Jessica Reeder worries about ticks and the diseases they carry. She had Lyme disease, her brother had Lyme disease, and every fall her children come home from school with notes reminding parents to do a nightly tick check. Even in Philadelphia, where Reeder lives, the bloodsuckers lurk in the woods around the playground. Her family used to go tent camping with friends, but they stopped after a few people in the group contracted Lyme.

“It just got to the point where people were too stressed out about it,” she says.

Reeder made sure her Shih Tzu, Rory, got the canine Lyme vaccine, but must protect the human members of her family the old-fashioned way: bug spray, long pants tucked into socks, and frequent tick checks. There’s no Lyme vaccine on the market for humans.

Valneva, a French biotech company focused on developing vaccines for infectious diseases, hopes to change that. Six years ago the company began working on a vaccine against Lyme disease, which is now part of phase II clinical trials in the United States and Europe.

A safe and effective Lyme vaccine would be a boon for public health. According to the Centers for Disease Control and Prevention (CDC), hundreds of thousands of people are likely diagnosed with Lyme annually in the U.S. Tens of thousands more develop Lyme each year in Europe. Caught early, the disease is usually easy to treat. But not every infected individual displays the hallmark symptom of Lyme — a bull’s-eye rash — and so the disease sometimes goes undetected. Left untreated, the bacteria can cause severe joint and nerve pain, memory problems, dizziness, and heart palpitations.

Valneva’s Lyme vaccine isn’t the first designed for people. Twenty years ago, Reeder could have been immunized. From 1999 to 2002, SmithKline Beecham — now GlaxoSmithKline — sold a Lyme vaccine called LYMErix. But the company pulled LYMErix off the market after a public backlash and a spate of lawsuits.

As STAT reported on August 22, any new Lyme vaccine will face intense public scrutiny. But even getting the new vaccine to market could prove challenging. Valneva is currently seeking a partner to help develop and commercialize the vaccine, and at least one major manufacturer is out of the running. GlaxoSmithKline had been supporting the new vaccine’s research and development, but in June the two companies terminated their partnership.

If the new vaccine does make it to market, will it fare any better than LYMErix? According to Gregory Poland, co-director of the Vaccine Research Group at the Mayo Clinic in Rochester, Minnesota, who has given scientific advice to Valneva, that’s “a multi-million dollar question.”

One factor that led to LYMErix’s demise hinged on how the vaccine worked. Lyme disease, named for the Connecticut town in which it was first discovered, is caused by a corkscrew-shaped bacterium called Borrelia burgdorferi that travels in the bellies of ticks. LYMErix prompted the immune system to generate antibodies against a protein on the surface of the bacteria called outer surface protein A (OspA). When a tick fed on someone who had been immunized, it ingested blood containing the Lyme-killing antibodies. Those antibodies traveled to the tick’s gut and wiped out the bacteria before it could enter the human body.

Twenty years ago, Americans could get a Lyme vaccine called LYMErix. Today, “you can protect your dog against Lyme disease, but not your children,” says Gregory Poland, co-director of the Vaccine Research Group at the Mayo Clinic. Visual: DjelicS via Getty Images

LYMERix worked, although imperfectly. A 1998 study in the New England Journal of Medicine looked at nearly 11,000 people who lived in Lyme-endemic areas and found that those who received three doses of LYMERix had a 76 percent reduction in Lyme disease the following year compared with those who didn’t receive the vaccine. But just a week after the study was published, another paper came out showing that one particular portion of the OspA gene bears a striking resemblance to a portion of a human gene that plays a role in the body’s immune response. While the second paper didn’t address vaccination, the researchers posited that, because of the similarity, some people infected with Lyme disease might develop an immune response against the human protein, leading to lingering inflammation and treatment-resistant Lyme arthritis. But it wasn’t a stretch to imagine that vaccination, which also prompts an immune response against OspA, might produce the same effect.

The Food and Drug Administration never found any compelling scientific evidence to support this theory, but that didn’t stop people who believed they were harmed by the vaccine from speaking out and filing a class-action lawsuit. Sales of LYMErix tanked, and in 2002 SmithKline Beecham withdrew the vaccine. The following year, the company paid more than a million dollars in legal fees to settle the class action lawsuit.

