Current Efforts in Lyme Disease

Research, 2023 Update

Original Report 2015
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Current Efforts in Lyme Disease Research 

Table of Contents

Introduction ............................................................................................................................... 2

History of NIAID’s Lyme Disease Research Program ............................................................. 2

Ongoing Research...................................................................................................................... 3

Fundamental Studies of Pathogen Biology ............................................................................ 4

Studies on Persistence ............................................................................................................ 5

Studies on Human Immunity to Infection .............................................................................. 6

Fundamental Studies of Tick Biology .................................................................................... 6

Studies on Lyme Disease Diagnostic Testing ........................................................................ 6

Studies on Lyme Vaccines ..................................................................................................... 7

Studies on Treatments for Lyme Disease ............................................................................... 7

Clinical Studies ....................................................................................................................... 8

Recent NIAID Lyme Disease Scientific Advances ................................................................... 8

NIH Collaborations with Other Federal Agencies and External Organizations ...................... 14

Funding Opportunities and Research Resources ..................................................................... 15

Future Plans/Directions ........................................................................................................... 15
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Current Efforts in Lyme Disease Research 

Introduction

Ticks can transmit a variety of disease-causing pathogens, including bacteria, viruses and 

parasites. Lyme disease, the most prevalent of the tick-transmitted infections in the United 

States, is named after a town in Connecticut where a group of arthritis cases in children 

appeared in the early 1970s. By the mid-1970s, the symptoms of the disease were being 

described, and the pathogen that causes Lyme disease was identified in the early 1980s by 

scientists from NIAID and Stony Brook University. The bacterium, transmitted by a bite of an 

infected Ixodes scapularis tick (the blacklegged or deer tick), is now named Borrelia 

burgdorferi after Willy Burgdorfer, a NIAID scientist who co-discovered the pathogen with 

other scientists. 

Lyme disease often begins with a circular or oval red rash called erythema migrans, which 

spreads from the bite site over several days. Other common symptoms include fever, 

headache, muscle and joint aches, and fatigue. Untreated, the infection can spread and lead

to multiple rashes, facial or Bell’s palsy (weakness of the muscles on one or both sides of 

the face), meningitis, and/or heart involvement. Later, individuals may develop Lyme 

arthritis, usually in the large joints such as the knees. 

The diagnosis of Lyme disease is based on signs and symptoms of the infection, history of 

exposure to infected blacklegged ticks, and laboratory tests. Serologic tests, which detect an 

individual’s antibody response to Borrelia, may take a few weeks after infection to become 

positive, highlighting the need for new diagnostic tests that can detect the earliest stages of 

infection. 

In most individuals, Lyme disease is effectively treated with oral antibiotics. Even with 

treatment, approximately10-20 percent of patients report a range of continuing symptoms, 

collectively called Post-Treatment Lyme Disease Syndrome (PTLDS). The reasons for these 

symptoms are unknown, though causes such as autoimmune disease, persistent infection, 

coinfections, other illnesses, or chronic inflammatory processes triggered by non-living 

bacterial components have all been considered.

Even in the absence of known tick exposure or laboratory-confirmed B. burgdorferi infection, 

some individuals report extended, often debilitating symptoms attributed to Lyme disease. This 

“chronic Lyme disease” syndrome has been dismissed by some while defended by others. 

Regardless of the cause, the suffering is real, and additional research is necessary to elucidate 

the causes of these symptoms, including investigations of B. burgdorferi and any role the 

bacteria may play in long-term disability.

History of NIAID’s Lyme Disease Research Program

Since the seminal discovery of B. burgdorferi in 1981, NIAID has supported an extensive 

and diverse research portfolio that encompasses basic and clinical research studies on Lyme 

disease. These studies are conducted by extramural and intramural investigators, including 
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scientists at NIAID’s Rocky Mountain Laboratories in Hamilton, Montana and at NIAID 

laboratories in Bethesda, Maryland. 

The Institute has remained at the forefront of Lyme disease research in addressing fundamental 

questions essential for progress in the field. NIAID’s many contributions include: 

• Helping to sequence the entire genome of B. burgdorferi and improving the molecular 

tools available for studying the organism and the host response to infection. Without 

these advances, research on the basic biology and disease-causing properties of B. 

burgdorferi would have lagged far behind that of other bacteria. 

• Sequencing the genome of the tick that transmits B. burgdorferi, in the northeastern, 

mid- Atlantic, and north-central United States: the blacklegged or deer tick, Ixodes 

scapularis. This updated and enhanced genome will enable a better understanding of the 

genetic basis of tick biology and tick/Borrelia interactions. Genomic data and 

bioinformatics tools for researchers are available in VectorBase.

