Halting Progress and Happy Accidents: How mRNA Vaccines Were Made
Thousands of miles from Dr. Barney Graham’s lab in Bethesda, Md., a frightening new coronavirus had jumped from camels to humans in the Middle East, killing one out of every three people infected. An expert on the world’s most intractable viruses, Dr. Graham had been working for months to develop a vaccine, but had gotten nowhere.
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.
A nose swab came back positive for a coronavirus, seeming to confirm Dr. Graham’s worst fears, only for a second test to deliver relief. It was a mild coronavirus, causing a common cold, not MERS.
Dr. Graham had a flash of intuition: Perhaps it would be worth taking a closer look at this humdrum cold virus.
It was an impulse born more of convenience and curiosity than foresight, with little to no expectation of glory or profit. 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.
The shots were developed at record speed, arriving just over a year after a mysterious pneumonia surfaced in China, while so much else — political feuds, public distrust and botched government planning — went wrong.
They remain a marvel: Even as the Omicron variant fuels a new wave of the pandemic, the vaccines have proved remarkably resilient at defending against severe illness and death. 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.
Skeptics have seized on the rapid development of the vaccines — among the most impressive feats of medical science in the modern era — to undermine the public’s trust in them. 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. Their experiments often failed. When the work got too crushing, some of them left it behind. And yet on this unpredictable, zigzagging path, the science slowly built upon itself, squeezing knowledge from failure.
The vaccines were possible only because of efforts in three areas. 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 third crucial line of inquiry began in the 1990s, when the U.S. government embarked on a multibillion-dollar quest to find a vaccine to prevent AIDS. That effort funded a group of scientists who tried to target the all-important “spikes” on H.I.V. viruses that allow them to invade cells. The work has not resulted in a successful H.I.V. vaccine. But some of these researchers, including Dr. Graham, veered from the mission and eventually unlocked secrets that allowed the spikes on coronaviruses to be mapped instead.
In early 2020, these different strands of research came together. The spike of the Covid virus was encoded in mRNA molecules. Those molecules were wrapped in a protective layer of fat and poured into small glass vials. When the shots went in arms less than a year later, recipients’ cells responded by producing proteins that resembled the spikes — and that trained the body to attack the coronavirus.
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. “It was kind of miraculous.”
In December 1996, President Bill Clinton invited Dr. Anthony S. Fauci to the Oval Office to brief him on that era’s grave pandemic, AIDS, which by then had killed more than 350,000 people in the United States and six million more globally.
Dr. Fauci, the top government scientist investigating the virus, was feeling oddly hopeful. For the first time since the virus emerged, annual AIDS deaths in the country had fallen, thanks to several new drugs that were tested and approved after years of intense public pressure by patient activists.
But the most valuable tool remained missing from their arsenal: a vaccine. And the president was impatient.
As the men walked out to the Rose Garden, Dr. Fauci recalled, the president turned to him and said: “You’ve known about AIDS as a disease since 1981. How come you guys don’t have a vaccine yet?”
Dr. Fauci, taken aback, told the president that research efforts thus far had been largely uncoordinated. 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.
Mr. Clinton turned to his chief of staff, Leon Panetta. “You think we can do that?” he asked.
“You’re the president of the United States,” Mr. Panetta recalled saying. “You can do whatever the hell you want.”
Dr. Fauci figured they were flattering him. Vaccine research was hardly exciting science and had long taken a back seat to efforts to cure cancer and heart disease. But five months later, Dr. Fauci got a call from one of the president’s speechwriters. Mr. Clinton was going to give a commencement address at Morgan State University in Baltimore and wanted to announce the vaccine research center. Could Dr. Fauci supply a description? “I was completely shocked,” Dr. Fauci said.
One of the first scientists to be recruited to the new effort was Dr. Graham. A bearded virologist with a calm demeanor, who at 6-foot-5 towered over most of his colleagues at Vanderbilt University in Nashville, he had begun his career as a clinician. But in 1982, when he was just starting as chief resident at the hospital, he had a shattering experience.
A homeless man arrived in the emergency room with delirium, skin lesions and multiple infections in his lungs, liver and spleen. Looking at his chart, Dr. Graham was stunned at the collapse of the man’s immune system, and suspected a new virus that was spreading among drug users and gay men. He was right: The man had AIDS.
Soon patients with the same array of symptoms filled the hospital — often young men, skeletal and desperately ill, filling the staff with despair.
“It was scary — horrible,” Dr. Graham said. However mysterious the virus, he vowed to find a way to prevent it from spreading. “I want to be a virologist,” he told the head of an infectious disease department. “What do I do?”
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. Among them was Dr. Graham. It now has a staff of 444, with a budget of about $180 million.
