As the threat of Lyme disease grows and fears surrounding it spread faster than the ticks that carry the infection, researchers are developing two vaccine or vaccine-like approaches to prevent this increasingly problematic disease. But don’t expect to get one soon. They are at least three to five years away from clinical use, according to their developers.
That may seem like a long time to wait, especially since there are several Lyme disease vaccines available for dogs. But it’s taken researchers almost two decades to get this close — for the second time. Developers have faced an uphill battle since LYMErix, a short-lived human vaccine, was pulled from the market in 2002 amid low demand and lawsuits over potential side effects, not to mention mounting distrust in vaccines.
“There was a huge dampening of enthusiasm after LYMErix failed,” said Sam Telford, professor of vector-borne infections and public health at Tufts University, who helped run the LYMErix clinical trial. “Companies said, ‘Look, we just don’t want to go there.’ There was a lot of negativity around making a new Lyme disease vaccine.”
As work moves forward on these two new approaches, here’s the question on many minds: Is the market ready for a new Lyme disease vaccine?
A closer look at the new products
One of the new approaches is a vaccine, which works by stimulating the immune system to make antibodies that can attack Borrelia burgdorferi and other types of Borrelia, the bacteria that cause Lyme disease. The other is an injection of a single antibody.
Both use a similar approach to the one taken by LYMErix. Here’s a breakdown of the process:
When an infected tick bites someone and begins to feed on their blood, Lyme-causing bacteria can slowly travel from the tick’s gut to its salivary glands and then transfer from biter to bitee. But if the person’s blood contains antibodies against the bacteria, they can kill Borrelia in the tick’s gut before the bacteria has a chance to travel to the salivary glands, preventing transmission to the human.
The vaccine, called VLA15, is being developed by Valneva, a biotech company headquartered in France.
It targets the six most common types of Borrelia, said Thomas Lingelbach, president and chief executive of Valneva. This means it would work in North America as well as in Europe, where Lyme disease is a growing menace.
In addition to testing VLA15 in adults, Valneva is planning a trial in children as young as 5, and may eventually include children under 5. This would broaden its market to include parents who are eager to have their children vaccinated. That’s an advantage over LYMErix, which was limited to ages 15 to 70.
While there are steps people can take to prevent Lyme disease, including wearing protective clothing, using insect repellent, and checking for ticks after being outside, many of these techniques are tough to do consistently — especially with children, said Dr. Lise Nigrovic, a pediatric emergency physician at Boston Children’s Hospital who studies Lyme disease. She recently published a study showing that only 1 in 5 kids with Lyme disease recall having a tick bite.
“There’s a lot of worry about Lyme disease, to the degree that some parents are telling children they shouldn’t play outside or limiting hours,” Nigrovic said. “They’re behaving differently because of that worry. So vaccines are attractive.”
The Food and Drug Administration gave VLA15 fast-track designation in July 2017. Valneva completed initial safety studies in a Phase 2 clinical trial and, according to a company press release, VLA15 “had no associated safety concerns.” The company is now working to determine the dose. Based on current estimates, Lingelbach said Valneva plans to test the vaccine in a clinical trial of at least 15,000 people, and it should be available in four or five years.
The FDA approval process is long. But Telford said it may be easier for VLA15 than it was for LYMErix, given how many more people today know about Lyme disease and may enroll in trials.
“Finding people is going to be a cinch compared to what it was like in the 1990s,” he said. “I don’t see why they couldn’t have it benefiting people by 2024.”
A different approach, being developed by the University of Massachusetts Medical School, is called Lyme pre-exposure prophylaxis (Lyme PrEP). Unlike a vaccine, Lyme PrEP delivers a single defensive antibody, said Dr. Mark Klempner, the executive vice chancellor for MassBiologics and a professor of medicine at the university, who is leading efforts to develop the product.
According to Klempner, this approach could reduce the likelihood of side effects. It would also make the recipient immune to Lyme disease the day he or she gets the injection, instead of waiting a few weeks for immunity to develop as most vaccines require — or even longer for vaccines with multiple doses, as were needed for LYMErix.
Some critics worry that since these new approaches protect only against Lyme disease, recipients may be less careful about preventing tick bites and so expose themselves to other tick-related diseases like babesiosis. But Klempner said specificity is necessary.
