For decades, fear and failure in the hunt for an RSV vaccine. Now, success.

For decades, fear and failure in the hunt for an RSV vaccine. Now, success.

In the mid-1960s, researchers at D.C.’s top pediatric hospital set out to vanquish a diabolical virus that filled wards with wheezing infants each winter.

Their weapon: a vaccine designed to target respiratory syncytial virus, known as RSV. The virus had been identified only a decade earlier but was already known to be one of the most challenging illnesses to rattle the lungs of young children, surpassing influenza.

There was every reason to think the vaccine would succeed. Scientists grew the virus in a laboratory, then inactivated it with a chemical — similar to the method used to create the world-changing polio shot.

Instead of a miracle, a catastrophe began to unfold.

Not only did the vaccine not protect infants from getting infected, paradoxically, it made their illness much worse. A 14-month-old and a 16-month-old died.

Scientists spent decades trying to unravel why the shot backfired. A cadre of dedicated researchers continued to work on the virus, without success. Then, a scientific breakthrough helped jolt the field back to life about a decade ago — sparking efforts that are, this year, finally showing success.

Two RSV vaccines, one developed by pharmaceutical giant GSK and another from Pfizer, have protected older adults in large-scale trials in recent months. Separately, a preventive injection of a monoclonal antibody developed by AstraZeneca and Sanofi provided long-lasting protection in a major trial. And a Pfizer trial testing whether a shot late in pregnancy can provide spillover protection to newborns is expected to report results this fall.

“We call it the renaissance of RSV,” said Octavio Ramilo, an infectious-diseases pediatrician at Nationwide Children’s Hospital in Columbus, Ohio. “After all these years … it’s a very exciting time for us.”

This dramatic shift, with the world’s biggest drug companies racing to dominate a potential multibillion-dollar market and defeat a virus that causes 58,000 hospitalizations of children younger than 5 in the United States each year, started with a seminal, submicroscopic discovery in 2013.

In his office at the University of Texas at Austin, structural biologist Jason McLellan holds the breakthrough in his hands: two colorful, 3D-printed blobs. Each one is a giant blowup of a protein that sits on the outside of RSV.

One blob resembles a lollipop. The other, a golf tee.

To the untrained eye, the differences appear subtle, not revolutionary. But deciphering these slight differences in shape and finding ways to incorporate those insights into vaccines helped overcome decades of failure in the battle against RSV — and is beginning to fundamentally reshape how vaccines are designed against other pathogens, too.

A crunch in laboratory space at the National Institutes of Health helped forge the partnership that would propel the search for an RSV vaccine.

As a graduate student, McLellan learned to use a powerful technique called X-ray crystallography to reveal the nooks and crannies of proteins — the building blocks of life — in atomic-level detail. Motivated to use the method to have an impact on human health, he joined a leading laboratory focused on HIV in 2008.

The lab, led by Peter Kwong, was on the fourth floor of NIH’s Vaccine Research Center on the sprawling Bethesda, Md., campus. But space was tight, so McLellan ended up working out of an outpost on the second floor, next to Barney Graham, a viral immunologist who had been recruited to NIH to develop a clinic to test HIV vaccines, but only joined on the condition that he could continue his basic research lab with a focus on RSV.

Until then, RSV was not on McLellan’s radar. He barely knew what it was. He wasn’t alone. For most people, it is a nuisance without a name — one of the many colds that people contract repeatedly over a lifetime. Only at the opposite ends of life, among the very young and the very old, does it tend to cause serious complications and turn life-threatening.

But Graham had been pursuing an RSV vaccine since the early 1980s at Vanderbilt University. He and McLellan started to talk about partnering.

It was, McLellan recalled, seen as a risky career move. HIV is scientifically prestigious and well-funded. RSV was regarded as a niche.

He recalled a colleague cautioning him: “As a young scientist looking to start his own lab one day, would you rather start your lab as someone who helped create an HIV vaccine? Or someone who worked on RSV, a small field that doesn’t attract funding and resources?”

While RSV lacks the scientific cachet and name recognition of HIV, the dream of defeating the virus is near and dear to many physicians. They watched vaccines transform the risk of other childhood diseases, while intensive care units steadily and predictably filled with babies sick with RSV each winter. Parents who have seen their children wrapped in tubes as they fight for each breath will never forget the fear.

There were other obstacles, too. The tragic legacy of the failed vaccine trial had created extreme hesitation to test a vaccine in young children. But careful work beginning in the 1980s had shown that there was a less direct route to provide protection. Antibodies are passed down during pregnancy, which gives infants temporary protection against a range of pathogens.

That work opened the door to antibody drugs that mimic that dose of maternal immunity. But monthly infusions are an expensive solution, available only to a fraction of infants.

“Giving a vaccine to pregnant women is mimicking an actual process: Moms who have had RSV are boosted … and those babies will have higher immunity at birth and lower risk of getting infected in the first few months of life,” said Flor Muñoz, a pediatrics infectious-diseases specialist at Baylor College of Medicine.

With a vaccination route established, all that was needed was a potent vaccine. But that eluded scientists, for a reason McLellan and Graham would help reveal.

Vaccines teach the immune system to hunt viruses by presenting a version of the virus, or a hallmark feature of the pathogen. RSV’s surface is studded with the F protein, a molecular key that helps the virus fuse to cells and infect them.

