August 25, 2021 • 30 mins
How did scientists figure out how to make a coronavirus vaccine two years before coronavirus struck? And what the hell is a spike protein?
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Speaker 1 (00:08):
School of Humans. In nineteen sixty six, an outbreak of
respiratories and sicial virus spread through Washington DC. RSV is
a highly contagious virus that usually pops up in the
colder months. It can block the airways of infants and
cause pneumonia in older adults. Tens of millions of people
(00:28):
get sick from it every year, and thousands die. To
stop those deaths, a team at the National Institutes of
Health created some RSV vaccines and tested them in babies,
mostly babies from poor black families. The trial went badly,
really badly. Dozens of infants got a new RSV vaccine,
(00:49):
and not only did the vaccine not protect them from
the virus, it actually seemed to expose them to graver sickness.
So the vaccinated babies who caught RSV fared worse than
those who got no vaccine at all. Eighteen of those
kids ended up in the hospital and two of them die.
As far as vaccine trials go, it was a total disaster.
(01:12):
It's a cruel irony of vaccine development that those two
kids deaths fifty years ago indirectly led to one of
the greatest successes in the history of modern drugs. The
COVID nineteen vaccines, the single biggest breakthrough in coronavirus vaccine research,
was inspired by scientists who wanted to protect kids from RSV,
and because of that work, they figured out how to
(01:34):
make a vaccine for coronavirus two years before the first
case of COVID nineteen. In this episode, we're going to
get a little technical on you, but it's necessary in
order to get to the heart of how these vaccines work.
From iHeartRadio and School of Humans, I'm Sean Revive and
this is long shot. Yeah, people want, you know, they
(02:00):
want to see smoking vessels of like Purvalla, but you know,
by all just for not chemists. That's Jason McClellan. He
works at the University of Texas in Austin, and he's
telling us that his office isn't as exciting as visitors
might think. I mean, when people come to visit, we
add food, gallering and things because they want to see yellow.
But like everything the work of his water, it's like biological.
(02:23):
I'm in Austin, Texas, at the University of Texas. I'm
in one of the departments called a Molecular Biosciences department.
I'm a structural biologist. Structural biologists zoom a way in
on large molecules or groups of molecules and figure out
how their parts are put together and why they work
the way they do. They spend a lot of time
(02:45):
looking at proteins, which play a ton of roles in
the body of humans and other living things. Proteins help
you grow, digest food, fight disease, stay energized. They also
help bind cells together and transport nutrients. Some hormones like insulin,
are proteins. Antibodies are proteins, Enzymes are proteins. Hemoglobin, which
(03:07):
is the dominant component of our blood, is a protein.
Structural biologists like Jason want to know exactly what proteins
look like. Without the structures, we don't really know what
these proteins look like. We draw them as ovals or squares.
But once we determine their structures, we're able to like
three D print the actual molecule essentially and know where
every amino acids is located on the protein, how the
(03:29):
proteins fold The structure leads to function. So by understanding
the structure, we know something about how the protein works.
And if you know how proteins work and how they look.
You can figure out ways to alter them, change amino acids,
maybe make the protein more stable, or chop off some parts.
We don't want to try to make them the best
(03:50):
possible vaccine antigens. Understanding what specific proteins do is the
key to the COVID vaccines. But it's not like Jason
went to college and majored in proteins. Oh, it was
a kind of winding path, I guess. I went to
college Wayne State University in Detroit, Michigan. I wanted to
(04:11):
do pre med and be a doctor. Most I was
just trying to think of things I could do to
help people. But early on I realized I really liked chemistry.
Was quick good at chemistry, so I went to graduate school.
I've learned a technique called X ray crystallography, and that's
one of the methods for determining structures of proteins. But
(04:32):
ultimately I wanted to do a bit more than just
determine destructures. I wanted to try to have some applied
research to create things that could end up going into
humans and improve human health. Around two thousand and eight,
Jason heard about a guy at the NIH doing a
lot of cool stuff with HIV, looking closely at the
virus's structure and trying to design a vaccine. He joined
(04:54):
the lab there, and while at the NAH he ended
up working with a doctor and virologist named Barney Graham,
a world expert on RSV. The RSV vaccine that failed
back the sixties was made by weakening a strain of
the virus by passing it through animal tissue or human cells.
That's the way the great vaccine creators of the past,
like Maurice Hilleman made their vaccines. Jason and doctor Graham
(05:17):
wanted to create a vaccine in a totally different way.
They wanted to manipulate a specific protein of the RSV virus,
the one the virus uses to infect human cells. It's
called the f protein f as in fudge, and it
comes in two forms or a scientists say two confirmations,
prefusion and post fusion. Here's Jason to explain more. Proteins
(05:42):
exist in some initial confirmation on the surface of the virus.
That's what we call the prefusion confirmation. Then there's an
event that causes the protein to begin refolding and rearranging,
much like a transformer, going from a car to a robot.
Parts of it, parts of the protein, just start moving
and refolding, and it ends up forming an intermediate confirmation
(06:04):
where it's part of the protein into our host cell membrane.
That's pretty confusing, so let's try and visualize it. There's
a virus cell and a human cell. We'll picture them
as tennis balls. The virus tennis ball has its protein
on its surface, sort of shape like a cone or
a stubby mushroom stalk. That's its f protein. So the
(06:29):
virus tennis ball looks for human tennis balls in the body,
and when it finds one, here's what happens. The mushroom
stalk stretches and elongates and attaches itself to the human
tennis ball. So it's like a bridge between the two
tennis balls, human and virus. So it's stock between the
host cell membrane and the viral membrane. The membrane of
(06:49):
a cell is like its skin. It separates the inside
of the cell from whatever is on the outside, and
then it bends back around like a hairpin to bring
the two membranes together, and then it adopts this final
state called the postfusion state. So after the stock on
the virus tennis ball has elongated and attached itself to
the human tennis ball, it folds itself in half in
(07:11):
order to bring the two tennis balls together. That's the fusion.
