USA TODAY International Edition

Unsung scientists, unheard- of speed

Created in a day, vaccine built on decade of work

- David Heath and Gus Garcia- Roberts

Jennifer Haller layered a blue denim shirt over a gray tank top that morning, knowing she would later need to bare one shoulder. Her husband, always on her case about skipping breakfast, scrambled some eggs. The night before, she had read news online that the first person would get an experiment­al vaccine against the novel coronaviru­s at Kaiser Permanente in the morning. She wondered if that person might be her.

When she arrived at the research center, not far from Seattle’s iconic Space Needle, the whole world was standing by. It had been 75 days since news broke of unexplaine­d cases of pneumonia seeming to emanate from a seafood market in Wuhan, China, and 66 days since scientists in the United States stared at the virus’s genetic code and vowed to conjure a vaccine to shut it down, at a recordshat­tering pace.

Doing so was a bet that, a few years ago, would have felt as audacious as sending a man to Mars. Vaccines took decades to develop. Their history was littered with missteps and disappoint­ment. Jonas Salk’s polio vaccine came only after 50 years of trial and error. Vaccines for HIV and Zika still elude scientists.

Now the country was in the grip of a disease that had infected 172,000 people, killed 6,700 and was accelerati­ng unimpeded. Dr. Anthony Fauci, who had quickly become the voice of the scientific community, was already predicting a vaccine within as little as a year, a projection many of

his colleagues considered wildly optimistic.

But Fauci knew something many did not. Members of his team at the National Institutes of Health and an affiliated biotech company had been preparing for years for just this moment, just this vaccine. The liquid about to go into Haller’s arm was the culminatio­n of years of research by a handful of scientists who, by virtue of luck and foresight, were prepared for one virus more than almost any other: a coronaviru­s.

Had this virus come 10 years earlier, or even five, science would not have been ready.

At the start of the pandemic, no one could have foreseen how controvers­ial a COVID- 19 vaccine would become – that the country would soon be stewing in anti- science sentiment, awash in misinforma­tion and cleaved by mistrust.

When Haller had answered a callout from a friend to “Fellow Humans” to participat­e in a 14- month medical trial, she’d barely blinked. The 43- year- old mom had stepped up because it was the right thing to do in an awful moment.

As she clicked through the news on her phone and surveyed the medical staff and journalist­s surroundin­g her that morning, she was just figuring out that she was making history. She was the first COVID- 19 vaccine trial subject.

A pharmacist in an N95 mask, protective goggles and blue latex gloves held up a syringe. The needle slid in.

The experiment had begun.

Unsung scientists

Then- President Donald Trump credited his Operation Warp Speed for the fast developmen­t of the vaccine, and marshaling the resources of public health agencies no doubt played a critical role. So did committing $ 9 billion for human trials and manufactur­ing the vaccine even before it was tested, banking on a green light from the U. S. Food and Drug Administra­tion.

But the real credit for the rapid turnaround belongs to a series of uncelebrat­ed discoverie­s dating back at least 15 years – and a constellat­ion of unsung scientists.

Chief among them is Barney Graham, now 67, who had spent much of his career trying to understand why two infants died in a disastrous 1966 vaccine trial for a virus that remains the leading cause of hospitaliz­ation for young children. The tragedy slowed the developmen­t of a vaccine for respirator­y syncytial virus ( RSV) for decades, and it haunted Graham. He continued his research for 31 years until, in 2013, he had a major breakthrou­gh – one that would become vital to developing a COVID- 19 vaccine.

In recent years, as deputy director of the National Institutes of Health’s Vaccine Research Center, Graham’s mission had been to make a vaccine fast enough to stop a pandemic. He was looking for a good virus candidate.

A towering, gentle man with a medical degree and a doctorate in immunology, Graham had gotten close once before when the mosquito- borne Zika virus reached the U. S. in 2016. Thousands of babies were born with severely shrunken brains, a deformity known as microcepha­ly.

The Zika vaccine candidate held the speed record for getting from initial research into a clinical trial – roughly seven months – but that pandemic subsided before Graham could complete the small trial, leaving the world with no vaccine for Zika.

At the end of 2019, Graham was months into plans to make another vaccine at supersonic speeds. He had chosen a virus called Nipah. Spread by bats, it last broke out in India in 2018, killing 17 of the 19 people it infected in Kerala.

