Phase 1 Challenge Study Using rDEN2delta30-7169 to Evaluate Host-Pathogen Interactions in Primary, Homotypic, and Heterotypic Dengue Virus Infection

Background: Dengue is a viral disease spread by mosquitoes. Most people bitten by mosquitoes carrying dengue viruses do not get sick, but severe cases can cause shock, internal bleeding, and death. There are no treatments for dengue. To develop treatments, researchers need to understand more about what dengue viruses do in the body. Objective: To infect healthy people with a mild dengue virus to study how their body responds. Eligibility: People ages 18 to 50 years with or without a history of dengue virus infection. Design: Participants will be screened. They will have a physical exam with blood tests. The tests will show whether they have ever been infected with dengue or related viruses in the past. At their first study visit, participants will receive an injection of dengue virus into the arm. The injected virus is weaker than the natural virus, so any symptoms should be milder. Participants will have a total of 11 study visits over 6 months; 8 of those visits will be in the first month. Blood will be drawn at each visit. Some visits will include ultrasound exams of their internal organs. They will discuss any symptoms they are having. Any rashes they develop may be photographed. Two procedures are optional: Participants may have up to 5 lymph node aspirations and 3 bone marrow biopsies during the study. For both procedures, a needle will be inserted into the tissues to draw out immune cells. Two more visits are optional: 1 visit up to 2 months before receiving the virus, for lymph node or bone marrow samples, and 1 about a year after for a blood draw.

* INCLUSION CRITERIA: To be eligible to participate in this study, an individual must meet all the following criteria: 1. Aged 18 to 50 years. 2. In good general health as evidenced by medical history, physical examination, and laboratory screening results 3. Willing to allow storage of samples and data for future research. 4. Willing to forgo receipt of any vaccine in the 28 days preceding the challenge strain through the 28 days following administration of the challenge strain. For participants opting for LN FNA or bone marrow sampling on day 57, they must be willing to forgo any vaccine through day 57. For those opting for FNA or bone marrow sampling on day 180, they must be willing to forgo any vaccine for at least 28 days before sampling. 5. For individuals who can become pregnant: use of at least one method of effective contraception (see below) from at least 28 days prior to challenge through 60 days after challenge. 6. Able to provide informed consent. 7. Willing to adhere to lifestyle considerations for the duration of the study. 8. Willing to avoid travel to a dengue-endemic area as defined by the CDC from 1 month before administration of challenge through day 28. For participants opting for LN FNA or bone marrow sampling on day 57, they must be willing to forgo travel through day 57. 9. Serologic evidence of previous dengue virus infection consistent with our serology criteria. a. For the flavivirus-naive group, they must have no history of flavivirus vaccination or medical illness concerning for a flavivirus infection. If there is uncertainty about a previous flavivirus exposure, then confirmatory antibody testing against the virus of interest must be negative. 10. Agree to avoid participation in other clinical studies requiring investigational interventions through day 180. 11. Agree to avoid blood and plasma donation outside this study through day 57. Contraceptive requirements: Participants who can become pregnant must agree to use at least one method of effective contraception as outlined below from at least 28 days before through 60 days after challenge to avoid any potential risk from the product on the pregnancy or fetus. Participants who can become pregnant must have a negative serum pregnancy test on day 0 before receiving rDEN2delta30-7169. If a participant becomes pregnant or suspects they are pregnant during the study, they should inform the study staff and their primary care physician immediately. Acceptable forms of contraception are listed below and are consistent with prior studies using this product: * Intrauterine device or equivalent. * Hormonal contraceptive (e.g., consistent, timely, and continuous use of contraceptive pill, patch, ring, implant, or injection that has reached full efficacy prior to challenge). * Condom, diaphragm, or cervical cap plus spermicide. * A stable, long-term monogamous relationship with a partner who does not pose any potential pregnancy risk, e.g., has undergone a vasectomy at least 6 months prior to administration of challenge strain or is of the same sex as the participant. * A hysterectomy and/or a bilateral tubal ligation, bilateral oophorectomy, or post-menopausal status defined as age \>=45 years and at least 1 year since last menstrual period. Participants who become pregnant after challenge but before day 180 will be excluded from any further research procedures. If the participant agrees, we will collect and report pregnancy outcomes through day 180, which is the final required study visit. EXCLUSION CRITERIA: An individual who meets any of the following criteria will be excluded from participation in this study: 1. Pregnancy. 2. Lactation during the first 28 days of the study. 3. Baseline absolute neutrophil count (ANC) \=1.5 mg/dL. 5. Baseline ALT \>=1.25 x upper limit of normal. 6. Requiring a potent anticoagulator like a direct acting oral agent or warfarin during the first 28 days of the study. 7. History of or positive test result for HIV, hepatitis B, or hepatitis C. 8. History of a tetravalent, chimeric, or subunit dengue vaccine. 9. Has any of the following: 1. More than 10 days of systemic immunosuppressive medications (\>=10 mg prednisone dose or its equivalent) or cytotoxic medication within the 30 days prior to administration of challenge strain or immunomodulating therapy within 180 days prior to administration of challenge strain. 2. Received blood products, including immunoglobulin products, within 120 days prior to administration of challenge strain. 3. History of serious reactions to vaccines. 4. Hereditary, acquired, or idiopathic forms of angioedema. 5. Idiopathic urticaria within the past year. 6. Asthma that is not well controlled or required emergency care, urgent care, hospitalization, or intubation during the past two years or that requires the use of oral or intravenous steroids. 7. Type 1 or type 2 diabetes mellitus that is not well controlled (hemoglobin A1c \>8). 8. Clinically significant autoimmune disease or immunodeficiency. 9. Blood pressure \>=180/110 (stage 3 hypertension) on at least 2 measures. 10. Documented diagnosis of a bleeding disorder (e.g., factor deficiency, coagulopathy, or platelet disorder requiring special precautions). 11. Significant bruising or bleeding difficulties with subcutaneous injections or blood draws. 12. Malignancy that is active or treated malignancy for which there is no reasonable assurance of sustained cure, or malignancy that is likely to recur during the study period. 13. Asplenia or functional asplenia. 14. Current alcohol or drug abuse or addiction. 10. Any medical, psychiatric, or social condition that, in the judgement of the investigator, is a contraindication to protocol participation. Co-enrollment guidelines: Co-enrollment in other interventional 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 principal investigator in consultation with the sponsor medical monitor (SMM). Study staff should be notified of co-enrollment on any other protocol as it may require the approval of the principal investigator (in consultation with the SMM).