The goal of this study is to characterize the immune response, both innate and adaptive, as well as locally and systemic, to intradermal (ID) vaccination in healthy individuals. The intervention involves intradermal administration of an FDA-approved intramuscular seasonal influenza vaccine, using an FDA-approved device MicronJet. Investigators will measure antibody titers, cell subtypes, and multi-omic profiles, by collecting skin and peripheral blood at baseline and at several time points after vaccination. The primary objective is to identify baseline correlates of immune response in the skin and peripheral blood to the seasonal influenza vaccine. The investigators secondary goals are to describe the inflammatory response in the skin over time.

Subjects will remain on study and may optionally repeat study visits (including vaccination) annually through the 2025-26 influenza season, with final study follow-up up to 1 year after vaccination. Sampling individual subjects across several influenza seasons will allow for monitoring of multi-season responses.

Skin, blood, nasal mucosal lining fluid, nasopharyngeal cells, saliva, and skin microbe samples will be collected at various timepoints before and up to 365 days after vaccination to explore short and long-term effects of immunization. Subjects may optionally provide stool samples.

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

1. Provision of signed and dated informed consent form

2. Stated willingness to comply with all study procedures and availability for the duration of the study, as well as have deidentified samples and data stored for future research.

3. Able to proficiently speak, read, and write English.

4. Male or female, aged 18-40 years old at time of initial enrollment

   a. Participant is allowed to participate in subsequent influenza seasons even if they will be >40 years old.

5. In good general health as evidenced by medical history

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

1. CBC with differential, lymphocyte phenotyping with T, B, and natural killer cells (TBNK), complete metabolic panel, anti-CMV immunoglobulin (Ig) G and IgM, and/or anti-Epstein-Barr virus (EBV) antibody panel values outside of the Yale Department of Laboratory Medicine normal reference ranges and deemed clinically significant by the PI at the time of screening.

2. Positive result for anti-HIV 1/2 antibody screening at the time of screening.

3. Prior receipt of a current seasonal influenza vaccine (for the season of participation).

4. History of allergy or hypersensitivity to any components of the study vaccine (e.g., egg protein).

5. History of severe reactions to vaccines.

6. Use of an oral glucocorticoid within the past 30 days.

7. Receipt of a live-attenuated vaccine within the past 3 months.

8. Receipt of any experimental vaccine.

9. Receipt of any other type of vaccine (non-live and non-experimental, e.g., tetanus, diphtheria, and pertussis [TDaP]) within the past 3 months.

10. Planned vaccination before day 100 after study vaccination.

11. Current or recent use (within the past 90 days) of immunoglobulin therapy.

12. Surgery within the past 8 weeks, or planned surgery before day 28.

13. Current (within the past 30 days) treatment for active malignancy.

14. Cancer chemotherapy in the past 2 years.

15. Administration of any blood products within 90 days of the screening, or planned administration before day 100.

16. History of parasitic, amebic, fungal, or mycobacterial infections within the past 1 year, with the exception of tinea pedis and onychomycosis.

17. History of autoimmune or autoinflammatory disease.

    a. In particular skin-related (i.e. psoriasis, lichen planus, lupus, neutrophilic dermatoses, atopic dermatitis)

18. History of keloids

19. History of a bleeding disorder.

20. Current use (within the past 30 days) of illicit drugs (per subject report), with the exception of marijuana.

21. Current alcohol use disorders (criteria per Diagnostic and Statistical Manual of Mental Disorders, fifth edition), within the past 30 days.

22. Serious, ongoing, uncontrolled infection within the past 30 days as per the judgement of the PI.

23. History of Guillain-Barre syndrome (GBS).

24. BMI ≥ 30.

25. Known or suspected immunodeficiency within 1 year, including documented HIV infection.

26. Pregnancy or planning to become pregnant during the study period. (Women of childbearing potential must have a negative urine or serum pregnancy test at screening.)

27. Presence of conditions that, in the judgment of the PI, may put the individual at undue risk or compromise the scientific objectives of the study.

Co-enrollment guidelines: Co-enrollment in other trials is restricted, other than enrollment on observational studies. Consideration for co-enrollment in trials evaluating the use of a licensed medication will require the approval of the PI. Study staff should be notified of co-enrollment on any other protocol as it may require the approval of the PI.

Human data generated in this study will be shared for future research as follows:

• De-identified data in an NIH-funded or approved public repository, including

  • genetic data in the database of Genotypes and Phenotypes (dbGaP).
  • gene expression and chromatin profiling data in the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO).
  • sequencing data in the NCBI Sequence Read Archive (SRA).
  • flow cytometry data in FlowRepository.

• De-identified or identified data with approved outside collaborators under appropriate agreements.

Data will be shared before publication through presentations at meetings and seminars; raw and complete data sets will not be shared until the time of publication or shortly thereafter.