Another Shot

Lyme disease has grown explosively in the two-plus decades since the last vaccine was pulled from the market. How enthusiastic will the reception be for a new one?

If you want to get vaccinated against Lyme disease today, your choices are limited. In fact, you'd have to find a rogue veterinarian willing to experiment on you. The only options on the market are for dogs.

This wasn't always the case. In December 1998, drug-maker SmithKline Beecham Plc (now GSK Plc) got approval for the first Lyme vaccine for humans, Lymerix. Ads for the shot featured a woman on a verdant lawn who warns: "I got Lyme disease last spring, and I'm being treated for serious health problems. I couldn't prevent it then, but now you could." Lymerix was shown to prevent the disease about 75% of the time, which is pretty efficacious; the annual flu shot is between 40% and 60% effective, depending on the year. And Lymerix was an ingenious scientific achievement. It neutralized the bacteria that causes Lyme while it was still in the tick.

But Lymerix faced obstacles. Regulators had given it a lukewarm endorsement. In the mid-1990s, only about 16,000 cases of Lyme were reported in the US each year, mainly clustered in the Northeast where the black-legged deer ticks that spread the disease were most common. It wasn't a national concern. One doctor testifying on an advisory committee called it a "yuppie vaccine" for people who "pay a lot of money for their Nikes and their Esprit" and are "going to travel to Cape Cod."

Lymerix was also approved the same year that a British physician named Andrew Wakefield published an explosive (and, eventually, discredited) paper linking the common childhood vaccine for measles, mumps and rubella to growing diagnoses of autism. When his theories crossed the Atlantic, they joined forces in the US with another vaccine myth in circulation: that a harmless, mercury- based vaccine preservative was also causing autism in kids. This combination essentially ushered in the modern era of vaccine hesitancy. And with so much anti-vax sentiment bubbling, it didn't take long for concerns about the new Lyme shot to emerge, too.

About a week after the New England Journal of Medicine published Lymerix's Phase III trial data, Allen Steere, one of the discoverers of Lyme, unwittingly helped launch what would become an all-out war on the vaccine. In Science, Steere and his collaborators suggested a theory for why some people with Lyme experienced arthritis. Their bodies, they wrote, might be having an autoimmune response to a small part of a protein, called OspA (for "outer surface protein A"), on the Lyme bacteria because it was structurally similar to a human protein.

"If you think about what we do in terms of personal protection and mitigation, it really hasn't worked"

OspA was what Lymerix targeted—and soon after it hit the market in 1999, people who'd been vaccinated started reporting troubling side effects such as joint pain. They blamed Lymerix and sued SmithKline Beecham, though regulators found no merit in the concerns, and the hypothesis Steere and his colleagues proposed was ultimately not supported. (SKB settled a half-dozen class-action lawsuits by paying attorneys' fees.) The theory "was picked up and blown all out of proportion," says Steere, who's a professor of medicine at Harvard Medical School and a rheumatologist at Massachusetts General Hospital in Boston.

And there was yet another issue. A vaccine called RotaShield, which was designed to prevent kids from catching rotavirus, the most common cause of diarrhea in young children, was withdrawn from the market after investigations revealed it significantly increased chances of a serious bowel obstruction in infants. "This was a one, two, three hit on vaccines," says Paul Offit, director of the Vaccine Education Center at Children's Hospital of Philadelphia and an adviser to the Food and Drug Administration. "Vaccines like Lyme suffered from all that."

In 2002, three years after Lymerix's introduction, it was shelved. Predictions suggested that fewer than 10,000 people would get the vaccine that year. The maker of ImuLyme, a potential competitor, never even tried for FDA approval, presumably because of the hassle SKB faced and the lukewarm regulatory environment. The success of a vaccine is often as much about feelings as facts, and the feeling at the time was that one for Lyme was either unnecessary or unsafe.