And so when the f protein has already elongated and
then folded, it's in its postfusion form. By then it's
too late. You want to teach your body to fight
the prefusion form before the mushroom stock has folded and
attached to the human cell. And so, if you think
(07:34):
of your immune system as a security guard, you want
to train your immune system to recognize the form that
might impact you, like the dangerous form, and that's the
prefusion form. If you train it to recognize the postfusion form,
the prefusion form can still sneak by you. So in
order to train the immune system to recognize the prefusion
form of rsv F proteins, Jason needed to keep the
(07:56):
proteins in their prefusion unfolded form. But that isn't easy.
First of all, rsv F proteins really want to go
into their post fusion form. Second, proteins are tiny. It's
not like they could go in with tweezers and hold
the F protein in place. The F protein has a
molecular mass of fifty seven point four kilo daltons, which
(08:18):
means it's weight in Grahams has twenty one zeros. After
the decimal point, it's really difficult to see what they
look like, much less alter their behavior. And nobody could
figure out how do we create a form of the
prefusion molecule that will stay in the prefusion shape and
allow us to purify it and inject it into evil.
But in twenty thirteen they had a breakthrough. They were
(08:41):
finally able to determine the exact structure of the prefusion
form of the rsv F protein. Plus they figured out
how to keep it in that form, how to keep
it from elongating, and we could start making changes like
adding in little molecular staples to link two regions together
so that we the one part couldn't pull away from
the other. And that work. We were eventually able to
(09:01):
make four different changes to the protein that really locked
it in the prefusion confirmation and allowed its use as
a vaccine antigen. Basically, they discovered how a sort of
staple the mushroom stock in place, and when Barney immunized
mice and compared postfusion versus prefusion, the mice receiving the
(09:21):
prefusion form of the F protein elicited neutralizing antibodies about
ten times higher than those that received the postfusion This
is huge. This was the first time structural biology had
helped discover a new way to stop a virus. Science
magazine called it one of the top ten breakthroughs of
twenty thirteen, and their success in stabilizing the F protein
(09:44):
made them want to try the same process with other
similar viruses. What else could we take this new approach,
the structure based approach, and apply to what other pathogens
are important? And that was around the time that the
MIRS coronavirus had emerged in the Saudi Arabia and the
Middle East. That's Middle East respiratory syndrome, which is caused
(10:06):
by a coronavirus called MRS Covey. The disease was first
reported in Saudi Arabia in twenty twelve. It causes bad
respiratory illness, fever, cough, shortness of breath, and it can
eventually kill you with pneumonia and kidney failure. Even today,
(10:27):
there are still cases that pop up on occasion. Thirty
five percent of people infected with it were dying. It's
a real lethal virus, and we thought that this would
be a good target to try to take everything we
had just learned about RSV and apply it to not
just mers, but coronaviruses in general, because we knew Stars
coronavirus had emerged in China in two thousand and two
(10:49):
and it caused an epidemic. Remember Eddie Holmes spoke about
the First Stars in episode one. I realized is that
raccoon dogs. They were implicated in the First Stars I
break of two thousand and two two thousand and three
because they were positive. First came Stars one, then came
Mrs Here's Jason again, and then ten years later we
saw Mirrors emerge. We felt like maybe we were on
(11:10):
a ten year cycle or something where we keep having
coronaviruses emerge into the human population, and so we wanted
to figure out how can we do structure based vaccine
design or coronaviruses to make the best possible vaccine antigens.
Jason and Barney Graham wanted to use their ability to
zoom in on viruses and their ability to play around
(11:31):
with them to make better vaccines. Since Mrs Covey was
on their radar, they focus on that virus MERS has
a protein very similar to the F protein of RSV.
It's called the spike protein. The spike protein acts pretty
similarly to the F protein, it just has this additional part.
(11:52):
If you're thinking about the F protein as a mushroom stock,
the spike protein is kind of like a full mushroom
with a cap. When attacking a human cell, the cap
of the spike protein binds to a certain enzyme on
the surface of the human cell. The enzyme is called
the ACE two receptor. The ACE two receptor sort of
pops off the spike protein's cap, and then the spike
(12:14):
protein stalk does all the things the F protein does.
Based on decades of literature, for many researchers, it was
clear that the spike protein is a key component of
any vaccine because when humans are infected with coronaviruses, they
make a large antibody response to the spike protein because
it's really that that's the major protein on the surface
(12:36):
of the of the virus. So we know we needed
to use spike protein as the vaccine but we also
know that the spike protein can change shapes and isn't
so stable, so then you know what form do you
want to use. Our previous work, it's shown that what
you really want to immunize with is a prefusion stabilized
form that that can't change shape. So that way we
(12:57):
train our immune system to recognize the shape of the
spike protein as it exists on the surface of the virus.
So with coronavirus, they knew they wanted to stabilize the
spike protein, the key protein on its surface. They wanted
to make sure it did not elongate. The spike protein
was pretty unstable. Its stock was liable to elongate and
(13:18):
go to post fusion form on the drop of a dime,
and they had trouble even seeing its structure. To make
it easier, they switched to another virus, one that we've
all gotten, HKU one. That's one of the four coronaviruses
that we've probably all been infected with. It's one of
the many causes of the common cold. And for whatever reason,
(13:39):
the spike protein from HK one was actually pretty stable
and it was amenable to the structured determination efforts, and
we brought in another group, doctor Andrew Ward's group at
the Script's Research Institute. He's an expert in cryoelectron microscopy,
and working together they were able to get that first
structure of a human coronavirus spike protein in the prefusion shapes.
(14:02):
Now we had our first blueprint to start making changes
tweaks to stabilize spike proteins of coronaviruses. Using this blueprint,
Jason's post duc Nian Chung Wang look closely at the
mirror structure here, he is, it's actually pretty boy, but
it's also increasing. Why is it boring and why is
(14:24):
it interesting? Is that we got to try okay and
again most of the time it's got to feel yeah,
it's not that too easy. Nianshuang tested more than one
hundred different mutations to the spike protein until finally coming
across two changes that stabilized it, that kept the spike
in its pre fusion form, and it was really stable.
