Halting Progress and Happy Accidents: How mRNA Vaccines Were Made

A new coronaviruses jumped from camels to humans in the Middle East, killing one out of every three people. Dr. Graham had been working on a vaccine for months, but had not been able to get it.

He was worried that the virus, Middle East Respiratory Syndrome, or MERS, could have caused a scientist in his lab to get sick after a pilgrimage to Mecca.

A second test was needed after a nose sample came back positive for a coronaviruses. It was a mild coronaviruses that caused a cold.

Dr. Graham had a hunch that it would be worth taking a closer look at the cold virus.

It was an impulse born of convenience and curiosity, with little to no expectation of glory or profit. Critical discoveries were made because of the decision to study a colleague's cold. It would lead to the creation of the vaccines that protect hundreds of millions of people from Covid-19.

The shots arrived just over a year after a mysterious pneumonia surfaced in China, and so much else went wrong, including political feuds, public distrust and bungled government planning.

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. Pfizer, BioNTech and Moderna say that they can adapt the vaccines quickly, to fend off any new version of the virus that evolution brings next.

The rapid development of the vaccines, one of the most impressive feats of medical science in the modern era, has been seized on by skeptics to undermine the public's trust in them. The breakthrough 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 multimillion-dollar program to speed the development and manufacture of vaccines, drugs and diagnostic tests to fight the new virus.

The scientists who made the vaccines possible scrounged for money and battled public indifference. Their experiments failed often. Some of them left it behind when the work got too much. The science slowly built itself, squeezing knowledge from failure.

Efforts in three areas made the vaccine possible. More than 60 years ago, the first discovery of the genetic molecule that helps cells make proteins was made. Two scientists in Pennsylvania decided to use the molecule to command cells to make tiny pieces of viruses that would strengthen the immune system after a few decades.

The second effort took place in the private sector, as companies in Canada in the field of gene therapy searched for a way to protect fragile genetic molecules so they could be safely delivered to human cells.

In the 1990s, the U.S. government embarked on a quest to find a vaccine to prevent AIDS. A group of scientists were funded by that effort to try and find a way to stop the H.I.V. viruses from invading cells. The work did not result in a vaccine. Dr. Graham was one of the researchers who deviated from the mission and unlocked secrets that allowed the spikes on coronaviruses to be mapped.

The different strands of research came together. The spike of the Covid virus was caused by the expression of genes. The molecules were wrapped in fat and poured into glass. When the shots went into effect less than a year later, recipients' cells responded by making a type of molecule that resembled the spikes.

The promise of basic scientific research is that once in a while, old discoveries can be plucked from obscurity to make history.

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, said that it was all in place. It was a miracle.

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President Bill Clinton and Vice President Al Gore were given a lesson on the biology of AIDS by the top government scientist investigating H.I.V.

In December 1996, President Bill Clinton invited Dr. Fauci to the Oval Office to brief him on AIDS, which had killed more than 350,000 people in the United States and six million more globally.

Dr. Fauci, the top government scientist, was feeling hopeful. The number of AIDS deaths in the country has fallen for the first time since the virus emerged thanks to several new drugs that were tested and approved after years of intense public pressure by patient activists.

A vaccine was missing from their arsenal. The president was impatient.

The president turned to Dr. Fauci and said, "You've known about AIDS as a disease since 1981." How come you don't have a vaccine yet?

Dr. Fauci told the president that research efforts had been largely uncoordinated. He made a bold pitch for 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 Leon Panetta. He asked if he could do that.

Mr. Panetta said that he was the president of the United States. You can do whatever you want.

Dr. Fauci thought they were nice to him. Cancer and heart disease have long taken a back seat to vaccine research. Dr. Fauci received a call from one of the speechwriters. Mr. Clinton wanted to announce a vaccine research center at Morgan State University, where he was going to give a graduation address. Could Dr. Fauci give a description? Dr. Fauci said he was completely shocked.

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Barney Graham is a doctor in Georgia.

Dr. Graham was one of the first scientists to be recruited. He was an infectious diseases doctor at the University of Nashville and had begun his career as a clinician. He had a shattering experience when he was just starting as a chief resident.

A homeless man was in the emergency room with a lot of infections and delirium. Dr. Graham was shocked by the collapse of the man's immune system and suspected a new virus that was spreading among drug users and gay men. The man had AIDS.

Soon patients with the same symptoms filled the hospital, filling the staff with despair.

Dr. Graham said it was horrible. He vowed to find a way to stop it from spreading. He told the head of the infectious disease department that he wanted to be a virologist. What do I do?

The Vaccine Research Center opened in 2000 with a budget of $43.9 million and a staff of 56. Dr. Graham was among them. It has a budget of about $180 million and has a staff of 444.