But there was a problem with using the F protein as the basis of a vaccine. It is a fickle shapeshifter, and scientists were having trouble nailing down what, exactly, it looked like in its most fleeting form — before it latched onto cells.

McLellan used X-ray crystallography to determine the precise shape of the F protein, showing that before RSV gets into cells, it assumed an elusive lollipop shape. Afterward, it looked like a golf tee.

To build the best vaccine, scientists wanted to train the immune system to look for the lollipop, like catching arsonists before they’ve dropped the match. To do that, researchers would need to find a way to freeze the F protein into the ephemeral lollipop form.

McLellan worked like a molecular sculptor, using tiny chemical tweaks to mold the F protein in place. Chemical bonds worked akin to molecular staples, and McLellan found ways to fill cavities in the protein to make it rock-solid. He and colleagues generated more than 150 variations of the F protein before settling on a final product.

Graham took that version and found it provoked a powerful protective immune response in mice and monkeys.

William Gruber, a senior vice president of vaccine clinical research and development at Pfizer, who has been working on RSV vaccine development for 40 years, recalls a 2013 voice mail from his old college roommate, Graham.

Graham said he and his wife, Cynthia, were going to take a last-minute road trip to see the foliage during a government shutdown. They arranged a visit.

The old friends sat down to catch up over takeout from a Mediterranean restaurant, and Gruber congratulated his old roommate on recent work in deciphering the lollipop structure of the F protein.

Graham said there was more. His travel to an infectious-diseases conference where he had intended to present the next step of the research had been restricted because of the government shutdown. He showed Gruber the work he and McLellan had done to stabilize the protein.

“We excused ourselves. We weren’t rude, we left the table to come and talk about the data,” Gruber said.

The power of tailoring vaccines to match the shape of the virus became evident in June, when GSK became the first to show success with an RSV vaccine that incorporated a stabilized F protein. In August, Pfizer followed with positive results. Johnson & Johnson and Moderna are testing their own RSV vaccines based on the lollipop version of the F protein. A trial during pregnancy run by Pfizer is expected to report results this fall. A similar trial run by GSK has been put on hold because of a safety signal, but no specifics have been disclosed about the issue.

AstraZeneca and Sanofi partnered to create a potent monoclonal antibody that could be used, similar to a vaccine, to provide protection through an RSV season. A single shot was recently shown to be 75 percent effective at preventing infants from needing medical care over five months.

The insight into the RSV “structure is really driving all the new work that’s been done on RSV — vaccines and antibodies,” said Jon Heinrichs, global head of innovation and emerging sciences at Sanofi. “You’ve seen how many companies have jumped into the vaccine … field [for older adults] — a lot of that work, if not all, owes it to the work at NIH.”

Graham and McLellan had long assumed that RSV would be the proving ground for the concept that shape matters in designing better vaccines. But their similar work on coronavirus spike proteins — fueled by the emergency of the pandemic — propelled the idea into the scientific mainstream.

In his office, McLellan rattles off a “hit list” of other viruses, and even bacterial pathogens, that are the next targets. Respiratory viruses such as human metapneumovirus or parainfluenza virus 3. Herpes viruses. Bunyaviruses, which can cause hemorrhagic fevers. Nipah virus, a bat-borne virus that can cause deadly outbreaks.

To stop viruses that cause human suffering or could seed a future pandemic, members of McLellan’s labs start with a focus on the tiniest details. In a basement laboratory outfitted with two room-sized million-dollar microscopes, they work steadily through that list by zooming in on the intricate curves and loops and bumps of those viruses, one by one.

The tools have evolved since RSV. Instead of laboriously crystallizing a viral protein and bombarding it with X-rays, the scientists flash-freeze proteins and scatter a beam of electrons off them.

To discern the 3D shape of a coronavirus spike or the protein that allows human metapneumovirus to latch onto cells, scientists start by mass producing those viral proteins and purifying them. They load and flash-freeze samples on tiny, copper-colored rings called grids.

Elizabeth McFadden, a graduate student at the University of Texas at Austin, is using the technique to examine how an antibody binds to spikes from a coronavirus that is similar to the Middle East respiratory syndrome virus. It’s painstaking, expensive work — time on the microscope costs about $1,500 per day.

After the samples are loaded first thing in the morning, McFadden works at a control room outside the microscope. She “atlases” the grids, scanning through them quickly to find which ones are promising, where the ice is the right thickness to see the proteins. She cringes when a “ladder of junk” shows up, but zooms in on shadowy grayish blurs that are the coronavirus spike, with a mushroom shape.

Working on the microscope is a science and an art — the manual work of staring at blurry blobs for hours each day and picking samples to scan at higher resolution, paired with the judicious use of powerful automated tools that help make sense of millions of images. McFadden uses a tool with the not-so-elegant name “blob picker” to find the proteins that are most promising. Together, these images help the scientists construct a 3D picture of the proteins, by stitching together views from all angles.

Even as the scientists have moved on to new viruses, they are waiting for good news on RSV — and the conclusion of a six-decade-long quest.

“It’s like our baby,” McLellan said. “This is my first virus I was working on, and kind of slaving away at it — and it’s really changed the field.”

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