Highlights in Lyme disease research 2024-2026

The following is an edited transcript from a Center for Lyme Action “State of Lyme Disease Research” online presentation delivered by Nicole Bell, CEO of Galaxy Diagnostics, on April 30, 2026.

The State of Lyme Disease Research paper was published in 2023 by the Center for Lyme Action. The core argument was that Borrelia burgdorferi is a key driver of what researchers are now calling IACI, or infection associated chronic illness. The paper has been used to educate clinicians, patients, including policy makers and has been well received across the ILADS community and beyond. This then will cover the new findings that have been released since then, from 2024 to 2026, focusing on select research in three areas, 1.) diagnosis, 2.) the link to chronic conditions and 3.)  treatment.

To build this list, The Center for Lyme Action and Nicole Bell, CEO of Galaxy Diagnostics reached out directly to the top researchers in the Lyme disease (LD) space and asked them, what are the papers that you’re the most excited about? The result is a curated, not exhaustive set, but it is representative.

Diagnostics

Diagnosis is where the most urgent failures in the current system concentrate. Patients are being missed at the exact moment where treatment could make the greatest difference, and therefore let’s examine what the research is telling us.

Today’s diagnostic standard is broken. The rash based diagnosis is less than 50% accurate but the rash is still being given enormous diagnostic weight that the data doesn’t support. The CDC two-tier test and the ELISA tests used in Canada miss most early cases. Clinicians still don’t fully appreciate the magnitude of the problem, but new solutions are on the horizon.

The bull’s-eye or EM rash that everyone associates with LD occurs in only about 14% of patients and as low as 6% in other studies. Even in these cases it is incorrectly diagnosed in 20% of cases.

The more typical EM rash, or atypical EM rashes represent about 58% of infections. Those have misdiagnosis rates at even higher, closer to 36%. And then some patients, about 28%, have no rash at all. And when you add it all up, more than half of patients, 52%, will be misdiagnosed based upon rash presentation alone. Clinicians will see these patients years after that initial misdiagnosis. The patient who was told, no rash, no Lyme, really could have been failed decades before they came to the doctor’s office.

The ELISA tests used in Canada miss one third of those that truly do have the disease but physicians haven’t been informed of this nor have they been told the accuracy falls off sharply after 2 years. The worst thing you can do for a patient is give them a false negative diagnosis.

For a while now the standard two-tier test used in the U.S. is about as accurate as a coin flip, but this study from Bay Area Lyme actually confirms that it’s worse than a coin flip. Bay Area Lyme has been collecting patient samples for over a decade, and several of the studies in this section were made possible by their work. Access to these well-characterized samples from the biobank is essential to advancing diagnostic development, and we are all grateful for this resource.

Presently there is no FDA approved test that can rule out Lyme. None of the LD tests used in the U.S. and Canada have been clinically validated to be useful. None have been approved by the FDA. Instead the tests have been cleared, meaning that they are on par with tests that are already available. They don’t have to demonstrate that they are clinically valid. If future tests are clinically validated then we can have confidence in the results they produce.

The role of biobanks in research 

In this study, they looked at 466 early Lyme cases enrolled over a decade, and 253 of those patients had a 3-month follow-up visit. At the first blood draw, only 23% of patients tested positive. That means 77% of patients were missed. These patients were in endemic areas, so physicians treated with antibiotics even when patients tested negative. Something that’s equally important, is that of the patients who initially tested negative with IgG, only 4% later converted to a positive at the 3-month visit. So early antibiotic treatment prevents the immune response the test is looking for. So if you treat early, which you should, the test may never become positive, and so a negative follow-up draw is not evidence that the patient wasn’t infected.

And then this paper came out in May 2026, and it’s a head-to-head comparison of four FDA-cleared Lyme tests, both standard and modified two-tier algorithms, again, using the Bay Area Lyme Biobank samples.

Need for novel diagnostics for early LD that do not rely on patients immune responses

In early-stage disease, these tests miss between 64% and 78% of patients. The timing issue is also very clear. Within the first week of symptom onset, the majority of patients tested negative on every single algorithm. And so detection only improved after 2 weeks, by which point optimal treatment timing has really passed. So the earlier you test, the less reliable the test is, and so a negative test does not rule out Lyme. The conclusion is pretty clear. We need tests that detect the infection directly, not tests that rely upon the patient’s immune response.

