The significance of the news was clear right away to Graham: There could be not one, but two vaccines by year’s end. If the Pfizer vaccine worked well, odds were good for a vaccine from biotechnology firm Moderna, since they both relied on the spike protein that Graham’s lab helped design and a technology never before harnessed in an approved vaccine.
For months, people had asked Graham about the pressure he must have been feeling on the leading edge of an all-hands effort to invent the tools that could end the pandemic. He was too busy to give it much thought — his summer “vacation” had meant scaling back to 40- to 50-hour workweeks. But the news released a gush of emotion that stunned even him.
“I just let it all go,” Graham said. “I was sobbing, I guess, is the term.”
His son and grandchildren, ages 13 and 5, burst into his office, fearing something had gone terribly wrong.
The world’s hopes have weighed heavily on the quest to develop coronavirus vaccines, with an especially intense focus on two front-runners: one from Moderna, the other from Pfizer and BioNTech. Both were a speedy, but risky — even controversial — bet, based on a promising but still-experimental medical technology. Why, some scientists debated in the spring and summer, would the United States gamble on a type of vaccine that had never been deployed beyond clinical trials, when the stakes were so high?
If, as expected in the next few weeks, regulators give those vaccines the green light, the technology and the precision approach to vaccine design could turn out to be the pandemic’s silver linings: scientific breakthroughs that could begin to change the trajectory of the virus this winter and also pave the way for highly effective vaccines and treatments for other diseases.
Vaccine development typically takes years, even decades. The progress of the last 11 months shifts the paradigm for what’s possible, creating a new model for vaccine development and a toolset for a world that will have to fight more never-before-seen viruses in years to come. But the pandemic wasn’t a sudden eureka moment — it was a catalyst that helped ignite lines of research that had been moving forward for years, far outside the spotlight of a global crisis.
The Vaccine Research Center, where Graham is deputy director, was the brainchild of Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases. It was created in 1997 to bring together scientists and physicians from different disciplines to defeat diseases, with a heavy focus on HIV.
Long before the pandemic, Graham worked with colleagues there and in academia to create a particularly accurate 3-D version of the spiky proteins that protrude from the surface of coronaviruses — an innovation that was rejected for publication by scientific journals five times because reviewers questioned its relevance. His laboratory partnered with one of the companies, Moderna, working to develop a fast and flexible vaccine technology, in the hope that science would be ready to respond when a pandemic appeared.
“People hear about [vaccine progress] and think someone just thought about it that night. The amount of work — it’s really a beautiful story of fundamental basic research,” Fauci said. “It was chancy, in the sense that [the vaccine technology] was new. We were aware there would be pushback. The proof in the pudding is a spectacular success.”
Turning human cells into bespoke protein factories
The leading coronavirus vaccine candidates in the United States began their development not in January when a mysterious pneumonia emerged in Wuhan, China, but decades ago — with starts and stops along the way.
Since 1961, scientists had known about messenger RNA, the transient genetic material that makes life possible, taking the instructions inscribed in DNA and delivering those to the protein-making parts of the cell. Messenger RNA is a powerful, if fickle, component of life’s building blocks — a workhorse of the cell that is also truly just a messenger, unstable and prone to degrade.
Some scientists believed from the start that it would be possible to repurpose this basic cellular function for medicine. In 1990, a Hungarian-born scientist at the University of Pennsylvania, Katalin Kariko, brashly predicted to a surgeon colleague that his work would soon be obsolete, replaced by the power of messenger RNA therapies. That same year, a team at the University of Wisconsin startled the scientific world with a paper that showed it was possible to inject a snippet of messenger RNA into mice and turn their muscle cells into factories, creating proteins on demand.
“That was something that was amazing,” said Melissa Moore, an RNA scientist who joined Moderna as chief scientific officer four years ago.
If custom-designed RNA snippets could be used to turn cells into bespoke protein factories, messenger RNA could become a powerful medical tool. It could encode fragments of virus to teach the immune system to defend against pathogens. It could also create whole proteins that are missing or damaged in people with devastating genetic diseases, such as cystic fibrosis. But there were all kinds of practical problems to be solved first.
Despite the excitement, scientists had trouble getting RNA into cells because it is so fragile. And when they succeeded, they would soon discover RNA caused an inflammatory reaction.
A friendly competition over a photocopier in the late 1990s led to a major breakthrough. Kariko, working in the University of Pennsylvania’s neurosurgery department, was trying to turn RNA into a therapy for strokes. In line, she bragged to Drew Weissman, a physician-scientist who worked in a different building but used the same copier to print out scientific articles, about the molecule she had become obsessed with.
