How The mRNA Vaccines Were Made: Halting Progress and Happy Accidents - The New York Times
Jan 15, 2022 9 mins, 31 secs
Barney Graham, an immunologist and virologist recently retired from the Vaccine Research Center of the National Institutes of Health.Credit...Johnathon Kelso for The New York Times.

Now he was terrified that the virus, Middle East Respiratory Syndrome, or MERS, had infected one of his lab’s own scientists, who was sick with a fever and a cough in the fall of 2013 after a pilgrimage to the holy city of Mecca.

It was a mild coronavirus, causing a common cold, not MERS.

Graham had a flash of intuition: Perhaps it would be worth taking a closer look at this humdrum cold virus.

Yet the decision to study a colleague’s bad cold gave rise to critical discoveries.

Together with other chance breakthroughs that seemed insignificant at the time, it would lead eventually to the mRNA vaccines now protecting hundreds of millions of people from Covid-19.

And the manufacturers, Pfizer, BioNTech and Moderna, say that mRNA technology will allow them to adapt the vaccines quickly, to fend off whatever dangerous new version of the virus that evolution brings next.

But the breakthroughs behind the vaccines unfolded over decades, little by little, as scientists across the world pursued research in disparate areas, never imagining their work would one day come together to tame the pandemic of the century.

The pharmaceutical companies harnessed these findings and engineered a consistent product that could be made at scale, partly with the help of Operation Warp Speed, the Trump administration’s multibillion-dollar program to hasten the development and manufacture of vaccines, drugs and diagnostic tests to fight the new virus.

For years, though, the scientists who made the vaccines possible scrounged for money and battled public indifference.

The first began more than 60 years ago with the discovery of mRNA, the genetic molecule that helps cells make proteins.

A few decades later, two scientists in Pennsylvania decided to pursue what seemed like a pipe dream: using the molecule to command cells to make tiny pieces of viruses that would strengthen the immune system.

The second effort took place in the private sector, as biotechnology companies in Canada in the budding field of gene therapy — the modification or repair of genes to treat diseases — searched for a way to protect fragile genetic molecules so they could be safely delivered to human cells.

The spike of the Covid virus was encoded in mRNA molecules.

The extraordinary tale proved the promise of basic scientific research: that once in a great while, old discoveries can be plucked from obscurity to make history.

“It was all in place — I saw it with my own eyes,” said Dr.

Elizabeth Halloran, an infectious disease biostatistician at the Fred Hutchinson Cancer Research Center in Seattle who has done vaccine research for over 30 years but was not part of the effort to develop mRNA vaccines.

Fauci recalled, the president turned to him and said: “You’ve known about AIDS as a disease since 1981.

Then he made a bold pitch: a research facility where scientists from different disciplines could talk to one another and collaborate, with the goal of putting vaccines into arms rather than proving that their own discipline had the answers.

Vaccine research was hardly exciting science and had long taken a back seat to efforts to cure cancer and heart disease.

Clinton was going to give a commencement address at Morgan State University in Baltimore and wanted to announce the vaccine research center.

Fauci said.

The Vaccine Research Center opened its doors in 2000 at the National Institutes of Health’s campus in Bethesda, Md., with an annual budget of $43.9 million in today’s dollars and a staff of 56.

Graham said: “If we could figure out how to make an H.I.V.

Some of the researchers at the center decided to try a new, more theoretical approach, though it was a long shot.

They would map the detailed atomic structure of H.I.V.’s spike, a protruding protein that allows the virus to invade human cells.

They would then try to identify the part of the spike that was most vulnerable to antibodies, components of the immune system that recognize viruses and can block spikes from entering other cells.

Ultimately, the goal was to make a vaccine that showed the body a harmless version of that same section of spike.

A vaccine would ideally use only the shape that elicited powerful antibodies against an initial form of the spike, to have the best shot at keeping the virus out.

But the scientists struggled for years to determine which shape to choose.

In 2008, a 27-year-old named Jason McLellan from outside Detroit applied to join a group at the Vaccine Research Center working on just that problem.

But by the time he was hired by the center, Dr.

McLellan began studying the structure of a protein that helps the virus fuse with cells.

In the 1950s, the molecule at the heart of the mRNA vaccines was cloaked in mystery.

An elusive molecule known as X (pronounced “eeks,” because its name had been proposed by French scientists) was the messenger.

The scientists figured out that X carried copies of segments of the DNA code to ribosomes, cellular machines that could read the code and pump out its corresponding proteins.

The scientists named the molecule messenger RNA, or mRNA.

“Molecular biologists were much more excited about DNA and proteins,” said Doug Melton, a Harvard biologist who in 1984 figured out how to make mRNA in a lab.

For decades, few scientists paid attention to these delicate molecules.