But times change—at least, that's what Pfizer Inc., in partnership with French drugmaker Valneva SE, is betting. Phase III trials are underway for their Lyme vaccine (dubbed VLA15 for now), which is expected to be available in 2026. So far scientists and executives at the companies suggest it's likely to be safe and effective, since it works much the same way Lymerix did.

In the decades since Lymerix failed, Lyme has become the most common vector-borne (tick, mosquito, flea, etc., to human) illness in the US. The companies' hunch is that its explosive growth will convince Americans that they need and want a Lyme shot. And for millions of people who'd like to avoid a potentially chronic illness, this will be welcome news. Still, there's vaccine fatigue or antipathy to contend with. Enough people eschewed vaccines entirely to prolong the pandemic. There's even been a recent resurgence of measles.

Regardless, it's hard to argue against the need for a Lyme vaccine. "There's a lot of interest," says Paul Auwaerter, clinical director of the infectious disease program at the Johns Hopkins University School of Medicine and an investigator in Pfizer's Phase III trials. "If you think about what we do in terms of personal protection and mitigation, it really hasn't worked."

What would go on to be called Lyme disease was first recognized in the mid-'70s after a cluster of people—including, bizarrely, kids—suddenly presented with symptoms that resembled those of rheumatoid arthritis, such as swollen joints, in and around the town of Lyme, Connecticut. The main culprit, it was revealed in the early '80s, was a newly discovered bacterium called Borrelia burgdorferi that had hitched a ride in the midgut of the tiny deer tick.

Lyme has baffled medical science ever since. Sometimes transmission is clear, thanks to the appearance of a distinctive bull's-eye rash. Sometimes the rash looks different—a solid oval, say. In about a third of cases, there's no rash at all. Often, people have no idea they've been bit by a tick, especially if it's a nymph. They're about as big as a poppy seed, whereas an adult deer tick is the size of an apple seed.

The disease isn't always easy to diagnose and treat. Lyme tests typically look for antibodies to the bacteria and so can be negative for weeks after an infection. Symptoms—fatigue, joint pain, fever—can also take weeks or more to appear and are similar to those of many other illnesses. And while some patients respond to a quick round of antibiotics, for others symptoms can persist for a lifetime.

Each year, prior to the pandemic, about 35,000 cases of Lyme were reported to the Centers for Disease Control and Prevention. That number was by all accounts a wild undercount, because the system relies on busy health-care providers to submit records. In 2021, to get a sense of the real numbers, CDC researchers looked at insurance claims and concluded about 476,000 people are diagnosed and treated for Lyme each year. (This is likely inaccurate as well, because not everyone who's treated for Lyme winds up having it.) Many celebrities have gone public with their diagnoses. Kelly Osbourne, daughter of Ozzy, wrote about her long-term battle with Lyme in her memoir. Alec Baldwin, Kathleen Hanna, Kris Kristofferson, Avril Lavigne, Amy Schumer and Ben Stiller are some of the other famous Lyme sufferers. Lyme was even at the center of a multiseason story arc on The Real Housewives of Beverly Hills.

Ticks reproduce at an incredible rate, with adult females laying thousands of eggs at once. They're also extremely durable. Deer ticks can go months without a blood meal and survive days underwater. Deer and small rodents are essential to ticks' survival. They lay their eggs on deer, and then the nymphs fatten up on rodents before jumping back to deer. (Contrary to popular belief, mice, not deer, are usually the source of a Lyme infection.) As our world has encroached upon those of animal and insect, more opportunities have been created for Lyme to spread to humans.

Research suggests that as many as three-fourths of people contract Lyme at home—not hiking or camping, but grilling, gardening and playing in the backyard. It's no longer merely a problem for the Nikes and Esprit crowd, either. The deer tick is now found all along the East Coast, as well as in the Midwest and Pacific states. The number of counties where deer ticks are present has more than doubled in about the last two decades. In Western Europe, estimates of cases treated run as high as about 200,000 annually. "There's much more of it around," says Annaliesa Anderson, Pfizer's head of vaccine research and development, citing climate change as another reason for Lyme's spread. "Ticks thrive in the summer, and we're seeing longer summers. We're seeing winters that aren't quite as cold, so there isn't quite a big freeze-off of the ticks." She adds, "There's an expectation that numbers are going to go up."