• Supporting researchers to sequence the genome of the white-footed mouse, 

Peromyscus leucopus, the primary wild animal reservoir for B. burgdorferi. 

• Supporting basic research on disease transmission, including research on ticks and 

their role in the disease cycle, tick biology and behavior, tick/pathogen and tick/host 

interactions, and the role of tick microbiome in pathogen development, as well as the 

effect of climate change on the distribution of ticks and the pathogens they transmit. 

• Supporting fundamental research on the human immune response to B. burgdorferi, 

identifying bacterial factors involved in that response, and studying disease 

pathogenesis. The identification of potential biomarkers of B. burgdorferi has informed 

current diagnostic tests and continues to be explored for development of improved tests. 

• Addressing questions concerning the efficacy of long-term antibiotic therapy for the 

treatment of PTLDS through the support of three placebo-controlled clinical trials. The 

peer-reviewed, published results of these studies demonstrate that prolonged antibiotic 

therapy does not have a sustained benefit and that risks to the patient outweigh the 

benefits.

• Investigating the control of Lyme disease and other tick-borne pathogens by 

developing novel tick control approaches based on our understanding of tick 

interactions with the environment, the pathogens, and the vertebrate hosts. Tick 

control approaches may involve the use of repellents and the treatment of wildlife 

and pets. 

Ongoing Research

The overarching goals of the NIAID Lyme disease research program are to develop better

methods of diagnosing, treating, and preventing this disease in humans. To accomplish these 

objectives, the NIAID Lyme disease research portfolio includes a broad range of activities 

focusing on the pathogen, the vector, and the vertebrate hosts. Guided by the NIH Strategic Plan 
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for Tickborne Disease Research, this research is conducted by extramural and intramural 

investigators and spans basic science through human clinical research studies. Many projects are 

investigator-initiated efforts, but several are the result of targeted grant and small business 

initiatives. To encourage new grant applications that focus on advancing the priorities identified 

in the strategic plan, NIAID, along with other institutes, reissued a Notice of Special Interest 

(NOT-AI-23-013) Advancing Research for Tickborne Diseases. NIAID is committed to actively

expanding the Lyme disease research portfolio to address high-priority areas such as persistence 

of infection after antibiotic treatment and the development of diagnostics for both early and latestage disease. 

NIAID uses all of these approaches to maintain a dynamic and multifaceted Lyme disease 

research portfolio that addresses key basic, translational, and clinical research questions. The 

NIAID Lyme disease research portfolio includes systematic studies on microbial physiology; 

molecular, genetic, and cellular mechanisms of pathogenesis; mechanisms of protective 

immunity; tick biology and ecology; tick/pathogen and tick/vertebrate host interactions

including the role of tick microbiome in pathogen development and influence on disease 

transmission; effect of co-infections with other tick-borne diseases; efficacy of different 

modes of antibiotic therapy; and development of more sensitive and reliable diagnostic tests 

for both early- and late-stage Lyme disease.

Additional information on NIAID-funded Lyme disease research and tick-borne disease

research is available on the NIAID Lyme disease website. Detailed information about NIH 

funding for Lyme disease research is available on the NIH Categorical Spending page, 

accessible from the NIH Research Portfolio Online Reporting Tools (RePORT) website. 

Project lists are available at the RePORT website that show funding amounts for each project 

and the NIH Institute or Center that has provided the support. These lists can be downloaded 

for further analysis. All funded extramural NIAID research projects are competitively awarded 

based on the NIH dual-level peer review process. The first level of peer review is conducted 

by a panel of scientific experts, and the second level of review by the NIAID Advisory 

Council before support is initiated. Research in the intramural program undergoes a rigorous, 

retrospective peer review process every four years by a Board of Scientific Counselors (BSC). 

The results of this review are used to determine future resource allocations. This process 

ensures that only highly meritorious science is supported. 

The following summary highlights current major areas of research in NIAID’s extramural and 

intramural Lyme disease research portfolio:

Fundamental Studies of Pathogen Biology 

NIAID supports multiple studies on the underlying biology of B. burgdorferi. This research 

helps scientists better understand how the pathogen infects the host, multiplies, survives, and 

ultimately causes human disease. An improved understanding of pathogen biology can lead to 

the identification of new targets for future diagnostics, therapeutics, and vaccines.

Examples of this research include: 

• A comprehensive analysis of B. burgdorferi surface proteins and their cellular 

counterparts that could help scientists understand how the bacteria interact with 

human cells and tissues, which may lead to new targets for vaccines.
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• Research on the proteins and cellular structures used by B. burgdorferi and 

related bacteria to travel through the body and affect multiple body sites. 

• Studies aimed at understanding the surface composition of B. burgdorferi at the 

biochemical and molecular levels, which may lead to novel ways of disrupting the 

interaction of the bacteria with the host or to novel vaccine/diagnostic targets for 

future testing. 