(14:47):
It stayed all in the pre fusion shape. What was
exciting is that the region where we made these changes
is very similar between different coronavirus spikes, So the same
changes we could also introduce them into stars. Kobe from
two thousand and two, and that led to stabilization. So
my twenty seventeen we really had this method, kind of
(15:08):
a universal method for stabilizing data coronavirus spikes in their
prefusion confirmation. But there was one problem with their success
stabilizing the MERS spike protein. Nobody really cared. It flew
away under the radar because by then it was evident
that MERS, as dangerous as it was, didn't spread very easily.
(15:30):
A few people were getting MERS a vaccine for it
didn't seem super important. Yeah, it's kind of painful. At
that time, most coronavirus at that time was not considered
a big issue because there are few our cases, so
people didn't pay matt attention on that kind of coronavirus.
(15:53):
Although their work didn't get much attention, they knew they
had a vaccine technology ready to be put into action.
By twenty seventeen, they were prepared to test their stabilizing
spike protein method on another coronavirus. They just needed an outbreak.
And then two years later we found out in the
beginning of twenty twenty that this new virus that was
(16:15):
causing pneumonia outbreaks in Wuhan China was a coronavirus and
very similar to Stars Kobe Ie. They'd finally have a
chance to test out the spike protein in real life,
but a big question remained, would it work in people.
Jason and his team spent years figuring out how to
(16:37):
keep a spike protein stable and use that to make
a new kind of vaccine, but they needed an outbreak
to test it on real people infected by a coronavirus.
Then all of a sudden, they have a real time
pandemic crashing down on the world. The reports were coming
out of these pneumonia clusters in Wuhan. We could just
see it following along on science, Twitter and on the news,
(16:59):
and so people were already kind of nervous, especially in
the coronavirus feel that we could be looking at the
beginnings of a coronavirus outbreak. And then it was early
in January when it was learned that in fact, it
is a coronavirus, a beta coronavirus that's similar to the
first Stars Kobe from two thousand and two. At this point,
(17:20):
Jason's working at the University of Texas and he's on
vacation with his family. Barney Graham called me. He said
he was in contact with the US CDC Chinese CDC.
They were going to try and work quickly work with Maderna.
Maderna was then an upstart company based in Cambridge, Massachusetts
that had never brought a vaccine to market, but they
tested several vaccines for other viruses, and Barney Graham had
(17:42):
a plan to work with them on a bat born
virus called NIPA, but when the novel coronavirus came along,
doctor Graham told Maderna they should focus on that instead,
and he wanted to know if we were interested in
continuing our collaboration to determine the structure of the stars
Kobe to spike protein and use that information to create
(18:03):
the vaccine antigens. Jason texted his graduate student Daniel Rapp
and told him they were going to be busy the
next few days. Based on this information, we were sort
of ready to go. That's Daniel, because we've been studying
these spike proteins for such a long time. We knew
how to effectively stabilize spike in the pre fusion confirmation
and that acts as a really good vaccine candidate, and
(18:24):
so during that time we were kind of just like
sitting on our hands, like really anxiously waiting for that
information to become available to everybody, because that was the
thing that was holding us back from getting started back
to Jason, and then we just kind of had to
wait a couple of these because nothing we could really
do until the genome sequence became available so we could
see what the sequence of this spike protein was. On
January eleventh, a scientist in China made it available for all.
(18:46):
That was John jen Jang who sent the sequence to
Eddie Holmes in Australia, who then posted it online. Jason
got the sequence and started working on a vaccine with
his team the next day. So what does it actually
mean to get a virus's genetic sequence. The sequence is
kind of like it's barcode. You're scanning the letters in
its genome to figure out actually what it is and
how it works. It's essentially a file like somebody can
(19:09):
just you know, it's an attachment, the text file that
somebody can send us containing the sequence, just a bunch
of letters, so like computer code. And then we have
to figure out what changes we want to make very
quickly just by taking that sequence and aligning it to
the other spike sequences. We knew right where to put
the two changes that we had identified earlier, so that
(19:30):
was probably done within a couple of hours. Just the
design of these constructs. Remember, Jason's team is looking for
a way to alter the proteins on the surface of
the virus so they won't go into that post fusion confirmation.
The change that Niche Wong and the team had discovered
working with mers is called the two P mutation. The
P stands for prolene, one of twenty amino acids that
(19:53):
are the building blocks of all living things. Proleins are
special because they're the most rigid amino acid and because
they are rigid. Swapping out two other amino acids for
two proteins at a certain joint of the spike protein
keeps the mushroom stock in place, meaning it keeps it
in pre fusion form. But Jason and his team couldn't
(20:17):
just do the two P mutation on the laptop. They
had to do it in real life. There are companies
out there that can take a modified genetic sequence like
the one they designed at UT and turn it into
something physical. And you need to turn it into a
biological substance. Like actual DNA. And so that's where we
need to work with the companies, where we send them
(20:38):
the file and they're able to synthesize DNA and send
it send it back to us, and then we have
to stitch some of it together and do some other things.
And so in the lab we were working with the DNA.
When Jason says he's working with DNA, he essentially means
that they're making changes to genes in order to program
human cells to produce the stable spike proteins. Remember this
(20:59):
is the key to the whole vaccine. Our own cells
will be the factories that produce the stable spike proteins,
and the DNA is the thing sending those instructions via
messenger RNA. So that way the cells realized the instructions
have changed, the recipe has changed, if you will, and
they just make a protein containing proteins at those positions
(21:20):
instead of the original amino acids at those positions. I
think within ten days, maybe a bit more, Nianchwang had
had cloned like ten different plasmids. Plasmids are like small
snippets of DNA molecules, ending Chwang was working around the
clock to stitch them together. Into a full DNA strand
that could encode for the spike proteins. Meanwhile, Barney Graham's
(21:43):
lab was talking to MODERNA telling them how to stabilize
the spike protein with a two P mutations, like what
spike protein to encode in the mRNA, where to put
the stabilizing prolein mutations. Then came January thirtieth, twenty twenty.