The N.I.H. spent more than a billion dollars on a network of clinical trial sites for experimental H.I.V. vaccines. There are about 85 H.I.V. shots that have been tested. None of them have worked.

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A human T-cell is depicted under attack by H.I.V.

Vaccines give the immune system a preview of an invading microbe so it can prepare a strong defense against the real thing.

There were a lot of reasons H.I.V. was impossible to vaccine against. The immune system is vulnerable to protective mechanisms used by other viruses. Dr. Graham said that if we could figure out how to make an H.I.V. vaccine, all the problems with other viruses would be solved.

The researchers at the center decided to try a new approach, though it was a long shot. The atomic structure of H.I.V.'s spike would be mapped. They would try to identify the part of the spike that was most vulnerable to the components of the immune system that can block spikes from entering other cells. The goal was to make a vaccine that would show the body a harmless version of the spike.

They knew it would be difficult. H.I.V. spikes change shape constantly, taking one form before invading a cell and another when the virus slips in. To have the best shot at keeping the virus out, a vaccine should only use the shape that elicited the strongest antibodies against the initial spike. The scientists had trouble deciding which shape to choose. It was like trying to grab a piece of candy.

In 2008, a young man from outside Detroit applied to join a group at the Vaccine Research Center working on a problem. His father ran a grocery store while his mother ran the home. He was the first in his family to earn a college degree after attending Wayne State University.

He would study X-ray crystallography at graduate school to learn how to make tiny crystals of proteins and then use X-rays to figure out their three-dimensional structure.

He was hired by the center and by the time he was there, he was tired of chasing the shape of one molecule after another. H.I.V. would matter to him because he wanted to work on molecules that matter to human health.

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The New York Times reported that Peter Kwong, chief of the structural biology section at the National Institutes of Health, studies the rare human antibodies that could attack H.I.V.

Within six months, Dr. McLellan was flummoxed by H.I.V. and wanted to apply its lessons to another pathogen.

He asked his boss, Peter Kwong, to start working on a more manageable virus.

It was time to take aim at something that was more tractable.

With H.I.V. killing more than one million people a year, Dr. Kwong wanted to stay focused.

The proposal for pursuing other targets was put to a vote of his entire team by Dr. Kwong, just as he did the matters of whom to hire and what equipment to buy. The result was almost unanimous.

Dr. McLellan didn't have to look very far. He was working in a spillover area on another floor, and was sitting next to Dr. Graham, who had been studying respiratory syncytial virus. They got to talking, and Dr. McLellan began studying the structure of aprotein that helps the virus.

Several R.S.V. vaccines are in clinical testing because of their success in stabilizing that protein.

Their happenstance collaboration would prove critical for understanding the new virus that would emerge more than a decade later.

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Dr. Drew Weissman, third from right, and Dr. Katalin Karik, third from left, in 2001.

The molecule at the center of the vaccine was shrouded in mystery. Midcentury biologists knew that the blueprints for making genes resided in the middle of cells, and that ribosomes produced the proteins. They did not know how the genetic blueprints ended up in the cellular factories.

On April 15, 1960, at a frenzied and ecstatic meeting00606-5? The molecule known as X was the messenger.

The scientists figured out that X carried copies of the DNA code to ribosomes, which could read it and pump it out. The scientists named the molecule after it.

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A transmission electron microscope image of messenger RNA.

Dr. Drew Weissman, a physician and infectious disease expert 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. He spent years in the lab of Dr. Fauci at the N.I.H. testing a treatment for AIDS that turned out to be toxic.

He was at the copy machine in the department of medicine when a woman approached him. The scientist from Hungary was as excited as Dr. Weissman was. She came to the United States two decades ago when her research program ran out of money. She had been marginalized in American research labs, with no permanent position, no grants and no publications. She knew that she would only be allowed to stay if another scientist took her in.

Her obsession was the same thing. She believed that it would spur many medical innovations, despite the fact that it was clinically useless. If scientists knew the genetic code of the cell, they could force it to make any type of molecule.

I said that I am an RNA scientist. Dr. Weissman was told by Dr. Karik that he could do anything with RNA. He asked if she could make a vaccine.

Dr. Karik said he could do it.

Commercial vaccines used to carry modified viruses into the body to train the immune system to fight invading microbes. The body's cells would be able to pump out their own viruses with the help of an mRNA vaccine. This approach would prompt a more robust immune response than traditional vaccines could, according to Dr. Weissman.

Few scientists thought it would work. It seemed like a vaccine candidate was a molecule that was fragile. Reviewers were not impressed. The university gives new faculty members seed money to start.

It was easy to make a synthesis in the lab. The cells were instructed to make a specific proteins by the mRNA that was inserted into them. The animals got sick when they were injected with the messenger RNA.

Their fur got ruffled and they stopped running. Nobody knew why.

