Jason McLellan was waiting for a pair of snowboard boots to be heat-molded to his feet when he answered a call that likely saved millions of lives. Barney Graham, a virologist with the National Institutes of Health, had reached him in a ski shop in Park City, Utah, to ask for his help in developing a vaccine to fight a novel coronavirus that had emerged in China just weeks earlier.
McLellan, a structural biologist at the University of Texas at Austin, immediately messaged Daniel Wrapp, one of the top graduate researchers in his lab, telling him they were joining Graham’s effort. At that moment, the pair knew something few in the world did. Working mostly unnoticed, McLellan and his team had pioneered an entirely new process of vaccine development, one that held great promise against coronaviruses.
Five days after McLellan’s call from Graham, in January 2020, Chinese scientists published the genetic code of SARS-CoV-2; Wrapp needed only an hour to identify a way to lock the virus’s spike protein into a shape that impeded its latching on to cells and made it vulnerable to attack from the human immune system. It was a crucial first step in creating a vaccine. A furious flurry of scientific back-and-forth followed, among McLellan, Graham, and vaccine development teams at the NIH and drugmaker Moderna. Six weeks later, Moderna’s mRNA-1273 vaccine was ready for testing. The Food and Drug Administration authorized it for emergency use just ten months after that.
Developing a vaccine that quickly against a new virus would have been unthinkable a few years earlier. But in 2013, McLellan engineered a stunning breakthrough against another virus that also had no treatment—respiratory syncytial virus, or RSV. This common viral infection fills hospital beds with sick children and kills thousands of adults over age 65 each year. For decades, researchers had tried—and failed—to produce an RSV vaccine. Yet today, thanks to the same McLellan discovery that led to the COVID-19 vaccines, an inoculation could finally be available within the next year or two. McLellan’s work may again prove a lifesaver. And he’s just getting started.
You’d be forgiven for mistaking Jason McLellan for a college student. It’s not just that the 41-year-old wears the standard-issue uniform of sneakers, worn jeans, and an untucked T-shirt. It’s also his laid-back vibe—chomping on a caffeine-rich gum called MEG—his youthful face, and his rough-edged, coffee-colored beard. “He doesn’t want to be a Harvard professor,” says Dan Leahy, the former chair of UT’s molecular biosciences department, who recruited McLellan from Dartmouth five years ago. “He just wants a corner to do his science—and eat good barbecue.”
Time spent trimming his beard or dry-cleaning a blazer could be time spent in his lab, and little enthralls McLellan more than puzzling out the structure of a protein at the atomic level. Growing up in a suburb of Detroit, McLellan often played with Legos, and when he learned about structural biology during his senior year at Wayne State University, his fascination with tiny building blocks became a calling. “I really enjoy determining the three-dimensional structures of proteins,” McLellan said during one of our Zoom conversations, “and I’ve always found viruses fascinating.”
After finishing his doctorate in biophysics at Johns Hopkins in 2008, McLellan received multiple job offers. He wanted to go where he could not only satisfy his curiosity about the structure of proteins but also use that information to save lives. He found that opportunity at the NIH Vaccine Research Center, in Bethesda, Maryland.
Antigens are like mug shots that the immune system uses to identify intruders. And RSV’s F protein is like an intruder who dons a disguise after being spotted robbing a bank.
There, McLellan joined so many scientists working to find a vaccine for HIV, the virus that causes AIDS, that there wasn’t room for him on the fourth floor with the others. Instead, he took a spot on the second floor, near the lab of Barney Graham, who had devoted his career to studying RSV. After the NIH failed at a series of HIV vaccine efforts, McLellan began to wonder whether the lab shouldn’t try its approach on a less complex virus—such as RSV.
That’s not to say RSV is simple. Disastrous vaccine trials in the mid-sixties resulted in two of the vaccinated children dying and most getting sicker than the unvaccinated kids who also had caught RSV. Those trials chilled RSV vaccine progress for decades, even though nearly everyone in the U.S. has had RSV at some point, and many get it multiple times. Studies have found that RSV infections cost the United States more than a billion dollars annually in medical expenses. The virus is particularly dangerous to infants.
When four-month-old Indie Cardenas, of Midland, was first diagnosed with RSV in May, her lungs became inflamed, blocking her airways, and her oxygen levels dropped so low that she turned blue. She was transferred to Covenant Children’s Hospital, in Lubbock, for specialized care and intubated the next day. “We thought it was going to be a two-day or three-day stay at the hospital,” said her mother, Bianca Cardenas. But Indie, whose Down syndrome makes her especially vulnerable to respiratory illness, spent more than a month fighting RSV before recovering. She may join the numerous children who experience long-term effects from bouts with the illness. RSV kills somewhere between 100 and 500 U.S. children and about 14,000 adults age 65 and older each year, according to the Centers for Disease Control and Prevention.
