The only vaccine ever approved to protect against Lyme disease was pulled off the market in 2002, and drugmakers have yet to offer an alternative. What's taking so long? Cassandra Willyard investigates.

Matt Hansen

A couple of months ago, Karl Grossman awoke in the middle of the night with a terrible itch on the back of his thigh. He suspected a tick, but he couldn't get a clear view of the spot, even with a mirror, so he went back to bed. The next morning, he asked his wife to take a look. At first she thought the dark spot might be a freckle, but then she looked closer and saw legs. “It was the tiniest little pinhead deer tick,” Grossman says—a hitchhiker he probably picked up working in his vegetable garden.

These bloodsuckers are more than just an annoyance. The ticks can carry Borrelia burgdorferi, the bacterium that causes Lyme disease. The first symptoms are typically mild—a rash that looks like a bull's-eye, followed by fever, headaches and fatigue. But, if left untreated, the disease can cause temporary facial paralysis, shooting pains, bouts of arthritis and even speech and memory problems. Lyme disease is the most common tick-borne illness in the Western world, with approximately 30,000 cases reported annually in the US. But the number of people infected could be far higher. Last summer, the US Centers for Disease Control and Prevention (CDC) released a preliminary estimate based on insurance claims, lab results and population surveys that indicates roughly 300,000 people are diagnosed with the disease each year. (The gap may be because many Lyme diagnoses go unreported.) In Europe, estimates range between 65,000 and 85,000 cases per year.

Lyme is a near constant threat in the sleepy hamlet of Noyac, where Grossman lives. The town lies near the tip of New York's Long Island, less than 30 miles as the crow flies from Lyme, Connecticut, the town from which Lyme disease takes its name. Grossman moved to the area in the 1970s and quickly fell in love with the wooded landscape. But the forest lost some of its appeal as the deer tick population expanded. Grossman, a journalist, began writing about Lyme disease, and the stories he heard about its ill effects worried him. “I don't consider Lyme a minor disease,” he says. So, in 1999, when he learned that a vaccine to prevent infection had just become available, “I jumped to get the shots,” he says.

The vaccine's protection, however, was never meant to last forever, and the immunity that Grossman once had has probably worn off. He would gladly seek a booster shot, but vaccination is no longer an option—at least not for humans. The manufacturer of the vaccine that Grossman received voluntarily pulled the product—called LYMErix—off the market in 2002. Similar vaccines can be had from other manufacturers, but they're only approved for dogs. Although the company behind LYMErix, SmithKline Beecham, which merged with Glaxo Wellcome in 2000 to become the drug giant GlaxoSmithKline, claimed their decision was due to poor sales, the withdrawal followed a flurry of lawsuits that claimed the vaccine could cause arthritis and other problems, as well as backlash from Lyme advocacy groups over these alleged ill effects. Since then, no other company has offered up an alternative.

Stanley Plotkin, an emeritus professor at the University of Pennsylvania in Philadelphia, finds the situation frustrating. “We know how to make a vaccine,” says Plotkin, whose adult son nearly died of a rare complication of Lyme disease in 2005. “We have a vaccine for dogs that is based on the same principle, but we have no vaccine for humans,” he says. “I find it to be a public health failure that is shameful for the medical and public health community.”

Today a new crop of Lyme vaccine candidates is in the works. Last year, for example, Baxter broadcast the successful clinical trial results of its new vaccine to prevent Lyme disease. That product is now on hold, though, as the company ponders its next move. In March, Reuters reported that the Illinois-based healthcare company was considering auctioning off its entire vaccines division. “We are exploring options for moving the Lyme program forward, including a sale of the program,” says Brian Kyhos, a spokesperson for Baxter. But even if the vaccine does move forward, it might not be able to overcome the financial and social obstacles that led to LYMErix's demise.

