Will New Lyme Disease Approaches Change Patient Care?
Nearly 50 years after Lyme disease was first recognized in the US, its diagnosis and treatment remain remarkably familiar. Clinicians still rely on antibody-based tests that can miss early infections, and for most patients, a short course of antibiotics—typically doxycycline, amoxicillin, or cefuroxime—is the standard of care. Although such therapies are highly effective for a majority of patients, they’ve changed little over decades, even as Lyme disease has become the nation’s most common vector-borne illness and cases continue to rise as ticks spread into new geographic regions.
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“It’s frankly depressing that we’ve been doing the same things for Lyme that we’ve done for 25 years, the span of my career,” said Linden Hu, MD, a professor of molecular biology and the codirector of the Lyme Disease Initiative at Tufts University School of Medicine. “For some of it, it’s because the treatments actually do work, but for many other things, like prevention and early detection and chronic Lyme disease, we’ve clearly not been doing a great job.”
Now, after years of relatively little movement, researchers are pursuing a broader range of strategies to improve Lyme disease care, from more sensitive diagnostics to retooled vaccines and a handful of novel therapeutic treatments. At the same time, experts caution that such approaches face practical hurdles that may limit their ability to change clinical practice and patient care.
Near-Term Hope in Diagnostics
More than 89 000 cases of Lyme disease were reported to the US Centers for Disease Control and Prevention in 2023, a 3-fold increase from the 21 000 cases reported 20 years earlier. But because not all cases are submitted for national surveillance, recent estimates suggest that about 476 000 people in the US are diagnosed and treated for Lyme disease each year. In western Europe, where it is also the most common tickborne illness, 200 000 cases are treated annually.
Caused by the bacterium Borrelia burgdorferi and transmitted through the bite of infected Ixodes scapularis ticks, Lyme disease is generally curable when recognized and treated promptly—but diagnosis isn’t always straightforward.
The erythema migrans rash—the classic indicator of Lyme disease—does not appear in all patients. Beyond physical examination findings, clinicians look for flu-like symptoms and may rely on a 2-tier serological blood test that detects antibodies against the bacterium rather than the organism itself.
“The challenge in using indirect testing is we’re waiting for antibody responses, which could take 2 to 6 weeks to generate,” said Paul Auwaerter, MD, director of the Fisher Center for Environmental Infectious Diseases at Johns Hopkins School of Medicine. This, he said, has created a window early in infection when patients may test negative despite having Lyme disease. He emphasized that the current tests are reliable once patients have been infected for several weeks and have long-term symptoms such as Lyme arthritis, a late-stage complication characterized by sudden, severe swelling in large joints.
Nevertheless, the limitations of the current testing strategy have consequences, including delayed diagnosis.
John Aucott, MD, director of the Johns Hopkins Lyme Disease Clinical Research Center, said that improvements would be helpful not just for acute Lyme disease but “even more importantly” for posttreatment Lyme disease syndrome (PTLDS), a chronic condition similar to post–COVID-19 condition, or long COVID, with no known treatment or cure. Studies show that a delayed start to treatment is a risk factor for developing PTLDS.
Aucott noted that most Lyme disease advancements in development are diagnostic, with more companies entering the field in recent years. Several experts pointed to the LymeX Diagnostics Prize, a multiphase public-private partnership competition run by the US Department of Health and Human Services, as a sign of growing investment.
“We’ve pushed the limits on improving antibody testing, so the work now is in finding alternatives,” Aucott said.
Investigators are developing polymerase chain reaction tests that look directly for bacterial DNA or antigens, while others are exploring host-response approaches that analyze patterns of gene expression in the immune system, potentially aided by artificial intelligence, to distinguish Lyme disease from other illnesses. Hu also noted that improved tests could not only help clinicians identify Lyme disease earlier but also better characterize patients for clinical trials and biomarker research.
Researchers are also hoping that advances in diagnostics will come from a better understanding of PTLDS. Through a series of National Institutes of Health–funded studies, investigators including Aucott and Hu are observing research participants from the earliest stages of Lyme disease to identify clinical and biological markers—including immune responses and autoantibodies—that may predict who goes on to develop persistent symptoms. The findings could ultimately improve diagnosis or guide the development of targeted therapies.
Even so, no single diagnostic breakthrough is imminent. Developing a test that detects the bacterium itself has proved difficult because B burgdorferi is typically present in skin or tissue and only in blood in very low numbers, which makes direct detection technically challenging.
“Looking at different ways to try to achieve earlier diagnosis remains one of the holy grails,” Auwaerter said.
A New Vaccine Attempt
In 1998, the US Food and Drug Administration (FDA) approved LYMErix, the first—and so far only—vaccine against Lyme disease. Although studies found it effective, the manufacturer voluntarily withdrew the vaccine from the market in 2002 after disappointing sales and concerns about possible adverse effects, though subsequent reviews did not confirm a causal link.
This experience cast a long shadow.
“The LYMErix experience may have dissuaded pharmaceutical companies from dipping their toes into it for a number of years,” Auwaerter said. “It’s only the last 3 to 4 years that there’s been a recharged interest in these prevention aspects.”
The vaccine candidate LB6V, developed by Pfizer and Valneva, is furthest along. The multivalent vaccine has completed a phase 3 trial, and in March the companies reported it demonstrated 73% efficacy against Lyme disease cases. Although it missed its main statistical goal because fewer trial participants developed Lyme disease than expected, the developers remain confident in the “clinically meaningful” protection provided. It’s being evaluated by the FDA and, if approved, it could be released within a few years. According to Auwaerter, it would have broad indications, considering it was tested on participants as young as 5 years.
Still, a number of other challenges may limit its impact.