It was an exciting day. We Daniel was harvesting. He's
talking about his grad student, Daniel Repp, the purified spike
(22:05):
proteins that were produced by the cells we had growing
in the lab. So we was able to harvest the spike,
purify it and start freezing cryoEM grids. cryoEM stands for
cryoelectron microscopy, a method for seeing proteins at atomic resolution. First,
Daniel would flash freeze the proteins in ice on a
(22:27):
tiny mesh disc. Then he'd use an electron microscope to
take thousands of two dimensional images of the proteins. A
computer program then use those pictures to create a three
D image showing the structure of the proteins. That allowed
us to start the data collection that night, and we
could see the individual spike proteins for the first time,
(22:48):
and within twenty four hours we had collected a complete
data set and we got the first looks at the
molecular shape of the coronavirus spike protein. Within about thirty
days we had determined in a manuscript submitted that paper
has been sighted close to four thousand times now we have.
We were sharing the coordinates of the structure, the blueprint
(23:09):
of the structure to people all over the world. We
were shipping the plasmids that we had made two hundred
groups or so. Is that way they could make the
spike protein in their labs for diagnostics, for antibody isolation
or additional structural studies. So it is a really crazy
time early last year. Now they knew exactly how to
stabilize the spike protein the mushroom shape on the surface
(23:31):
of the coronavirus. They'd actually created stabilized spikes in the lab,
and the pharmaceutical company Baderna would use these stabilize spikes
as building blocks for the vaccine. They are just directly
synthesizing the mRNA, but it's still at the instructions level,
such that when the RNA is injected into a person
(23:51):
that person sells read the recipe and make a protein
that contains two proteins at these positions rather than the
other amino acids that the virus normally uses. RNA is
the sort of middleman between DNA and the spike proteins.
We'll learn more about this in the next episode, but
the saying amongst scientists is that DNA makes RNA, makes
(24:16):
proteins makes life. Maderna's vaccine sort of skips the DNA
step and sends the mRNA or messenger RNA directly into
the body. Maderna encapsulates the mRNA in a fatty sphere
called a lipid nanoparticle. Another thing we'll talk about in
an upcoming episode. That bubble helps the mRNA get to
(24:37):
ourselves without falling apart, and when it does, our selves
get the recipe from making two p mutated spike proteins.
They make them, and the immune system sees these coronavirus
proteins in their prefusion form, and the immune system learns
that they are a threat. It learns that a spike
protein in the folded hairpin shape is an enemy and
(24:59):
the body has to fight it and stop it from spreading.
If you get infected with coronavirus. The body now knows
what to do when it comes across the spike protein
in pre fusion form. It knows how to keep you
from getting sick. They tested the vaccine in mice and
saw that it produced an antibody response, and then they
(25:20):
readied it for humans. By March twenty twenty, Maderna had
enough vaccine to be used for a phase one clinical trial.
That material was shipped to the different sites in the
US where they began immunizing the first forty five people
with different doses, testing side effects, dose response, the level
(25:41):
of antibodies being produced. Yeah, I think it's like it's
like sixty three days or sixty five days something. After
the genome sequence was made available online, the first people
are being immunized, which is incredible. Um. Hi, my name
is Nicolas Nicola in the second episode was one of
those first people. I was part of the Phase one
of modernas vaccine trial for COVID. Feisser and Johnson and
(26:07):
Johnson also used the two P mutation for their COVID vaccines.
It's the driving force behind all the vaccines that Americans
are getting and of some other vaccines being made around
the world. The last year is difficult because there's a
lot of mixed emotions because there are certain scientific successes
that we would normally celebrate, but the whole time the
economy is being devastated. People are losing their jobs, hospitalizations, deaths.
(26:31):
So it's really a range of mixed emotions where we're
excited for the science and everything we've been working on
for years being translated into a vaccine that was looking
very promising, but at the same time also just really devastating.
We spoke with Jason in March of this year. At
the time, three vaccines were already approved for emergency use
by the FDA, More than thirty million Americans had already
(26:54):
been fully vaccinated, and millions more were scrambling for appointments.
Me and my producer Gabby had gotten the Maderna shot
a few days earlier, but Jason still hadn't been vaccinated.
He was young and healthy, not a frontline worker, happy
to wait his turn. He got his first shot a
couple of weeks later. The search for an RSV vaccine
(27:26):
after that trial went bad in the sixties inspired the
technology used in today's COVID vaccines. But what about RSV
that virus that still kills thousands of people every year.
It's normally a virus that peaks in winter, but it's
been surging in children this summer alongside of and maybe
even because of the surge in the coronavirus delta variants.
(27:47):
There's still no vaccine for RSV on the market, but
they're working on it. Last year November October of twenty twenty,
prefusion f proteins have gone into phase three clinical trials,
and yeah, we're really excited about that. It's taken a
long time, that's sort of the normal vaccine development timelines,
starting a thirteen with the antigen just entering phase three
(28:09):
clinical trials in twenty twenty, but yeah, everything still looks
really good and we're really excited by it. Scientific failure
and scientific success are unstable concepts, about as unstable as
prefusion spike proteins. When a trial for an RSV vaccine
failed about as badly as a vaccine trial can fail,
(28:30):
it led to a newer and better way of making vaccines.
Fifty years later in twenty seventeen, when they stabilize the
spike protein, Jason and Nichuang and Daniel and everyone else
they worked with. All they got was crickets, but they
did it anyway. Here's Daniel Rapagin. Yeah, it's it's a
little surreal because we would be doing this work whether
(28:50):
or not COVID nineteen became a pandemic. We would still
be studying the spike protein figuring out how it worked.
But it's been a little surreal to have so much
attention paid to our work because, like as I've been
describing to you, we do things that most people would
think of is just like minutia, Like if there wasn't
a pandemic, we would still be doing this and people
would wonder why. The best example of it is, for
(29:13):
the past like five or six years, I've been telling
people I studied coronaviruses, and up until like a year ago,
people would say, what's a coronavirus. On the next episode
of long Shot, we'll speak with the founders of Moderna,
a company that started with essentially zero employees before becoming
one of the biggest names in COVID nineteen vaccines. We'll
(29:34):
also find out what role Jennifer Aniston played in that
origin story. Today's episode of long Shot was produced, written,
and narrated by me Sean Revie. My co producer is
Gabby Watts. Special thanks to Noel Brown and iHeartRadio and
journalist Alan Dove and Ryan Cross. Executive producers are Virginia Prescott,
(29:55):
Brandon Barr and Else Crowley. Long Shot was scored by
Jason Shannon. The score was mixed by Vic Stafford. Sound
design and audio mix was by Harper Harris with Tunewelder
(30:22):
School of Humans
School of Humans. In nineteen sixty six, an outbreak of
respiratories and sicial virus spread through Washington DC. RSV is
a highly contagious virus that usually pops up in the
colder months. It can block the airways of infants and
cause pneumonia in older adults. Tens of millions of people
(00:28):
get sick from it every year, and thousands die. To
stop those deaths, a team at the National Institutes of
Health created some RSV vaccines and tested them in babies,
mostly babies from poor black families. The trial went badly,
really badly. Dozens of infants got a new RSV vaccine,
(00:49):
and not only did the vaccine not protect them from
the virus, it actually seemed to expose them to graver sickness.