A vaccine that could prevent most of those deaths has remained elusive because an unstable protein on the virus’s surface—the F protein—changes form when it attaches to cells inside the human body. That transformation makes the virus hard to target. Viruses bind to and enter cells so they can hijack the cell’s machinery to replicate. Often, the protein that binds to a cell is also the part of the virus that the immune system recognizes as a threat, called an antigen. Antigens are like mug shots that the immune system uses to identify intruders. And RSV’s F protein is like an intruder who dons a disguise after being spotted robbing a bank. The key to an effective RSV vaccine, then, is to lock that protein into its original shape—before it can make that costume change—and induce the immune system to produce antibodies against that original shape.
The problem was, back when McLellan first set his sights on RSV, no one knew what the F protein really looked like because proteins are too tiny to see except with specialized methods and tools, such as X-ray crystallography or cryo-electron microscopes. McLellan had access to that equipment at the NIH, and Graham persuaded McLellan to map both the pre- and post-change versions of the F protein. “It sounded really important,” McLellan says. “Man, if you can save the lives of tens of thousands . . . that seems like a great thing to make a vaccine for.”
It took three years for McLellan to map out the post-change, or “post-fusion,” version of the F protein, a necessary step to test antibody response and to understand how the protein morphs from one shape to another. Two years after that, in 2013, he finished mapping the pre-fusion version. “All of a sudden, we could see it,” Graham says. “But to capture it, we had to find an antibody that bound to it and then stabilize it.” They hoped to tweak the pre-
fusion structure of the F protein and force it to stay in that shape, leaving it vulnerable to the immune system’s attack. The team had spent two years testing thousands of human antibodies until they found one that neutralized the F protein. They could see the exact portion of the F protein that antibodies latched on to. McLellan added chemical bonds to the protein that would keep it locked into its pre-fusion shape—making it a key ingredient for a vaccine.
The NIH holds the patent on McLellan and Graham’s work, and after the researchers published their process, in 2013, Pfizer and other drug companies immediately began developing RSV vaccines. Trials began in 2017, and today drugmakers GSK, Janssen, Moderna, and Pfizer are each conducting phase III trials on their own vaccines—the final step before FDA approval. All of them use the pre-fusion F protein McLellan designed.
In June, GSK announced that its vaccine offered ““exceptional protection” against RSV in adults age sixty or older. Other trials are testing vaccines in pregnant women, designed to protect babies for several months after birth, when they’re most at risk of severe RSV disease. McLellan hopes to see results from those within the year, and Graham expects an RSV vaccine to be approved for either older adults or pregnant women by the end of 2023. “There are tons of failed phase III trials,” McLellan says, “so to show a path forward, to show this new concept works, is really exciting. That was why I wanted to do this type of work, to make an impact on human health.”
As significant as McLellan and Graham’s discovery was for RSV, it also served as proof of concept for a new way of developing vaccines. Ever since the development of the first vaccine, against smallpox in the eighteenth century, scientists had designed inoculations the same way: introduce a pathogen to the body so that the immune system learns what it looks like and mounts a response against it. Ideally, if scientists know what antigen on the pathogen induces the immune response, they might include only that antigen in the vaccine instead of a whole virus or bacterium, potentially reducing the vaccine’s side effects.
But with RSV, McLellan had instead taken what’s known as a structure-based design approach: determining the antigen needed for a vaccine against a particular disease, figuring out exactly what the antigen should look like to get the body’s best possible antibody response, and then building that antigen. He didn’t invent this concept, first theorized in the early 2000s, but he was the first to turn it into reality.
McLellan continued refining his process, while running his own lab at Dartmouth, before moving to Austin. Instead of using the antigen the pathogen provides, McLellan maps the protein structure of the virus and pinpoints where the body’s most potent antibodies attach. Next, he reverse engineers the protein with tweaks that will keep its structure stable enough to be included in a vaccine, where it stimulates the immune response. This same approach enabled the rapid development of Moderna’s, Pfizer’s, and other companies’ COVID-19 vaccines.
“We thought RSV would be the first, but coronavirus kind of scooped it,” McLellan says. “What the COVID vaccines did was shed more light, at least in the scientific community, on the role of structure-based vaccine design. And to see something we did prepandemic, just some basic science, ending up being in the arms of millions, billions of people—my own kids, my parents, my wife . . . It’s really incredible.”