Born to fight Borrelia

LYMErix originated in the late 1980s in a laboratory at the Yale School of Medicine at Yale University. A young physician named Erol Fikrig had just joined the university as an infectious disease fellow to gain some research experience. “I was gung-ho to learn molecular biology and apply it to clinical medicine,” Fikrig says. That desire landed him in the office of Richard Flavell, the newly minted chair of Yale's Department of Immunobiology. Flavell had taken an interest in Lyme, and “within an hour we had decided, why don't we make a vaccine against Lyme disease?” he recalls. Just two years later, the team had a promising candidate and a paper in Science¹. By 1992, SmithKline Beecham had licensed the vaccine.

LYMErix contains a protein found on the cell surface of B. burgdorferi called outer surface protein A, or OspA. The vaccine prompts the immune system to pump out antibodies against this molecule. But LYMErix doesn't work like a traditional vaccine: it kills B. burgdorferi in ticks, not in humans. When the tick feeds, blood laced with OspA-targeting antibodies travels into tick's gut and eliminates the bacterium before it can migrate into the tick's salivary glands and then into the host. “It was a really unique mode of action,” says Sam Telford, a tick expert at the Tufts University Cummings School of Veterinary Medicine in North Grafton, Massachusetts, who collaborated with Fikrig.

Karl Grossman

Tick target: Karl Grossman was vaccinated against Lyme disease in 1999; he would now like a booster shot.

And this novel mechanism seemed to work. In a randomized trial involving nearly 11,000 adults conducted between 1995 and 1996, three doses of the vaccine reduced the cases of Lyme disease by 76% with no serious side effects². But there was one niggling concern. A week after the results came out, rheumatologist Allen Steere, who had led the clinical trial, and his colleagues at Yale published a separate paper³.The team had found that a portion of OspA looks very similar to lymphocyte function–associated antigen 1 (LFA-1), a human protein involved in the body's immune response. They posited that this mimicry might explain why a small fraction of genetically susceptible people who seem to have been cured of B. burgdorferi infection continue to show symptoms of arthritis. Once the OspA is gone, the immune system mistakenly begins attacking LFA-1, triggering Lyme arthritis. The hypothesis didn't have anything to do with vaccination, but even Steere expressed concern that an OspA vaccine could have a similar effect.

The theoretical concern didn't stop the US Food and Drug Administration (FDA) from approving the vaccine for adults. But the worry followed LYMErix from the FDA to the CDC's Advisory Committee on Immunization Practices (ACIP), a 15-member body that develops recommendations on how vaccines should be used. The committee struggled with other issues, too. Developing a recommendation for a Lyme vaccine was especially tricky because the risk of the disease varies from region to region. Clearly they couldn't recommend that everyone, including those in areas without Lyme disease, receive the shot.

Ultimately, the group decided to go with three different recommendations, depending on risk. But even for those in the highest risk group, the committee stopped short of a full recommendation, advising instead that the vaccine “should be considered.” “We thought better to be on the cautious side,” says Chinh Le, a retired infectious disease physician who was on the ACIP at the time. “We could always upgrade the recommendation.” Although LYMErix seemed effective and safe, the committee pointed out that individuals have other ways of preventing Lyme disease, such as wearing insect repellent and checking for ticks after being outside. What's more, they noted, Lyme disease is mild, readily diagnosed and easily treated even in its late stages. Some on the committee seemed to view the vaccine as a luxury for the anxious affluent rather than a public health necessity. At the ACIP meeting in June 1998, pediatrician Samuel Katz of Duke University Medical Center in Durham, North Carolina, commented that LYMErix was “as 'yuppie' a vaccine as I've ever heard of.”

Paul Offit, chief of infectious diseases at the Children's Hospital of Philadelphia in Pennsylvania, who was on the ACIP committee at the time, voiced concerns about the weakness of the recommendation privately and asked why the vaccine wasn't recommended for those in high-risk states. But he stopped short of voting against the proposed language. “I was brand new to the committee then. I was basically intimidated,” he says. “If I got to do it all over again, I would have done it differently.”

Offit says the action was unprecedented. “That's the first time, to my knowledge, that a vaccine had been licensed by the Food and Drug Administration, shown to be safe and effective, yet not recommended for those at risk for the disease,” he says. “By calling it a 'yuppie vaccine,' by damning it with the faint praise of a 'should be considered' recommendation, we killed it.”