In theory, scientists could coerce a cell to produce any type of protein, whether the spike of a virus or a drug like insulin, so long as they knew its genetic code.

An mRNA vaccine would instead carry instructions — encoded in mRNA — that would allow the body’s cells to pump out their own viral proteins.

It was a fringe idea that few scientists thought would work.

A molecule as fragile as mRNA seemed an unlikely vaccine candidate.

Weissman and Karikó inserted mRNA molecules into human cells growing in petri dishes and, as expected, the mRNA instructed the cells to make specific proteins.

The researchers discovered that cells protect their own mRNA with a specific chemical modification.

So the scientists tried making the same change to mRNA made in the lab before injecting it into cells.

It worked: The mRNA was taken up by cells without provoking an immune response.

Just as mRNA itself had been ignored, no one cared that they could get cells to accept mRNA.

But to work as a vaccine or a medicine, the fragile molecules would need to be shielded in the bloodstream to prevent degradation on their way to cells.

It was a partnership as improbable as any that helped lead to mRNA vaccines.

He found one in the field of biological membranes: the outer layer of fats, called lipids, that encases the trillions of cells in the body, separating the watery outside from the inside.

Cullis wondered if he could design his own lipid membranes to encase drugs or genetic material and transport it to cells.

Human cells had a system of elaborate defenses to prevent anything but food from entering.

The fatty bubbles would be charged when scientists loaded DNA inside, but the charge and toxicity disappeared once they were injected into the bloodstream.

The team also worked to ensure that cells did not simply break up the genetic material as soon as it arrived.

Cullis’s teams that worked with vaccine makers on wrapping an mRNA shot in lipids — a major departure from the scientists’ original goals.

The work on mRNA and the lipid coats were two pieces of the puzzle that came together in 2020 in the Covid vaccines.

But the third component was figuring out the precise mRNA code that would direct cells to make the most effective version of the coronavirus’s spike protein.

McLellan and Graham, who had been working together ever since their days sitting near each other at the Vaccine Research Center.

It was a class of viruses that usually caused nothing worse than a cold, attracting scant interest from funding bodies.

And for a young researcher trying to make his mark, the lack of attention to coronaviruses meant less direct competition for research grants and signature findings.

They had thwarted all efforts to make a vaccine.

The MERS spike was especially fearsome, so much so that the scientists struggled to reproduce and isolate it in the lab.

After years of Western scientists parachuting into lower-income countries for studies that excluded local researchers, especially during the AIDS crisis, governments had “become very protective of their samples,” Dr.

But it turned out to be a cold virus known as HKU1.

Like other coronaviruses, HKU1 had the dreaded spike — and, with some modifications, it held steadier than the one on the MERS virus.

Within a few years, the team — which now included Andrew Ward, an expert, at the Scripps Research Institute, in freezing proteins to hold them still under an electron microscope — had published intricate images of the HKU1 spike in Nature.

It was the first time scientists had visualized a human coronavirus spike protein in the initial form it took before latching onto cells.

Yassine said recently of his long-ago cold, “or you can consider it a blessing.”.

Now, the team set out to use what they had learned about the spike on the common cold virus to steady the proteins on their real adversary, MERS.

The trouble was, any spikes they made in the lab — by adding genetic instructions to mammalian cells in a flask — were rarely stable and kept changing shape, making them much less effective for use in a vaccine.

The scientists needed to lock the spike in place.

McLellan turned to the map he had built of the cold virus spike for clues.

Wang’s job, like those of many junior scientists in American research labs, was to put in the lonely hours at the lab bench needed to realize his boss’s improbable ideas.

Wang helped unearth his old findings to make a coronavirus vaccine.

A week later, he heard that the frightening new disease was caused by a coronavirus, the same class of pathogen that he had trained his focus on years earlier when most other scientists were ignoring them.

Yassine’s cold virus and MERS, the team zeroed in on the spikes and came up with genetic sequences within days, incorporating the crucial cementing technique that Drs.

The team’s stabilizing technique was crucial to the mRNA vaccines made by BioNTech (which by then had partnered with Pfizer) and Moderna, as well as certain non-mRNA vaccines.

Once Moderna and BioNTech scientists had genetic sequences for the spike, they then synthesized the mRNA molecules in their labs, applying the same chemical tweak that Drs.

Larry Corey, a virologist at the Fred Hutchinson Cancer Research Center and the director of the government’s 21-year-old network of clinical trial sites for testing H.I.V.

At about 100 sites, the program would simultaneously test four vaccines: the mRNA shot from Moderna, as well as non-mRNA formulations from Johnson & Johnson, AstraZeneca and Novavax.

By November, the first results were in from the trial of Pfizer-BioNTech’s mRNA vaccine

Graham knew, they could pave the way for other new shots against diseases as varied as the common cold, flu and cancer — and even against that most elusive virus, H.I.V

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