They studied the workings of the messenger RNA for seven years. Many experiments failed. They were wandering down an alley. Their problem was that the immune system attacks the mRNA and makes the animals sick while destroying it.

They solved the mystery. The researchers discovered that cells have a way to protect themselves. The scientists tried to make the same change in the lab before injecting it. It worked because the cells took up the mRNA without provoking an immune response.

The paper was rejected by Nature and Science. The study was published in a publication called Immunity. No one cared that cells could accept mRNA. It seemed to me that it wasn't academic interest.

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I said I am an RNA scientist. She told Dr. Drew Weissman in 1998 that she could do anything with RNA.

The discovery of Drs. Weissman and Karik could change the world. They knew how to protect it once it was inside the cell. To work as a vaccine or a medicine, the fragile molecule would need to be protected from degradation in the bloodstream.

The team of biochemists in the city of Vancouver had spent years changing the way genetic material is taken into cells. It was a partnership that helped lead to vaccines.

The leader of the team was a man who wanted to become an experimental physicist. He came to believe that the biggest discoveries in physics had taken place decades earlier. Like Dr. McLellan, Dr. Cullis was looking for better pastures.

The outer layer of fats, called lipids, that surrounds the trillions of cells in the body, separates the watery outside from the inside. Dr. Cullis wondered if he could design his own membranes to transport drugs or genetic material.

Gene therapy was a technique to modify certain genes to treat or cure disease in the 1990s. They needed a FedEx package to deliver the drugs to the patient. Inex, a firm co-founded by Dr. Cullis, set out to find one.

The project was very difficult. He was working with fat that was one hundredth the size of a cell. Human cells had a system of defenses. Some versions of his lipids were so toxic that they could rip apart cell membranes.

The breakthrough came when he and his team figured out how to change the positive charge on the coats. The charge and toxicity of the bubbles disappeared once they were injected into the bloodstream.

There was more money to be made in other types of drugs because of technical challenges. The new company Protiva, whose chief scientific officer was a soft-spoken biochemist named Ian MacLachlan, licensed the lipid technology for some applications.

In 2004, Dr. MacLachlan and his team made another important step forward, encased the genetic material inside the coats of the fat to make it harder for it to escape. The team worked to make sure that cells did not break up the genetic material when it arrived.

Dr. MacLachlan and Dr. Karik both tried to convince them to work together.

Business disputes made the way difficult. She cornered him at a conference and begged for his lipids. He said no because the university wanted the rights to Protiva. The second time was when Dr. MacLachlan flew to Germany to try to make a deal. Dr. Karik was in Vancouver. The company's offer was not serious according to Dr. MacLachlan. He said that their shareholders would have crucified them.

Protiva was involved in an intellectual property fight with a new firm. Dr. MacLachlan quit the company and bought a motor home to travel with his family.

It was Dr. Cullis and his teams that worked with vaccine makers to wrap an mRNA shot in lipids, a major departure from the scientists' original goals. Dr. Cullis said that they were not going in that direction.

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Sergio Flores for The New York Times reported on the expertise of the University of Texas at Austin.

The Covid vaccines had two pieces of the puzzle that came together in 2020. The third component was figuring out the exact code that would tell cells to make the most effective version of the coronaviruses spikeProtein.

The crucial bit of information came from the long standing collaboration between Drs. McLellan and Graham, who had been working together for years.

Dr. McLellan and Dr. Graham talked about what the new lab should focus on. His mentor had an answer for him. It was a class of viruses that caused nothing worse than a cold, and got little interest from funding bodies. It would be a big risk to assign a lab to them.

The Middle East has recently begun to see the spread of the disease. The deadly coronaviruses had emerged in Southern China. The lack of attention to coronaviruses meant less competition for research grants and signature findings for a young researcher trying to make his mark.

It seemed like we were on a 10-year clock for new events.

Like all coronaviruses, it had a curious feature that resembled H.I.V.: spikes on its surface that latched onto human cells. They were unable to make a vaccine. The scientists were unable to reproduce and isolated the spike in the lab because it was so fearsome. It was covered in a thick bush of sugars.

It was a nightmare according to Dr. McLellan.

Making matters worse, Dr. Graham failed to get samples from anyone who had been in the Middle East.

After years of Western scientists parachuting into lower-income countries for studies that excluded local researchers, governments have become very protective of their samples.

Dr. Graham thought that a young researcher in his lab might have been exposed to the Middle East Respiratory Syndrome. It was a cold virus called HKU1.

The world's most boring coronaviruses may hold critical lessons about the most dangerous ones.

The HKU1 had a spike, but it held its shape better 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 seen a human coronaviruses spike protein before it latched onto cells.

"You can consider it luck or it's a blessing," Dr. Yassine said recently of his cold.