• Investigations into how B. burgdorferi obtains critical nutrients within its human host, 

and on how critical survival genes are regulated within the bacteria. 

• Research on the underlying genetics and proteins that enable the bacteria to adapt to 

the very different internal environment of ticks and humans, and to switch between 

them.

Studies on Persistence

NIAID also supports basic research projects to address key questions about why Lyme disease 

symptoms persist in some individuals, even after completion of treatment. In 2022, NIAID 

published a call for research to better understand persistent symptoms associated with Lyme 

disease (RFA-AI-22-046). Multiple awards under this opportunity were made in July 2023. 

RFA-AI-22-046 is supporting research on the following topics: 

• The bacterial genetic basis for persistence of Borrelia burgdorferi.

• Predictive markers for PTLDS. 

• The role of the unique cell wall of Borrelia burgdorferi in PTLDS. 

• The underlying mechanism of neurologic symptoms in PTLDS.

• Clinical, immunologic and metabolic factors that relate to symptom phenotypes in 

patients with PTLDS.

Other examples of research on persistence include: 

• Investigations into how the bacteria respond to antibiotic stress.

• Research on how B. burgdorferi may trigger persistent symptoms in the absence of living 

bacteria, such as autoimmune or chronic inflammatory responses to bacterial 

components. 

• Investigations of persistent infections using xenodiagnosis, a strategy that attaches live, 

disease-free, laboratory-bred ticks to people after they’ve completed antibiotic therapy, 

to see if B. burgdorferi can be detected in these ticks.

• Studies on the mechanisms behind Lyme arthritis, a late manifestation of untreated 
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Lyme disease. 

Studies on Human Immunity to Infection

The immune system attacks different pathogens through various mechanisms, and pathogens in 

turn have evolved ways to partially evade those defenses. NIAID supports several research 

projects to better understand the interplay between the human immune system and B.

burgdorferi as well as the mechanisms involved in pathogen evasion or control. These studies 

will provide insight into multiple areas of Lyme disease research including persistence of 

symptoms and potential new tools for combating or preventing disease. Some examples 

include: 

• Research on bacterial factors that enable B. burgdorferi to evade multiple components of 

the immune system, such as antibody responses and critical elements of the early, innate 

immune response. 

• Mechanisms of antigenic variation on the bacterial surface.

• Studies on how B. burgdorferi is cleared from the skin after infection.

Fundamental Studies of Tick Biology 

NIAID supports basic research on Ixodes scapularis and other ticks that transmit the pathogens 

that cause Lyme disease and other infections. Ongoing efforts include: 

• Research on tick feeding including identifying recent blood meals, which will shed 

light on the animal reservoirs responsible for maintaining B. burgdorferi in nature.

• Studies on the factors in tick saliva that affect transmission. These factors include 

proteins that block blood clotting and the pain response to a tick bite. This affects the 

skin immune response and may enhance the bacteria’s chance of infecting humans.

• Studies on how ticks find their hosts, as well as studies characterizing Borrelia

transmission and the possibility of interrupting the natural cycle of disease. 

• Research on tick immunobiology and the role of the tick microbiome to better 

understand how Ixodes ticks recognize and respond to pathogens such as Borrelia 

burgdorferi. 

Studies on Lyme Disease Diagnostic Testing

NIAID has long called attention to the need for improved Lyme disease diagnostics. 

Currently, no point-of-care diagnostic test is available that can detect early Lyme disease. 

Such a diagnostic would enable physicians to make more informed treatment decisions when a 

patient in a Lyme-endemic area presents with symptoms consistent with Lyme disease. NIAID

efforts towards developing improved diagnostics include: 

• Developing and testing a new cytokine-based immunoassay for Lyme diagnosis which, 

if successful, could allow for earlier and more rapid diagnosis of Lyme disease. 
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• Identifying and characterizing metabolic biomarkers and biosignatures for improved 

diagnostics. These studies may contribute to new methods for detecting Lyme disease, 

including diagnosis of early-stage disease, accurate staging of disease, or indications of 

successful treatment. For example, researchers are exploring ways to detect smallmolecule metabolites in urine of early-stage Lyme disease patients, which would be very 

helpful in the clinic since urine is an easily obtainable sample.

• Utilizing new approaches to develop rapid point-of-care Lyme diagnostic tests, such as 

lateral flow technologies.

• Developing multiplex qPCR assays to simultaneously detect Lyme disease and 

coinfections such as babesiosis. 

