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....
Aged 18 to 50 years.
In good general health as evidenced by medical history, physical examination, and laboratory screening results
Willing to allow storage of samples and data for future research.
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.
Pregnancy.
Lactation during the first 28 days of the study.
Baseline absolute neutrophil count (ANC) <=750 cells/microL.
Baseline creatinine >=1.5 mg/dL.
Single group
rDEN2delta30-7169
Biological/VaccineThe rDEN2delta30-7169 strain is a live attenuated recombinant virus constructed by introducing a 30-nucleotide deletion (delta30) in 3 UTR of the wild type DEN-2 Tonga/74.
The frequency and severity of AEs through day 28 and SAEs through day 180.
Evaluate the safety of the challenge strain in all groups.
Fold difference between groups in peak viral RNAemia titers on any day from days 2 to 19.
Evaluate viral replication by qRT-PCR and compare the peak replication among groups.
Fold change in DENV1-4 neutralizing antibody GMTs between days 0 and 28 within each group.
Evaluate the immunogenicity of the challenge by examining the change in antibody titers in each group.
Differences in the change in IP-10 signaling between day 0 and days 2 to 19 among groups.
Evaluation of IP-10 over time will allow us to evaluate how prior DENV exposure influences the immune response to viral replication.
Difference between the bone marrow cellularity at day 5 versus the reference range within each group.
Cellularity is measured as the percentage of hematopoietic cells vs. fat in the marrow and will allow us to evaluate whether the marrow is suppressed or proliferative at day 5 in each group.
The magnitude of bone marrow DENV-specific antibody-secreting cells at day 57.
The presence of DENV-specific antibody-secreting cells in the bone marrow at day 57 would indicate that long lived immunity has been established and allow us to study the determinants of this immunity.
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