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1. [54]National

[55]

Coronavirus

A gamble pays off in 'spectacular success': How the leading coronavirus
vaccines made it to the finish line

Carolyn Y. Johnson05:55, Dec 07 2020
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On a Sunday afternoon in early November, US scientist Barney Graham got
a call at his home office in Rockville, Maryland, where he has
sequestered himself for most of the last 10 months, working
relentlessly to develop a vaccine to vanquish a killer virus.

It was Graham's boss at the National Institutes of Health, with an
early heads-up on news the world would learn the next morning: A
coronavirus vaccine from Pfizer and the German biotech firm BioNTech
that used a new genetic technology and a specially designed spike
protein from Graham and collaborators had proved stunningly effective.

The significance of the news was clear right away to Graham: There
could be not one, but two vaccines by year's end.

If the Pfizer vaccine worked well, odds were good for a vaccine from
biotechnology firm Moderna, since they both relied on the spike protein
that Graham's lab helped design and a technology never before harnessed
in an approved vaccine.

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For months, people had asked Graham about the pressure he must have
been feeling on the leading edge of an all-hands effort to invent the
tools that could end the pandemic. He was too busy to give it much
thought - his summer "vacation" had meant scaling back to 40- to
50-hour workweeks. But the news released a gush of emotion that stunned
even him.

"I just let it all go," Graham said. "I was sobbing, I guess, is the
term."

His son and grandchildren, ages 13 and 5, burst into his office,
fearing something had gone terribly wrong.
Professor Drew Weissman.
Carolyn Van Houten/The Washington Post
Professor Drew Weissman.

The world's hopes have weighed heavily on the quest to develop
coronavirus vaccines, with an especially intense focus on two
front-runners: one from Moderna, the other from Pfizer and BioNTech.

Both were a speedy, but risky - even controversial - bet, based on a
promising but still-experimental medical technology.

Why, some scientists debated in the spring and summer, would the United
States gamble on a type of vaccine that had never been deployed beyond
clinical trials, when the stakes were so high?

If, as expected in the next few weeks, regulators give those vaccines
the green light, the technology and the precision approach to vaccine
design could turn out to be the pandemic's silver linings: scientific
breakthroughs that could begin to change the trajectory of the virus
this winter and also pave the way for highly effective vaccines and
treatments for other diseases.

Vaccine development typically takes years, even decades. The progress
of the last 11 months shifts the paradigm for what's possible, creating
a new model for vaccine development and a toolset for a world that will
have to fight more never-before-seen viruses in years to come.

But the pandemic wasn't a sudden eureka moment - it was a catalyst that
helped ignite lines of research that had been moving forward for years,
far outside the spotlight of a global crisis.

The Vaccine Research Centre, where Graham is deputy director, was the
brainchild of Anthony Fauci, director of the National Institute of
Allergy and Infectious Diseases. It was created in 1997 to bring
together scientists and physicians from different disciplines to defeat
diseases, with a heavy focus on HIV.

Long before the pandemic, Graham worked with colleagues there and in
academia to create a particularly accurate 3D version of the spiky
proteins that protrude from the surface of coronaviruses - an
innovation that was rejected for publication by scientific journals
five times because reviewers questioned its relevance.

His laboratory partnered with one of the companies, Moderna, working to
develop a fast and flexible vaccine technology, in the hope that
science would be ready to respond when a pandemic appeared.

"People hear about [vaccine progress] and think someone just thought
about it that night. The amount of work - it's really a beautiful story
of fundamental basic research," Fauci said.

"It was chancy, in the sense that (the vaccine technology) was new. We
were aware there would be pushback. The proof in the pudding is a
spectacular success."

- - -
Dr Katalin Kariko.

Carolyn Van Houten/The Washington Post

Dr Katalin Kariko.

The leading coronavirus vaccine candidates in the United States began
their development not in January when a mysterious pneumonia emerged in
Wuhan, China, but decades ago - with starts and stops along the way.

Since 1961, scientists had known about messenger RNA, the transient
genetic material that makes life possible, taking the instructions
inscribed in DNA and delivering those to the protein-making parts of
the cell.

Messenger RNA is a powerful, if fickle, component of life's building
blocks - a workhorse of the cell that is also truly just a messenger,
unstable and prone to degrade.

Some scientists believed from the start that it would be possible to
repurpose this basic cellular function for medicine.

In 1990, a Hungarian-born scientist at the University of Pennsylvania,
Katalin Kariko, brashly predicted to a surgeon colleague that his work
would soon be obsolete, replaced by the power of messenger RNA
therapies.

That same year, a team at the University of Wisconsin startled the
scientific world with a paper that showed it was possible to inject a
snippet of messenger RNA into mice and turn their muscle cells into
factories, creating proteins on demand.

"That was something that was amazing," said Melissa Moore, an RNA
scientist who joined Moderna as chief scientific officer four years
ago.

If custom-designed RNA snippets could be used to turn cells into
bespoke protein factories, messenger RNA could become a powerful
medical tool.

