Human Immune Response to Ixodes Scapularis Tick Bites
- Conditions
- Tick ResistanceTick-borne DiseasesLyme Disease
- Interventions
- Device: Xenodiagnosis TicksProcedure: skin biopsyProcedure: blood draw
- Registration Number
- NCT05036707
- Brief Summary
Background:
Each year, the number of cases of tick-borne diseases increases. The deer tick (Ixodes scapularis) is the vector of at least 7 pathogens that cause human diseases, including Lyme disease. Researchers want to learn more to help them develop vaccines against ticks in the future.
Objective:
To learn how people s bodies, particularly the skin, respond to tick bites.
Eligibility:
Healthy adults aged 18 years and older who have no known history of a tick-borne disease or tick bite exposure.
Design:
Participants will be screened with a medical history, physical exam, and blood tests.
Participants will have 2 skin punch biopsies of healthy skin. For this, a sharp instrument will be used to remove a round plug of skin about the size of a pencil eraser. Participants will then have 10 clean laboratory-bred ticks placed at 2 different sites on their skin (20 ticks total). The ticks will be removed from the first site 1 day after placement and from the second site 2-4 days after placement. Participants will complete symptom diary cards. They will answer questions about itching at the tick feeding sites. They will give blood samples. Photos will be taken of the tick feeding sites. Skin punch biopsies will be collected at the sites of the tick bites.
Participants will repeat the tick feeding procedures 2 times, each 2-8 weeks apart. For the 2nd and 3rd procedures, 10 clean laboratory-bred ticks will be placed at 1 site. The ticks will be removed 2-3 days after tick placement. They will have telephone follow-up visits after each procedure.
After the final tick removal, participants will have follow-up visits in 4-6 weeks and again in 3 months. They will give blood samples and discuss how they are feeling.
Participation will last about 5-7 months.
- Detailed Description
Study Description:
This study aims to develop a model for acquired tick resistance in humans, characterize the acquisition of tick-associated skin immunity, and monitor the innate and adaptive immune response of Ixodes scapularis tick bites. The study will be a prospective, non-randomized, single-center study performed at the National Institutes of Health (NIH) Clinical Center. It will be performed under Investigational Device Exemption (IDE) G210153, and will be monitored as per National Institute of Allergy and Infectious Diseases (NIAID) and NIH regulations. Participants (35 adult healthy volunteers) will undergo up to 3 tick feeding placements, 2 to 8 weeks
apart. One to two punch skin biopsies (2-3 mm) from the tick bite sites will be collected at 1 day (early) and 2-4 days (late) after the first tick placement procedure. Skin biopsies of an unaffected site will be performed as a control. One to two punch skin biopsies (2-3 mm) from the tick bite sites will be collected at day 2-3 after the 2nd and 3rd tick placement procedures. Additionally, blood will be collected to evaluate systemic immune response to tick salivary proteins. Ticks will also be collected at each timepoint and gene expression will be analyzed to determine the effect of the human skin response on ticks.
Changes in resistance to tick bites can be evaluated by:
* Local reaction to the tick bite
* pruritus
* site reactions
* Blood flow index as measured by laser speckle contrast imaging
* Number of fed ticks
Changes in the immune response and cellular recruitment in the skin can be evaluated using:
Differential expression of immune transcripts and other skin associated transcripts using RNAseq or other high-throughput profiling of cells
Conventional histology and immunohistochemistry
Digital Spatial Profiling to determine cell type and other immune markers using a high-plex platform
Changes in the systemic immune response will be evaluated by:
Measurement of antibodies against tick salivary proteins will be assessed by enzyme-linked immunosorbent assay (ELISA) and
western blot
Novel state-of-the-art high resolution technologies to deeply characterize the immune response to tick bites over time, both phenotypically and functionally.
Changes in tick transcriptomic profile will be assessed by:
RNAseq: Ribonucleic acid (RNA) will be isolated from tick after they have been removed from subjects and unexposed ticks.
Differential expression profile will be performed and validated by NanoString
Objectives:
Primary Objectives:
1. Develop a model of acquired tick resistance in humans
2. Continue to assess the safety of tick feeding using laboratory-reared Ixodes scapularis larva in humans
Exploratory Objectives:
1. Comparison of the early and late immune response in the skin site of the bite of Ixodes scapularis after a single tick exposure.