Graham had a bold goal. He’d even picked a biotech company to make the Nipah vaccine: Moderna. During the Zika experiment, Moderna had developed a vaccine 10 times more potent than the DNA vaccine Graham himself had created. It relied on messenger RNA, sometimes called the “software of life” because it carries out the instructio­ns of our DNA. In a vaccine, mRNA instructs our bodies to produce just a piece of the virus, the protein on its surface.

Moderna is so dedicated to this new world of medicine that its name combines the word “modified” with RNA. Its technology expedites developmen­t of vaccines by persuading the body’s own genetic process to mimic a component of the virus and create antibodies. Although in its decadelong existence Moderna had never brought a vaccine to market, it had tested several experiment­al vaccines in a dozen small clinical trials.

As Graham got word through back channels that the new virus in China was probably a coronaviru­s, he reached out to Moderna’s CEO. We should scratch the Nipah plan, he urged Stephane Bancel in a Jan. 6 email, in favor of a different proof of concept related to the Wuhan outbreak.

“If it’s a SARS- like coronaviru­s, we know what to do,” Graham wrote. “This would be a great time to run the drill for how quickly can you have a scalable vaccine.”

Graham later laid out the idea for Fauci, his boss’s boss. Fauci hadn’t been aware until then how confident Graham was in his ability to make a coronaviru­s vaccine.

There had been two other novel coronaviru­ses since 2003, although neither SARS nor MERS were terribly contagious and neither became pandemics. In early January 2020, there was no reason to assume COVID- 19 would be any different. Yet Graham already had his team diving into how to defeat the new coronaviru­s just to prove it could be done. Fauci was sold.

“Let’s go full- blown,” he said. “Let’s make a vaccine.”

Fauci had already set aside $ 5 million for the small Nipah demonstrat­ion project. Graham asked if there would there be millions more available.

“Barney, let me worry about the money,” Fauci replied.

If everything went perfectly, Graham said a vaccine could be ready within 12 to 18 months – the prediction Fauci would soon make public.

Virus’s unique identity is revealed

Close to midnight on Jan. 10, Graham was relaxing at his suburban Maryland home when he finally got the news he’d been expecting: Chinese scientists had posted the genetic sequence for what they called the “Wuhan seafood market pneumonia virus.”

Early the next morning, Graham fired up his laptop. He navigated to a website used by scientists worldwide to share informatio­n and saw hundreds of rows of four letters – a, c, g and t – that revealed the virus’s unique identity. The reports were true. It was a novel coronaviru­s, SARS- CoV- 2, a new version of a family of infectious diseases.

According to news accounts, the virus so far had infected only 41 people and killed one.

Graham began texting, emailing and calling a handful of close associates. He reached Jason McLellan, a former NIH scientist now at the University of Texas. Another was a rising star he had known since she was a teenager, when she applied for an internship. Kizzmekia Corbett had been working in Graham’s lab since 2014, studying the best way to defeat coronaviru­ses with a vaccine.

The team began to tailor a vaccine to the new coronaviru­s. They had a big head start, having experiment­ed on coronaviru­s vaccines in mice for years in collaborat­ion with Moderna. The work happened on laptops, not in labs.

They moved fast, but carefully; the more accurate they were, the more effective the vaccine would be. It took them only a few hours.

The mRNA would be encased in a fat bubble and injected in a person’s arm. It was intended to produce a protein identical to the spike protein on the surface of the new virus. That protein, they hoped, would trigger the body to produce the right antibodies to fight back.

Graham convened over the phone with scientists at Moderna two days later to sketch out the road map. Moderna would produce the vaccine, using the genetic code Graham provided. It would be the only vaccine for which the government would lead the first clinical trial, a trial Graham wanted to launch in a matter of weeks.

In Graham’s mind, he had clicked a stopwatch: The race to a vaccine had begun.

First U. S. patient is confirmed

Eight days after Graham’s team designed a vaccine, the new coronaviru­s officially reached the United States. In a Seattle suburb, a 35- year- old man who’d just returned from Wuhan began coughing and throwing up. He’d never gone to the seafood market where the virus was believed to have spread. After four days of symptoms, he called a local urgent care clinic for guidance Jan. 19.

The clinic ran a batch of tests and found nothing. It overnighte­d the man’s nasal swab to the Centers for Disease Control and Prevention in Atlanta, gave him an N95 mask and told him to quarantine at home.

The next day, the man got a call. The test results had come back: He was the first patient in the United States confirmed to be infected with the new virus.

At the CDC’s request, Providence Regional Medical Center – which ran the urgent care center and had a hospital near Seattle in Everett – sprang into action. Using a protocol for Ebola, it sent emergency medical technician­s to pick up the infected man. The techs wore hazmat suits. They used a gurney equipped with an Iso- Pod, a plastic bubble to keep the virus from spreading.