To complement that research, the N.I.H. spent more than $1.5 billion over the same period on a network of clinical trial sites across the country for experimental H.I.V. vaccines. About 85 H.I.V. shots have been tested. None have worked.
Vaccines protect people by giving the immune system a preview of an invading microbe so it can prepare a strong defense against the real thing.
But H.I.V. proved impossible to vaccinate against, for a long list of reasons. Other viruses might use one or another protective mechanism to evade the immune system. But H.I.V. seemed to use all of them, Dr. Graham said: “If we could figure out how to make an H.I.V. vaccine, all the problems with other viruses would be solved.”
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.
They knew it would be difficult. H.I.V. spikes constantly change shape, taking one form before invading a cell and a different one when the virus slips in. 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. Mapping the spike was like trying to grab Jell-O.
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. When he was growing up, his father managed a grocery store and his mother ran the home. He attended Wayne State University on a full scholarship, becoming the first in his family to earn a college degree.
He would go on to graduate school to study X-ray crystallography, the difficult and painstaking art of making tiny crystals of proteins and then blasting them with X-rays to figure out their three-dimensional structure.
But by the time he was hired by the center, Dr. McLellan had tired of chasing the shape of one molecule after another, never knowing what it added up to. He wanted to work on molecules that would matter to human health, like H.I.V.
Within six months, though, Dr. McLellan was flummoxed by H.I.V. and wanted to apply its lessons to another pathogen.
So he approached his boss, Peter Kwong, with an unconventional proposal: Let’s start working on a more manageable virus.
It was time, Dr. McLellan said, to take aim at “something important, but something more tractable.”
Dr. Kwong was not keen on taking his eyes off H.I.V. With the virus killing more than one million people globally every year, Dr. Kwong believed that he had an obligation to stay focused.
Still, Dr. Kwong put his protégé’s proposal for pursuing other targets to a vote of his entire team, just as he did matters of whom to hire and what equipment to buy. The result was almost unanimous, Dr. Kwong recalled: “Try other things.”
Dr. McLellan didn’t have to look far. He had been working in a spillover area on another floor from Dr. Kwong’s lab, and was seated close to Dr. Graham, who for years had studied not only H.I.V., but respiratory syncytial virus, or R.S.V., a disease that can kill young children. They got to talking, and Dr. McLellan began studying the structure of a protein that helps the virus fuse with cells.
Over the next years, their success in stabilizing that protein opened the door to several R.S.V. vaccines now in clinical testing.
And though they never expected it, their happenstance collaboration would prove critical for understanding the scary new virus that would emerge more than a decade later.
A Pipe Dream
In the 1950s, the molecule at the heart of the mRNA vaccines was cloaked in mystery. Midcentury biologists knew that blueprints for making proteins — DNA — resided in the middle of cells, and that other structures within cells, called ribosomes, actually produced the proteins. But they didn’t know how the genetic blueprints found their way to the cellular factories.
On April 15, 1960, at a frenzied and ecstatic meeting in an office at Cambridge University, half a dozen stars of the nascent field of molecular biology — including the future Nobel Prize winners Francis Crick and Sydney Brenner — had an epiphany. 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.
But for all of their initial excitement, those heavyweights of the field didn’t do much more with mRNA. The molecule was nearly impossible to isolate from cells because it would fall apart as it was being removed.
“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. “mRNA was just annoying because it was so easily degraded.”
For decades, few scientists paid attention to these delicate molecules. They might never have made it into the Covid vaccines if not for a chance meeting between two academics at a Xerox machine at the University of Pennsylvania.
Dr. Drew Weissman, a physician and virologist so taciturn that his family liked to joke he had a daily word limit, was desperate for new approaches to an H.I.V. vaccine. Earlier in his career, he had spent years in Dr. Fauci’s lab at the N.I.H. testing a treatment for AIDS that turned out to be toxic.
One day in 1998, he was at the copy machine in Penn’s department of medicine when a woman approached him. Katalin Karikó, a 44-year-old scientist from Hungary, was as exuberant as Dr. Weissman was withdrawn. She had come to the United States two decades earlier when her research program at the University of Szeged ran out of money. But she’d been marginalized in American research labs, with no permanent position, no grants and no publications. She was searching for a foothold at Penn, knowing that she would be allowed to stay only if another scientist took her in.
Her obsession was mRNA. Defying the decades-old orthodoxy that it was clinically unusable, she believed that it would spur many medical innovations. 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.
“I said, ‘I am an RNA scientist. I can do anything with RNA,’” Dr. Karikó recalled telling Dr. Weissman. He asked her: Could you make an H.I.V. vaccine?
“Oh yeah, oh yeah, I can do it,” Dr. Karikó said.
Up to that point, commercial vaccines had carried modified viruses or pieces of them into the body to train the immune system to attack invading microbes. An mRNA vaccine would instead carry instructions — encoded in mRNA — that would allow the body’s cells to pump out their own viral proteins. This approach, Dr. Weissman thought, would better mimic a real infection and prompt a more robust immune response than traditional vaccines did.