So the vaccinated babies who caught RSV fared worse than
those who got no vaccine at all. Eighteen of those
kids ended up in the hospital and two of them die.
As far as vaccine trials go, it was a total disaster.
(01:12):
It's a cruel irony of vaccine development that those two
kids deaths fifty years ago indirectly led to one of
the greatest successes in the history of modern drugs. The
COVID nineteen vaccines, the single biggest breakthrough in coronavirus vaccine research,
was inspired by scientists who wanted to protect kids from RSV,
and because of that work, they figured out how to
(01:34):
make a vaccine for coronavirus two years before the first
case of COVID nineteen. In this episode, we're going to
get a little technical on you, but it's necessary in
order to get to the heart of how these vaccines work.
From iHeartRadio and School of Humans, I'm Sean Revive and
this is long shot. Yeah, people want, you know, they
(02:00):
want to see smoking vessels of like Purvalla, but you know,
by all just for not chemists. That's Jason McClellan. He
works at the University of Texas in Austin, and he's
telling us that his office isn't as exciting as visitors
might think. I mean, when people come to visit, we
add food, gallering and things because they want to see yellow.
But like everything the work of his water, it's like biological.
(02:23):
I'm in Austin, Texas, at the University of Texas. I'm
in one of the departments called a Molecular Biosciences department.
I'm a structural biologist. Structural biologists zoom a way in
on large molecules or groups of molecules and figure out
how their parts are put together and why they work
the way they do. They spend a lot of time
(02:45):
looking at proteins, which play a ton of roles in
the body of humans and other living things. Proteins help
you grow, digest food, fight disease, stay energized. They also
help bind cells together and transport nutrients. Some hormones like insulin,
are proteins. Antibodies are proteins, Enzymes are proteins. Hemoglobin, which
(03:07):
is the dominant component of our blood, is a protein.
Structural biologists like Jason want to know exactly what proteins
look like. Without the structures, we don't really know what
these proteins look like. We draw them as ovals or squares.
But once we determine their structures, we're able to like
three D print the actual molecule essentially and know where
every amino acids is located on the protein, how the
(03:29):
proteins fold The structure leads to function. So by understanding
the structure, we know something about how the protein works.
And if you know how proteins work and how they look.
You can figure out ways to alter them, change amino acids,
maybe make the protein more stable, or chop off some parts.
We don't want to try to make them the best
(03:50):
possible vaccine antigens. Understanding what specific proteins do is the
key to the COVID vaccines. But it's not like Jason
went to college and majored in proteins. Oh, it was
a kind of winding path, I guess. I went to
college Wayne State University in Detroit, Michigan. I wanted to
(04:11):
do pre med and be a doctor. Most I was
just trying to think of things I could do to
help people. But early on I realized I really liked chemistry.
Was quick good at chemistry, so I went to graduate school.
I've learned a technique called X ray crystallography, and that's
one of the methods for determining structures of proteins. But
(04:32):
ultimately I wanted to do a bit more than just
determine destructures. I wanted to try to have some applied
research to create things that could end up going into
humans and improve human health. Around two thousand and eight,
Jason heard about a guy at the NIH doing a
lot of cool stuff with HIV, looking closely at the
virus's structure and trying to design a vaccine. He joined
(04:54):
the lab there, and while at the NAH he ended
up working with a doctor and virologist named Barney Graham,
a world expert on RSV. The RSV vaccine that failed
back the sixties was made by weakening a strain of
the virus by passing it through animal tissue or human cells.
That's the way the great vaccine creators of the past,
like Maurice Hilleman made their vaccines. Jason and doctor Graham
(05:17):
wanted to create a vaccine in a totally different way.
They wanted to manipulate a specific protein of the RSV virus,
the one the virus uses to infect human cells. It's
called the f protein f as in fudge, and it
comes in two forms or a scientists say two confirmations,
prefusion and post fusion. Here's Jason to explain more. Proteins
(05:42):
exist in some initial confirmation on the surface of the virus.
That's what we call the prefusion confirmation. Then there's an
event that causes the protein to begin refolding and rearranging,
much like a transformer, going from a car to a robot.
Parts of it, parts of the protein, just start moving
and refolding, and it ends up forming an intermediate confirmation
(06:04):
where it's part of the protein into our host cell membrane.
That's pretty confusing, so let's try and visualize it. There's
a virus cell and a human cell. We'll picture them
as tennis balls. The virus tennis ball has its protein
on its surface, sort of shape like a cone or
a stubby mushroom stalk. That's its f protein. So the
(06:29):
virus tennis ball looks for human tennis balls in the body,
and when it finds one, here's what happens. The mushroom
stalk stretches and elongates and attaches itself to the human
tennis ball. So it's like a bridge between the two
tennis balls, human and virus. So it's stock between the
host cell membrane and the viral membrane. The membrane of
(06:49):
a cell is like its skin. It separates the inside
of the cell from whatever is on the outside, and
then it bends back around like a hairpin to bring
the two membranes together, and then it adopts this final
state called the postfusion state. So after the stock on
the virus tennis ball has elongated and attached itself to
the human tennis ball, it folds itself in half in
(07:11):
order to bring the two tennis balls together. That's the fusion.