Studies on Lyme Vaccines

The first Lyme disease vaccine, LYMErix, was approved for use in humans in 1998, but was 

voluntarily withdrawn by the manufacturer in 2001 after reduced public demand. Since that time, 

the incidence and geographic distribution of Lyme disease has grown, and NIAID is currently 

supporting research to develop and evaluate new vaccine candidates for Lyme disease. In 2019, 

NIAID issued a Funding Opportunity Announcement focused on Tick-borne disease prevention 

(RFA-AI-19-037). Current research efforts, partially supported by RFA-AI-19-037, include: 

• Identifying B. burgdorferi antigens that could be used in next-generation Lyme 

disease vaccines.

• Studying the potential of a “chimerotope” vaccine, modeled after a recently 

approved canine vaccine for use in the veterinary field. 

• Pursuing novel vaccine formulations and targets, including proteins in tick saliva that 

are critical for the transmission of B. burgdorferi to humans. Such proteins may hold 

potential as antigens for “anti-tick” vaccines.

• Research on reservoir vaccines to reduce Lyme disease in humans. These oral “bait” 

vaccines are designed to prevent a known reservoir, deer mice, from becoming 

infected, thereby interrupting the transmission cycle. Some groups are field testing their 

products with support from the Centers for Disease Control and Prevention (CDC) as 

well.

Studies on Treatments for Lyme Disease

NIAID supports discovery and translational research efforts to identify and develop novel therapies 

that are specific to B. burgdorferi. While most cases of Lyme disease can be effectively treated 

with standard antibiotics, a more narrow-spectrum therapeutic agent could have the advantage of 

clearing the infection with less disruption of the patient’s microbiome. NIAID also recognizes the 

importance of identifying appropriate therapeutic options for those patients who continue to 

experience symptoms after antibiotic treatment. Current research efforts include: 

• Assessing activity of small-molecule inhibitors against cultured B. burgdorferi and 

characterizing the mechanism of action.
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• Preclinical testing of a novel selective antibiotic in a mouse model of infection.

• Assessing the ability of existing, approved antibiotics to kill B. burgdorferi.

• Characterizing essential genes and/or molecular pathways in B. burgdorferi as new 

potential drug targets. 

• Comparing the outcome of different treatment regimens for meningitis in the pediatric 

population. 

Clinical Studies

NIAID intramural scientists on the Bethesda, Maryland campus conduct research to advance 

scientific knowledge of Lyme disease and translate these advances into clinical practice. Patients 

with Lyme disease are studied at the NIH Clinical Center with the goals of ameliorating disease 

and improving prognosis, as well as increasing the understanding of the laboratory diagnosis, 

clinical manifestations, and human immune responses associated with B. burgdorferi infection. 

More than 700 volunteers have been evaluated within studies focused on: 

• Evaluation, treatment, and follow-up of Lyme disease patients to assess clinical course 

and outcomes and define immune responses to infection. 

• Identification of biomarkers of infection and development of new diagnostic tools.

• Investigation of potential causes of PTLDS.

• Exploration of potential persistence of infection after completion of antibiotic therapy for 

Lyme disease.

• Characterization of the immune response to tick bites in humans and the development of 

tick immunity. 

• Information about these and other studies can be found on ClinicalTrials.gov, a registry and 

results database of publicly and privately supported clinical studies. 

Recent NIAID Lyme Disease Scientific Advances

NIAID intramural scientists are involved in multiple basic and clinical research studies to 

advance our understanding of Lyme and other tick-borne diseases. NIAID continues to invest 

in research programs to increase the understanding of complex vector-host-pathogen 

interactions and their influence on Lyme disease, with the ultimate goal of identifying new 

targets for intervention. 

Some recently published findings of NIAID intramural researchers are summarized below. 
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• Can we better define post-treatment Lyme disease symptoms? 

There is no standardized approach to define PTLDS. NIAID intramural researchers, in 

collaboration with extramural investigators, characterized patients with and without posttreatment Lyme disease symptoms and used statistical modeling to categorize patients and 

quantify the severity of their symptoms. While it still requires some optimization, this tool 

can be used to improve research and clinical care for patients with symptoms after 

treatment of Lyme disease. 

• What are common characteristics of Lyme neuroborreliosis patients?

In a retrospective observational study, NIAID intramural researchers described the 

features and outcomes of patients with early neurological Lyme disease presenting with 

facial palsy. The investigators showed that most patients presented in the summer months 

and had erythema migrans, which was frequently associated with systemic symptoms. 

These are important clues in the patient’s history that help with early diagnosis. Most 

patients had an excellent recovery, and the recovery was similar for patients who received 

antibiotics alone or both antibiotics and corticosteroids. 

• What is the long-term prognosis for pediatric Lyme disease patients?