It was a fringe idea that few scientists thought would work. A molecule as fragile as mRNA seemed an unlikely vaccine candidate. Grant reviewers were not impressed, either. His lab had to run on seed money that the university gives new faculty members to get started.
By that time, it was easy to synthesize mRNA in the lab to encode any protein. Drs. 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. But when they injected mRNA into mice, the animals got sick.
“Their fur got ruffled, they hunched up, they stopped eating, they stopped running,” Dr. Weissman said. “Nobody knew why.”
For seven years, the pair studied the workings of mRNA. Countless experiments failed. They wandered down one blind alley after another. Their problem was that the immune system sees mRNA as a piece of an invading pathogen and attacks it, making the animals sick while destroying the mRNA.
Eventually, they solved the mystery. 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.
Their paper, published in 2005, was summarily rejected by the journals Nature and Science, Dr. Weissman said. The study was eventually accepted by a niche publication called Immunity. Just as mRNA itself had been ignored, no one cared that they could get cells to accept mRNA. It seemed of academic interest, at best.
Despite the naysayers, Drs. Karikó and Weissman believed their discovery could change the world. They now knew how to protect mRNA once it was inside a cell. 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.
As it turned out, a team of biochemists in Vancouver had spent years quietly revolutionizing ways of ferrying genetic material into cells. It was a partnership as improbable as any that helped lead to mRNA vaccines.
The team’s ringleader was a lanky man named Pieter Cullis who had intended to become an experimental physicist, not a biochemist. But he came to feel that the biggest discoveries in physics had been made decades earlier, and went in search of emptier scientific pastures.
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. Dr. Cullis wondered if he could design his own lipid membranes to encase drugs or genetic material and transport it to cells.
In the 1990s, mRNA-based medicines were on hardly anyone’s radar, but gene therapy was in vogue as a technique to modify certain genes to treat or cure disease. For those drugs to successfully deliver a new gene to a patient, they needed a FedEx package of sorts. And Inex, a firm co-founded by Dr. Cullis, set out to find one.
The project was grindingly difficult. He was working with fat globules one hundredth the size of a cell. Human cells had a system of elaborate defenses to prevent anything but food from entering. And some versions of his lipids were extremely toxic and had electric charges that could rip cell membranes apart.
The big breakthrough came when he and his team figured out how to manipulate the positive charge on the fatty coats, said Thomas Madden, who worked with Dr. Cullis at Inex. The fatty bubbles would be charged when scientists loaded DNA inside, but the charge and toxicity disappeared once they were injected into the bloodstream.
But technical challenges remained, and the Vancouver chemists decided there was more money to be made in other sorts of drugs. Dr. Cullis shifted focus, licensing the lipid technology for some applications to a new company, Protiva, whose chief scientific officer was a soft-spoken biochemist named Ian MacLachlan.
In 2004, Dr. MacLachlan’s team made another crucial step forward: He encased the genetic material inside fatty coats in a way that would allow drug companies to increase production, and changed the ratios of lipids to keep more of the precious cargo from escaping. The team also worked to ensure that cells did not simply break up the genetic material as soon as it arrived.
Seeing those advances as critical to making mRNA-based medicine, Dr. Karikó tried to convince Dr. MacLachlan twice over the coming years to work together.
But business disputes got in the way. The first time, she cornered him at a conference and begged him for his lipids. He said no because her university insisted on getting the rights to Protiva’s intellectual property, Dr. MacLachlan said. The second time, around when Dr. Karikó began working for BioNTech, Dr. MacLachlan flew to their offices in Mainz, Germany, to try to make a deal. Dr. Karikó visited Vancouver, too. But Dr. MacLachlan said the company’s offer was not serious. “Our shareholders would’ve crucified us,” he said.
Protiva was also engaged in an intellectual property fight with a new firm co-founded by Dr. Cullis. Disenchanted, Dr. MacLachlan quit the company and bought a motor home to travel with his family.
Eventually it was Dr. Cullis’s teams that worked with vaccine makers on wrapping an mRNA shot in lipids — a major departure from the scientists’ original goals. “We were not going in that direction at all,” Dr. Cullis said.
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.
And that crucial bit of information came out of the longstanding collaboration between Drs. McLellan and Graham, who had been working together ever since their days sitting near each other at the Vaccine Research Center.
As Dr. McLellan prepared to open his own lab at Dartmouth in 2013, he and Dr. Graham discussed what the new lab should focus on. His mentor had a surprising answer: coronaviruses. It was a class of viruses that usually caused nothing worse than a cold, attracting scant interest from funding bodies. Devoting a lab to them would be a gamble.