And so when the f protein has already elongated and
then folded, it's in its postfusion form. By then it's
too late. You want to teach your body to fight
the prefusion form before the mushroom stock has folded and
attached to the human cell. And so, if you think
(07:34):
of your immune system as a security guard, you want
to train your immune system to recognize the form that
might impact you, like the dangerous form, and that's the
prefusion form. If you train it to recognize the postfusion form,
the prefusion form can still sneak by you. So in
order to train the immune system to recognize the prefusion
form of rsv F proteins, Jason needed to keep the
(07:56):
proteins in their prefusion unfolded form. But that isn't easy.
First of all, rsv F proteins really want to go
into their post fusion form. Second, proteins are tiny. It's
not like they could go in with tweezers and hold
the F protein in place. The F protein has a
molecular mass of fifty seven point four kilo daltons, which
(08:18):
means it's weight in Grahams has twenty one zeros. After
the decimal point, it's really difficult to see what they
look like, much less alter their behavior. And nobody could
figure out how do we create a form of the
prefusion molecule that will stay in the prefusion shape and
allow us to purify it and inject it into evil.
But in twenty thirteen they had a breakthrough. They were
(08:41):
finally able to determine the exact structure of the prefusion
form of the rsv F protein. Plus they figured out
how to keep it in that form, how to keep
it from elongating, and we could start making changes like
adding in little molecular staples to link two regions together
so that we the one part couldn't pull away from
the other. And that work. We were eventually able to
(09:01):
make four different changes to the protein that really locked
it in the prefusion confirmation and allowed its use as
a vaccine antigen. Basically, they discovered how a sort of
staple the mushroom stock in place, and when Barney immunized
mice and compared postfusion versus prefusion, the mice receiving the
(09:21):
prefusion form of the F protein elicited neutralizing antibodies about
ten times higher than those that received the postfusion This
is huge. This was the first time structural biology had
helped discover a new way to stop a virus. Science
magazine called it one of the top ten breakthroughs of
twenty thirteen, and their success in stabilizing the F protein
(09:44):
made them want to try the same process with other
similar viruses. What else could we take this new approach,
the structure based approach, and apply to what other pathogens
are important? And that was around the time that the
MIRS coronavirus had emerged in the Saudi Arabia and the
Middle East. That's Middle East respiratory syndrome, which is caused
(10:06):
by a coronavirus called MRS Covey. The disease was first
reported in Saudi Arabia in twenty twelve. It causes bad
respiratory illness, fever, cough, shortness of breath, and it can
eventually kill you with pneumonia and kidney failure. Even today,
(10:27):
there are still cases that pop up on occasion. Thirty
five percent of people infected with it were dying. It's
a real lethal virus, and we thought that this would
be a good target to try to take everything we
had just learned about RSV and apply it to not
just mers, but coronaviruses in general, because we knew Stars
coronavirus had emerged in China in two thousand and two
(10:49):
and it caused an epidemic. Remember Eddie Holmes spoke about
the First Stars in episode one. I realized is that
raccoon dogs. They were implicated in the First Stars I
break of two thousand and two two thousand and three
because they were positive. First came Stars one, then came
Mrs Here's Jason again, and then ten years later we
saw Mirrors emerge. We felt like maybe we were on
(11:10):
a ten year cycle or something where we keep having
coronaviruses emerge into the human population, and so we wanted
to figure out how can we do structure based vaccine
design or coronaviruses to make the best possible vaccine antigens.
Jason and Barney Graham wanted to use their ability to
zoom in on viruses and their ability to play around
(11:31):
with them to make better vaccines. Since Mrs Covey was
on their radar, they focus on that virus MERS has
a protein very similar to the F protein of RSV.
It's called the spike protein. The spike protein acts pretty
similarly to the F protein, it just has this additional part.
(11:52):
If you're thinking about the F protein as a mushroom stock,
the spike protein is kind of like a full mushroom
with a cap. When attacking a human cell, the cap
of the spike protein binds to a certain enzyme on
the surface of the human cell. The enzyme is called
the ACE two receptor. The ACE two receptor sort of
pops off the spike protein's cap, and then the spike
(12:14):
protein stalk does all the things the F protein does.
Based on decades of literature, for many researchers, it was
clear that the spike protein is a key component of
any vaccine because when humans are infected with coronaviruses, they
make a large antibody response to the spike protein because
it's really that that's the major protein on the surface
(12:36):
of the of the virus. So we know we needed
to use spike protein as the vaccine but we also
know that the spike protein can change shapes and isn't
so stable, so then you know what form do you
want to use. Our previous work, it's shown that what
you really want to immunize with is a prefusion stabilized
form that that can't change shape. So that way we
(12:57):
train our immune system to recognize the shape of the
spike protein as it exists on the surface of the virus.
So with coronavirus, they knew they wanted to stabilize the
spike protein, the key protein on its surface. They wanted
to make sure it did not elongate. The spike protein
was pretty unstable. Its stock was liable to elongate and
(13:18):
go to post fusion form on the drop of a dime,
and they had trouble even seeing its structure. To make
it easier, they switched to another virus, one that we've
all gotten, HKU one. That's one of the four coronaviruses
that we've probably all been infected with. It's one of
the many causes of the common cold. And for whatever reason,
(13:39):
the spike protein from HK one was actually pretty stable
and it was amenable to the structured determination efforts, and
we brought in another group, doctor Andrew Ward's group at
the Script's Research Institute. He's an expert in cryoelectron microscopy,
and working together they were able to get that first
structure of a human coronavirus spike protein in the prefusion shapes.
(14:02):
Now we had our first blueprint to start making changes
tweaks to stabilize spike proteins of coronaviruses. Using this blueprint,
Jason's post duc Nian Chung Wang look closely at the
mirror structure here, he is, it's actually pretty boy, but
it's also increasing. Why is it boring and why is
(14:24):
it interesting? Is that we got to try okay and
again most of the time it's got to feel yeah,
it's not that too easy. Nianshuang tested more than one
hundred different mutations to the spike protein until finally coming
across two changes that stabilized it, that kept the spike
in its pre fusion form, and it was really stable.
(14:47):
It stayed all in the pre fusion shape. What was
exciting is that the region where we made these changes
is very similar between different coronavirus spikes, So the same
changes we could also introduce them into stars. Kobe from
two thousand and two, and that led to stabilization. So
my twenty seventeen we really had this method, kind of
(15:08):
a universal method for stabilizing data coronavirus spikes in their
prefusion confirmation. But there was one problem with their success
stabilizing the MERS spike protein. Nobody really cared. It flew
away under the radar because by then it was evident
that MERS, as dangerous as it was, didn't spread very easily.
