[Ip-health] Washington Post: A gamble pays off in ‘spectacular success’: How the leading coronavirus vaccines made it to the finish line

Thiru Balasubramaniam thiru at keionline.org
Sun Dec 6 21:42:40 PST 2020


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

The astonishing, 11-month sprint harnessed new technology that will pave
the way for other vaccines and breakthrough medical treatments.

Inside the cold, complex world of getting a covid-19 vaccine into arms
After making a vaccine for coronavirus, you have to get it to the masses.
But that’s not so easy for a so-called cold chain vaccine, requiring exact
temps. (Lee Powell/The Washington Post)
By  Carolyn Y. Johnson
Dec. 6, 2020 at 8:00 a.m. EST

On a Sunday afternoon in early November, scientist Barney Graham got a call
at his home office in Rockville, Md., 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.

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.

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 Center, where Graham is deputy director, was the
brainchild of Anthony S. 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 3-D 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.”

Turning human cells into bespoke protein factories

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

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

“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 theorized, 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

“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 shape-shifting spike

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.


On Jan. 13, Moderna’s Moore came into work and found her team already busy
translating the stabilized 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 tumor
samples and developing personalized 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.

‘We feel like it’s our vaccine’

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 plowed $2 billion 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

“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 Nov. 9, McLellan told his group via a WhatsApp thread that the first
vaccine was 90 percent 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.”

Thiru Balasubramaniam
Geneva Representative
Knowledge Ecology International
41 22 791 6727
thiru at keionline.org

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