible
downstream effects of what gets
recommended for millions of kids.
And maybe it's not fair to put that all on
the researchers and the developers actually, I
think. They're asking for funding to do the work.
Funding's tight and limited, funders will give you
the bare minimum, to do the bare minimum. So you
can only test one schedule, and so you have to go
with what you have the data on already, or what
already looks promising instead of exploring what
the other options could be. To me, that's also
on the funders to really understand that as well.
I think another thing is - that people
may not know is just how important it is
to have clinical trial infrastructure, to have
better ways of running trials more efficiently,
but also just more sites, more people doing
these tests, being able to test multiple
vaccines and not having the situation
where people have to prioritize funding
for one vaccine over the other, at the
expense of testing the others as well.
But I think there's also another part to
the story as well in that, with malaria,
everybody knows about malaria. The burden's really
well known. So as soon as a malaria vaccine was
developed, countries were asking for it. They
knew they had a problem, they wanted the vaccine
and they're pushing to roll it out to protect
people, so those vaccines can have an impact.
But there are other vaccines that we've
tried to develop in the past where we
didn't have good data on the burden in all
the countries that possibly needed it. And so
I think the Hib vaccine was a good example.
It was developed, it was ready to be used,
but countries didn't know they had a problem.
So it was this huge delay in rollout. There's
so much more that needs to be done when
you're thinking about developing a vaccine,
beyond just developing the product,
thinking about how it's gonna reach people,
and how people are gonna understand whether
they need the vaccine, what the demand is.
That was quite an episode. That is our first
episode where we had a expert interviewee with
us the entire time. Thank you so much, Katharine.
And now it's time to conclude with what some
of the things, what are some of the things we
learned or that stuck out to us from this episode?
And I'm gonna start. Number one, how much
you can learn from patents. It turns out
that there are people who read them and then
they tweak them, and then they change them,
and then they make new inventions. I mean, that
really gave me hope for public knowledge again.
That was really cool to hear about.
Saloni, what did you, what stuck with you?
So I had a bunch of thoughts. The first
one, which I was thinking about before
we started recording was that, and
this is a very unpopular opinion,
but some PhDs are just better than others
and some fields are better than others too.
I know it's controversial, but I think more
students should go into infectious diseases,
and should go into vaccine development.
And I have many thoughts about which fields
should move into those, but I won't name them
- they'll probably, they'll know who they are.
The other was that I thought it was really
interesting to hear about the Jenner Institute,
and how it was set up in such a way that there
was a manufacturing facility that researchers
could work with, and they could learn from
that stage of the process in manufacturing.
And I thought maybe more institutes should
be set up like this, where you can see the
both the basic research and the translation and
the manufacturing happening in the same place,
and learn from these different stages. That I
thought was a really cool thing to learn about.
The other that stuck with me throughout this
episode was that malaria is very complicated,
especially compared to the other pathogens
that we've talked about in previous episodes.
It has many different stages of its
lifecycle, it changes shape. It's harder
to develop vaccines for malaria than for many
other diseases. And there were various parts
of that process that were just very tricky
to do scientifically. It was hard to find
good animal models that helped replicate
what the disease would be like in humans.
The next was that a lot of the research funding
for malaria was affected by priorities that
high income countries had. So in the 1950s
during the global Malaria eradication program,
the funding for research dried up and a lot of
researchers were made program operators in the
eradication program, and that stalled research
until the Vietnam War, where the US Army troops
were facing potentially drug resistant malaria,
and there was now a renewed need for research
into new malaria drugs, but also malaria
vaccines. And that is where the RTS,S vaccine
originally came from, was research from people
who were working on that during the Vietnam War.
So that stood out to me as well, that we sort
of think of research happening in the lab,
but it's really actually influenced by
all of these much broader considerations,
and the historical context, and things like that,
that I think people don't appreciate enough.
So the first one for me is
probably the cost, scalability,
and deliverability are actually really
important. People should think about them
earlier in the process. I think it's clear
from the R21 and RTS,S experiences that the
vaccines could have much greater impact
if those things were considered earlier.