(15:30):
A few people were getting MERS a vaccine for it
didn't seem super important. Yeah, it's kind of painful. At
that time, most coronavirus at that time was not considered
a big issue because there are few our cases, so
people didn't pay matt attention on that kind of coronavirus.
(15:53):
Although their work didn't get much attention, they knew they
had a vaccine technology ready to be put into action.
By twenty seventeen, they were prepared to test their stabilizing
spike protein method on another coronavirus. They just needed an outbreak.
And then two years later we found out in the
beginning of twenty twenty that this new virus that was
(16:15):
causing pneumonia outbreaks in Wuhan China was a coronavirus and
very similar to Stars Kobe Ie. They'd finally have a
chance to test out the spike protein in real life,
but a big question remained, would it work in people.
Jason and his team spent years figuring out how to
(16:37):
keep a spike protein stable and use that to make
a new kind of vaccine, but they needed an outbreak
to test it on real people infected by a coronavirus.
Then all of a sudden, they have a real time
pandemic crashing down on the world. The reports were coming
out of these pneumonia clusters in Wuhan. We could just
see it following along on science, Twitter and on the news,
(16:59):
and so people were already kind of nervous, especially in
the coronavirus feel that we could be looking at the
beginnings of a coronavirus outbreak. And then it was early
in January when it was learned that in fact, it
is a coronavirus, a beta coronavirus that's similar to the
first Stars Kobe from two thousand and two. At this point,
(17:20):
Jason's working at the University of Texas and he's on
vacation with his family. Barney Graham called me. He said
he was in contact with the US CDC Chinese CDC.
They were going to try and work quickly work with Maderna.
Maderna was then an upstart company based in Cambridge, Massachusetts
that had never brought a vaccine to market, but they
tested several vaccines for other viruses, and Barney Graham had
(17:42):
a plan to work with them on a bat born
virus called NIPA, but when the novel coronavirus came along,
doctor Graham told Maderna they should focus on that instead,
and he wanted to know if we were interested in
continuing our collaboration to determine the structure of the stars
Kobe to spike protein and use that information to create
(18:03):
the vaccine antigens. Jason texted his graduate student Daniel Rapp
and told him they were going to be busy the
next few days. Based on this information, we were sort
of ready to go. That's Daniel, because we've been studying
these spike proteins for such a long time. We knew
how to effectively stabilize spike in the pre fusion confirmation
and that acts as a really good vaccine candidate, and
(18:24):
so during that time we were kind of just like
sitting on our hands, like really anxiously waiting for that
information to become available to everybody, because that was the
thing that was holding us back from getting started back
to Jason, and then we just kind of had to
wait a couple of these because nothing we could really
do until the genome sequence became available so we could
see what the sequence of this spike protein was. On
January eleventh, a scientist in China made it available for all.
(18:46):
That was John jen Jang who sent the sequence to
Eddie Holmes in Australia, who then posted it online. Jason
got the sequence and started working on a vaccine with
his team the next day. So what does it actually
mean to get a virus's genetic sequence. The sequence is
kind of like it's barcode. You're scanning the letters in
its genome to figure out actually what it is and
how it works. It's essentially a file like somebody can
(19:09):
just you know, it's an attachment, the text file that
somebody can send us containing the sequence, just a bunch
of letters, so like computer code. And then we have
to figure out what changes we want to make very
quickly just by taking that sequence and aligning it to
the other spike sequences. We knew right where to put
the two changes that we had identified earlier, so that
(19:30):
was probably done within a couple of hours. Just the
design of these constructs. Remember, Jason's team is looking for
a way to alter the proteins on the surface of
the virus so they won't go into that post fusion confirmation.
The change that Niche Wong and the team had discovered
working with mers is called the two P mutation. The
P stands for prolene, one of twenty amino acids that
(19:53):
are the building blocks of all living things. Proleins are
special because they're the most rigid amino acid and because
they are rigid. Swapping out two other amino acids for
two proteins at a certain joint of the spike protein
keeps the mushroom stock in place, meaning it keeps it
in pre fusion form. But Jason and his team couldn't
(20:17):
just do the two P mutation on the laptop. They
had to do it in real life. There are companies
out there that can take a modified genetic sequence like
the one they designed at UT and turn it into
something physical. And you need to turn it into a
biological substance. Like actual DNA. And so that's where we
need to work with the companies, where we send them
(20:38):
the file and they're able to synthesize DNA and send
it send it back to us, and then we have
to stitch some of it together and do some other things.
And so in the lab we were working with the DNA.
When Jason says he's working with DNA, he essentially means
that they're making changes to genes in order to program
human cells to produce the stable spike proteins. Remember this
(20:59):
is the key to the whole vaccine. Our own cells
will be the factories that produce the stable spike proteins,
and the DNA is the thing sending those instructions via
messenger RNA. So that way the cells realized the instructions
have changed, the recipe has changed, if you will, and
they just make a protein containing proteins at those positions
(21:20):
instead of the original amino acids at those positions. I
think within ten days, maybe a bit more, Nianchwang had
had cloned like ten different plasmids. Plasmids are like small
snippets of DNA molecules, ending Chwang was working around the
clock to stitch them together. Into a full DNA strand
that could encode for the spike proteins. Meanwhile, Barney Graham's
(21:43):
lab was talking to MODERNA telling them how to stabilize
the spike protein with a two P mutations, like what
spike protein to encode in the mRNA, where to put
the stabilizing prolein mutations. Then came January thirtieth, twenty twenty.
It was an exciting day. We Daniel was harvesting. He's
talking about his grad student, Daniel Repp, the purified spike
(22:05):
proteins that were produced by the cells we had growing
in the lab. So we was able to harvest the spike,
purify it and start freezing cryoEM grids. cryoEM stands for
cryoelectron microscopy, a method for seeing proteins at atomic resolution. First,
Daniel would flash freeze the proteins in ice on a
(22:27):
tiny mesh disc. Then he'd use an electron microscope to
take thousands of two dimensional images of the proteins. A
computer program then use those pictures to create a three
D image showing the structure of the proteins. That allowed
us to start the data collection that night, and we
could see the individual spike proteins for the first time,
(22:48):
and within twenty four hours we had collected a complete
data set and we got the first looks at the
molecular shape of the coronavirus spike protein. Within about thirty
days we had determined in a manuscript submitted that paper
has been sighted close to four thousand times now we have.
