The goal of this study is to use the live attenuated Yellow Fever Vaccine (YFV) as a safe and effective model for viral infection to understand human immune response to viral antigens. Study participants will receive the yellow fever vaccine and participation in the study may be as short as one month or as long as one year, depending on immune responses.

Yellow fever (YF) is a viral disease that is transmitted to humans through the bite of an infected mosquito. Yellow fever is a life-threatening infection that can result in hepatitis, renal failure and coagulation abnormalities, and in severe cases, death. Yellow fever was a major public health threat in the colonial United States in the 18th and 19th centuries.

Yellow fever is endemic in over 40 countries, and approximately 125 countries require proof of vaccination for entry by travelers at risk. An estimated 200,000 cases of yellow fever occur annually in South America and Africa, making it an important vaccine-preventable disease among travelers to endemic areas. Yellow fever can be prevented by vaccination with the Yellow Fever Vaccine. Currently, the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) recommend yellow fever vaccination for persons ≥ 9 months of age who are traveling to or living in a yellow fever endemic area.

The Yellow Fever Vaccine is considered to be one of the safest and most effective viral vaccines ever developed. Yellow Fever Vaccine is known to stimulate broad-spectrum immune responses, including cytotoxic T cells, and Th1 and Th2 responses, as well as neutralizing antibody titers that can persist for up to 30 years, after a single vaccination. Despite the great success of this empiric vaccine, there has been relatively little understanding of the mechanisms by which Yellow Fever Vaccine induces such robust protective immune responses. The researchers hope to apply the best contemporary methods in immunology, genomics, and proteomics to characterize in detail a successful immune response to Yellow Fever vaccination. This characterization should identify new immunologic predictors that could serve as surrogates for future vaccine efficacy studies. In addition, these findings could guide development of a safer yellow fever vaccine (or the derivation of safer alternative vaccination regimens using the currently available vaccine).

This study plans to recruit both travelers to yellow fever endemic areas as well as non-travelers for participation. Healthy participants will be enrolled into four study arms. Arm enrollment is determined by Human Leukocyte Antigen (HLA) type, current needs of the lab and/or willingness to participate in sampling procedures. All participants receive Yellow Fever Vaccine on Day 0 at the FDA-approved dose and route of administration. Post-vaccination procedures are determined by arm assignment. Participants will be followed for up to 360 days post-vaccination.

Inclusion Criteria:

1. Able to understand and give informed consent
2. Age 18-45 years
3. Participant agrees not to take any live vaccines 30 days before or after (14 days for inactivated, including coronavirus disease 2019 (COVID-19) vaccination) yellow fever vaccination
4. Women of child bearing potential must agree to use effective birth control throughout the duration of the study. A negative urine pregnancy test must be documented prior to vaccination. Participants who have a history of surgical sterilization or post-menopausal status >1 year, are not required to have a pregnancy test.

Exclusion Criteria:

1. Prior receipt of a yellow fever vaccine
2. Lived in a country/area which is endemic for yellow fever
3. Travel to country/area which is endemic for yellow fever. Subject to investigator discretion
4. History of previous yellow fever, West Nile, Dengue, St. Louis encephalitis, Japanese encephalitis vaccination or infection
5. Any history of allergy to eggs, chicken or gelatin or to any previous vaccine
6. A history of a medical condition resulting in impaired immunity (such as HIV infection, cancer, particularly leukemia, lymphoma, use of immunosuppressive or antineoplastic drugs or X-ray treatment). Persons with previous skin cancers or cured non-lymphatic tumors are not excluded from the study
7. History of HIV infection
8. Active Hepatitis B or Hepatitis C infection
9. COVID-19 infection in the last 30 days. Symptoms of COVID-19 must be completely resolved before yellow fever vaccine receipt.
10. History of any chronic medical conditions that are considered progressive (ex, diabetes, heart disease, lung disease, liver disease, kidney disease, gastrointestinal diseases and uncontrolled hypertension). Use of systemic immunosuppressive medications (ex, prednisone) for 2 weeks or more in the past 3 months
11. History of excessive alcohol consumption, drug abuse, psychiatric conditions, social conditions or occupational conditions that in the opinion of the investigator would preclude compliance with the trial
12. Thymus gland problems (such as myasthenia gravis, DiGeorge syndrome, thymoma) or removal of thymus gland or history of autoimmune disorder
13. Recipient of a blood products or immune globulin product within 42 days of the vaccination visit. Participants who received COVID monoclonal antibodies (mAbs) for treatment are not excluded
14. Pregnant women and nursing mothers or women who are planning to become pregnant for the duration of the study
15. Any condition in the opinion of the investigator that would interfere with the proper conduct of the trial