top of page

As Lyme Disease Expands Its Reach, New Research Offers Hope

Public health warnings about vector-borne diseases in the US are heating up. In a May editorial, scientists from the Centers for Disease Control and Prevention (CDC) made a plea for a vaccine against West Nile virus, which is spread by mosquitoes and has no treatment. By midsummer, the CDC reported that as many as 450 000 people in the US may have a meat allergy from the bite of the lone star tick, while other CDC scientists warned that mosquitoes are becoming resistant to the insecticides used in abatement efforts. Mosquitoes struck in August, when public health officials reported 11 cases of locally acquired dengue fever in Florida and Maryland’s first known case of locally acquired malaria in more than 40 years. Meanwhile, the most common vector-borne disease in the US, Lyme disease, is on the rise. “Lyme disease is definitely increasing in the US as the environmental niche of the deer tick and deer populations expand,” John N. Aucott, MD, director of the Lyme Disease Research Center at the Johns Hopkins University School of Medicine, told JAMA in an interview. The incidence of Lyme disease in the US nearly doubled from 1991 to 2018, from 3.74 cases to 7.21 cases per 100 000 people, based on confirmed cases reported to the CDC. But the true numbers are believed to be much higher.

According to the nonprofit organization Fair Health, US private insurance claims with a Lyme disease diagnosis increased 357% in rural areas and 65% in urban areas from 2007 to 2021. Using insurance claims, the CDC estimates that as many as 476 000 people in the US are diagnosed with and treated for Lyme disease each year.

“In the last 20 years, the numbers of Lyme disease have really exploded,” said Linden Hu, MD, director of the Lyme Disease Initiative at Tufts University School of Medicine. “We’ve seen people get Lyme disease just from stopping at a rest stop in Massachusetts. So the number of people at risk is greater than it was before.”

Warmer temperatures are one of many factors contributing to the spread, the US Environmental Protection Agency (EPA) says. In North America and Europe, infected blacklegged ticks—also known as deer ticks—transmit the disease-causing bacterium Borrelia burgdorferi with their bites. These ticks thrive in regions with high humidity and temperatures higher than 45 °F, or around 7 °C. Shorter winters are also increasing the numbers of ticks and their activity, the EPA notes, causing more people to be exposed to the disease.

More exposure also translates to more patients with the poorly understood posttreatment Lyme disease syndrome (PTLDS). With no known treatment, the number of people afflicted with PTLDS continues to mount. “Estimates range from several hundred thousand to several million people; it’s not a small number,” Aucott said.

This July, citing an urgent need to understand these lingering symptoms, the National Institutes of Health (NIH) announced $3.2 million in first-year funding to support researchers studying PTLDS. Both Aucott and Hu are grantees. And facing increasing threats from tickborne infections, scientists are also working on vaccines and other novel approaches to prevent these illnesses in the first place. Lyme Disease’s Long Tail Most people with Lyme disease will recover fully after experiencing acute symptoms, which can include fever, headache, fatigue, muscle and joint aches, and swollen lymph nodes. But research suggests that between 10% and 20% of people who are infected will develop PTLDS.

“After antibiotic treatment for acute Lyme disease, people may feel better, but then they begin experiencing fatigue, joint pain, memory loss, and difficulty focusing, which can last months to years, even decades,” Hu said.

Hu listed a few hypotheses for how PTLDS develops in affected people. B burgdorferi infection may persist after antibiotic treatment. Parts of the organism may endure in the person’s body, activating an immune response. Or autoantibodies may form, causing damage to the brain or other organs.

Like post–COVID-19 condition, or long COVID, and myalgic encephalomyelitis and/or chronic fatigue syndrome, PTLDS is contested by some. “It’s frustrating because these symptom-based phenotypes are hard to confirm with blood tests or conventional imaging, which appear normal,” said Aucott. “So there is a controversy over whether posttreatment Lyme disease syndrome is a real disease.”

In 2018, using positron emission tomographic imaging, Aucott found that patients with PTLDS had widespread brain inflammation, which he said was similar to the chronic traumatic encephalopathy seen in some football players. And a functional magnetic resonance imaging study published last year revealed changes to the white matter in the frontal lobes of people with PTLDS.

“Using research-level imaging, we found that there is an underlying biology to patients’ cognitive symptoms, which is probably similar to the biology of long COVID and chronic fatigue syndrome,” Aucott said. “These are not psychosomatic illnesses.”

Hu is currently investigating differences among people who fully recover from Lyme disease and those who continue to have symptoms. One potential clinical marker of PTLDS may be antiphospholipid antibodies, a class of autoantibodies seen in other autoimmune diseases, such as lupus. “We have found prolonged and abnormally high levels of these autoantibodies in patients with persistent symptoms after Lyme disease,” Hu said.