The withdrawal of the vaccine had a chilling effect on the entire field, says Maria Gomes-Solecki, a veterinarian at the University of Tennessee. In the late 1990s, when LYMErix was first approved, she was working on developing a new and improved OspA vaccine. But when SmithKline Beecham pulled LYMErix off the market, Lyme vaccine research “basically went dead,” she says. “No one wanted to touch it.” Even Gomes-Solecki decided to go in a new direction. She repurposed her work into an oral vaccine for mice (one of the main reservoirs for Lyme disease). The Memphis-based company U.S. Biologic is now seeking approval from the U.S. Department of Agriculture to market the mouse vaccine, which would be delivered in pellets of food set out as bait.

SmithKline Beecham wasn’t the only company to pursue a human Lyme vaccine. Pasteur Mérieux Connaught (now Sanofi Pasteur) developed an OspA Lyme vaccine called ImuLyme and tested it in a large efficacy study. The ImuLyme results came out in the same July 1998 issue of the New England Journal of Medicine as the LYMErix results. But the company never applied for a license to market the vaccine.

More than a decade later, the pharmaceutical giant Baxter also tried developing a Lyme vaccine. The company completed a safety study in 2013, but despite promising results, never launched a follow-up. Today Takeda, the largest drug company in Asia, owns that vaccine and is evaluating whether to take it forward.

“Every manufacturer that has considered this since 2002 has judged that it’s unlikely that we’re going to make a profit on this vaccine,” Poland says. “In the second decade of the 21st century, you can protect your dog against Lyme disease, but not your children.”

There are signs, however, that the field is beginning to warm to a human Lyme vaccine. In December 2016, Congress established the Tick-Borne Disease Working Group to help identify research priorities. The diverse, 14-member working group within the Department of Health and Human Services includes researchers, physicians, patients and their family members, patient advocates, and employees from a variety of federal agencies. Last December, the group released its first report to Congress, calling for increased federal funding to address the “serious and growing threat” of tick-borne diseases.

This colorized image from a scanning electron microscope shows a grouping of spiral-shaped Borrelia burgdorferi bacteria, which live in the bellies of ticks and cause Lyme disease. Visual: CDC / Janice Haney Carr (content provided by Claudia Molins)

In April, the National Institutes of Health (NIH) announced that it intends to commit $6 million in fiscal year 2020 to more than a dozen projects aimed at the prevention of tick-borne diseases, including vaccine research.

Meanwhile, Valneva is conducting its phase II clinical trial in the U.S. to determine the final dose and vaccination schedule. The company should have the initial data by the middle of 2020. The next step will be to launch two efficacy trials including about 8,000 people each, one in Europe and one in the U.S. The company could seek regulatory approval in about five years.

Valneva’s new vaccine works like LYMErix, but with two key differences. LYMErix only provided protection against one strain of Borrelia found in North America, while Valneva’s vaccine protects against the six most common strains in the northern hemisphere, including those in Europe. Also, Valneva has eliminated the human protein-mimicking segment of the OspA protein and replaced it with a similar sequence from another strain as a “precautionary measure,” says Thomas Lingelbach, Valneva’s CEO. The company doesn’t have human efficacy data yet, but Lingelbach doesn’t expect that the swap will affect the vaccine’s ability to protect against the disease.

Demand for a Lyme vaccine should be greater than ever before. When LYMErix first hit the market in 1998, the number of reported cases was about 17,000. By 2017, that number had climbed to roughly 30,000 confirmed cases. And the CDC estimates that far more — some 300,000 people — are actually diagnosed each year. “In the ‘90s, Lyme disease sounded like some exotic thing that happened elsewhere,” Poland says. Today, especially in regions where Lyme disease is endemic, almost everyone knows someone who has been infected. The number of people who contract Lyme disease in Europe is harder to pin down, but some estimates point to as many as 200,000 cases each year.

And because the problem has grown, the medical experts who develop recommendations on how to use vaccines — the Advisory Committee on Immunization Practices in the U.S. — might look more favorably on a Lyme vaccine, says Stanley Plotkin, a physician and emeritus professor at the University of Pennsylvania. The committee gave LYMErix a tepid recommendation back in 1999. Even for adults in the highest risk group, it stopped short of a full endorsement. That likely wouldn’t happen today, Plotkin says, because “the need for a vaccine, both in Europe and the U.S., is manifest.”