That, basically, is why Pfizer and Valneva decided to try again. It also helps that they're not so much inventing as reinventing a vaccine by building off the science behind Lymerix. B. burgdorferi, the bacterium that causes Lyme, is what's known as a spirochete—a twisty structure with a striking resemblance to fusilli. In the early '90s researchers reported that when they exposed mice to a protein on B. burgdorferi's surface, OspA, it triggered the development of antibodies that protected them from infection. OspA only exists in ticks; in other hosts, it becomes a new protein, OspC. After Lyme-infected ticks fed on OspA-immunized mice, the ticks—to the surprise of the researchers—no longer had the disease. The ticks had been cleared of their infection by feeding on the mice. OspA "kills the bacteria in the tick before it has a chance to become infectious," says Sam Telford, a professor of infectious disease and global health at Tufts University who collaborated on some of the experiments. To a degree, it was immunization by proxy.

SKB licensed the technology for Lymerix from these researchers. The Pfizer-Valneva shot will be a more finely tuned version, targeting a smaller region of OspA. The more targeted the vaccine, the less risk there is of side effects. It will also protect against more types of B. burgdorferi. Lymerix was only formulated to protect against a version that's common in the US, but the new shot will target six, including those prevalent in Europe. It's also expected to work in children. (Lymerix wasn't recommended for kids.)

SKB licensed the technology for Lymerix from these researchers. The Pfizer-Valneva shot will be a more finely tuned version, targeting a smaller region of OspA. The more targeted the vaccine, the less risk there is of side effects. It will also protect against more types of B. burgdorferi. Lymerix was only formulated to protect against a version that's common in the US, but the new shot will target six, including those prevalent in Europe. It's also expected to work in children. (Lymerix wasn't recommended for kids.)

Phase III trials are slated to wrap up in 2025, and Pfizer's Anderson says they should show the new vaccine to be at least as effective as Lymerix. Recipients will likely need an annual booster after an initial series of three shots over the course of up to nine months.

Pfizer and Valneva aren't alone. Moderna Inc. has a shot in development using the same mRNA technology behind its Covid vaccine, and a group at the UMass Chan Medical School in Boston announced it was working on a vaccine-like preventive shot that would require a new dose annually.

How big the market for these vaccines will be is unclear. Neither Pfizer nor Valneva has published sales projections. Investment bank Leerink Partners LLC projects yearly sales of as much as $1.1 billion by 2032. BMO Capital Markets, a financial-services company, called the Pfizer-Valneva shot a "hidden gem" in a November report. BMO cited growing exposure to Lyme in the US and Europe, a lack of competition and anecdotal feedback to Pfizer executives (shared with BMO) about broad interest in clinical trials.

But any conversation about the future of Lyme vaccines is shaped by their past. Although Steere, one of the researchers who discovered the disease, turned out to be wrong about the autoimmune hypothesis, major media stories about people getting the Lymerix shot and suffering side effects— not just joint pain but, also, paralysis—terrified the public. Conspiracy theories proliferated: Lymerix wasn't pulled from the market because of sales but because something was wrong with the drug. Even though the cases of arthritis among vaccine recipients were roughly equal to the general population, the FDA found, some people "felt they were being deceived and that the process was not transparent," says Pat Smith, president of the volunteer-run Lyme Disease Association in Jackson, New Jersey.

Smith, who's had two daughters contract the illness, is a de facto spokesperson for people dealing with what's known as post-treatment Lyme. For much of the disease's history, patients who didn't recover after the usual course of antibiotics have faced intense skepticism from mainstream medical practitioners. The symptoms of Lyme, after all, look a lot like many other illnesses. Even with a diagnosis, no one-size-fits-all treatment exists.