After McLellan published his findings on the structure of RSV’s F protein in 2013, he began looking for another virus to target. That same year, the world was buzzing about an outbreak of a deadly new coronavirus causing Middle East Respiratory Syndrome, commonly known as MERS, that can result in fever, coughing, and shortness of breath, among other symptoms.
In 2013 McLellan relocated to Dartmouth, where he would spend the next three years focusing on the MERS virus’s spike protein—the same one all coronaviruses, including SARS-CoV and SARS-CoV-2, have on their surface. He was joined by Nianshuang Wang, a structural biologist from a small town in China who had traveled to the U.S. to work with McLellan after reading about his research on RSV. Wang says he wanted to do the same kind of work McLellan was doing because “it’s so promising for being used in a real vaccine for so many people.” It was Wang who cracked how to stabilize the coronavirus spike protein.
McLellan’s team filed a patent for that stabilized protein in October 2016 and submitted its work to top journals, including Science and Nature. The editors weren’t impressed, perhaps because MERS never spread far and killed fewer than five hundred people worldwide in its worst year. After five rejections, McLellan’s paper found a home in 2017 in PNAS, the proceedings of the National Academy of Sciences, a respected but second-tier journal. “We were very excited about it,” Graham says, “but the rest of the world just wasn’t all that excited.”
In fact, coronaviruses seemed to be of so little interest and pose so minor a threat that McLellan and his team at Dartmouth were denied a grant in 2017 for research aimed at creating a universal vaccine against all coronaviruses. Although National Institute of Allergy and Infectious Diseases reviewers rated McLellan’s proposal as “outstanding,” it was deemed a low priority.
While McLellan was working on MERS, former UT molecular biosciences chair Leahy began wooing his former Johns Hopkins student to Austin. McLellan visited Texas, and Leahy treated him to a whole mess of brisket from Franklin Barbecue while promising him extensive access to the two cryo-electron microscopes UT put into operation in December 2017 as part of a new $8 million research facility. In turn, McLellan told Leahy about the paper his team had just published on the MERS spike protein. Leahy said the work seemed “interesting.” He says now, “We didn’t realize it would be critical.”
In January 2018, when McLellan moved his lab from New Hampshire, he continued working on coronaviruses and on the family of viruses to which RSV belongs. Today he’s turned much of his focus to vaccine development for other coronaviruses, as well as additional viral and bacterial diseases, including pertussis, better known as whooping cough, whose current vaccines begin losing effectiveness within a few years after being administered.
He’s not stopping there. McLellan is working on a vaccine for another respiratory virus that most haven’t heard of—metapneumovirus, which can be deadly for immunocompromised patients, such as bone marrow transplant recipients. He’s also studying ways to prevent cytomegalovirus, the leading infectious cause of birth defects in the U.S. and a particularly dangerous virus for those with compromised immune systems. He’s targeting, as well, the tick-borne Crimean-Congo hemorrhagic fever, which kills three out of ten who get it. And while he’s doing all of that, other researchers are deploying the “reverse vaccinology” approach McLellan helped pioneer to work on vaccines against a range of diseases—everything from tuberculosis and malaria to Ebola and the flu.
His work has been such a game changer for vaccine development that it seems worth wondering if the words “Nobel Prize winner” may one day be uttered alongside McLellan’s name. Many of his colleagues seem to avoid saying “Nobel” as superstitiously as Shakespearean actors avoid saying “Macbeth.” But Leahy, at least, admits, “It’s certainly not out of the question to discuss.”
McLellan would be the last person to talk about what the Royal Swedish Academy of Sciences, which awards the prize, might think of him. He’s almost nerdishly humble about his work—happy to detail the technical aspects of his various breakthroughs, but with little to say about his role in those achievements. Yet I did catch McLellan in an uncharacteristically introspective mood in late August, just after Pfizer reported that its RSV vaccine for older adults proved 86 percent effective in preventing severe illness in trials. “I’m not Mr. Emotional,” McLellan said, “but even I get a lump in my throat on a day like today. With time, a really effective vaccine translates to thousands or even millions of people’s lives saved, people who will have more days on this earth and more hours with the people that they love. Now we’ve had two effective vaccines do that. It’s living the dream for a vaccinologist.”
Tara Haelle is an independent science and health journalist based in Dallas. She’s the author of The Informed Parent and Vaccination Investigation: The History and Science of Vaccines.
This article originally appeared in the November 2022 issue of Texas Monthly with the headline “Unmasking a Killer Virus.” Subscribe today.