Aucott has found that an autoantibody called peptidylarginine deiminase 2, or PAD2, is triggered by B burgdorferi. “If that is the operative mechanism for some people with posttreatment Lyme disease syndrome—and it won’t be for everyone—you could suppress the autoantibody production, which is the mainstay of treatment of autoimmune diseases,” he explained.

Another line of research aims to identify biomarkers that will predict who is likely to develop chronic symptoms. Aucott has identified persistently high levels of the blood protein chemokine CCL19 in people with PTLDS, which may reflect ongoing inflammation in tissues.

For now, there’s no standard therapy for PTLDS other than treating individual symptoms, such as postural orthostatic tachycardia syndrome (POTS). “We have treatment for POTS, which is also seen in chronic fatigue syndrome and long COVID,” Aucott said. He advises physicians to include PTLDS in their differential diagnosis if they identify POTS or other symptoms common to the syndrome. “Take the patient’s complaints seriously and treat the symptoms or enlist consultants who can,” he said.

Round 2 for Vaccines An effective vaccine, of course, would prevent both Lyme disease and its postacute sequelae. There is no such vaccine available today, but that wasn’t always the case. In 1998, the US Food and Drug Administration (FDA) approved a vaccine marketed as LYMErix, which reduced the incidence of Lyme disease by 76% in a phase 3 trial.

But the manufacturer took it off the market in 2002 as sales fell amid reports of adverse effects. A class action lawsuit against the manufacturer alleged that 121 recipients of the vaccine experienced adverse reactions including autoimmune arthritis.

A CDC and FDA analysis of data from the Vaccine Adverse Event Reporting System “did not detect unexpected or unusual patterns of reported adverse events following Lyme disease vaccine administration, other than hypersensitivity reactions, compared with adverse events observed in clinical trials.”

“There was no evidence that it wasn’t safe,” said retired entomologist Durland Fish, PhD, an emeritus professor of epidemiology at the Yale School of Public Health. Still, he explained, the company decided that the low sales didn’t offset the liability costs. (Yale researchers helped to develop and test the vaccine, but Fish was not involved.)

Now researchers are trying again. In 2022, Pfizer and Valneva initiated a phase 3 clinical study to evaluate their protein subunit vaccine candidate in Europe and the US. And this April, Moderna announced it is developing 2 messenger RNA (mRNA) vaccine candidates against Lyme disease.

Erol Fikrig, MD, section chief of infectious diseases at Yale School of Medicine, worked on LYMErix. He’s taking a different approach this time. Fikrig is developing an mRNA vaccine candidate that would produce immunity against the ticks themselves, not the pathogen they carry. His rationale: a vaccine that specifically protects against Lyme disease will not ward off other diseases the deer tick transmits, such as anaplasmosis, babesiosis, and Powassan virus.

Fish said he’s even more worried about some of these illnesses than Lyme disease. “Babesiosis is a malaria-like disease that is potentially fatal, particularly if acquired by blood transfusions or in people who are immunocompromised,” he said. “Although babesiosis is moving very slowly, eventually it will occur everywhere that Lyme disease does now. And Powassan virus, recently found in deer ticks, is also becoming more prevalent, and it’s untreatable.”

Fikrig’s “antitick vaccine” encodes a cocktail of 19 proteins found in tick saliva. Researchers believe these salivary proteins cause an immune response that leads to so-called tick immunity in some animals. Part of this immune response is visible at the site of the bite.

“The problem with most tick bites is that they go unrecognized,” Fikrig noted. However, if redness appears on the skin, people may remove the tick before it can transmit the pathogen. If they do develop Lyme disease symptoms, they might be more likely to remember the tick bite, leading to prompt treatment. Fikrig is also hopeful that the vaccine will cause ticks to feed poorly and fall off before releasing enough pathogen to cause illness. So far, the agent has been promising in animal models.

Further along is an investigational oral antiparasitic agent from Tarsus Pharmaceuticals that would prevent ticks from biting or from feeding long enough to transmit diseases. Hu, of Tufts, is helping to develop the medication, which he explained paralyzes and kills ticks. The drug—a formulation of lotilaner, a flea and tick medication approved for veterinary use in cats and dogs—is currently being evaluated in a phase 2a trial.

Beyond the Bull’s-eye In the meantime, as the deer tick’s geographic range expands, some health care professionals may be seeing Lyme disease for the first time or in greater numbers than before. The CDC tracks the distribution of medically important ticks and the human pathogens they carry. Over the past 20 years, the number of US counties in which blacklegged ticks have been documented has more than doubled and the bacterium that causes Lyme disease is now found in ticks in many counties in the northeast, mid-Atlantic, and upper Midwest.