The ACIP's decision had another, unintended effect: because LYMErix wasn't recommended for routine administration, it was not covered by the program that compensates individuals injured by vaccines. The National Vaccine Injury Compensation Program, funded by a tax on some vaccines, partially protects vaccine manufacturers from the burden of lawsuits. Without that protection, LYMErix “had to suffer the slings and arrows of personal injury lawyer litigation,” Offit explains.

And those slings and arrows came fast and furious. Grossman experienced no ill effects from the vaccine, but many others claimed they did. On 14 December 1999, a Philadelphia law firm filed a class action suit against SmithKline Beecham on behalf of more than 100 people who claimed LYMErix had harmed them, with many complaining of arthritis.

In 2001, the FDA advisory committee held a second meeting on LYMErix to address the safety concerns and examine the post-marketing data the manufacturer had agreed to provide when the vaccine was licensed. There didn't seem to be much scientific evidence that the vaccine could cause harm. In the massive clinical trial, those in the vaccinated group had no more cases of arthritis than those in the placebo group, and studies by SmithKline Beecham, the FDA and the CDC didn't find any evidence that the vaccine could cause arthritis. But the post-marketing study hadn't gathered enough participants to entirely refute the possibility either. Bernard Hoet, SmithKline Beecham's head of clinical safety and pharmacovigilance, explained that the study had enrolled only a few thousand people, a fraction of the 25,000 that the company had promised to include, because of poor demand. Many on the committee felt like the data weren't strong enough to stamp out lingering safety concerns. “The same questions persist, and I'm worried that the clinical data are not going to be forthcoming,” said committee member Patricia Ferrieri, a microbiologist at the University of Minnesota in Minneapolis. She then asked the manufacturer to examine the strength of its attachment to the vaccine. “Do you want it to be out there in the market?”

The testimony from people claiming to have been harmed by LYMErix, however, was unequivocal. “This vaccine is not causing just some minor joint pain, it is destroying lives. It is destroying the lives of our most healthiest population,” said Jenny Marra, a nurse who received the vaccine. “They thought they were protecting themselves from a horrible disease. Instead, they've gotten an even worse disease, one that cannot be treated or cured.”

On 26 February 2002, GlaxoSmithKline withdrew LYMErix. “The reason is there's just no demand for it,” company spokeswoman Ramona Dubose told the Associated Press. Despite an aggressive direct-to-consumer advertising campaign warning of the danger lurking just beyond people's back doors, sales had shrunk from $40 million in 1999 to just $5 million by 2001, and the company projected that only 10,000 people would request the vaccine in 2002 (ref. 4). Robert Perry, a spokesperson for GlaxoSmithKline, says the company discontinued the vaccine for commercial reasons, but he declined to comment further on the history of the vaccine.

Critics of the vaccine were overjoyed: “It's a crummy vaccine that's probably caused significant injury to people, but information wasn't shared with the FDA or the public,” Karen Forschner, head of the Lyme Disease Foundation, a now-defunct advocacy group, told the New Jersey Star-Ledger⁵.

Just a few months later, a team of researchers from the University of Pennsylvania published an analysis indicating that the vaccine could be cost-effective for high-risk groups living in the areas hardest hit by Lyme, but the message came too late. LYMErix had already been withdrawn. “Those who might truly have benefited from the vaccine will remain at risk,” wrote Leonard Sigal, a rheumatologist at the University of Medicine and Dentistry of New Jersey in New Brunswick, in an accompanying editorial.

Telford and many others saw the withdrawal as a missed opportunity. “It just seems like a public health nightmare that you have a perfectly effective vaccine, and it's not being used for public heath purposes simply because we're afraid of lawyers.”

Room for more?

