Baiting Mice to Beat Lyme Disease

Ticks can tap into people's deepest fears and suck the joy out of a summer day. Every tick bite comes with a list of questions. Was the tick carrying Borrelia burgdorferi, the causative agent of Lyme disease? And, if so, will the infection be spotted and treated in time or lead to costly long-term health problems? These questions are not easily answered, and there is currently no human vaccine to protect against Lyme disease. But the expanding geographical habitats of ticks and corresponding increase in Lyme disease burden mean the need for strategies that control the spread of disease is more pressing than ever. One such strategy targets a central player in the chain of transmission: mice.

Blacklegged Ticks and White-Footed Mice

Lyme disease is the most common tick-borne disease affecting humans in North America and Europe, resulting in and costs every year. While the disease can mostly be treated with antibiotics, if it is not diagnosed quickly, it may lead to severe disease with long-term health problems involving the heart, joints and nervous system.

Blacklegged (Ixodes) ticks are the primary disease vectors for B. burgdorferi spirochaetes. Ticks acquire B. burgdorferi when they feed on mammals that carry the bacterium in their blood. After hatching, ticks go through larval and nymph stages until they reach the adult form after about 2-3 years. Both larvae and nymphs can become infected with bacteria while feeding on an infected host. The bacteria are then transferred to the next life stage and can be spread by a nymph or adult female tick the next time they draw blood.

A diagram of ticks at various life stages and their sizes relative to a U.S. dime. — Blacklegged ticks are the primary vectors for *B. burgdorferi*, with nymphs being the main vector for humans.
Source: Centers for Disease Control and Prevention/Wikimedia Commons, Public Domain

While the bacteria infect a variety of animals, small rodents—specifically white-footed mice (Peromyscus leucopus) in North America and bank voles (Myodes glareolus) and Apodemus mice in Europe—are primary reservoirs. Reducing infection in mice could, therefore, significantly decrease the number of infected ticks (specifically nymphs, the main vector for humans) and be a game-changing ecological intervention to keep B. burgdorferi—and Lyme disease—in check.

Bait Boxes for Rodents: Breaking the B. burgdorferi Transmission Cycle

With that in mind, scientists are developing targeted strategies to minimize B. burgdorferi infections in mice, including topically treating animals with tick-targeting chemicals or baiting them with edible pellets containing pesticides, antibiotics or vaccines. Because white-footed mice tend to stay within a defined area of 0.1-1 hectares (0.25-2.5 acres), strategic placement of bait stations can target most mice living within that area on a residential property.

Bait-Boxes With Topical Acaricides

involves luring animals into a bait box where they either brush their fur against acaricide-treated surfaces or pick up treated nesting material.

Topically applied acaricides, like permethrin or fipronil, kill ticks attached to or attempting to attach to a rodent by targeting the insects’ nervous system or other vital functions. Once applied to mice, permethrin remains biologically active on the host for about 3-4 weeks, while fipronil has a longer residual activity of 4-6 weeks.

A white-footed mouse. — Acaricides applied to the fur of white-footed mice kills ticks attached or attempting to attach to the rodents.
Source: Charles Homler/Wikimedia Commons via a CC BY-SA 3.0 license

The overall advantage of acaricides is that they can limit the number of larvae and nymphs completing their blood meal on the target rodent, decrease the prevalence of ticks and rodents harboring B. burgdorferi and reduce the number of host-seeking (questing) ticks more broadly. Because there are fewer ticks that can reproduce, the population of new nymphs—key spreaders of B. burgdorferi—will be reduced in the next life cycle.

One commercial product () uses cotton-based permethrin for nesting material. A study in a wooded residential environment demonstrated that, compared to control (untreated) areas, the product resulted in at 1 and 2 years post-intervention, respectively. In the same study, another system ()—in which a treated wick is placed in a bait box, transferring acaricide to mice as they enter the box—achieved 84% and 79.1% control of host-seeking nymphs after 1 and 2 years, respectively.

Food-Bait Laced With Acaricides, Antibiotics or Vaccines

Another approach involves integrating directly into mouse food-bait.

Food-Bait With Acaricides

Orally delivered acaricides are commonly used in dogs, but not commercially available for use in rodents. presented to white-footed mice indicated that the low dose application of fipronil could effectively control blacklegged tick larvae. The larvae were manually applied to treated and untreated mice, then collected after detaching from the mice. The fipronil provided 100% control of larvae that tried to attach up to 15 days post-treatment. Larvae on treated mice cannot feed to repletion or detach and eventually die.

Diagram of effects of acaricide food bait. — White-footed mice are key reservoirs of pathogens like *B. burgdorferi*, which can be passed to ticks during feeding. Food-bait containing acaricides, like fipronil, can disrupt transmission of the bacteria. (Click image for a larger view.)
Source: Poche D.M., et al./*Parasites & Vectors*, 2020 via a CC BY 4.0 International license

The efficacy of oral acaricides can decline over time, as drug levels in the rodent host decrease. (deer mice) were offered peanut butter bait laced with 2 different concentrations of fluralaner (another oral acaricide), and then larvae of blacklegged ticks were placed on the mice. On day 2 post-feeding, 97% and 94% of the ticks were killed in the 50 mg/kg and 12.5 mg/kg fluralener groups. On day 28, the efficacy was only at 3% and 4%, respectively. More research is needed to understand how to overcome this limitation.