We were sharing the coordinates of the structure, the blueprint
(23:09):
of the structure to people all over the world. We
were shipping the plasmids that we had made two hundred
groups or so. Is that way they could make the
spike protein in their labs for diagnostics, for antibody isolation
or additional structural studies. So it is a really crazy
time early last year. Now they knew exactly how to
stabilize the spike protein the mushroom shape on the surface
(23:31):
of the coronavirus. They'd actually created stabilized spikes in the lab,
and the pharmaceutical company Baderna would use these stabilize spikes
as building blocks for the vaccine. They are just directly
synthesizing the mRNA, but it's still at the instructions level,
such that when the RNA is injected into a person
(23:51):
that person sells read the recipe and make a protein
that contains two proteins at these positions rather than the
other amino acids that the virus normally uses. RNA is
the sort of middleman between DNA and the spike proteins.
We'll learn more about this in the next episode, but
the saying amongst scientists is that DNA makes RNA, makes
(24:16):
proteins makes life. Maderna's vaccine sort of skips the DNA
step and sends the mRNA or messenger RNA directly into
the body. Maderna encapsulates the mRNA in a fatty sphere
called a lipid nanoparticle. Another thing we'll talk about in
an upcoming episode. That bubble helps the mRNA get to
(24:37):
ourselves without falling apart, and when it does, our selves
get the recipe from making two p mutated spike proteins.
They make them, and the immune system sees these coronavirus
proteins in their prefusion form, and the immune system learns
that they are a threat. It learns that a spike
protein in the folded hairpin shape is an enemy and
(24:59):
the body has to fight it and stop it from spreading.
If you get infected with coronavirus. The body now knows
what to do when it comes across the spike protein
in pre fusion form. It knows how to keep you
from getting sick. They tested the vaccine in mice and
saw that it produced an antibody response, and then they
(25:20):
readied it for humans. By March twenty twenty, Maderna had
enough vaccine to be used for a phase one clinical trial.
That material was shipped to the different sites in the
US where they began immunizing the first forty five people
with different doses, testing side effects, dose response, the level
(25:41):
of antibodies being produced. Yeah, I think it's like it's
like sixty three days or sixty five days something. After
the genome sequence was made available online, the first people
are being immunized, which is incredible. Um. Hi, my name
is Nicolas Nicola in the second episode was one of
those first people. I was part of the Phase one
of modernas vaccine trial for COVID. Feisser and Johnson and
(26:07):
Johnson also used the two P mutation for their COVID vaccines.
It's the driving force behind all the vaccines that Americans
are getting and of some other vaccines being made around
the world. The last year is difficult because there's a
lot of mixed emotions because there are certain scientific successes
that we would normally celebrate, but the whole time the
economy is being devastated. People are losing their jobs, hospitalizations, deaths.
(26:31):
So it's really a range of mixed emotions where we're
excited for the science and everything we've been working on
for years being translated into a vaccine that was looking
very promising, but at the same time also just really devastating.
We spoke with Jason in March of this year. At
the time, three vaccines were already approved for emergency use
by the FDA, More than thirty million Americans had already
(26:54):
been fully vaccinated, and millions more were scrambling for appointments.
Me and my producer Gabby had gotten the Maderna shot
a few days earlier, but Jason still hadn't been vaccinated.
He was young and healthy, not a frontline worker, happy
to wait his turn. He got his first shot a
couple of weeks later. The search for an RSV vaccine
(27:26):
after that trial went bad in the sixties inspired the
technology used in today's COVID vaccines. But what about RSV
that virus that still kills thousands of people every year.
It's normally a virus that peaks in winter, but it's
been surging in children this summer alongside of and maybe
even because of the surge in the coronavirus delta variants.
(27:47):
There's still no vaccine for RSV on the market, but
they're working on it. Last year November October of twenty twenty,
prefusion f proteins have gone into phase three clinical trials,
and yeah, we're really excited about that. It's taken a
long time, that's sort of the normal vaccine development timelines,
starting a thirteen with the antigen just entering phase three
(28:09):
clinical trials in twenty twenty, but yeah, everything still looks
really good and we're really excited by it. Scientific failure
and scientific success are unstable concepts, about as unstable as
prefusion spike proteins. When a trial for an RSV vaccine
failed about as badly as a vaccine trial can fail,
(28:30):
it led to a newer and better way of making vaccines.
Fifty years later in twenty seventeen, when they stabilize the
spike protein, Jason and Nichuang and Daniel and everyone else
they worked with. All they got was crickets, but they
did it anyway. Here's Daniel Rapagin. Yeah, it's it's a
little surreal because we would be doing this work whether
(28:50):
or not COVID nineteen became a pandemic. We would still
be studying the spike protein figuring out how it worked.
But it's been a little surreal to have so much
attention paid to our work because, like as I've been
describing to you, we do things that most people would
think of is just like minutia, Like if there wasn't
a pandemic, we would still be doing this and people
would wonder why. The best example of it is, for
(29:13):
the past like five or six years, I've been telling
people I studied coronaviruses, and up until like a year ago,
people would say, what's a coronavirus. On the next episode
of long Shot, we'll speak with the founders of Moderna,
a company that started with essentially zero employees before becoming
one of the biggest names in COVID nineteen vaccines. We'll
(29:34):
also find out what role Jennifer Aniston played in that
origin story. Today's episode of long Shot was produced, written,
and narrated by me Sean Revie. My co producer is
Gabby Watts. Special thanks to Noel Brown and iHeartRadio and
journalist Alan Dove and Ryan Cross. Executive producers are Virginia Prescott,
(29:55):
Brandon Barr and Else Crowley. Long Shot was scored by
Jason Shannon. The score was mixed by Vic Stafford. Sound
design and audio mix was by Harper Harris with Tunewelder
(30:22):
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