Replacing 2-tier testing with a single highly sensitive test 

Sex, Menopausal Status Tied to Severity of Early Lyme Disease Presentation

The findings from this Johns Hopkins study has real implications for patients. It is a prospective study of 243 antibiotic-naive adults, all presenting with an EM rash. The study found significant differences in both testing performance and disease severity based upon sex and menopausal status.

Compared to women overall, men were nearly twice as likely to test positive on the two-tier test. They had more severe symptoms and presented with larger rashes.

And that gap widens when you compare men specifically to premenopausal women. So men were almost 3 times more likely to test positive, and the symptoms were more than twice as severe.

What this means clinically is that the test is harder to trust in younger women. They mount a less robust immune response during early infection, the disease looks less dramatic and as a result, they’re more likely to be missed. This helps explain something seen frequently at Galaxy Diagnostics, where women are diagnosed as they approach menopause. Not because they were recently infected, but because as their hormone levels change, their symptoms intensify and look more like what you would see in men. The underlying infection may have been there for years, but the symptom profile changes, and that helps to drive the diagnosis.

Two new approaches with improved performance over the standard tests

This 2025 study introduces a hybrid Lyme ELISA, a novel single-tier test.

demonstrating over 90% sensitivity in early-stage LD, significantly outperforming standard two-tier testing. By simultaneously detecting antibodies to VlsE and C6 antigens, the assay offers high specificity and provides a faster, more accurate diagnostic option for all stages of infection.

The first is out of research out of NIH, and it uses a redesigned ELISA that requires two Borrelia targets to bind simultaneously before calling a positive. And this dual binding requirement reduced false positives while improving sensitivity. And actually, 15 out of 15 early cases were accurately diagnosed within the first 7 days of symptoms, compared to 76% with the modified two-tier test. This is currently in prospective clinical trials.

Hickman AF, Weber AF, Horn EJ, Gwynne PJ. The multiplexed single-tier inBIOS Lyme Detect Multiplex ELISA is more sensitive than standard two-tier tests in the early stages of Lyme disease. J Clin. Microbiol. 63(11):e00629-25; 2025 Nov 12: https://doi.org/10.1128/jcm.00629-25

The second method was developed by inBIOS, and this screens for antibodies against 9 Borrelia proteins, and then uses the machine learning algorithm to call the result.

Multiple weak signals can be combined to give a more confident positive. And in early patients tested within the first 7 days, it improved detection from 10% to 30%, and this is currently in research use only. Both approaches show that smarter antibody testing leads to an improvement.

Immunoassay for improved LD diagnosis across all disease stages

Building on that theme of machine learning and multiplex antibody testing is a preprint from Stafford and colleagues at ACES Diagnostics, and takes a similar conceptual approach, but runs on the Luminex platform, which matters, because Luminex is already installed in most large reference laboratories.

The test, called LymeSeek looks at antibody responses to 10 Borrelia antigens, and using the John Hopkins slice cohort, the results are striking with 100% sensitivity in early Lyme at diagnosis, 100% sensitivity again at the 3-month post-treatment visit, and 95% sensitivity in PTLDS patients, compared to 43% for the standard two-tier algorithm in that same U.S. group.

The important caveat that the paper explicitly flags is that a positive test can’t distinguish between active and resolved infection with persistent antibodies. It’s still an antibody approach, so it addresses the sensitivity problem, but it doesn’t solve the is-the-person-currently infected question, but that said, this is a meaningful step forward, and ACES is currently commercializing the technology and targeting FDA submission in the coming year.

The Structural Effort to Push for Better Diagnostics

The structural effort to push better diagnostics is meant to proceed all the way to the market. The LymeX Diagnostic Prize is a private-public partnership between the Stephen and Alexandra Cohen Foundation and the U.S. government’s Health and Human Services (HHS) department. It launched in 2022 and has, in each phase, offered both prize money and structured support to teams that are developing better testing solutions for Lyme disease.

The idea is to create a competitive pipeline, not just fund individual research, but to actively accelerate the development to the FDA. There are 7 teams that started Phase 4 and this program supports teams through FDA submission. can diagnose active infection. Not just exposure history, not just antibody evidence of prior response, but active ongoing infection, because this is the gap that’s been in the field for decades.