While anti-vaccine sentiment is still a problem today, as evidenced by the increasing number of measles cases in the U.S., “I think the tide has begun to change,” Poland says. Lise Nigrovic, a pediatrician and emergency room physician at Boston Children’s Hospital and a former member of the Tick-Borne Disease Working Group, argues that unlike with a disease such as measles, which spreads quickly from person to person and where ensuring high vaccination rates becomes crucial to maintaining herd immunity, Lyme vaccination is more of an individual choice and less likely to be an anti-vaccination target.

But Valneva can’t bring the vaccine to market without a commercial partner. “The ideal partner will have deep experience in developing and commercializing vaccines, as well as an in-depth understanding of Lyme disease,” Lingelbach says. But finding that partner could prove challenging.

When GlaxoSmithKline terminated its partnership with Valneva in June, that put one of the five top-earning vaccine makers out of the running. Only one of the remaining four, Merck, confirms it is working on a Lyme vaccine. “Our researchers involved in early discovery are looking at the space,” said Pamela Eisele, global communications director at Merck, by email. Neither Pfizer nor Novovax has a Lyme vaccine in development. And Sanofi Pasteur did not respond to repeated requests for comment.

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Convincing the public to get immunized could also prove challenging. Valneva has yet to determine the number of vaccine doses, and when those doses must be administered. But Lingelbach anticipates people will need three shots over the first two to six months, a booster after a year, and then additional boosters perhaps every three years. That’s inconvenient, especially for adults who don’t visit the doctor regularly.

There’s also the perception of safety. “Vaccines have this really high bar because they’re given to healthy people who don’t have a disease,” Nigrovic says. “So even just the hint of a problem, it makes people really nervous,” even if there’s no evidence the problem is linked to the vaccine.

The controversy around LYMErix has faded from the public’s awareness. “Time has done some healing,” says Richard Marconi, a microbiologist at Virginia Commonwealth University. But the report from the Tick-Borne Disease Working Group also makes it clear that the perceived damage inflicted by LYMErix has not been entirely forgotten. One of the group’s recommendations was to support the development of safe and effective human Lyme vaccines. But in a dissenting minority response, the authors write: “the search for a new vaccine should only commence when the science behind the past vaccine failure is understood.”

Among Lyme advocates and the chronic Lyme community especially, skepticism about a Lyme vaccine persists. According to Patricia Smith, author of the minority response and president of the Lyme Disease Association, a patient advocacy group based in New Jersey that has funded research on chronic Lyme and co-funded a center at Columbia University dedicated to studying the condition, the LYMErix situation was “very troubling.”

“Certainly we’re not averse to vaccines,” Smith says, but she’s frustrated that little effort went into finding an explanation for why so many people reported ill health effects from LYMErix. Smith does not find Valneva’s decision to remove the controversial portion of OspA from the new vaccine all that reassuring because it was never clear that piece of the protein was to blame for the symptoms people reported. “We’re very concerned by it,” she says. “We don’t know what is going to happen with this one.”

Because of LYMErix’s troubled past, Marconi still argues that avoiding OspA might be the best strategy for new vaccines. He has spoken with a handful of vaccine manufacturers and says the companies are wary about the backlash that could accompany another OspA vaccine. (He did not provide the company names to Undark, citing confidentiality agreements.) Marconi helped develop a canine vaccine, and is now working on a human vaccine that would target two other Borrelia proteins. But Plotkin says some companies might find an OspA vaccine attractive because they already know the approach can protect against the disease. “The probability of an OspA vaccine working is very high and that reduces the risk for manufacturers,” he says.

Lingelbach hopes that opening a direct line of communication between Valneva and the Lyme advocacy groups will help dispel concerns about OspA. “We are in contact with many key opinion leaders and plan to take a more proactive approach,” he says. “We encourage patients and advocacy groups to reach out to us and we’ll work with them to establish a dialogue.”

Reeder, however, doesn’t need much convincing. She wants her kids to be protected without having to dose them in DEET every day. If a new vaccine becomes available, she says, “we definitely would look into it.”

Cassandra Willyard is a freelance journalist based in Madison, Wisconsin. She has written for The New York Times, Discover, Popular Science, Scientific American, Nature, and many other publications.