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Characterization of Skin Immunity to Aedes Aegypti Saliva in Dengue-endemic Participants in Cambodia

Primary Purpose

Vector Borne Diseases

Status

Completed

Phase

Phase 1

Locations

Cambodia

Study Type

Interventional

Intervention

Mosquito Feeding

About this trial

This is an interventional basic science trial for Vector Borne Diseases focused on measuring Vector-Borne Diseases, Immune Response, Mosquito Feeding, Arbovirus, Southeast Asia

Eligibility Criteria

18 Years - 45 Years (Adult)All SexesDoes not accept healthy volunteers

INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

-Provision of signed and dated informed consent form

Stated willingness to comply with all study procedures and availability for the duration of the study
Male or female, aged 18 - 45 years
Live within approximately 15 km of study site
In good general health as evidenced by medical history
Willing to allow biological samples to be stored for future research.
A female is eligible for this study if she meets 1 of the following:
- Of non-childbearing potential (i.e., women who have had a hysterectomy or tubal

ligation or are postmenopausal, as defined by no menses in >=1 year).

--Of childbearing potential but has negative urine pregnancy test on Day 0

Agrees to not use scented lotions, deodorants, or topical creams on each feeding day.
Agrees to not take aspirin or any other NSAID (ex. ibuprofen) within 7 days of a biopsy.
Agrees to not use oral or topical antihistamines or steroid creams or ointments throughout the

study without prior permission of Principal Investigator (PI).

EXCLUSION CRITERIA:

-Any underlying or current medical condition that, in the opinion of the investigator, would

interfere with participation in the study.

-History of severe allergic reaction (including to mosquito or other insect bites) with generalized

urticaria, angioedema, anaphylaxis, anaphylactoid reaction or any other reaction described by

the participant and deemed severe by the PI.

Self-reported or known history of alcoholism or drug abuse within 6 months prior to enrollment
Self-reported or known history of psychiatric or psychological issues that require treatment and

are deemed by the PI to be a contraindication to protocol participation.

-Any use of medications that affect blood clotting within 3 months or history of abnormal blood

clotting

-History of significant scarring such as keloids after previous biopsies, lacerations, abrasions,

surgeries, or other skin procedures (e.g., cosmetic piercings) that are deemed by the PI to be a

contraindication to protocol participation.

-Pregnant or breastfeeding.

Sites / Locations

Kampong Speu Referral Hoispital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Mosquito Feeding

Arm Description

Each participant will receive one mosquito feeding with 5 starved female Aedes aegypti mosquitoes.

Outcomes

Primary Outcome Measures

Measurement of Change in Early and Late Innate Immune Responses Using Gene Expression and Flow Cytometry in Participants' Skin

Measurement of changes in the early and late innate immune response and cellular recruitment in bitten skin versus unbitten skin by: a) immunohistochemistry of target proteins at Day 0 timepoints b) immunophenotyping of innate immune cell subsets in dissociated skin sample at Day 0 timepoints c) determination of cytokine profile in dissociated skin sample supernatant at Day 0 timepoints d) differential cDNA expression prepared from skin RNA and analyzed via RNASeq at Day 0 timepoints

Measurement of Changes in the Adaptive Immune Response and Cellular Recruitment in the Skin of Bitten Versus Unbitten Skin After Sixth and Final Feeding in Each Vector Group.

Measurement of changes in the adaptive immune response and cellular recruitment in bitten skin versus unbitten skin by: a) immunohistochemistry of target proteins at Day 2 timepoints b) phenotyping of adaptive immune cell subsets in dissociated skin sample at Day 2 timepoints c) determination of cytokine profile in dissociated skin sample supernatant at Day 2 timepoints d) differential cDNA expression prepared from skin RNA and analyzed via RNASeq at Day 2 timepoints

Secondary Outcome Measures

Flow Cytometry Analysis of PBMCs Collected Day 0 (Baseline) and Days 2 and 14 After Feeding for Saliva-specific T-cells

Describing and understanding cellular immunity to Aedes saliva in heavily exposed individuals will simulate endemic conditions and will inform vaccine design in these target populations.