“When you try and hit many birds with one stone, you run the risk of having a lot more off-target effects,” he said. “Our approach is to go for the most important one first, which is Lyme disease. I think everybody concurs that this is the biggest public health issue of the tick-transmitted diseases.”
Klempner’s team aims to open a Phase 1 clinical trial for Lyme PrEP in 2020, and he said the product could be available as soon as 2022.
The rise and fall of LYMErix
Part of the industry’s reluctance to develop a new vaccine dates back to the 1990s, when two pharmaceutical companies, SmithKline Beecham (now GlaxoSmithKline) and Pasteur Mérieux Connaught (now Sanofi (SNY) Pasteur), were going head-to-head developing Lyme disease vaccines. A few days before Christmas in 1998, LYMErix won the race and received FDA approval.
It would prove to be an inauspicious time to bring a new vaccine to the market.
Initially, the vaccine fared well, with 1.4 million doses distributed by July 2000. One early issue was that LYMErix required three shots over 12 months and it wasn’t clear how long immunity would last. Another was that it wasn’t approved for anyone under age 15. And some people felt that it should have been more effective, since it worked in just about 80% of those who got the vaccine.
Safety concerns began to emerge soon after people began getting LYMErix. Some recipients began to report joint pain and other effects that they attributed to the vaccine. Within a year of the vaccine’s approval, a class action lawsuit was filed against SmithKline Beecham on behalf of 121 people. Although the suit was eventually settled — it provided no compensation to the plaintiffs — publicity about it dampened interest in the vaccine.
Meanwhile, growing distrust of vaccines may have compounded LYMErix’s struggles.
When a 1998 report in the Lancet identified a purported link between the common MMR vaccine and autism, the study — since retracted and considered fraudulent — sparked a spike in worry about the safety of vaccines. In October 1999, a new vaccine against rotavirus, the most common cause of diarrhea in infants and young children, was withdrawn from the market after its use was linked to a higher than expected risk of a potentially deadly bowel blockage known as intussusception.
An advisory panel convened in 2001 by the FDA did not find any evidence that LYMErix caused arthritis in humans or an unexpected number of adverse events. But growing suspicion of vaccines in general and publicity about possible side effects had already taken a toll on LYMErix’s uptake. SmithKline Beecham projected sales of only 10,000 doses for 2002.
The company withdrew LYMErix in February 2002, citing poor market performance.
“It was a fiasco that has really never occurred to any other vaccine,” said Dr. Stanley Plotkin, an emeritus professor of pediatrics at the University of Pennsylvania and veteran vaccine researcher. “Activity in the field has been subdued because companies are afraid that the same thing that happened to GSK will happen to them.”
Pasteur Mérieux Connaught never applied for a license for its vaccine, then called ImuLyme, despite conducting promising testing and clinical trials.
In April 2013, Baxter International (BAX) released promising data about a Lyme vaccine it was developing. But Baxter soon sold off its vaccine portfolio. It eventually wound up with Shire, which decided not to pursue the vaccine.
At some point after the demise of LYMErix, Telford said he recognized that it would be cheaper to revive a vaccine he believed to be safe and effective and began trying to bring LYMErix back. But, he said, GlaxoSmithKline (GSK) was unlikely to turn over the product if the company could be liable for future issues.
“I’m very discouraged after 34 years of working on Lyme disease,” Telford said. “I’m actually so frustrated that I might put the recipe out onto YouTube and say, make it yourself.”
Possible side effects and a vaccine-hesitant climate haven’t, however, completely dampened the canine vaccine market. Since the first Lyme disease vaccine for dogs became available in the early 1990s, several more have been developed and millions of dogs have been vaccinated.
The road ahead
In some ways, the market for a Lyme disease vaccine is much promising today than it was two decades ago. For one, the number of people affected by the infection has grown dramatically over the past 20 years.
In 1998, the year LYMErix was approved, 16,802 cases of Lyme disease were confirmed in the U.S. Today, around 30,000 confirmed cases are reported each year, but the CDC estimates that the true number is closer to 300,000 per year and has increased steadily over the past 25 years. In Europe, the number of reported cases in 2010 was more than seven times higher than in 1990.