Together with investigators from Children’s National, NIAID intramural investigators 

characterized the long-term outcomes of pediatric Lyme disease patients in the 

Washington, DC area. This was a cross-sectional evaluation to assess parent- and patientreported outcomes. Most participants reported full resolution of symptoms, with the 

majority recovering within 6 months after completing antibiotic treatment. At the time of 

study completion, 6% of children still experienced symptoms attributed to Lyme disease 

and 1% experienced symptoms significant enough to impair daily functioning. This study 

supports previous data that the overall prognosis for children to make a complete recovery 

from Lyme disease is excellent. For the small number of children who do not experience 

full recovery, more research is needed to better define the course and pathogenesis of their 

prolonged symptoms, as well as novel targeted therapies to relieve their suffering. 

• Can we improve the tools we use to detect the bacteria that cause Lyme disease?

Together with investigators at Columbia University, intramural investigators helped

develop the TBD Capture Sequencing Assay (TBDCapSeq). The TBDCapSeq is a probebased capture assay targeting the eleven most common tick-borne agents found in the US. 

For B. burgdorferi and Babesia microti, the sensitivity of TBDCapSeq was comparable 

and occasionally exceeded the performance of agent-specific quantitative PCR and 

resulted in 25 to > 10,000-fold increase in pathogen reads when compared to unbiased 

high-throughput sequencing. The TBDCapSeq could have a major impact in studies of 

tick-borne pathogens by improving detection and facilitating genomic research that was 

previously unachievable with standard sequencing approaches. 

• How can we measure and monitor responses to treatment? 

Together with investigators at Tufts, NIAID intramural researchers showed that B.

burgdorferi can accumulate intact phospholipids from its environment, and that antibody 

responses to host phospholipids occur in mice and patients with acute Lyme disease. Serial 

samples during treatment and recovery showed a marked decline in antibody titers, 

suggesting that these antibodies may be of value in monitoring the response to treatment. 
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• Is xenodiagnosis a useful tool to detect whether B. burgdorferi can persist after 

treatment?

Whether B. burgdorferi can persist after antibiotic therapy is an area of ongoing debate. 

Studies in animals showed that B. burgdorferi DNA can be detected in tissues after 

antibiotic therapy and that xenodiagnostic ticks feeding can acquire the bacteria. To 

address this controversy, NIAID intramural scientists and researchers from Tufts and Yale 

University performed the first study in humans using xenodiagnosis with I. scapularis 

ticks to identify B. burgdorferi. The phase I study, published in 2014, showed the 

procedure was safe and well tolerated. A phase 2 xenodiagnosis study has been performed 

(see ClinicalTrials.gov identifier NCT02446626), in collaboration with Tufts University, 

New York Medical College, Mansfield Family Practice and Stony Brook University. Data 

from this study are currently being analyzed. 

 

• How can we accelerate fundamental research to enhance our understanding of B. 

burgdorferi biology?

Many components of the Lyme disease bacterium are unique and of unknown 

significance to pathogenesis. Targeted mutagenesis and complementation are important 

tools for studying genes of unknown function in the Lyme disease spirochete B. 

burgdorferi. Recently, a powerful new tool has been adapted to the study of spirochetes, 

allowing visualization of living cells. With this work, researchers have developed vital 

new tools for molecular genetic investigations in B. burgdorferi. This will enable the 

identification and characterization of essential genes and pathways in B. burgdorferi,

which could become future targets for novel drugs and vaccines. 

• How can we prevent infection?

NIAID intramural researchers are also interested in the potential promise of an ‘anti-tick’ 

vaccine. Recruitment recently began for a clinical research protocol to study the human 

immune response to tick bites, with the ultimate goal of identifying potential vaccine 

targets (see ClinicalTrials.gov identifier NCT05036707). While still in the early 

preclinical research stage, this approach potentially offers a novel strategy to prevent 

Lyme disease and other tick-borne illnesses. 

NIAID also supports extramural scientists who are investigating multiple aspects of Lyme 

disease. This includes basic, translational, and clinical studies. Some of the most recent 

research is described here, highlighting the diversity of studies funded. 

• Why are different species of Borrelia associated with different symptoms?

Different species of Borrelia colonize different tissues and cause distinct manifestations of 

Lyme disease. For example, B. burgdorferi is associated with arthritis, while late-stage 

infections with B. afzelii and B. garinii commonly involve dermatologic and neurologic 

symptoms, respectively. There are several proteins on the surface of Borrelia that allow 

them to stick to host cells and tissues, and it is thought that variation in these outer surface 

proteins may account for the differences seen between species. One protein that varies 

significantly between different species is OspC. NIAID-supported researchers found that 
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different OspC proteins bind different components of the extracellular matrix, which is a 

network of molecules that line the tissues of the body. They found that different OspC 

variants promote the infection of distinct tissues in a mouse model of Lyme disease. This 

work highlights the importance of the OspC protein in determining which specific 

symptoms are associated with infection by different Borrelia species. 