Two broad approaches are in development. The first is direct detection, looking for the bacteria itself, either its DNA or specific biomarkers that are in patient samples. The second uses patterns of immune response to signal active infection. 

A urine antigen-based approach

One development worth highlighting is that at the end of 2025, Galaxy Diagnostics  partnered with Dr. Brandon Jutras at Northwestern, and both have been working together as part of the competition on a urine antigen-based approach. Dr. Jutras identified specific bacterial cell wall components as a highly specific marker for active Lyme infection. This is currently being validated in the lab with plans to release it later this year. This paper by Birkaya et al. was published last month, and it really explains the science behind why urine is such a compelling sample type for direct detection. Borrelia produces roughly 38,000 tiny little membrane vesicles per organism in culture over a 10-day period. These vesicles are small enough to travel throughout the body, including into the nervous system and joints, which helps explain how Borrelia drives widespread inflammation, even when the bacteria are concentrated elsewhere.

These vesicles are also filtered by the kidneys and excreted in the urine, along with the proteins they contain. And so this particular paper found 289 distinct Borrelia proteins in human urine samples. And this is the biological justification for urine-based testing. The bacteria shed these vesicles continuously, the kidneys clear them and you can detect the proteins directly without a patient immune response.

References

Birkaya B, Byne A, Irfan S, Gallagher J et al. Characterization of Borrelia-Derived Extracellular Vesicles: Implications for Pathogenesis and Diagnostics. Microorganisms. 14(3):600; 2026 Mar 7: https://doi.org/10.3390/microorganisms14030600

McClune ME, Ebohon O, Dressler JM….. Steere AC, Jutras BL et al., The peptidoglycan of Borrelia burgdorferi can persist in discrete tissues and cause systemic responses consistent with chronic illness. Sci Transl Med. 2025 Apr 23;17(795):eadr2955. https://www.science.org/doi/10.1126/scitranslmed.adr2955

For Clinicians: The link between Lyme disease and chronic conditions

It’s really critical for clinicians that they understand the link between Lyme disease and chronic conditions. This is the science explaining where the patients you’ve been treating for years, the ones that came to you after being dismissed elsewhere, as to how they got to this state.

From the 2023 paper we know that Borrelia is not a typical infection. It doesn’t infect and just leave. It actually disables the immune system from the very start, it leaves   debris that drives inflammation long after treatment and it crosses critical barriers such as the blood-brain barrier and the placenta. It hijacks key immune pathways in ways that we are only beginning to understand.

Each paper in this section adds a new dimension to that picture and together they make a compelling picture of why so many patients remain ill after standard treatment. 

This paper from researchers in Vienna is really an elegant piece of mechanistic work that shows why Borrelia is hard for the immune system to fight.

The question is what happens to the skin’s immune cells during a tick bite before the bacteria even arrive? The skin has specialized immune cells called Langerhans cells that act as a first alarm. The research shows that tick saliva reprograms these cells before Borrelia enter the picture. The saliva shifts them from an alert fight-ready state into a tolerating stand-down state. When Borrelia arrive the effect is then amplified and the cells double down on tolerance rather than sounding the immune system alarm. The result is that the immune response that should be clearing the infection doesn’t mount properly, why immune memory isn’t effective, why reinfections are common and why some patients never produce a strong enough response to test positive in the first place. 

The role Borrelia peptidoglycan may play in chronic illness

This is from Dr. Brandon Jutras’ lab at Northwestern, and it’s directly relevant to both chronic symptoms and what Galaxy Diagnostics is working on. Every time Borrelia divides, it sheds roughly 45% of its cell wall into the surrounding environment. When antibiotics kill the bacteria, particularly the cell wall-disrupting ones, like amoxicillin and ceftriaxone, there’s an even larger burst of cell wall material released all at once.

Here’s the important distinction that the paper makes, is that the cell wall material comes in two forms. Smaller fragments, and then large, intact polymer chains. The fragments are cleared from the body pretty quickly, but the intact polymer form isn’t. It accumulates in the liver and persists there for weeks. It’s also been found in the joint fluid of post-treatment Lyme arthritis patients. In fact, in 27 of the 30 samples tested after antibiotic treatment.