Aucott wants clinicians to know that the telltale rash associated with Lyme disease is unlikely to have the classic bull’s-eye appearance. “Only 20% or 30% of Lyme disease rashes have the bull’s-eye pattern, so patients and physicians often misattribute the rash to a spider bite or something else,” he said. In addition, a rash behind the knee or on the scalp is frequently missed. Sometimes there is no rash. “The differential diagnosis should be based on a summer flu-like illness, with or without a rash,” Aucott said.

Confirming Lyme disease with a serum antibody test can also be problematic, he explained. The test results will be negative during the first few weeks of infection, when antibodies aren’t yet present; it can take 4 to 8 weeks before an antibody test is definitive. Following treatment, a serology test result will remain positive as the immune system continues churning out antibodies against the disease. “Some clinicians will keep treating the patient with antibiotics because the patient’s test is still positive, which is totally incorrect,” Aucott said.

Clinicians can also be uncertain about when to treat tick bites with doxycycline, according to Gary P. Wormser, MD, chief of the Division of Infectious Diseases at New York Medical College. “It’s not recommended to prophylax unless a confirmed deer tick has been on the person for at least 36 hours, which is how long it takes to transmit Lyme disease,” he said. He suggests that clinicians ask the patient how long the tick fed. Treating every tick bite with doxycycline can potentially promote resistance to other bacterial infections, such as staphylococcus.

“We need a test that will be more sensitive for early Lyme disease,” Wormser said. “And more important, we need a way to differentiate active disease from prior resolved infection, which would make life a lot easier for patients and treating physicians.”

Alpha-Gal What? Lyme disease isn’t the only tickborne illness causing concern in the US. Almost half a million people in the US may have developed alpha-gal syndrome (AGS), a potentially life-threatening allergy to a sugar molecule found in meat from mammals; milk and other dairy products; and some pharmaceutical products, such as gel capsules that contain gelatin made from beef or pork. The bite of the lone star tick transmits galactose-α-1,3-galactose, or alpha-gal, causing some recipients to develop a mild to severe allergic reaction to red meat and other animal products.

According to the CDC’s July 28 Morbidity and Mortality Weekly Report, more than 110 000 suspected AGS cases were documented from 2010 to 2022, but that number represents only people who have been tested for alpha-gal–specific immunoglobulin E antibodies.

“Our surveillance is based on lab testing and is, therefore, only capturing a portion of people who actually have alpha-gal syndrome,” said CDC epidemiologist Johanna S. Salzer, DVM, PhD, senior author of the report. “This is a condition that requires multiple visits to health care providers,” she said, many of whom have never heard of it. “So there are many hurdles for individuals to be correctly diagnosed with AGS.”

All told, Salzer’s team estimated that since 2010, somewhere between 96 000 and 450 000 people in the US might have been affected by AGS.

Salzer also coauthored a companion study that surveyed 1500 clinicians nationwide on their knowledge about AGS in the spring of 2022. More than three-quarters had little or no understanding of the condition; almost half who had heard of it didn’t know the correct diagnostic test to order; and only 5% said they were very confident diagnosing or managing it. Although new cases increased by approximately 15 000 each year from 2017 to 2021, few clinicians reported diagnosing and managing patients with AGS in the previous year.

Even for physicians who are aware of AGS, diagnosing it can be challenging because the symptoms are broad and variable. “Some patients experience the classic middle-of-the-night anaphylactic reaction, but others only have [gastrointestinal] symptoms,” Salzer said, adding that the allergy symptoms can be intermittent.

Earlier this year, the American Gastroenterological Association issued guidance for identifying and managing AGS in patients with symptoms such as abdominal pain, diarrhea, nausea, or vomiting. The only treatment for AGS is to avoid eating meat and products derived from mammals and protecting against subsequent tick bites, which can make the allergy worse.

People in the US are most at risk for AGS in areas where lone star ticks have established populations, in southern, midwestern, and mid-Atlantic states. But studies suggest climate change is likely to expand the range of the lone star tick across the eastern seaboard and into the upper Midwest.

Following CDC recommendations, clinicians can also advise their patients to protect themselves against tick bites by using insect repellent, wearing long-sleeved shirts and pants, treating clothing and gear with products containing 0.5% permethrin, running clothing through the drier to kill ticks, showering to wash unattached ticks off the body, and installing screens on windows.

Article Information

Anita Slomski Published Online: September 6, 2023. doi:10.1001/jama.2023.15358

Conflict of Interest Disclosures: Dr Hu reported having financial relationships with Moderna and Tarsus. Dr Fikrig reported that he is funded by the NIH, the Cohen Foundation, and the Howard Hughes Medical Institute’s Emerging Pathogens Initiative. Dr Wormser reported receiving research grants from Biopeptides Corp and Pfizer Inc; being an expert witness in malpractice cases involving Lyme disease; and serving as an unpaid board member of the nonprofit American Lyme Disease Foundation. No other disclosures were reported.

bottom of page