Full Information

NCT ID

NCT04350905

First Posted

April 16, 2020

Last Updated

March 21, 2022

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

1. Study Identification

Unique Protocol Identification Number

NCT04350905

Brief Title

Characterization of Skin Immunity to Aedes Aegypti Saliva in Dengue-endemic Participants in Cambodia

Official Title

Characterization of Skin Immunity to Aedes Aegypti Saliva in Dengue-Endemic Participants in Cambodia

Study Type

Interventional

2. Study Status

Record Verification Date

April 9, 2021

Overall Recruitment Status

Completed

Study Start Date

October 27, 2020 (Actual)

Primary Completion Date

April 9, 2021 (Actual)

Study Completion Date

April 9, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

5. Study Description

Brief Summary

Background: Mosquito-borne viruses like dengue cause major illness and death worldwide, particularly in Southeast Asia. When mosquitoes deliver a virus into the skin of humans, they also leave saliva. Researchers want to learn more about skin immunity to mosquito saliva. They hope this will help with future vaccines and treatments for these diseases. Objective: To compare the early and late innate immune response in the skin of Aedes aegypti bitten versus unbitten skin. Eligibility: Healthy people ages 18-45 who live within about 15 km of the study site in Chbar Mon Design: Participants will have 3 visits. The baseline/screening visit will include: Medical and medication history Questions about participants demographic information, mosquito biting risk factors, and responses to mosquito or other insect bites Physical exam Urine sample for some participants Mosquito feeding. A feeding device will be placed on the participant s arm for up to 20 minutes. The insects will feed through a mesh on the bottom of the feeding device. Participants may be given standard treatments for any skin reactions. Blood tests Four skin biopsies taken from bitten and unbitten skin. Local anesthetic will be administered, and a small tool will be used to remove the participant s skin. Participants will have a second visit the next day. They will have a physical exam and blood tests. They will have 1 skin biopsy. Participants will have a final visit about 2 weeks later. They will have a physical exam and blood tests. During the study, participants will be asked to take measures to prevent more mosquito bites.

Detailed Description

Mosquito-borne viruses continue to cause significant global morbidity and mortality, particularly in Southeast Asia. When mosquitoes deliver the virus into the skin of humans while probing for a blood meal, they deposit also saliva, which contains a myriad of pharmacologically active compounds that modulate the host immune system. Little is known about skin immunity to mosquito saliva, particularly in endemic volunteers as most clinical studies are performed in na(SqrRoot) ve individuals who have never or rarely been exposed to a particular mosquito vector. People living in endemic areas have had long-term repeated exposure to these vectors and therefore have different immune response to mosquito saliva, which could interfere with mosquito-borne disease vaccine effectiveness. Characterization of skin immunity via various technical modalities will be important in order to identify critical aspects of the innate and adaptive immune responses after a vector bite. Here, we will execute a paired study of exposed-unexposed skin to carefully examine the innate and adaptive immune responses in the skin and blood to exposure of the saliva of Aedes aegypti, the mosquito vector of dengue, Zika, and chikungunya viruses. We will enroll 42 participants to undergo vector feeding and give blood samples at baseline and 2 and 14 days later. Additionally, participants will give skin punch biopsy samples of bitten (exposed) and unbitten (unexposed) skin. For analysis, we will group 10-12 participants in each of 4 technical modality cohorts or groups : 1) immunohistochemistry, 2) RNA sequencing, 3) flow cytometry, and 4) T-cell receptor sequencing. With the current rise of vector-borne diseases in the United States and around the world, we hope the results of this study contribute to future vaccine design and clinical development strategies for vector#borne diseases.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Vector Borne Diseases

Keywords

Vector-Borne Diseases, Immune Response, Mosquito Feeding, Arbovirus, Southeast Asia

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Model Description

Participants were all exposed to 5 uninfected Aedes aegypti mosquitos on their forearm. Biopsies were taken of bitten and unbitten skin.

Masking

None (Open Label)

Allocation

N/A

Enrollment

42 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Mosquito Feeding

Arm Type

Experimental

Arm Description

Each participant will receive one mosquito feeding with 5 starved female Aedes aegypti mosquitoes.

Intervention Type

Other

Intervention Name(s)

Mosquito Feeding

Intervention Description

Mosquito feedings will be conducted with Aedes aegypti colonies raised at the CNM (National Malaria Center) Malaria and Vector Research Laboratory (MVRL), an established state of the art insectaries for mosquitoes was built in 2014 to ACL2 (arthropodcontainment level 2)-level specifications.