Weissman had done a fellowship in Fauci’s laboratory at NIH, studying the immune cells involved in vaccine responses. He asked Kariko if she could make some RNA for an HIV vaccine idea he was pursuing. She did, and he found the RNA stimulated an inflammatory response — bad news for Kariko’s efforts to turn it into a stroke therapy.
Weissman noted that mice injected with messenger RNA would suffer every side effect, from feeling lousy and losing their appetites to dying. The two began puzzling out a way to overcome the problems. But it was far from a hot area of science. Kariko bitterly recalled how she struggled for grants, making less money than many lab technicians.
“We went to biotech companies, pharmaceutical companies to try and get funding, and they weren’t interested,” Weissman said. “They said RNA was too fragile and they didn’t want to work with it.”
In 2005, the pair discovered a way to modify RNA, chemically tweaking one of the letters of its code, so it didn’t trigger an inflammatory response. Deborah Fuller, a scientist who works on RNA and DNA vaccines at the University of Washington, said that work deserves a Nobel Prize.
Kariko and Weissman set up a company to turn their discovery into medicine, but eventually, Kariko moved to BioNTech, a German firm working on developing RNA therapies — even though it meant leaving her husband in Philadelphia for 10 months of the year.
“I told my husband when I decided to go to Germany, ‘I just want to live long enough that I can help the RNA go to the patient,’ ” Kariko said. “ ‘I want to see . . . at least one person would be helped with this treatment.’ ”
In parallel, scientists had been developing ways to encapsulate and transport large and unwieldy molecules beginning in the 1960s. The technology matured over the decades, with hopes it could be used to deliver entirely new types of drugs into cells, but messenger RNA posed a bigger challenge than other targets.
“It’s tougher — it’s a much bigger molecule, it’s much more unstable,” said Robert Langer, a bioengineer at Massachusetts Institute of Technology and a co-founder of Moderna.
Ugur Sahin, chief executive of BioNTech, said it was thrilling when he and colleagues in 2016 developed a nanoparticle to deliver messenger RNA to a special cell type that could take the code and turn it into a protein on its surface to provoke the immune system. This, they theorized, was key to using a tiny amount of material — each dose of mRNA vaccine his company developed against coronavirus relies on an amount that’s about a fifth the weight of a penny to stimulate a powerful immune response.
Unlike fields that were sparked by a single powerful insight, Sahin said that the recent success of messenger RNA vaccines is a story of countless improvements that turned an alluring biological idea into a beneficial technology.
“This is a field which benefited from hundreds of inventions,” said Sahin, who noted that when he started BioNTech in 2008, he cautioned investors that the technology would not yield a product for at least a decade. He kept his word: Until the coronavirus sped things along, BioNTech projected the launch of its first commercial project in 2023.
Messenger RNA has never been used in an approved medical product, an oft-repeated fact that has added to its mystique. There isn’t yet a long safety track record, but the platform has been in human tests for years, including in tens of thousands of people in the coronavirus vaccine trials. Even before the coronavirus emerged, the technology had reached a tipping point where it seemed a matter of time before it would begin to have an impact on medicine.
“It’s new to you,” Fuller said. “But for basic researchers, it’s been long enough. . . . Even before covid, everyone was talking: RNA, RNA, RNA.”
The shape-shifting spike
All vaccines are based on the same underlying idea: training the immune system to block a virus. Old-fashioned vaccines do this work by injecting dead or weakened viruses. Newer vaccines use distinctive bits of the virus, such as proteins on their surface, to teach the lesson. The latest genetic techniques, like messenger RNA, don’t take as long to develop because those virus bits don’t have to be generated in a lab. Instead, the vaccine delivers a genetic code that instructs cells to build those characteristic proteins themselves.
To do that, scientists have to choose which telltale part of the virus to show the immune system. Long before the pandemic, Graham’s research had revealed that some virus proteins change shape after they break into a person’s cells. A vaccine based on the wrong shape could effectively train the immune system to be an ineffective sheriff, never stopping vandals or burglars before they wreak their havoc. Graham had used this insight to design a better vaccine against respiratory syncytial virus; it made Science magazine’s shortlist of 2013′s most important scientific breakthroughs.
Coronaviruses seemed like an important next target. Severe acute respiratory syndrome had emerged in 2003. Middle East respiratory syndrome (MERS) broke out in 2012. It seemed clear to Graham and Jason McLellan, a structural biologist now at the University of Texas at Austin, that new coronaviruses were jumping into people on a 10-year-clock and it might be time to brace for the next one.