When they arrived at the hospital, they wheeled him to the biocontain­ment unit, with a special air flow system to prevent the virus from escaping his sealed room. Doctors examined the man via a video camera.

Public health officials scrambled to track down at least 50 people who’d had contact with the man in the five days since his return from China. They never found anyone sick, leaving them unsure how contagious this new disease might be. The Seattle Times quoted health experts saying not to worry too much; coronaviru­ses aren’t usually that contagious until someone has symptoms.

From Davos, Switzerlan­d, a CNBC correspond­ent asked Trump on Jan. 22 if he was concerned about a pandemic.

“No, we’re not at all. We have it totally under control. It’s one person coming in from China,” Trump said, referring to the patient in Seattle. “It’s going to be

just fine.”

Although it still wasn’t clear how urgent a vaccine would become, Moderna was already starting to produce the one Graham and his colleagues had developed. NIH put out a notice to 10 sites it uses for vaccine trials, asking them to get ready to test the experiment­al concoction on humans. On Jan. 27, Dr. Lisa Jackson at Kaiser Permanente Washington in Seattle learned that she would oversee that trial.

Mouse studies show promise

Experts knew there had never been a vaccine created in less than four years. That was for the mumps, and even that vaccine was an outlier. “I think the goal of 18 months is one that will be very, very difficult to achieve,” Michael Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota, said in the early months. “But it just may be our moon shot.”

By Feb. 19, Graham and his team had the first good news from a two- week mouse study. Blood drawn from vaccinated mice showed they were producing antibodies to fight the virus. Corbett designed that study, gave mice the vaccine and analyzed the results.

For Graham, the mouse results were reaffirmation that he was right to be so sure of the vaccine, confidence earned by devoting so much of his life to trying to develop a vaccine for RSV.

Graham had spent much of his career at Vanderbilt University, where he focused on HIV as well as RSV. He brought that work with him to NIH when he was recruited there in 2000.

RSV sends as many as 125,000 children to the hospital each year. It also holds a special place in the history of vaccines. In one clinical trial in 1966, 31 infants were given the trial vaccine. Twenty of them later caught the disease. Of those, 16 ended up in the hospital and two died.

McLellan, a young postdoctor­al fellow at NIH when he began working with Graham, says his mentor was devastated to see children with RSV struggling to breathe. Starting in 2009, Graham worked shoulder to shoulder with McLellan. Together, they were going to solve the riddle of how to make a safe vaccine for RSV.

With some vaccines, such as the one Salk created for polio, scientists took a live virus and killed it. The dead virus went into the syringe, then into arms. It was imprecise science and, in the case of polio, hugely effective.

That approach did not work for RSV; the dead virus made children more vulnerable to the illness. Graham suspected that to unravel the situation, he needed to understand precisely how viruses attack human cells.

Proteins on the surface of a virus attach themselves to a cell membrane, tearing open a pathway for the virus to invade the cell. Graham wanted to understand how the protein accomplish­ed its mission. McLellan wasn’t sure how useful this pursuit would be. It hadn’t worked for HIV.

They wanted to see for the first time what the protein on RSV looked like. McLellan used an antibody, isolated from a human, to pin the protein and make it stable. Using an advanced technique known as X- ray crystallog­raphy, he then froze and X- rayed it.

As he sat next to Graham at a scientific event in China, McLellan pulled up the image. It looked nothing at all like Graham had expected. It turned out that a protein looks different after it attacks a cell – before, it’s like a lollipop; after, it’s like a golf tee.

When surface proteins bind with a cell, they resemble the attack of the creature in “Alien.” A peptide shoots out and latches onto cells, then rips the cell membrane apart, giving the virus access to the cell. Our immune systems produce different antibodies for different shapes. The wrong antibody offers less protection – and could even make the virus worse.

Graham recognized immediatel­y that this level of precision was a game changer. The research is now being used to develop an RSV vaccine, the vaccine Graham thought might be his legacy. Instead, when MERS broke out in Saudi Arabia in September 2012, his team began researchin­g the structures of proteins on coronaviru­ses.

McLellan continued to work with Graham, even after he moved on to Dartmouth College and later the University of Texas. By 2017, they had figured out how to defeat coronaviru­ses with a vaccine and published a major scientific article, one that nearly all vaccine makers would one day rely on for COVID- 19.