• Can biochemical differences be detected in patients with early and post-treatment 

Lyme disease symptoms? 

Molecular-level changes that occur during infection can be detected in patient blood. To 

better understand these changes, NIAID-supported investigators completed a 

comprehensive analysis to identify biochemical differences in the blood of patients with 

early localized Lyme disease and early disseminated Lyme disease, compared to healthy 

individuals. Their findings provided insights into specific molecular pathways that are 

affected by B. burgdorferi infection. Work from the same group used a similar 

methodology to identify metabolites that can distinguish patients with post-treatment 

Lyme disease symptoms from clinically cured patients over time. Studies like these 

provide important insights into the pathogenesis of Lyme disease. Further, the 

identification of biomarkers unique to different stages of disease could provide the basis 

for diagnostics that can inform patient treatment. 

• How do Borrelia and other spirochetes achieve their unique ‘corkscrew’ swimming 

movements?

Many bacteria move using external flagella, thread-like structures that move to propel the 

bacterium forward. Borrelia bacteria are classified as spirochetes, which have a distinctive 

spiral shape. Interestingly, while spirochetes have flagella, they are located internally 

beneath the outer cell membrane, and anchored on either end of the bacterium. Molecular 

motors coordinate the rotation of these internal flagella, allowing the spirochetes to move 

forward in a corkscrew-like fashion. Many research efforts have attempted to characterize 

the molecular mechanisms underlying this unique motility. For example, a recent NIAIDsupported study used a combination of genetics and powerful imaging techniques to 

characterize some of the components of the motor, shedding light on the assembly and 

function of this unique molecular structure. 

• What can we learn about Lyme disease transmission from studying I. scapularis

immune pathways? 

If we can understand how a tick’s immune system works, we may be able to harness it 

against Borrelia burgdorferi and control bacterial transmission to the vertebrate hosts. In 

this publication, the authors established that a mammalian immune molecule called 

interferon gamma, when ingested by ticks in the bloodmeal, not only triggers the tick 

immune response but also is crucial for tick metamorphosis and organ development. This 

interaction is controlled by a tick receptor called Dome1. By understanding how Dome1 

regulates tick immunity and developmental processes, it could be targeted to inhibit or 

block these essential tick pathways.

• How do molecular components of the tick gut impact tick biology and B. burgdorferi

transmission?

After being taken up by a tick during a blood meal, B. burgdorferi spends most of its time 
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in the tick gut. The bacterium has evolved to survive in this environment, including 

interacting with the thick, mucus-like layer called the peritrophic membrane (PM), which 

helps protect the cells lining the gut. NIAID-supported investigators identified a protein, 

PM_CBP, which is essential to the integrity of this barrier. They showed that immunizing 

ticks with antibodies against PM_CBP could substantially reduce both acquisition of B. 

burgdorferi by the tick, and transmission of the bacteria from ticks to mice. The data 

suggested that the anti-PM_CBP antibodies disrupt the peritrophic membrane, suggesting 

that this may expose the bacteria to a more hostile environment within the tick gut. A 

second NIAID-supported study from the same research group showed that antibodies 

against another tick gut protein reduced B. burgdorferi survival in the tick. Such studies 

help further our fundamental understanding of tick biology and tick-pathogen interactions. 

They could also ultimately inform novel strategies, such as anti-tick vaccines, to prevent 

the spread of Lyme disease and other tick-borne illnesses. 

• Can we identify an antibiotic that selectively kills Borrelia? 

While standard antibiotics can effectively treat most Lyme disease cases, they also disrupt 

the microbiome, which is important to maintaining human health and immunity. A drug 

that specifically kills Lyme-causing bacteria without affecting the microbiome would be 

ideal. In work that was partially supported by NIAID, researchers screened soil-dwelling 

bacteria that produce compounds with antibacterial properties. They were able to identify 

and purify a compound that was potently active against Borrelia burgdorferi and related 

bacterial species, but not against most other bacteria including those commonly found in 

the gut microbiome. This work and other NIAID-supported efforts have the potential to 

improve the available treatment options for patients suffering from Lyme disease. 

• Could a vaccine provide resistance to tick bites?

Some animals that are repeatedly exposed to tick bites develop ‘resistance’ in the form of 

an inflammatory immune response at the site of the tick bite that impacts tick feeding and 

attachment. Based on this observation, NIAID-supported researchers developed an 

mRNA-based vaccine designed to deliver a cocktail of 19 antigens that are found in tick 

saliva. When uninfected ticks were allowed to feed on immunized guinea pigs, they 

exhibited severely impaired feeding, and began to detach after 48 hours. In a second 

experiment using B. burgdorferi infected ticks, the researchers found that the vaccine also 

protected the animals from B. burgdorferi transmission. 