It could encode fragments of virus to teach the immune system to defend
against pathogens. It could also create whole proteins that are missing
or damaged in people with devastating genetic diseases, such as cystic
fibrosis. But there were all kinds of practical problems to be solved
first.

Despite the excitement, scientists had trouble getting RNA into cells
because it is so fragile. And when they succeeded, they would soon
discover RNA caused an inflammatory reaction.

A friendly competition over a photocopier in the late 1990s led to a
major breakthrough.

Kariko, working in the University of Pennsylvania's neurosurgery
department, was trying to turn RNA into a therapy for strokes. In line,
she bragged to Drew Weissman, a physician-scientist who worked in a
different building but used the same copier to print out scientific
articles, about the molecule she had become obsessed with.

Weissman had done a fellowship in Fauci's laboratory at NIH, studying
the immune cells involved in vaccine responses. He asked Kariko if she
could make some RNA for an HIV vaccine idea he was pursuing. She did,
and he found the RNA stimulated an inflammatory response - bad news for
Kariko's efforts to turn it into a stroke therapy.

Weissman noted that mice injected with messenger RNA would suffer every
side effect, from feeling lousy and losing their appetites to dying.
The two began puzzling out a way to overcome the problems.

But it was far from a hot area of science. Kariko bitterly recalled how
she struggled for grants, making less money than many lab technicians.

"We went to biotech companies, pharmaceutical companies to try and get
funding, and they weren't interested," Weissman said. "They said RNA
was too fragile and they didn't want to work with it."

In 2005, the pair discovered a way to modify RNA, chemically tweaking
one of the letters of its code, so it didn't trigger an inflammatory
response. Deborah Fuller, a scientist who works on RNA and DNA vaccines
at the University of Washington, said that work deserves a Nobel Prize.

Kariko and Weissman set up a company to turn their discovery into
medicine, but eventually, Kariko moved to BioNTech, a German firm
working on developing RNA therapies - even though it meant leaving her
husband in Philadelphia for 10 months of the year.

"I told my husband when I decided to go to Germany, 'I just want to
live long enough that I can help the RNA go to the patient,' " Kariko
said. " 'I want to see ... at least one person would be helped with
this treatment.' "

In parallel, scientists had been developing ways to encapsulate and
transport large and unwieldy molecules beginning in the 1960s.

The technology matured over the decades, with hopes it could be used to
deliver entirely new types of drugs into cells, but messenger RNA posed
a bigger challenge than other targets.

"It's tougher - it's a much bigger molecule, it's much more unstable,"
said Robert Langer, a bioengineer at Massachusetts Institute of
Technology and a co-founder of Moderna.

Ugur Sahin, chief executive of BioNTech, said it was thrilling when he
and colleagues in 2016 developed a nanoparticle to deliver messenger
RNA to a special cell type that could take the code and turn it into a
protein on its surface to provoke the immune system.

This, they theorised, was key to using a tiny amount of material - each
dose of mRNA vaccine his company developed against coronavirus relies
on an amount that's about a fifth the weight of a penny to stimulate a
powerful immune response.

Unlike fields that were sparked by a single powerful insight, Sahin
said that the recent success of messenger RNA vaccines is a story of
countless improvements that turned an alluring biological idea into a
beneficial technology.

"This is a field which benefited from hundreds of inventions," said
Sahin, who noted that when he started BioNTech in 2008, he cautioned
investors that the technology would not yield a product for at least a
decade. He kept his word: Until the coronavirus sped things along,
BioNTech projected the launch of its first commercial project in 2023.

Messenger RNA has never been used in an approved medical product, an
oft-repeated fact that has added to its mystique. There isn't yet a
long safety track record, but the platform has been in human tests for
years, including in tens of thousands of people in the coronavirus
vaccine trials.

Even before the coronavirus emerged, the technology had reached a
tipping point where it seemed a matter of time before it would begin to
have an impact on medicine.

"It's new to you," Fuller said. "But for basic researchers, it's been
long enough. ... Even before Covid, everyone was talking: RNA, RNA,
RNA."

- - -

The spike protein for the coronavirus.

University of Texas at Austin

The spike protein for the coronavirus.

All vaccines are based on the same underlying idea: training the immune
system to block a virus.

Old-fashioned vaccines do this work by injecting dead or weakened
viruses. Newer vaccines use distinctive bits of the virus, such as
proteins on their surface, to teach the lesson.

The latest genetic techniques, like messenger RNA, don't take as long
to develop because those virus bits don't have to be generated in a
lab. Instead, the vaccine delivers a genetic code that instructs cells
to build those characteristic proteins themselves.

To do that, scientists have to choose which telltale part of the virus
to show the immune system.

Long before the pandemic, Graham's research had revealed that some
virus proteins change shape after they break into a person's cells. A
vaccine based on the wrong shape could effectively train the immune
system to be an ineffective sheriff, never stopping vandals or burglars
before they wreak their havoc.

Graham had used this insight to design a better vaccine against
respiratory syncytial virus; it made Science magazine's shortlist of
2013′s most important scientific breakthroughs.