Subsequent­ly, Corbett worked with others to test possible vaccines, with a special focus on MERS. Working with Moderna, she helped inject mice and then drew blood to test for antibodies.

Doctor gets troubling news

Back in Seattle, the first human trial for the coronaviru­s vaccine was about to start. A process that typically takes months – approving a study design – became Jackson’s sole priority and was completed in days. The plan was to give different doses to four groups of 15 adults, ages 18 to 65. Two shots would be given 28 days apart, with months of follow- up.

The point was to see whether the vaccine had side effects, begin to settle on its proper dose and determine whether it was producing neutralizi­ng antibodies to stop a virus.

Kaiser Permanente’s Jackson was hiring nurses and getting supplies ready when bad news struck at a suburban hospital.

Quite a few patients at Kirkland’s EvergreenH­ealth Hospital had pneumonia. As medical director of infectious disease, Dr. Francis Riedo knew this wasn’t unusual during the winter but, since the CDC had just loosened the criteria for coronaviru­s testing, Riedo decided to test two of the patients. He chose them based on which were in hospital rooms that could easily be sealed off if the results came back positive.

Swabs were collected and sent to the local public health office. The next morning, Riedo was shocked by the results: Both patients had COVID- 19.

One – a man in his 50s who had never left the country – died that same day. The other, who came from a nearby nursing home, died later. The two patients had no connection.

Riedo realized that the virus had been circulatin­g in the Seattle area for weeks. The epidemic, he concluded, was already out of control.

Two residents of a nearby nursing home, Life Care Center of Kirkland, also tested positive. Fifty more were awaiting results. At a standing- room- only press conference the next day, Riedo predicted: “What we’re seeing is the tip of the iceberg.”

Overnight, Seattle became the nation’s first hot spot. The CDC flew in experts. A school district decided to shut down. Gov. Jay Inslee declared a public health emergency. Within a few days, much of the rest of the country would go into a lockdown.

Haller volunteers for vaccine trial

Amid this frenzy, Haller, an operations manager at a Seattle tech company and a mother of two, started paying close attention. Her mother and stepfather lived not far from the nursing home, and Haller was worried about them.

On March 3, she was scrolling through Facebook when a friend’s post stopped her. He had linked to Kaiser’s signup page as a favor for a nurse working on the vaccine. This was the Phase 1 trial that Graham, now exclusivel­y working from home, had set in motion and was helping oversee.

Haller didn’t care about the $ 1,100 stipend being offered to trial participan­ts. She had always felt that as a white person living a middle- class life, she should give something back. She also was game for taking risks.

So, she clicked on the link and filled out a form that asked only one question aside from her age and basic contact informatio­n: “Are you willing to attend 11 in- person study visits and have 4 phone visits over a 14- month period?” She clicked submit.

Haller put it out of her mind until two days later, when someone from Kaiser called. She answered questions about her health history and whether she could make all the appointmen­ts.

From there, things moved quickly. Haller went into Kaiser’s offices a couple of days later for blood draws, a physical exam and more questions.

Because of so much earlier research, led by Graham and Moderna, no one involved expected the vaccine to make the disease worse. Still, side effects are common in vaccine trials, including pain at the injection site, tiredness, headache, muscle pain, chills, joint pain, swollen lymph nodes, nausea and vomiting, and fever.

If any serious side effects emerged that weren’t expected, the trial would be immediatel­y suspended – even halted for good.

Haller knew she was essentiall­y a guinea pig. It didn’t faze her.

The first U. S. vaccine

As the coronaviru­s outbreak in Seattle grew, officials at NIH feared the crisis could shut down the vaccine trial at Kaiser. They went back through the list of potential sites and added Emory University in Atlanta as a secondary hub on March 12.

Emory scrambled to put together a protocol. The Atlanta trial would be led there by Drs. Nadine Rouphael and Evan Anderson, both veterans of infectious diseases and vaccines.

Kaiser told Haller to report to its downtown Seattle office the morning of March 16 and asked her if she would be willing to have the Associated Press there to record it. She signed the waiver.

When she walked into the downtown office, she still had little clue how much attention she was about to get. After the shot, she was asked to wait a couple of hours just in case there were any reactions. She felt fine.

Shortly before she walked out, notifications on her cellphone started going off. The first text came from her mother. “Just received a call from Deborah Horne at KIRO TV. … They would like to talk with you and want you to call.”

Hours later she was live on CNN and MSNBC.

“I’m excited to be the first person,” Haller told MSNBC’s Ari Melber. “This is crazy.”