• Could persistent pieces of the bacteria be the cause of PTLDS in some people?

Lyme disease is generally responsive to antibiotic therapy. However, a subset of patients 

reports a wide range of symptoms that continue for months to years after treatment. Using 

a mouse model of Lyme disease, NIAID-supported researchers found that infectious 

bacteria are rapidly eliminated after antibiotic treatment, but that inflammatory, 

immunogenic antigens can persist near cartilage after treatment and might contribute to 

persistent symptoms. 

• Could PTLDS in some people be caused by an autoimmune or inflammatory 

response?

While Lyme arthritis can develop in individuals that did not receive antibiotic treatment for 

their infections, it can also develop in individuals that were treated with antibiotics. One 
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hypothesis is that post-treatment Lyme disease symptoms are caused by autoimmune and/or 

inflammatory responses that continue even after the infection is cleared. NIAID-funded 

researchers characterized patients with post-infectious Lyme arthritis who had various 

systemic autoimmune joint diseases that developed after antibiotic treatment. They reported 

that patient symptoms improved upon treatment with anti-inflammatory therapies. The 

same research group also performed RNA sequencing of joint tissue in post-infectious 

Lyme arthritis patients and found that they had increased markers of inflammation, and

decreased expression of genes involved in tissue repair. This result suggested that the 

immune response in these patients may prevent appropriate tissue repair and maintenance 

long after completion of antibiotic treatment and clearance of active infection. 

• How does coinfection with other tick-borne infections impact pathogenesis? 

Babesia microti is a parasite transmitted by the same tick species that transmits 

Borrelia burgdorferi, and people can become infected with the two pathogens at the 

same time. Recently, researchers used a mouse model of the two infections to 

investigate how each pathogen influences the other. They showed that infection with 

the B. microti parasite enhanced the severity of Lyme disease-like symptoms in the 

mice, while B. burgdorferi appeared to limit the growth and effects of B. microti. 

• How does B. burgdorferi change as it moves between mammal and tick?

Transmission of B. burgdorferi between the tick vector and a mammalian host requires the 

bacterium to sense and adapt to these distinct environments. NIAID-supported 

investigators have recently isolated and purified the biochemical machinery involved in 

RNA transcription. This led to the development of a new research tool that will facilitate 

studies of B. burgdorferi gene expression to better understand this important process. 

Certain proteins in the bacterium act as ‘dimmer switches,’ controlling the extent to which 

different genes are ‘turned on’ (i.e., transcribed and made into protein) in response to 

various environmental cues. Researchers are working to identify these regulatory proteins 

and characterize their functions. For example, multiple recent studies have explored the 

role of the regulatory protein DksA in enabling Borrelia to adapt to the mammalian host. 

One group characterized which genes were up- or down-regulated by DksA. A second 

study more specifically defined the interactions between DkSa and other proteins using a 

biochemical system. The research groups characterized environmental stressors, including 

acidity and high-salt content, that DksA responds to. Both studies also demonstrated that 

DksA is essential to the ability of B. burgdorferi to infect mice. 

• Can Borrelia colonize the central nervous system? 

Lyme disease can lead to various neurologic symptoms, including central nervous system 

manifestations. Using a mouse model of infection, NIAID-supported researchers recently 

demonstrated that several Borrelia species can colonize the dura mater—the thick outer 

membrane that covers the brain and spinal cord. Colonization of the dura mater was 

associated with a local inflammatory immune response. Interestingly, an inflammatory 

response was also observed inside the brain, even though the bacteria themselves were not 

able to infiltrate beyond the dura mater. These responses may contribute to the various 

pathologies observed in Lyme disease patients. 

• Could studying non-immune biomarkers be the key to developing a reliable 
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diagnostic for early Lyme disease?

Currently available diagnostics focus on detecting immune system response to Borrelia 

species, but a group of NIAID-funded scientists recently tried a different approach. These 

scientists were able to identify 45 biomarkers the distinguished individuals with early 

Lyme disease from endemic and nonendemic controls. The 45 biomarkers are all linked to 

metabolic processes that are known to be altered during Lyme disease. In the future, the 

group will evaluate whether the identified biomarkers can distinguish between patients 

with Lyme disease and those with diseases that have similar clinical presentations to Lyme 

disease.

• Could biomarkers for Lyme disease provide the basis for a rapid point-of-care test?