“The good thing about the Pfizer vaccine is that somebody is trying to bring something on the market for Lyme disease,” Nicole Baumgarth, DVM, PhD, a professor of immunology and infectious diseases and the director of the Lyme and Tickborne Diseases Research and Education Institute, said. “And in my mind, that’s about as far as it goes in terms of good news.”
Although LB6V uses an updated formulation that intentionally omits the specific amino acid segment that sparked safety concerns with LYMErix, Baumgarth noted that the new vaccine candidate uses the same outer surface protein A (OspA) target as the first-generation vaccine. “We took it off the market, and 20 years later, we’re basically just replacing it with the same antigen,” she said.
She also has concerns with the vaccine’s mechanism. Unlike those that lessen disease severity, the goal of LB6V is to prevent infection altogether. “It's not like the COVID vaccine where you can argue, ‘Well, even if you get infected, you have a milder course of disease,’” she said. “This one is all or none.”
Another concern among experts is the dosing schedule. The vaccine requires 3 initial shots over the first 9 months followed by a booster.
“It doesn’t offer immediate protection, Auwaerter said. “It takes a while, and it’s repeated visits.”
Hu fears it won’t receive widespread uptake: “The more tools we have to prevent, the better, but it’s going to be hard to get people to sign on for 4 doses.”
Even then, Baumgarth isn’t convinced it will be effective.
Although the duration of immunity is still being evaluated, she predicts it will likely lapse within a year and questioned whether a vaccine requiring repeated doses over a relatively short period of protection would be well suited to an era in which warming temperatures are lengthening the time ticks remain active.
“With this, you will barely make it through the tick season,” she said. “And as the climate is changing, the tick season is becoming longer.”
Prevention Holds Promise
As vaccine development moves forward, researchers are investigating other ways to prevent Lyme disease—including innovations that could appeal to people in need of more immediate protection.
One strategy uses a monoclonal antibody that targets the same OspA found in B burgdorferi as LB6V. But unlike vaccination, which requires weeks or months for immunity to develop, this type of preexposure prophylaxis could offer near-immediate results.
“Within 2 days of being infused, you’re protected,” said Auwaerter, who serves as a scientific consultant to antibody developer Tonix Pharmaceuticals. Although it could achieve higher levels of protection than a vaccine, he acknowledged it would likely require annual infusion in a medical setting and could be expensive to make and administer.
Baumgarth said the therapy could be particularly attractive for those with short-term exposure risks.
“You can say, ‘I’m going on a long vacation where I’ll be outside, so I’ll take it,’” she said, noting the antibody’s long half-life could provide protection for 5 to 6 months.
Another strategy takes aim not at the bacterium but at the host.
Tarsus Pharmaceuticals is studying the oral drug lotilaner, which is already approved as an eye drop for the treatment of demodex blepharitis in humans and as a flea- and tick-killing chewable tablet for pets.
“We’ve been giving this to our dogs and cats for a long time,” Baumgarth said.
Using a similar action, this new version aims to kill ticks soon after they attach, which would prevent them from transmitting Lyme disease or other pathogens.
“Ticks have to be attached for about 36 hours or longer to effectively transmit,” Auwaerter said. “If ticks attach but then fall off within hours, you’re essentially protected from acquiring Lyme disease.”
Hu said that although there are concerns with “any drug that stays in your body for a long time,” the strategy could offer a practical advantage over vaccines for people with unexpected outdoor exposure.
“If you’ve forgotten you’re going camping, you can just take the drug and be protected immediately,” he said.
Auwaerter added that, combined, these offerings could provide choice to patients.
“There’s lots of potential here to really tailor a particular prevention treatment that would be adopted by an individual,” Auwaerter said.
Still, experts emphasized that these investigational products remain years away from routine clinical care. And in that time, Lyme disease cases will continue to expand into new regions of the US due to shifting land use, reforestation, and growing populations of deer and small mammals that serve as reservoirs for tickborne pathogens. Baumgarth asserted that preventing disease ultimately means targeting these environmental factors.
“Ticks transmit 17 different pathogens that we know of,” she said. “You’re not going to make 17 different vaccines.”
She noted that researchers have explored vaccinating wild mice by coating bait pellets with a vaccine that the rodents consume or modifying habitats to reduce tick populations, but all experimental approaches face substantial hurdles.
“There is no easy solution,” she said.
For now, the most effective ways to prevent Lyme disease are still decidedly the simplest: using US Environmental Protection Agency–registered tick repellents, wearing protective clothing, performing tick checks after spending time outdoors, and promptly removing attached ticks.
“It works,” Baumgarth said. “It just requires awareness of clinicians and education of the public—especially among those outside of traditionally endemic areas—and behavior changes, which are sometimes the hardest ones to actually implement.”
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Article Information
Published Online: August 7, 2026. doi:10.1001/jama.2026.15548Conflict of Interest Disclosures: Dr Hu reported receiving research grants to his institution from MassBiologics, Moderna, and Tarsus and a consulting services grant to his institution from Pfizer. He also reported serving on the scientific advisory board for Global Lyme Alliance and Bay Area Lyme Foundation and serving on the research committee of Infectious Diseases Society of America. He also reported receiving royalties for chapters on Lyme disease from UpToDate and that he has a patent pending on a diagnostic test not discussed in the article. Dr Auwaerter reported conducting Lyme disease research for Pfizer and performing scientific consulting for Tonix and Tarsus. Dr Aucott reported serving on the adjudication committee for a Tarsus study, consulting for Pfizer on Lyme epidemiology and background related to vaccine uptake and acceptance, and advising the LymeX Diagnostics Prize. He also reported serving on the scientific advisory committee for the Cohen Foundation. No other disclosures were reported.