2. Determine the effects of repeated tick feeding on the immune response at the tick bite site in human skin and development of tick resistance.
3. Analyze the evolution of the systemic immune response to tick bite in participants after multiple tick exposures and validate development of reliable biomarkers of tick exposure.
4. Analyze gene expression of Ixodes scapularis larvae feeding on humans and determine the effects of immune response of subjects
repeatedly bitten on larvae gene expression.
Endpoints:
Primary Endpoints:
1. Pruritus at the site of tick attachment in the first 24 hours of tick placement over the three placements as measured by a positive slope
over the three placements of the numerical rating score. The slope of other pruritus scores at 24 hours and at Day 2-4, and the number of attached ticks collected from participants over the three placements will also be measured.
2. Monitor safety adverse events (AEs) using reporting tools and Sponsor safety monitors.
Exploratory Endpoints:
1. Compare the results from the skin biopsies acquired with the first tick placement. Our hypothesis is that there will be differential phenotypic, transcriptomic, and immunohistochemical differences between:
* Exposed (bitten skin at day 1) and unexposed (unbitten skin)
* Exposed (bitten skin at day 2-4) and unexposed (unbitten skin)
* Exposed (bitten skin at day 1) and exposed (bitten skin at day 2-4)
Measurement of changes will be assessed by:
* Differential expression of immune transcripts and other skin associated transcripts using RNAseq
* Conventional histology and immunohistochemistry
* Digital Spatial Profiling to determine cell type and other immune markers using a high-plex platform
2. Compare the changes in the local immune response and cellular recruitment between the 1st, 2nd and the 3rd tick exposures and correlate with measures of itching, blood flow index and number of attached ticks and the feeding status.
We postulate that differences between the timepoints will become more marked with multiple exposures. We hypothesize that there will be differential phenotypic and transcriptomic differences between:
Exposed (bitten skin at day 2-3, exposure 2) and exposed (bitten skin at day 2-3, exposure 3)
Correlate these changes with measures of resistance to tick feeding (itching, number and level of feeding of attached ticks, blood flow index).
3. Compare the development of antibody responses against Ixodes scapularis salivary protein antigens between the 1st, 2nd, and the 3rd tick exposures and correlate antibodies against tick salivary proteins with measures of resistance (itching, erythema, blood flow index, number of fed ticks).
Explore the development of the host response in blood using high resolution technologies such as immunophenotyping, proteomics and
transcriptomics and compare the responses between the 1st, 2nd, and the 3rd tick exposures.
4. Using RNAseq technology, measure changes in gene expression of ticks fed at early timepoint (1 day) vs late timepoint (2-4 days) vs unfed ticks and of ticks fed at 1st, 2nd, and 3rd placements. Correlation of pruritus and changes in tick gene expression.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 60
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description 1 skin biopsy Healthy Volunteer 1 blood draw Healthy Volunteer 1 Xenodiagnosis Ticks Healthy Volunteer
- Primary Outcome Measures
Name Time Method Assessment of Safety of the device. Use toxicity tables and safety monitoring as specified in the protocol. continuous Ongoing assessment of safety.
Develop a model of acquired tick resistance in humans. Use validated pruritus scales, numerical rating system, verbal rating system, and visual analogue system. end of study Clinical measures of tick immunity.
- Secondary Outcome Measures
Name Time Method Exploratory: Analyze gene expression of Ixodes scapularis after feeding on humans using RNASeq. continuous Measure changes in gene expression of ticks fed at the various time points.
Exploratory: Determine the effects of repeated tick feeding on immune response at tick bite site and the development of resistance. Use RNASeq,histology, immunohistochemistry, digital spatial profiling, clinical itch scales, site reactions, tick... continuous Compare changes in early and late local immune response and cellular recruitment between the 1st and 3rd tick exposures.
Exploratory: Compare early and late immune response in skin after Ixodes scapularis bite. Use RNASeq, histology, immunohistochemistry, digital spatial profiling to explore. continuous Compare early and late immune response in the skin using skin biopsies collected at Day 1 and Day 4.
Exploratory: Analyze the evolution of the systemic immune response to tick bite by measuring antibodies response (ELISA and western blot) against Ixodes scapularis salivary protein antigens. continous Compare the development of antibody responses against Ixodes scapularis salivary antigens between the 1st, 2nd, and 3rd tick feedings.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States