Why does that form matter? The form matters because the intact polymer is biologically active in the way that the fragments aren’t. So, it drives an immune response and cellular changes that parallel what we see in patients with chronic illness following infection, and it’s the form that lingers long after treatment ends. The team at Northwestern also developed a test in antibodies that can specifically detect the intact polymer and distinguish it from the fragments, which has very important diagnostic implications.

The practical message is, when the treated patient remains sick, this may be part of the why. Even if the antibiotics clear the bacteria, the debris can still be there, and not all debris is equal.

Borrelia trigger and immune alarm system that stays stuck

This work from Indiana University is a little unexpected. Borrelia triggers an immune alarm system that the body normally reserves for viruses. The bacteria secrete a molecule that activates a pathway called STING which typically responds to viral DNA. And when STING is activated, it triggers the production of type 1 interferons, which are a signaling protein that ramp up that immune response.

Early in infection, this is actually helpful. It recruits immune cells and reduces the bacterial load. But when that alarm stays on chronically, it shifts from protective to damaging, and persistent interferon activation drives ongoing inflammation and tissue damage. And this is the same pathway being studied intensively in long COVID.

The molecular switches involved, STING and TBK1, are already established as drug targets, which means this opens up a real door for targeted treatment in Lyme along with chronic persistent forms as well.

Call for research on dysautonomia caused by Borrelia

This is a review paper from Johns Hopkins, and it makes a pretty straightforward but important point, is that Borrelia has every biological tool needed to cause autonomic dysfunction and POTS, and yet no study has ever formally investigated whether or not it does. The paper documents the plausible mechanisms, nervous system involvement, nerve damage, autoimmune responses, disrupted blood-brain barrier function, and every one of these is documented in Lyme, and every one is a known pathway to dysautonomia.

Yet, it remains unstudied in the PTLDS population, even though effective treatments for POTS are actively being trialed in long COVID patients. This paper really calls for that research, and it’s also a useful tool to share with colleagues who question whether Lyme can cause the autonomic system symptoms that patients describe.

Does LD cause gynecological conditions and problems for newborns?

This paper from MIT asks a question that’s genuinely never formally been studied. Does LD increase risk for gynecological conditions? The research combined mouse experiments with analysis of three massive human health databases, including data from roughly 110 million patients across 30 health systems.

First in mice, Borrelia was found in the uterus and surrounding tissues within weeks of infection, and persisted essentially for the entire lifespan of the animal. Infected mice developed uterine inflammation and cysts.

Then in the human data, consistent across all three independent databases, women diagnosed with Lyme showed significantly elevated risk of endometriosis, miscarriage, uterine fibroids, heavy periods, painful periods, and uterine polyps. Critically, these conditions developed after the Lyme diagnosis, not before. And the association’s held even after controlling for antibiotic use. 

For patients with reproductive complications following Lyme, there’s now research that supports that this is an issue, and not just clinical intuition of the linkage.

As far as reproductive consequences of LD, this review paper covers something that has been strangely absent from the research agenda. Can Borrelia be transmitted from a mother to a baby?

It’s been known since 1985 that Borrelia can cross the placenta, and case reports followed through the 1990s, but then research essentially stopped around 2000. The documented cases that are summarized in this review article are pretty sobering. They include miscarriages, cardiac malformations, stillbirths, early neonatal deaths. Only a handful of the documented cases actually had normal outcomes.

In 2026, the WHO added congenital Lyme to its International Disease Classification System, a formal acknowledgement that this is recognized, but U.S. medical guidelines still really make no recommendation for exposed newborns. The incidence of perinatal transmission is unknown, but the outcomes are very serious. Any clinician treating a Lyme-positive woman who is either pregnant or planning to become pregnant, this is really a conversation worth having.

Treatment: Superior efficacy of combination antibiotic therapy

The core problem with treatment hasn’t changed, that the standard monotherapy fails a meaningful percentage of patients leaving them with chronic debilitating symptoms and their lives reflect this. New work is beginning to show us where potential solutions lie. What is needed are new approaches that are proven in controlled clinical trials, not just case series or clinician experience. The good news is that the research community is finally building that evidence base, and let’s take a look at what’s coming.