I also thought that just within that
process, it's not just the broader concerns,
but at every stage of vaccine development, these
things are really important. Like how you develop
the adjuvants and how expensive those are, or
how that affects the efficacy of the vaccines,
and how accessible they might be later on as well.
And then things like, how does the dosing of the
vaccine that's being developed affect how easy
it is to scale it up, across countries, or across
millions of children, I think is something that
people underappreciate. And then similarly, the
vaccination schedules - the fact that the malaria
vaccine is taken at different ages than other
childhood vaccines, and how that affects uptake
of the vaccines, is something that was new to me.
And just this idea of making things more efficient
at all of these stages could be really important.
I've been reading the book The Origins of
Efficiency by Brian Potter, and one of the key
things that stood out to me from that book was
just how much progress we've made in medicine,
but also engineering, and all parts of life
were from improving the efficiency of things
that people have already discovered, and that
that stage can often make the difference between
something that is possible versus something
that's actually used by millions of people,
and I think that's actually
a huge part of the picture.
The other thing that I have always been
thinking about is just how different things
could have been. Like what others, what other
alternative universe we could have lived in,
if things were different. And the key
things that I think about here are:
one, how things would be different if
there was more funding. And second,
how different things would be if there was better
infrastructure for running clinical trials.
And we talked about a bunch of examples of how
that could have been different. So one, that
probably would've sped up the developments of the
RTS,S vaccine, the first malaria vaccine. Having
the clinical trials sites set up earlier, that
would've made a difference. Having more funding,
that would've made a difference. But then we also
talked about other vaccine candidates for malaria,
and how more funding for that research could
have changed the picture and sped up the trials
for those vaccines. And then finally, the
rollout of the malaria vaccines that have
already been approved could be sped up with more
funding. And that funding was the constraint,
and still is the constraint, to
getting that out to more children.
And I think that often people think of
this as purely a scientific problem,
but I think that's not the case, and
that in many situations when we're
talking about diseases that affect people and
poor countries, often commercial incentives,
and funding, and the historical context and all
of these things actually have a very big impact.
I think it's really easy to look back and think
about how things could have been done differently
with hindsight. But it's really important
to remember that these were really uncharted
times for this type of vaccine, and it's really
quite amazing what was achieved over the time.
Obviously, we all wish things could have been done
faster and can keep going faster in the future,
but it is quite remarkable what was achieved. But
I think it's important that we do look back. I
think we should all be looking at the experiences
of the past and learning from them so we can
improve what we're doing as we're developing
future vaccines; learn from those mistakes.
And you know, now as a funder, I'm trying
to take a lot of those lessons and those
experiences and apply them to the development of
next gen malaria vaccines and Strep A (Group A
Streptococcus) vaccines and any other products
we end up working on at Coefficient Giving.
What you just mentioned, made me realize that the
alternative universe that we could have lived in:
it could have been faster, but it also could have
been slower, and I hadn't thought about that.
I think my main takeaway from looking
backwards into the past today is about
the present and about the future.
And it's that we live at a time of
scientific wonder. We - people who invented
world-changing technology are among us today.
Invention is often a process of building on other
people's work, tinkering, tinkering in the lab,
and taking care of those lab notebooks, looking
in an electron microscope, trying an experiment,
changing what you started with, trying another
experiment. And these people are heroes.
They're real people. Sometimes you can
even get them to come on your podcast,
thank you very much, Katharine. And to anyone
listening, you may know one of these people,
and society may not recognize it yet, and they're
still inventing and they're still trying stuff.
You may become one of these people in the
future. And when it comes to science, we are
all in this together. We're trying to figure
out what is true and what we should do next.
So I just wanna end by saying,
Katharine, thank you very much.
This was very enjoyable and I'm very
excited about everything that comes next.
Thank you. It's been great
to be here. Great to chat.
If you enjoyed this episode, you should rate us
on Spotify or Apple or wherever you listen to this
and share it with everyone you know, including any
parasites that you are currently infected with.
Maybe they are heroes too, you never know,
they could contribute in their own way.
Please share this one in particular with
anyone who's considering starting a PhD.
Yes!
Great. See you next time everyone!
Bye!
Bye!
Bye!