Food-Bait With Antibiotics

Orally delivered antibiotics (e.g., doxycycline) administered through rodent bait stations can directly suppress the growth of B. burgdorferi in the mouse reservoir. showed no B. burgdorferi infection in 102 small mammals administered doxycycline, and a 10-fold reduction in infection prevalence of questing nymphs.

However, there are concerns regarding the development of broad-spectrum antibiotic resistance to doxycycline when used long-term in the environment. Other studies have used hygromycin A, which is highly selective against spirochetes like B. burgdorferi and may be a promising alternative. , the drug cleared B. burgdorferi infections in Mus musculus (house mice) as well as white-footed mice and was as effective as doxycycline. In contrast to other clinically used antibiotics, it was less disruptive to the animals’ fecal microbiome. However, regulatory and ecological concerns about deploying an antibiotic in the wild remain.

Food-Bait With Vaccines

Anti-Borrelia vaccines reduce the transmission of Borrelia to ticks. , using Escherichia coli as a delivery system. Vaccines have been developed for human and animal use, but was withdrawn due to autoimmune safety concerns and challenges with false positive diagnostic tests. Currently, a rodent-targeted OspA vaccine presented in food-bait () is available on the market.

When a tick feeds on a vaccinated animal, the antibodies generated by the vaccine enter the tick and bind to the OspA on the bacteria’s surface, preventing the bacteria from attaching to the tick’s midgut cells and moving to the salivary glands. This stops transmission when the tick feeds again. On the host side, while a vaccinated animal can still become infected, the infection will be suppressed by the antibodies.

Diagram depicting bacteria in a tick gut. — *B. burgdorferi* expresses several proteins on its surface that enable colonization of the tick gut, including OspA. Vaccines target this protein to disrupt colonization and transmission. (Click image for a larger view.)
Source: Strnad, M., et al./*Virulence*, 2023 via a CC By 4.0 International license

Lab and field studies with OspA vaccine baits have shown proof-of-concept that vaccinated mice reduce transmission of B. burgdorferi to ticks. Based on , interventions with rodent-targeting-vaccines (RTVs) reduced prevalence of infected ticks by 23-76% at 2 and 5 years, respectively. The protective antibody levels in the mouse population of the same study ranged from 10-33%. The long timeframe was chosen because the 2-year enzootic cycle of B. burgdorferi could only be disrupted if the field sites were treated for at least 3 years.

demonstrated a statistically significant reduction in infected mice on the residential properties that participated in the study. The researchers also investigated the best presentation and formulation for the food-bait to maximize the uptake of the deployed vaccine.

Indeed, the pellets used in LymeShield, for instance, have "" to minimize attraction of non-target animals. According to U.S. Biologic, the company that produces LymeShield, ~80% of mice in field trials of bait availability. A single bait-unit (approximately 2,000 m²) with annual ongoing of around $500.

Challenges on the Road to Rodent-Targeted Lyme Prevention

The global increase in Lyme disease burden and first studies on the effects of RTVs suggest that this approach could provide a solution for controlling disease on residential properties. But the move from traditional vaccines, designed to protect individual organisms, to vaccines that function in an environmental context also brings several challenges.

For one, RTVs are deployed in different ecological settings with various human and non-human populations. The behavior of these different populations and their interactions, socioeconomic factors and environmental concerns will play a considerable role in the success of these interventions. Mouse and tick populations can also vary from location to location and season to season; food bait could attract more than mice, or no mice at all.

There’s also a cost component. Residents might find the commercial products too expensive, and while the collaboration within a neighborhood is likely to yield the best results, people might not work together or be able to afford to shield their communal areas. While to implement Lyme disease interventions at community scale (e.g., surveillance, academic-public health collaborations, trials of control measures), most of them are still in pilot mode, or have been partially adopted. There is no systematic large-scale deployment of new tools like reservoir vaccines or mouse-targeted acaricides.

Environmental concerns play a role in evaluating the benefit of bait-based interventions, too. Field trials must prove safety for humans and other species in the affected area and demonstrate efficacy in different settings. The results are then subjected to regulatory requirements, which still vary across countries and need harmonization.

The Bottom Line

Despite the challenges, the growing global health burden of Lyme disease and the increasing cost for health systems propel the search for new solutions. New approaches in the pipeline—like targeting mice through specially designed baits—could shift Lyme disease prevention from reactive treatment to ecological control. Interventions that disrupt the enzootic cycle of Lyme disease plug into One Health frameworks integrating human, animal and ecosystem health, while underscoring the growing interest and need for public investment and international collaboration.

Learn more about research pertaining to the prevention, treatment and diagnosis of Lyme disease in this episode of Meet the Microbiologist featuring Linden Hu, M.D.