First, the same Bay Area Lyme Biobank study that we looked at in the diagnostic section also has a treatment story. Of the 253 patients with 3-month follow-up data, 22% reported ongoing symptoms after antibiotic treatment. Most commonly, these were joint pain, fatigue, and muscle pain. And of those patients, only 35% went back to see their provider. Consequently two-thirds of early Lyme patients with persistent symptoms after treatment did not seek additional medical care. This is a critical care gap where more physician and patient education is needed. The message is that early Lyme is not a one-and-done encounter. These patients deserve a follow-up at 3 months, and persistent symptoms are a clinical signal, not something to dismiss

This Tulane paper appeared in a 2024 ILADS presentation, but it bears repeating here, because the findings have real clinical implications. The study compared monotherapy versus combination antibiotic regimens in an infected mouse model, specifically checking whether treated mice could still transmit Borrelia to feeding ticks, or known as xenodiagnostics, where you look at the tick to see if there’s still Borrelia in the animal.

With every monotherapy tested, and 8 were tested, they left viable, transmissible infection found in the ticks that fed on the mice. The combination therapies tested, 7 different combinations, cleared it completely, with zero transmission across the board. This is animal data, not a human trial, but the signal is consistent, and it supports what many ILADS clinicians have observed clinically, that combination therapy may be what’s needed for effective treatment.

Pre-existing antibiotic that clears Borrelia at lower doses while sparing the microbiome

This is an exciting treatment paper out of Northwestern, and the headline’s striking. A better antibiotic for Lyme might… already exist, that’s FDA approved for other indications. This looked at 466 FDA-approved compounds at low doses against Borrelia and other bacterial cultures. And the goal was to find a drug that selectively kills Borrelia without broad-spectrum collateral damage. Piperacillin emerged as the standout candidate. In mice, piperacillin cleared Borrelia at a dose 100 times lower than doxycycline and critically, it had negligible impact on the gut microbiome.

The piperacillin group maintained a healthy microbiome diversity, but the doxycycline  group showed a radical disruption of the microbiome composition. For patients who’ve struggled with the GI consequences of long-term doxytherapy, this matters a lot. Piperacillin is the beta-lectam antibiotic that’s used intravenously in hospital settings. Human trials are obviously a great next step as this appears to be well worth exploring.

Psilocyban-assisted therapy

This is a pilot study from Johns Hopkins, which tested psilocybin-assisted therapy in 20 patients with PTLDS, or post-treatment Lyme disease syndrome. All had CDC-confirmed Lyme disease, and all were experiencing active PTLDS symptoms, with a median duration of nearly 6 years.

The protocol was 2 psilocybin sessions over an 8-week program, and the result was general symptom burden dropped 40% from baseline, and that reduction held at the 6-month follow-up. Quality of life scores improved 13%, and improvements were seen across depression… depressive symptoms, sleep, fatigue, and pain. This was a small, open-label pilot with no control group, but a 40% symptom reduction sustained at 6 months.

This is remarkable in patients who’ve been suffering for an average of 6 years. And there’s also a plausible biological rationale. Psilocybin has shown effects on neural inflammation and immune modulation. Both are relevant to PTLDS, and so this is early stage, but it’s worth watching.

Finally, the infrastructure to build the evidence base is coming together. The Lyme Clinical Trials Network, funded by the Cohen Foundation, and then also has sites funded by Bay Area Lyme and NIH, currently has 7 active studies. Multiple institutions, multiple approaches, and real rigor, this is really the infrastructure that the field has needed. These trials are worth knowing about and monitoring for new studies that get added.

In conclusion with the 3 different sections presented there are 3 main takeaways. Diagnostics. The current is broken, and we have the data to prove it, but better tests are coming. Chronic conditions, the biology of why patients get missed and stay sick is really no longer theoretical. We’re beginning to really understand these core mechanisms.

Then on treatment, better solutions are in progress, and there’s a clinical trials network building to build that evidence base. And so the science is there, and what it needs now is action and more investment to get it here sooner. 

That is where the Center for Lyme Action comes in. The Center for Lyme Action was started in 2019 because they realized while the private foundations were doing a tremendous amount of work that private money was just not going to be enough. What we really needed to do was leverage the power of the federal government.