But MERS had recently begun spreading in camel barns and slaughterhouses in the Middle East. Only 11 years earlier, another deadly coronavirus, SARS, had emerged in Southern China. 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.
“As we were talking about it, it seemed like we were maybe on a 10-year clock for new spillover events,” Dr. McLellan said.
MERS, like all coronaviruses, had a curious feature reminiscent of the shape-shifting proteins on H.I.V.: squirmy spikes on its surface that latch onto human cells. 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. It was large, covered in a thick bush of sugars and highly unstable.
“It was pretty much a nightmare,” Dr. McLellan said.
Making matters more difficult, Dr. Graham had failed to secure samples from anyone infected with MERS in the Middle East.
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. Graham said.
When a young Lebanese-American flu researcher in his lab, Hadi Yassine, recovered from an illness after a trip to Mecca, Dr. Graham thought he might have been infected with MERS. But it turned out to be a cold virus known as HKU1.
It was then that Dr. Graham had his insight: The world’s most boring coronaviruses may hold critical lessons about the most dangerous ones.
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.
“You can consider it luck,” Dr. 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. Making a vaccine depended on it.
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. It was a complex task, so Dr. McLellan turned to the map he had built of the cold virus spike for clues.
Working alongside Dr. McLellan on that problem in his Dartmouth lab was Nianshuang Wang, a postdoctoral fellow from China, who believed that SARS and MERS presaged worse coronavirus outbreaks to come.
Dr. 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. The biggest discoveries often depended on those researchers, many of them ambitious students from outside the United States, who work on launching their own careers even as they play background parts in someone else’s.
In this case, Dr. Wang was working on a virus he knew well. The son of peasant farmers from a small village in eastern China, he as a child had become interested in the scientific concepts behind animal life, and later helped a Chinese team make crucial discoveries about MERS. Having read about Dr. McLellan’s R.S.V. research, Dr. Wang applied to join his Dartmouth lab, and was soon assigned the task of holding the MERS virus’s ungainly spike proteins still.
Part of what made them so prone to shape shifting was that they had pockets of empty space. So Drs. McLellan and Wang first tried filling them with a molecular glue — “cavity filling,” Dr. McLellan called it. Next they tried inserting two molecules that, when close enough, formed a bond, cementing a moving part of the spike to a steadier one. But both of those methods failed.
A third approach produced excellent results. Using their map of HKU1 as a rough guide, they zeroed in on a particularly loose joint of the spike and added two stiff amino acids. Those changes made the entire thing more rigid.
By the time they refined the method, however, the MERS epidemic was long over, and interest in coronaviruses had faded. Rejected by five prestigious scientific journals, the study ended up buried in a less prominent publication and a 2017 patent filing.
That was Dr. Wang’s only first-author journal article to come out of some three years of work — far short of what he needed for the prestigious academic job in the United States that he craved.
The lack of recognition stung, Dr. Wang said: It had been punishing, often boring work that had starved him of time with his wife and young daughter and left the family without much money.
But any lingering resentment disappeared when, in early 2020, a few months before leaving Dr. McLellan’s new lab at the University of Texas at Austin for a pharmaceutical company, Dr. Wang helped unearth his old findings to make a coronavirus vaccine.
“A small little thing can actually change the field, and even change the world,” Dr. Wang said. “That was the first thought for me.”
‘Back in the Saddle’
At 5:30 a.m. on Dec. 31, 2019, Dr. Graham, who regularly started his days before dawn, was working in his home office when he saw a news release from ProMed, a listserv for infectious disease experts around the world. A new pneumonia was spreading in Wuhan, China. At 5:54, he sent an email to his lab group: “We should keep an eye on this.”
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.
He called his old collaborator Dr. McLellan, whose lab had been splitting time between coronaviruses and other pathogens. When his cellphone rang, Dr. McLellan was browsing in a ski shop in Park City, Utah, while waiting for his snowboarding boots to be heat-molded. When he saw the caller ID, he thought Dr. Graham was calling to wish him a belated Merry Christmas.
Instead Dr. Graham told Dr. McLellan the grim news. “We need to get back in the saddle,” he said. “This is our time.”
Dr. McLellan texted his lab to let them know the news. Several days later, when Chinese researchers posted the virus’s genetic sequence online, they got to work.
Using what they had learned working on Dr. 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. McLellan and Wang had refined.
And on Feb. 15, Dr. Graham and Dr. McLellan published a paper detailing the spike’s structure on a website for scientific manuscripts. The study was later published in Science.
“That meant a lot,” Dr. McLellan said. “Because we published where to put the stabilizing mutations, other companies could use it.”
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. Weissman and Karikó had learned 15 years earlier. They wrapped their genetic cargo in protective fatty coats like those first dreamed up by the Canadians. They poured the resulting clear liquid into tiny glass vials and shipped them off for the first human tests.