SmithKline Beecham wasn't the only drug manufacturer working on a vaccine for Lyme disease in the 1990s. Pasteur Mérieux Connaught had developed a similar vaccine called ImuLyme, and both companies published their phase 3 data in the same issue of the New England Journal of Medicine⁶. But LYMErix beat ImuLyme to market, and Pasteur Mérieux Connaught never sought regulatory approval. “I don't know exactly what the reasoning was,” says Plotkin, who was the medical and scientific director at Pasteur Mérieux Connaught during the vaccine's development and now continues to serve as an executive advisor to Sanofi Pasteur, the current incarnation of the company. “I think it was the consideration that the market was not large enough for two vaccines.”

Meanwhile, two researchers in Long Island—Benjamin Luft, an infectious disease specialist at the Stony Brook University School of Medicine, and John Dunn, a microbiologist at the Brookhaven National Laboratory—were working on their own version of the OspA vaccine. “We were very interested in the heterogeneity of Borrelia,” Luft says. “It was quite diverse when you looked at it across the Northern Hemisphere.” So instead of focusing on one OspA protein from a single species, the pair began to engineer a new protein by assembling chunks of OspA from a variety of species⁷.

Luft never saw SmithKline Beecham as a competitor. LYMErix was designed to protect against the American strain of B. burgdorferi; Luft was focused on a universal vaccine. “We were going to be the new and improved,” he says. So when LYMErix received approval, Luft was delighted. “We thought that they had done all the heavy lifting for us,” he says. The promise of a Lyme vaccine that would be effective in Europe sparked the interest of Baxter, which already had a vaccine for tick-borne encephalitis, and in 2002 the company licensed the technology.

But Baxter seemed to be in no hurry to get the vaccine to market. “They went through a very rigorous due diligence process,” Luft says, replicating all the studies Luft and Dunn had done in their own labs. The abundance of caution may have been due, at least in part, to SmithKline Beecham's experience with LYMErix. “That was a sour taste in everybody's mouth,” Telford says.

In March 2011, Baxter finally launched a clinical study at eight sites in Austria and Germany to test the vaccine's safety and immunogenicity in more than 1,500 people. The first results, published last year, seemed promising⁸. The 300 participants who received the vaccine experienced mostly mild adverse reactions and no serious events. And after three doses of the vaccine plus a booster, the participants produced high levels of OspA-specific antibodies. “Based on the results of this study, we are fully committed to further investigating the candidate vaccine in larger populations,” Noel Barrett, vice president of research and development in Baxter's vaccines business, said in a press release in April 2013.

But the company has yet to launch an efficacy study. Gary Wormser, an infectious disease physician at New York Medical College in Valhalla who has served as a consultant for Baxter, met with the company in 2012 to discuss the possibility of opening study sites in the US, but he says no one followed up. “Baxter has been in and out of doing Lyme vaccines for as long as I can remember,” he says. “They seem to get excited for a bit, and then they fizzle out.” This year the company's quest to develop a Lyme vaccine may have fizzled out for good. In March, Baxter began searching for a buyer for its vaccines division.

Back to the drawing board

Development of a Lyme vaccine may have stalled at Baxter, but in government and academic laboratories across the country, the search for new ways to block infection continues. The OspA vaccine kills B. burgdorferi in the tick's gut. For that strategy to work, the blood the tick ingests has to contain relatively high levels of anti-OspA antibodies. LYMErix required three doses to induce high antibody levels, and had it stayed on the market, users probably would have needed booster shots “somewhere between every two and every seven years,” Fikrig speculates. So many researchers are focused on finding targets that will lead to a more convenient vaccine.

Maria Esteve-Gassent, a microbiologist at Texas A&M University's College of Veterinary Medicine & Biomedical Sciences in College Station, is working on a vaccine that targets B. burgdorferi once it enters the host. In February, she and her colleagues reported some success in preventing infection in mice using a piece of a protein called BB0172. When vaccinated mice were bitten by infected ticks, about half escaped infection⁹.

Even Fikrig, who is still at Yale, has gone back to the drawing board. This time he's working on a vaccine that would act against components of the tick's saliva. When the tick feeds, B. burgdorferi “goes into the skin in a concoction of tick spit,” Fikrig says, “and some of those tick molecules have pharmacologic activities that help the process.” A vaccine that targets some of those tick proteins could block transmission and possibly even stop other tick-borne infections. Individually, the molecules Fikrig has identified don't seem to provide as much protection as OspA, but he and his colleagues are working on a cocktail that may fare better.