Rapid, sensitive diagnostics for Lyme disease are needed. Recent work by both NIAID 

intramural investigators and extramurally-supported researchers aims to develop a pointof-care test. The researchers first screened a set of known Lyme disease biomarkers for 

their ability to indicate infection. They then tested for the top three biomarkers in samples 

from people with early Lyme disease, from healthy individuals from areas where Lyme 

disease is endemic, and from people with Lyme arthritis. These data were compared to 

results obtained using the standard two-step testing procedure. Overall, the new set of 

biomarkers was more sensitive than standard Lyme disease tests. While the assay will 

require more refinement and testing, these promising results open the possibility of 

developing a point-of-care test. 

• Are monoclonal antibodies an effective prevention strategy for Lyme disease? 

Monoclonal antibodies are a promising preventative strategy for many infectious diseases. 

However, one challenge for their use as a prophylaxis against Lyme disease is that the 

antibodies would need to remain in circulation at high enough levels to provide protection 

for the entire tick season (a 6- to 8-month window). The Borrelia outer surface protein A 

(OspA) antigen is known to induce an effective immune response against Lyme disease. 

Along with the Department of Defense Tick-Borne Disease Research Program, NIAID 

provided support for a study which demonstrated that antibodies modified for increased 

stability had a longer half-life in non-human primates, and that administering the 

monoclonal antibody effectively protected the primates from infection. Based on this 

preclinical work, researchers conducted a Phase 1 clinical trial to assess the safety and 

blood levels of the modified antibody, sponsored by MassBiologics of UMass Medical 

School. Data from this study are currently being analyzed. 

NIH Collaborations with Other Federal Agencies and External Organizations 

NIH participates in the Department of Health and Human Services (HHS) Tick Borne Disease 

Partners along with representatives from the Office of the Secretary of HHS, CDC, and the 

Food and Drug Administration (FDA) to facilitate coordination and planning among 

participating agencies. The group convenes twice a year to review the state of the science in 

Lyme disease research and has conducted public webinars over the past few years to brief the 

scientific and patient communities on topics of interest, including the state of diagnostics, the 

persistence of infection in animal model systems, emerging ticks and tick-borne pathogens, as 

well as vaccine research and development efforts.
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NIAID actively participated in the HHS Tick Borne Diseases Working Group, which was 

established by Congress in 2016 as part of the 21st Century Cures Act to help ensure 

interagency coordination. The final report to Congress was submitted in February 2023. 

NIAID is also currently collaborating with the CDC and other HHS agencies in the 

development of the National Vector-borne Disease Strategy as mandated in the Kay Hagan 

Tick Act. In addition, the Institute is a collaborator in the HHS LymeX Innovation 

Accelerator. 

NIH is partnering with the CDC, FDA, university researchers, and industry to develop improved 

diagnostics using the CDC Lyme disease serum repository for new and existing assay 

validation. The repository contains serum from Lyme disease patients and other disease 

etiologies that can be used as positive and negative controls. NIH provided support for the 

development of the repository. 

Funding Opportunities and Research Resources

NIAID maintains several websites to inform the research community about current grant 

opportunities and contract solicitations. In 2022, NIAID’s Division of Microbiology and 

Infectious Diseases published RFA-AI-22-046, ‘Understanding Persistent Signs and 

Symptoms Attributed to Post-Treatment Lyme Disease (RO1 Clinical Trial Not Allowed).’ 

Applications received in response to the RFA will be reviewed in March 2023, with selected 

applications to be funded later in fiscal year 2023. 

In addition, NIAID has a comprehensive set of product development services and research 

tools and technologies to facilitate development and evaluation of vaccines, diagnostics, and 

therapeutics. These resources for researchers make critical data, expertise, standardized 

research materials, and state-of-the-art technologies available to eligible investigators 

worldwide at no charge. The purpose of these resources is to lower the financial risk to product 

developers by providing limited, but critical, information to fill specific gaps in the product 

development pipeline. Currently, NIAID is utilizing its preclinical resources to develop an 

improved methodology for culturing B. burgdorferi, which grows slowly and is very difficult to 

culture, particularly from patient samples. By developing better ways to grow the bacteria, 

NIAID hopes to enable faster and more efficient laboratory research on the pathogen. 

Future Plans/Directions 

NIAID’s Lyme disease research portfolio will continue to encompass basic, translational, and 

clinical research studies, as well as studies on the tick vector and tick/pathogen interactions.

NIAID’s Strategic Plan for Tickborne Disease Research will guide the focus of ongoing and 

future research efforts. Priority areas will include fundamental research on the biology and 

pathogenesis of B. burgdorferi and its interactions with the tick vector, as well as translational 

research efforts aimed at advancing better detection and diagnostics, developing novel vaccines 

and other prevention strategies, and improving treatment for Lyme disease. Research on 

treatments for Lyme disease will incorporate efforts to assess new therapeutic strategies, and 

NIAID will also continue to focus on the development of tools and resources for researchers to

accelerate research efforts.