Coronaviruses seemed like an important next target. Severe acute
respiratory syndrome had emerged in 2003. Middle East respiratory
syndrome (MERS) broke out in 2012. It seemed clear to Graham and Jason
McLellan, a structural biologist now at the University of Texas at
Austin, that new coronaviruses were jumping into people on a
10-year-clock and it might be time to brace for the next one.

When a postdoctoral fellow in Graham's laboratory travelled to Saudi
Arabia for the annual pilgrimage to Mecca, and returned home with a
respiratory infection, Graham and colleagues worried that it might be
MERS. To their relief, it was not MERS, but HKU1 - a coronavirus that
causes common cold symptoms.

That infection opened Graham's eyes to an opportunity. HKU1 was merely
a nuisance, as opposed to a deadly pneumonia; that meant it would be
easier to work with in the lab, since researchers wouldn't have to don
layers of protective gear and work in a pressurised laboratory.

If they could figure out how to stabilise the spike proteins for HKU1,
they could use those insights to do the same for other coronaviruses.

Their studies showed that the spike protein folded like origami, from a
thumb tack-like shape before fusing with cells, to a rodlike shape
afterward.

They wanted the immune system to learn to recognise the thumb tack
spike, so McLellan tasked a scientist in his laboratory with
identifying genetic mutations that could anchor the protein into the
right configuration.

It was a painstaking process for Nianshuang Wang, who now works at a
biotechnology company, Regeneron Pharmaceuticals. After trying hundreds
of genetic mutations, he found two that worked. Five journals rejected
the finding, questioning its significance, before it was published in
2017.

"People generally at that time said, 'Coronavirus is not a big
concern,' " Wang said. "They didn't get the idea that this can be a
great technology in the disease, to prevent another coronavirus
pandemic."

Last winter, when Graham heard rumblings of a new coronavirus in China,
he brought the team back together. Once its genome was shared online by
Chinese scientists, the laboratories in Texas and Maryland designed a
vaccine, utilising the stabilising mutations and the knowledge they had
gained from years of basic research - a weekend project thanks to the
dividends of all that past work.

But the stabilised spike was just one piece of a vaccine - Graham
needed a technology that could deliver it into the body - and had
already been working with Moderna, using its messenger RNA technology
to create a vaccine against a different bat virus, Nipah, as a dress
rehearsal for a real pandemic.

Moderna and NIH set the Nipah project aside and decided to go forward
with a coronavirus vaccine.

On January 13, Moderna's Moore came into work and found her team
already busy translating the stabilised spike protein into their
platform.

The company could start making the vaccine almost right away because of
its experience manufacturing experimental cancer vaccines, which
involves taking tumour samples and developing personalised vaccines in
45 days.

At BioNTech, Sahin said that even in the early design phases of its
vaccine candidates, he incorporated the slight genetic changes designed
in Graham's lab that would make the spike look more like the real
thing. At least two other companies would incorporate that same spike.

- - -

If all goes well with regulators, the coronavirus vaccines have the
makings of a pharmaceutical industry fairy tale. The world faced an
unparalleled threat, and companies leaped into the fight. Pfizer
ploughed US$2 billion (NZ$2.84b) into the effort. Massive infusions of
government cash helped remove the financial risks for Moderna.

But the world will also owe their existence to many scientists outside
those companies, in government and academia who pursued ideas they
thought were important even when the world doubted them.

Some of those scientists will receive remuneration, since their
inventions are licensed and integrated into the products that could
save the world.

As executives become billionaires, many scientists think it is fair to
earn money from their inventions that can help them do more important
work. But McLellan's laboratory at the University of Texas is proud to
have licensed an even more potent version of their spike protein,
royalty-free, to be incorporated into a vaccine for low and middle
income countries.

Weissman, a basic researcher who has been nervously tracking the
progress of the RNA vaccines on which so much depend, was overjoyed by
the first success.

"They're using the technology that (Kariko) and I developed," he said.
"We feel like it's our vaccine, and we are incredibly excited - at how
well it's going, and how it's going to be used to get rid of this
pandemic."

On November 9, McLellan told his group via a WhatsApp thread that the
first vaccine was 90 per cent effective.

"Full spike with 2P," McLellan wrote, referencing the fact that the
Pfizer and BioNTech vaccine used a spike protein that contained the
mutations they'd discovered. "Barney just called to congratulate us."

Graham is matter-of-fact, rather than exuberant, and quickly changes
the subject to the immense amount of work that remains to be done.

Historic scientific news must now be transformed into a tool that is
mass produced, distributed and used widely around the world to blunt
the sickness and suffering of this winter - and to lift the pall this
pandemic has cast over virtually every aspect of daily life.

He recalled that his 5-year-old granddaughter recently heard the family
talking about "getting back to normal" if a vaccine is successful.

"She looked up and said, 'What is normal life, what do you mean by
that?' " Graham said. "Half of her memorable life has been like this."

The Washington Post
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