The team decided to use what they had learned about the spike on the common cold virus to steady the proteins on their real adversary, the Middle East Respiratory Syndrome. Making a vaccine was dependent on it.

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A coronaviruses particle.

The problem was that the spikes they made in the lab were not stable and kept changing shape, making them less effective for use in a vaccine.

The spike had to be locked in place. It was a complex task, so Dr. McLellan turned to the map he had built for clues.

Nianshuang Wang, a graduate student from China, was working in the lab of Dr. McLellan and was the one who believed that the outbreak of coronaviruses would get worse.

Dr. Wang was a junior scientist in the lab who had to put in the lonely hours to realize his boss's ideas. Many of the biggest discoveries depended on the researchers who were ambitious students from outside the United States who were trying to launch their own careers.

In this case, Dr. Wang was working on a virus. The son of a peasant farmer in eastern China became interested in the scientific concepts behind animal life when he was a child, and later helped a Chinese team make important discoveries about the Middle East Respiratory Syndrome. Dr. Wang applied to join his lab and was assigned the task of holding the MERS virus's ungainly spike proteins still.

They had pockets of empty space that made them prone to shape shifting. They tried to fill them with a glue calledcavity filling. They tried to put two molecules in the spike that would form a bond and hold it together. Both methods failed.

Excellent results were produced by a third approach. They used their map of HKU1 as a rough guide to find a loose joint of the spike. The changes made it more rigid.

By the time they refined the method, interest in coronaviruses had faded. Rejected by five prestigious scientific journals, the study ended up buried in a less prominent publication.

Dr. Wang had only one first-author journal article to come out of three years of work, which was far short of what he needed for a prestigious academic job in the United States.

The lack of recognition left Dr. Wang without much money and deprived him of time with his wife and young daughter.

Dr. Wang helped uncover his old findings to make a coronaviruses vaccine a few months before leaving Dr. McLellan's lab at the University of Texas at Austin for a pharmaceutical company.

Dr. Wang said that a small little thing can change the world. That was the first thing that came to my mind.

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The Dale and Betty Bumpers Vaccine Research Center is in Rockville, Md.

Dr. Graham was working in his home office when he saw a news release about infectious disease experts around the world. There was a new pneumonia in China. He sent an email to his lab group at 5:54.

He heard that the new disease was caused by a coronaviruses, the same class of pathogen that he had trained his focus on years earlier.

His lab had been splitting time between coronaviruses and other pathogens. When his cellphone rang, he was in a ski shop in Park City, Utah, waiting for his boots to be heat-molded. He thought Dr. Graham was calling to wish him a Merry Christmas when he saw the caller ID.

Dr. Graham told Dr. McLellan the bad news. He said that they need to get back in the saddle. This is our time.

Dr. McClellan sent a text to let them know the news. The Chinese researchers got to work after they posted the genetic sequence online.

The team came up with genetic sequences within days using the techniques they had learned working on Dr. Yassine's cold virus and the new cementing technique that Drs. McLellan and Wang had refined.

Dr. Graham and Dr. McLellan published a paper detailing the spike's structure on a website for scientific manuscripts. Science published the study.

That meant a lot to Dr. McClellan. Other companies could use it because we published where to put it.

The stabilizing technique of the team was crucial to the creation of the mRNA vaccines made by BioNTech, as well as certain non-mRNA vaccines.

The same chemical tweaking that Drs. Weissman and Karik had learned 15 years earlier was applied to the mRNA molecule by Moderna and BioNTech scientists. They wore protective coats like the ones the Canadians dreamed of. They put the clear liquid into glass and shipped it off for the first human tests.

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Dr. Graham, President Biden, Dr. Francis Collins, and Kizzmekia Corbett are pictured. Pete Marovich for The New York Times reported on a visit to the Viral Pathogenesis Laboratory by the scientists who explained the role of spike proteins to Mr. Biden.

The government once again relied on its past investments in H.I.V. for Moderna's all important clinical trials. Dr. Fauci said it was time to pivot.

The program would test four vaccines at about 100 sites, including the Moderna shot. Pfizer decided to test the vaccine on its own.

Dr.Corey said they wanted them to succeed.

The team recruited 30,000 people. It took 2,000 people a day to enroll, more than had ever been attempted for a trial.

The first results from the trial were in November.

It was the culmination of decades of discoveries that had been dismissed as uninteresting. Hundreds of researchers tried, failed, reversed course and madeIncremental progress in different fields, never knowing if their efforts would ever pay off.

Dr. Graham knew that if the Covid vaccines worked, they could pave the way for other new shots against diseases as varied as the common cold, flu and cancer.

The results of the study were better than anyone had dared to hope, and he got a call from his home office on the afternoon of Nov. 8.

He told his wife that it worked. Two of his grandsons hugged him from the front of his office desk. His wife and son hugged him. The virologist cried.