Getting vaccine candidates from the laboratory into the clinic will require deep pockets, however. “It's about half a billion dollars to license a vaccine,” Plotkin says. And other than Baxter, drug companies haven't seemed willing to make the gamble. “It's not that there aren't enough candidate vaccines,” Plotkin says. “The issue is getting a manufacturer to develop such a vaccine to bring it to licensure.” After all, there is no guarantee that a new vaccine wouldn't suffer the same fate as LYMErix. The ACIP could alleviate some of that concern, Plotkin adds, by stating that they would recommend a safe and effective vaccine for Lyme disease. “An advanced commitment would make all the difference,” he says.

But that's not really how the ACIP operates, Le explains. “We don't discuss a product until it is licensed by the FDA,” he says. “It doesn't make sense for us to speculate on how to issue new recommendations when there's no new product on the market.” Whereas Plotkin advocates for a new vaccine, Telford has launched a campaign to bring back LYMErix. “Why on earth do we need a new vaccine,” he says, “when we've got a perfectly good old one sitting on the shelf?”

Any Lyme vaccine will likely face an uphill battle. Steere no longer has concerns that vaccination with OspA can induce autoimmune problems¹⁰. “There's really no evidence that the vaccine caused arthritis or severe side effects that should limit its use,” he says. And he points out that the original hypothesis was “all blown out of proportion and misinterpreted.” But because of the controversy over LYMErix, some people may never fully trust the safety of a vaccine against Lyme.

Even Baxter's vaccine, which has yet to be tested in an efficacy trial, has already been the subject of intense scrutiny. After The Lancet Infectious Diseases published the clinical trial results, Raphael Stricker and Lorraine Johnson of the International Lyme and Associated Diseases Society (ILADS), a nonprofit based in Bethesda, Maryland, penned a letter to the journal, accusing the study's authors of attempting to avoid discussion of the side effects of LYMErix¹¹. Stricker is careful to point out that ILADS isn't opposed to a vaccine for Lyme disease. “As a group we are pro-vaccination,” he says. However, “the new vaccine is very similar to the one that was pulled from the market,” he adds. “To go ahead and make a vaccine that may have the same problems as the last one just doesn't seem to make much sense.”

Baxter's vaccine actually doesn't include the controversial chunk of OspA that Steere singled out in his 1998 Science paper. But that doesn't assuage Stricker's concern. “I'm not sure that particular part was the problem,” he says.

Some even viewed the CDC's new estimate suggesting that 300,000 people may be infected each year as a ploy to drum up demand for Baxter's Lyme vaccine. “A premarketing campaign for the vaccine is already apparent,” wrote Jessica Bernstein, a California-based psychologist with Lyme disease, in an op-ed she penned for the commentary website Truthout. There has even been backlash against the vaccines that protect dogs from the disease.

Still, Plotkin is optimistic that if a vaccine can make it through the development gauntlet, it will be embraced. “The psychological situation has changed. A lot more people are concerned about Lyme disease,” he says. “While there will be people, no doubt, who will refuse to take any vaccine, I do think that there are plenty of people who will want it.”

Grossman is certainly willing. Ticks are rampant where he lives. “You go anywhere outside, and you're a tick target,” he says. Grossman didn't contract Lyme disease from the tick he picked up in the vegetable garden. But in June he got another bite. And this time, he developed a small rash. It wasn't the hallmark bull's-eye, but his physician advised him to take antibiotics to stave off the disease, nonetheless.

In the past three decades, the tick that carries B. burgdorferi has dramatically expanded its range, bringing Lyme disease with it. “It's all very well and good for us to say, 'You need to protect yourself. You need to wear repellent. You need to do tick checks,'” Telford says. “But right now we urgently need another tool to reduce risk. A vaccine would be very useful.” The trick will be convincing drugmakers that it would also be profitable.

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