“Crazy is one word for it,” Melber joked, making Haller laugh.

Haller’s shot marked an enormous milestone for Graham and his team. It had been only 66 days since the Chinese posted the genetic sequence. They had proven that vaccines can be ready for human tests quickly. Graham remained fully confident in the vaccine, later confiding to a reporter that at that point he already expected it to be about 80% effective.

If he turned out to be right, expectatio­ns about the speed of vaccine developmen­t would change forever.

“If it’s a SARS- like coronaviru­s, we know what to do.” Barney Graham Jan. 6, 2020, email to Moderna CEO

First results of the trial arrive

In Atlanta, another snag cropped up. A courier service was trying to deliver vaccines for the Emory leg of the trial from a repository in Maryland. However, flights from the nation’s capital kept getting canceled as the U. S. was finally shutting down. That was a problem, because the vaccine solution would degrade if it was not kept frigidly cold.

After two days of delays at Reagan National Airport, a courier service that specialize­s in shipping medical products gave up on flights and used its own delivery vehicles to drive down to Atlanta instead. It packed the vaccine containers in dry ice, dropping them off March 26.

The first shot was given there the next morning – nearly two weeks after Haller had kicked off the Phase 1 trial.

Anderson worked from early morning to late at night managing the trial. A key part of the analysis, being done largely at Vanderbilt University, was to test the subjects’ blood samples for antibodies that would block the virus. That data was discussed in regular conference calls with Graham and the team at NIH, along with others involved in analyzing the data.

Accounts vary on exactly when the researcher­s knew the trial was a success. Anderson recalls seeing the data on his computer; Jackson remembers hearing about it in a conference call.

Graham pegs it to an email from researcher­s at Vanderbilt on May 9. They had the results of antibodies examined from the first eight volunteers. The tall S curves on the chart told the story – the higher the top of the S, the better. When Vanderbilt researcher­s took antibodies from the volunteers’ blood and tested them on infected cells in the laboratory, the virus stopped replicatin­g.

Graham was expecting the vaccine to produce neutralizi­ng antibodies, but not this strong. The highest dose tested was dropped because it produced the most side effects, including fever, but otherwise there were no major safety concerns.

In a conference call with all the key players, the team gave each other verbal high fives for a job well done.

On May 18, Moderna made the unusual decision to release those early findings in a press release. The company’s stock soared that day, up 250% since December. Haller figured out she probably was one of the eight volunteers studied – and was pleased that the vaccine seemed to work.

Within days, Moderna announced plans for a 600- volunteer Phase 2 trial to establish a dose. That trial was barely underway when the company started crafting the Phase 3 study, which would balloon to 30,000 participan­ts, using the most promising dose from Phase 1 instead. Time was of the essence.

They believed the vaccine was safe; now they had to see whether it worked.

Read Part 2 in Tuesday’s USA TODAY

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 ?? PHOTOS BY USA TODAY AND THE USA TODAY NETWORK ?? The NIH team included Barney Graham, clockwise from top left; Jason McLellan, who went on to the University of Texas; Dr. Anthony Fauci; and Kizzmekia Corbett.
PHOTOS BY USA TODAY AND THE USA TODAY NETWORK The NIH team included Barney Graham, clockwise from top left; Jason McLellan, who went on to the University of Texas; Dr. Anthony Fauci; and Kizzmekia Corbett.
 ?? TED S. WARREN/ AP ?? Jennifer Haller of Seattle, at home with dog Meg, was the first person in the U. S. to receive a shot of a potential vaccine for COVID- 19.
TED S. WARREN/ AP Jennifer Haller of Seattle, at home with dog Meg, was the first person in the U. S. to receive a shot of a potential vaccine for COVID- 19.
 ?? PROVIDENCE REGIONAL MEDICAL CENTER ?? The nation’s first confirmed COVID- 19 patient is moved to Providence Regional Medical Center in Everett, Wash., in an Iso- Pod.
PROVIDENCE REGIONAL MEDICAL CENTER The nation’s first confirmed COVID- 19 patient is moved to Providence Regional Medical Center in Everett, Wash., in an Iso- Pod.
 ?? TED S. WARREN/ AP ?? Workers from a disaster recovery team line up before entering the Life Care Center in Kirkland, Wash., to clean and disinfect the facility on March 11, 2020, during a coronaviru­s outbreak.
TED S. WARREN/ AP Workers from a disaster recovery team line up before entering the Life Care Center in Kirkland, Wash., to clean and disinfect the facility on March 11, 2020, during a coronaviru­s outbreak.

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