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.
Study Description: This is a phase 1 challenge trial where healthy adults with no flavivirus antibodies (naive), dengue virus serotype 2 (DENV2)-dominant antibodies (homotypic), or non-DENV2-dominant antibodies (heterotypic) will be infected with the live attenuated DENV2 challenge strain rDEN2delta30-7169. We will evaluate the safety and immunogenicity of the challenge strain as well as how immune history influences IP-10 signaling, bone marrow cellularity, and the development of bone marrow DENV2-specific cells. Exploratory objectives include examining the immunological and clinical impact of homotypic and heterotypic infection, how viral replication affects the bone marrow and induces protective or dysregulated immune responses, and the determinants of long-lived immunity to inform dengue vaccines and therapeutics. We hypothesize that the challenge strain will be safe. The heterotypic group is predicted to have the highest viremia as measured by RNA (viral RNAemia) and boost in neutralizing antibodies, and the homotypic challenge group will have the lowest. We also expect that the heterotypic group will have the biggest changes in IP-10 signaling between days 0 and 19. During acute infection, we expect that the heterotypic and naive groups will have altered bone marrow cellularity such that it differs from the reference range, but the homotypic group will not have altered cellularity. At day 57, we expect that there will be DENV-specific antibody secreting cells in the bone marrow. Primary Objective: Evaluate the safety, viral RNAemia, and immunogenicity of rDEN2delta30-7169 in those with distinct DENV infection histories. Secondary Objectives: Compare chemokine signaling and the magnitude of DENV2-specific antibody-secreting cells in the bone marrow among groups. Evaluate the bone marrow cellularity during infection within each group. Primary Endpoints: 1. Safety: The frequency and severity of adverse events (AEs) through day 28 and serious adverse events (SAEs) through day 180 regardless of prior immune history. 2. Viral RNAemia: Fold difference between groups in peak viral RNAemia titers on any day from days 2 to 19. 3. Immunogenicity: Fold change in DENV1-4 neutralizing antibody geometric mean titers (GMTs) between days 0 and 28 within each group. Secondary Endpoints: 1. Differences in the change in IP-10 signaling between day 0 and days 2 to 19 among groups. 2. Difference between the bone marrow cellularity at day 5 versus the reference range within each group. 3. The magnitude of bone marrow DENV-specific antibody-secreting cells at day 57.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
200
The 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.
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
RECRUITINGThe frequency and severity of AEs through day 28 and SAEs through day 180.
Evaluate the safety of the challenge strain in all groups.
Time frame: Through Day 180
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.
Time frame: Through Day 19
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.
Time frame: Through Day 28
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.
Time frame: Through Day 19
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.
Time frame: At Day 5
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.
Time frame: At Day 57
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