"Covid fundamentally changed the way that Americans think about vaccines. Lyme is not immune to it"

What's emerged to deal with this population is a cottage industry of medical practitioners who specialize in diagnosing and treating these cases—sometimes plying intensive, expensive and still-unproven therapies to treat people who may or may not even have Lyme. People suffering from the disease, as well as their loved ones, advocate for better prevention and treatments. But fears linger; they live with symptoms such as arthritis and worry the vaccine would lead to others suffering, too. "We are interested in the possibility of a vaccine," Smith says. "The issue is the safety and efficacy."

Of course, even if the vaccine is deemed safe and effective, some people will shun it. Vaccine hesitancy became a major public-health issue during the pandemic, despite the more than 1.1 million US deaths from Covid. Matt Motta, a political scientist at Boston University's School of Public Health who studies hesitancy, has tracked how fears about Covid vaccines affected thinking about other treatments. In a forthcoming study, based on research conducted in April 2020, Motta and his colleagues found that of the 28% of respondents who didn't intend to get a Covid vaccine, 63% said they would also not be "very likely" to get immunized against Lyme. Overall, less than half of respondents were "very likely" to get a Lyme shot when one became available. "Covid fundamentally changed the way that Americans think about vaccines. Lyme is not immune to it," Motta says.

Valneva's chief executive officer, Thomas Lingelbach, essentially writes this group off. "You will never be able to convince them. It was true 20 years ago, and it's still true today," he says. "And so our approach is an approach of education and communication." To that end, Pfizer says it plans to study the shot in people who've had or have Lyme—if you've had it once, you can get it again. And both companies have tried to explain how their vaccine will differ from Lymerix.

A change they've made is to remove the string of genetic code tied to the allegations of side effects, replacing it with that from another type of OspA. "Even if there was a perceived risk," Pfizer's Anderson says, "the way that this vaccine has been made is that risk has been taken out." But not everyone's concerns have been alleviated. Earlier this year, Pfizer dismissed about half the patients recruited for Phase III trials, citing violations of good clinical practices at sites run by Boston-based Care Access. (Care Access didn't respond to requests for comment. At the time, the company said it disagreed with Pfizer's decision.) Pfizer said vaccine safety was not at issue, but in the Lyme community the news fed the suspicion that this vaccine had safety problems, too. The dismissal pushed the projected year the vaccine will enter the market from 2025 to 2026.

Regardless of interest, before anyone can get the shot, regulators have to approve it. But the enthusiasm behind that thumbs-up is critical. In the US, some manufacturers are protected from lawsuits by the National Vaccine Injury Compensation Program, which was created in the '80s following large jury awards for vaccine-related problems that public-health officials largely believed were unfounded. The program provides compensation to patients found to have legitimate claims from a kitty amassed through vaccine taxes in what's popularly known as "vaccine court." But Lymerix wasn't covered by the program, because the drug didn't meet its criteria, which include "routine administration to children or pregnant women." It was only recommended for people age 15 to 70 who had frequent exposure to tick-infested areas.

If the new vaccine gets a "soft" yes, the companies could again be vulnerable to lawsuits. "We're going to be right back to where we were 20 years ago," says Offit, the director of the Vaccine Education Center and an FDA adviser, who was also on Lymerix's clinical recommendation committee. "The key is to make sure that these days this company is not subjected to outrageous litigation." It's too early to know how likely a soft yes is. The CDC is researching what concerns health-care providers and the public may have with a Lyme vaccine. Kiersten Kugeler, an epidemiologist at the CDC's division of vector-borne diseases, says, "Having a safe and effective vaccine that is FDAapproved for Lyme disease would be so important."

A full-throated endorsement would've been far more helpful two decades ago. Telford, the Tufts epidemiologist, says it kills him to think about how the market for Lyme vaccines would have developed—the kind of competition that would have sprung up to produce more effective versions. "We would have had other options now," he says. Not to mention many fewer people with a mysterious, debilitating disease.