When a postdoctoral fellow in Graham’s laboratory traveled to Saudi Arabia for the annual pilgrimage to Mecca, and returned home with a respiratory infection, Graham and colleagues worried that it might be MERS. To their relief, it was not MERS, but HKU1 — a coronavirus that causes common cold symptoms.
That infection opened Graham’s eyes to an opportunity. HKU1 was merely a nuisance, as opposed to a deadly pneumonia; that meant it would be easier to work with in the lab, since researchers wouldn’t have to don layers of protective gear and work in a pressurized laboratory.
If they could figure out how to stabilize the spike proteins for HKU1, they could use those insights to do the same for other coronaviruses. Their studies showed that the spike protein folded like origami, from a thumb tack-like shape before fusing with cells, to a rodlike shape afterward.
They wanted the immune system to learn to recognize the thumb tack spike, so McLellan tasked a scientist in his laboratory with identifying genetic mutations that could anchor the protein into the right configuration. It was a painstaking process for Nianshuang Wang, who now works at a biotechnology company, Regeneron Pharmaceuticals. After trying hundreds of genetic mutations, he found two that worked. Five journals rejected the finding, questioning its significance, before it was published in 2017.
“People generally at that time said, ‘Coronavirus is not a big concern,’ ” Wang said. “They didn’t get the idea that this can be a great technology in the disease, to prevent another coronavirus pandemic.”
Last winter, when Graham heard rumblings of a new coronavirus in China, he brought the team back together. Once its genome was shared online by Chinese scientists, the laboratories in Texas and Maryland designed a vaccine, utilizing the stabilizing mutations and the knowledge they had gained from years of basic research — a weekend project thanks to the dividends of all that past work.
But the stabilized spike was just one piece of a vaccine — Graham needed a technology that could deliver it into the body — and had already been working with Moderna, using its messenger RNA technology to create a vaccine against a different bat virus, Nipah, as a dress rehearsal for a real pandemic. Moderna and NIH set the Nipah project aside and decided to go forward with a coronavirus vaccine.
On Jan. 13, Moderna’s Moore came into work and found her team already busy translating the stabilized spike protein into their platform. The company could start making the vaccine almost right away because of its experience manufacturing experimental cancer vaccines, which involves taking tumor samples and developing personalized vaccines in 45 days.
At BioNTech, Sahin said that even in the early design phases of its vaccine candidates, he incorporated the slight genetic changes designed in Graham’s lab that would make the spike look more like the real thing. At least two other companies would incorporate that same spike.
‘We feel like it’s our vaccine’
If all goes well with regulators, the coronavirus vaccines have the makings of a pharmaceutical industry fairy tale. The world faced an unparalleled threat, and companies leaped into the fight. Pfizer plowed $2 billion into the effort. Massive infusions of government cash helped remove the financial risks for Moderna.
But the world will also owe their existence to many scientists outside those companies, in government and academia who pursued ideas they thought were important even when the world doubted them. Some of those scientists will receive remuneration, since their inventions are licensed and integrated into the products that could save the world.
As executives become billionaires, many scientists think it is fair to earn money from their inventions that can help them do more important work. But McLellan’s laboratory at the University of Texas is proud to have licensed an even more potent version of their spike protein, royalty-free, to be incorporated into a vaccine for low and middle income countries.
Weissman, a basic researcher who has been nervously tracking the progress of the RNA vaccines on which so much depend, was overjoyed by the first success.
“They’re using the technology that [Kariko] and I developed,” he said. “We feel like it’s our vaccine, and we are incredibly excited — at how well it’s going, and how it’s going to be used to get rid of this pandemic.”
On Nov. 9, McLellan told his group via a WhatsApp thread that the first vaccine was 90 percent effective.
“Full spike with 2P,” McLellan wrote, referencing the fact that the Pfizer and BioNTech vaccine used a spike protein that contained the mutations they’d discovered. “Barney just called to congratulate us.”
Graham is matter-of-fact, rather than exuberant, and quickly changes the subject to the immense amount of work that remains to be done. Historic scientific news must now be transformed into a tool that is mass produced, distributed and used widely around the world to blunt the sickness and suffering of this winter — and to lift the pall this pandemic has cast over virtually every aspect of daily life. He recalled that his 5-year-old granddaughter recently heard the family talking about “getting back to normal” if a vaccine is successful.
“She looked up and said, ‘What is normal life, what do you mean by that?’ ” Graham said. “Half of her memorable life has been like this.”
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