Primary Outcome Measure Information:

Title

Measurement of Change in Early and Late Innate Immune Responses Using Gene Expression and Flow Cytometry in Participants' Skin

Description

Time Frame

Day 0 timepoints

Title

Measurement of Changes in the Adaptive Immune Response and Cellular Recruitment in the Skin of Bitten Versus Unbitten Skin After Sixth and Final Feeding in Each Vector Group.

Description

Time Frame

Day 2 (48 hr post feeding)

Secondary Outcome Measure Information:

Title

Flow Cytometry Analysis of PBMCs Collected Day 0 (Baseline) and Days 2 and 14 After Feeding for Saliva-specific T-cells

Description

Describing and understanding cellular immunity to Aedes saliva in heavily exposed individuals will simulate endemic conditions and will inform vaccine design in these target populations.

Time Frame

Day 14

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

45 Years

Accepts Healthy Volunteers

Eligibility Criteria

INCLUSION CRITERIA: In order to be eligible to participate in this study, an individual must meet all of the following criteria: -Provision of signed and dated informed consent form Stated willingness to comply with all study procedures and availability for the duration of the study Male or female, aged 18 - 45 years Live within approximately 15 km of study site In good general health as evidenced by medical history Willing to allow biological samples to be stored for future research. A female is eligible for this study if she meets 1 of the following: Of non-childbearing potential (i.e., women who have had a hysterectomy or tubal ligation or are postmenopausal, as defined by no menses in >=1 year). --Of childbearing potential but has negative urine pregnancy test on Day 0 Agrees to not use scented lotions, deodorants, or topical creams on each feeding day. Agrees to not take aspirin or any other NSAID (ex. ibuprofen) within 7 days of a biopsy. Agrees to not use oral or topical antihistamines or steroid creams or ointments throughout the study without prior permission of Principal Investigator (PI). EXCLUSION CRITERIA: -Any underlying or current medical condition that, in the opinion of the investigator, would interfere with participation in the study. -History of severe allergic reaction (including to mosquito or other insect bites) with generalized urticaria, angioedema, anaphylaxis, anaphylactoid reaction or any other reaction described by the participant and deemed severe by the PI. Self-reported or known history of alcoholism or drug abuse within 6 months prior to enrollment Self-reported or known history of psychiatric or psychological issues that require treatment and are deemed by the PI to be a contraindication to protocol participation. -Any use of medications that affect blood clotting within 3 months or history of abnormal blood clotting -History of significant scarring such as keloids after previous biopsies, lacerations, abrasions, surgeries, or other skin procedures (e.g., cosmetic piercings) that are deemed by the PI to be a contraindication to protocol participation. -Pregnant or breastfeeding.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jessica E Manning, M.D.

Organizational Affiliation

National Institute of Allergy and Infectious Diseases (NIAID)

Official's Role

Principal Investigator

Facility Information:

Facility Name

Kampong Speu Referral Hoispital

City

Chbar Mon

ZIP/Postal Code

05251

Country

Cambodia

12. IPD Sharing Statement

Citations:

PubMed Identifier

24044424

Citation

Durnez L, Mao S, Denis L, Roelants P, Sochantha T, Coosemans M. Outdoor malaria transmission in forested villages of Cambodia. Malar J. 2013 Sep 17;12:329. doi: 10.1186/1475-2875-12-329.

Results Reference

background

PubMed Identifier

29617849

Citation

Manning JE, Morens DM, Kamhawi S, Valenzuela JG, Memoli M. Mosquito Saliva: The Hope for a Universal Arbovirus Vaccine? J Infect Dis. 2018 Jun 5;218(1):7-15. doi: 10.1093/infdis/jiy179.

Results Reference

background

PubMed Identifier

20865069

Citation

Huy R, Buchy P, Conan A, Ngan C, Ong S, Ali R, Duong V, Yit S, Ung S, Te V, Chroeung N, Pheaktra NC, Uok V, Vong S. National dengue surveillance in Cambodia 1980-2008: epidemiological and virological trends and the impact of vector control. Bull World Health Organ. 2010 Sep 1;88(9):650-7. doi: 10.2471/BLT.09.073908. Epub 2010 Apr 7.

Results Reference

background

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Characterization of Skin Immunity to Aedes Aegypti Saliva in Dengue-endemic Participants in Cambodia

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