Defining Skin Immunity of a Bite of Key Insect Vectors in Humans

Vector-borne diseases continue to cause significant morbidity and mortality worldwide despite
ongoing control efforts. Vectors like sand flies and mosquitoes deliver the pathogen into the
skin of humans while taking a blood meal. Most vaccines under development ignore the
importance of the complex infectious inoculum delivered by the vector and the local immune
response that occurs at the site of the bite. In addition, many preclinical studies are
carried out in animal models that do not replicate the natural route of infection,
transmission by vector bites, and often bypass the skin interface altogether. As such, these
studies do not evaluate what role the vector plays in the initiation of these infections.
Further compounding this problem, many clinical studies are performed in na(SqrRoot) ve
individuals who have never been exposed to the vector, while those living in endemic areas
will have had long-term exposure to vectors through uninfected bites.

A cumulative body of evidence from animal models demonstrates that a variety of
vector-derived components are co-delivered with the pathogen and may play an important role
in the establishment of infection. There is limited knowledge of the effect of these
vector-derived factors on the immune response in human skin and their potential impact on
infection establishment.

In this protocol, we will examine the early skin immune response to bites of three
arthropods: the mosquito Aedes aegypti, the vector of Zika, dengue, and chikungunya viruses;
the mosquito Anopheles gambiae, the vector of malaria; and the sand fly Lutzomyia
longipalpis, the vector of leishmaniasis. We will also explore how multiple vector bite
exposures over time modulate future immune response at the bite site. Healthy participants
will come to the National Institutes of Health (NIH) and undergo feeding by one of the three
vectors, then have three skin punch biopsies performed by trained medical practitioners to
evaluate local immune response. Participants in Cohort A will have one feeding; participants
in Cohort B will have 4 feedings, each 2 weeks apart. Biopsies will be collected after the
final feeding. Blood will be collected after the one feeding in Cohort A and after the fourth
and final feeding in Cohort B to assess systemic immune response.

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.

- INCLUSION CRITERIA:

Individuals must meet all of the following criteria to be eligible for study participation:

- Healthy women and men who are greater than or equal to 18 and less than or equal to 64
years of age.

- Able to provide informed consent.

- Willingness to complete all study visits and comply with all study requirements.

- Willing to have samples 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 greater thanor equal
to 1 year).

- Of childbearing potential but agrees to practice effective contraception or
abstinence for 4 weeks prior to enrollment through the completion of the study.
Acceptable methods of contraception include a male partner who is sterile and is
the sole sexual partner of the female participant or a male partner who uses a
condom with spermicide plus 1 or more of the following that is used by the
female: 1) implants of levonorgestrel; 2) injectable progestogen; 3) an
intrauterine device with a documented failure rate of <1%; 4) oral
contraceptives; and 5) double barrier method including diaphragm.

- Agrees to not use scented lotions, deodorants, or topical creams on each feeding day.

- Agrees to not take aspirin or any other NSAID within 7 days of a biopsy.

- Agrees to not use topical steroid creams or ointments throughout the study without
prior permission of Principal Investigator (PI).

- Vector-specific antibody enzyme-linked immunosorbent assay (ELISA) to one of the three
vectors (the one to which the individual is assigned) is <2.5 standard deviations
above the negative control.

EXCLUSION CRITERIA:

Individuals meeting any of the following criteria will be excluded from study
participation:

- Any underlying or current medical condition that, in the opinion of the investigator,
would interfere with participation in the study.

- Any participant that is HIV positive.

- A clinically significant (as determined by the PI) baseline Grade 1 or greater
toxicity by the toxicity table.

- History of severe allergic reaction (including to mosquito or other insect bites) with
generalized urticaria, angioedema, anaphylaxis, or anaphylactoid reaction.

- Prone to allergic responses and/or significant history of allergies, including
seasonal or specific allergies as determined by the PI.

- Receipt of any investigational drug that is unlicensed within 3 months or 5.5 half-
lives (whichever is greater) prior to enrollment.

- Receipt of any unlicensed vaccine within 6 months prior to enrollment.

- Self-reported or known history of alcoholism or drug abuse within 6 months prior to
enrollment, or positive urine test for drugs of abuse at screening (excluding positive
test for tetrahydrocannabinol [THC] or its metabolites if usage is less than 3 times
per week).

- 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, history of abnormal
blood clotting, or result outside of the normal laboratory range for measurements of
prothrombin time (PT), partial thromboplastin time (PTT), or international normalized
ratio (INR) that may suggest a problem with blood clotting.

- History of significant scarring 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.

Co-enrollment Guidelines: Co-enrollment in other trials is restricted, but may take place
after consultation with the study staff and approval from the PIr