The extent of the infection has also expanded. Since the first cluster of confirmed cases was reported in Old Lyme, Conn., in 1977, Lyme-causing ticks are now found in 44 states. A 2016 study found that the ticks that spread Lyme disease were found in 44% more counties than in 1996. Coastal states and north central states still have the highest number of cases, with Pennsylvania topping the list with more than 9,000 confirmed cases in 2017.
“It’s a widespread disease and it’s ridiculous not to try to prevent it,” said Plotkin.
As more people get Lyme disease, the economic burden for diagnosing and treating it has also ballooned. A 2015 study found that Lyme disease might cost the U.S. health care system up to $1.3 billion per year.
“There’s a hunger in the market for something to prevent the infection,” Nigrovic said.
But developers will need to grapple with some challenges, including ones that linger from the withdrawal of LYMErix.
For one, public attitudes toward vaccines are perhaps even less inviting today than they were in 1998.
“There’s still this anti-vaccine thread which is independent of Lyme disease,” Nigrovic said. “That’s going to be something that comes into play.”
Any Lyme disease vaccine would likely be optional, which could reduce opposition from vaccine hesitancy groups. But there is another possible point of contention: VLA15 and Lyme PrEP both target the same protein on Borrelia bacteria that LYMErix did — outer surface protein A (OspA).
The approach used to target OspA in LYMErix was linked to concerns that arose about potential side effects. While studies have not confirmed the connection, VLA15 uses a slightly modified vaccine approach and Lyme PrEP delivers a single antibody directly — both of which could circumvent the purported issue. But Telford said some people might still take issue with a vaccine that targets OspA.
“I anticipate Valneva is going to have a problem with activists,” he said, noting that he had informally spoken with some community groups. “The broad statement was ‘No OspA vaccine, no how.'”
Dr. Phillip Baker, the executive director of the American Lyme Disease Foundation, a volunteer-run nonprofit, agreed. “They’re already criticizing the vaccine and it hasn’t even been released,” he said. “There’s so much misunderstanding about Lyme disease. There’s an element of suspicion.”
However, Roberta Clarke, a health care marketing expert and associate professor emeritus at Boston University who has had Lyme disease three times, said some people in the Lyme disease activism community may support a new preventive approach — particularly people who have had Lyme disease and feel frustrated by current treatments, which usually consist of antibiotics.
Telford said some activists are also calling for more research funding to be directed to tick-related diseases.
“We all know there’s a problem here. People are fed up,” he said. “There are people who are angry enough that they’re pestering their legislators to do something about it.”
And it may be working. In 2016, Congress established the Tick-Borne Disease Working Group, which submitted its first report in 2018. The National Institutes of Health also recently issued a call for tick-related illness prevention proposals with $6 million allocated to fund projects in 2020.
Lorraine Johnson, chief executive of LymeDisease.org, a nonprofit advocacy group, said developers of the new approaches can avoid one problem she observed with LYMErix: a lack of communication between the manufacturer and the community. “You would really like to see the manufacturers reaching out to the Lyme community and working with them in a much more collaborative, forthcoming, full-disclosure sort of way,” she said.
Lingelbach said Valneva is engaging with opinion leaders and patient advocacy groups, but said it’s difficult given how far out the company is from licensing its vaccine.
Johnson also said it’s too soon to tell how activists and community members will respond to VLA15.
“The Lyme community is not anti-vaccine,” she said. “It’s just a question of whether it’s the right vaccine at the right time and if [developers] are engaging with the community as collaborative partners.”
Companies will also need to engage physicians this time around, Plotkin said. LYMErix was marketed directly to consumers, but Plotkin said Valneva should involve physicians to ensure they are aware of and feel comfortable recommending the vaccine.
Along with “a very nuanced public health rollout,” Nigrovic said strong safety and effectiveness data could outweigh past distrust.
Klempner was optimistic. “We’ve learned some very important lessons from the LYMErix debacle, as I think some people would categorize it,” he said. “It certainly remains the only safe and effective vaccine that’s been pulled from the market.”
During LYMErix’s brief stint on the market, Clarke was among the recipients. Having had Lyme disease twice, she decided to try the vaccine. Even after receiving the final LYMErix shot, Clarke said she got Lyme disease for a third time.
Despite this, Clarke said she’d still give a new vaccine a try.
“If the research is strong enough to show that it’s effective and the side effects are minimal, sure,” Clarke said. “Of course.”