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.

Study Overview

• Status: Recruiting
• Conditions: Healthy Volunteers; Dengue; Human Challenge Trial
• Intervention / Treatment: Biological: rDEN2delta30-7169

Detailed Description

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
• Enrollment (Estimated): 200
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Camila D Odio, M.D.; Phone Number: (240) 338-4945; Email: camila.odio@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: NIH Clinical Center Office of Patient Recruitment (OPR); Phone Number: TTY dial 711 (800) 411-1222; Email: ccopr@nih.gov
      • Contact: Camila Odio, B.S.; Phone Number: 614-582-6126; Email: camila.odio@nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

• 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) <=750 cells/microL.
4. Baseline creatinine >=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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Heterotypic; Those with their highest titer to a non-DENV2.	Biological: rDEN2delta30-7169; 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.
Experimental: Homotypic; Those with a DENV2-dominant serotype.	Biological: rDEN2delta30-7169; 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.
Experimental: Naive; Those with no exposures to flaviviruses	Biological: rDEN2delta30-7169; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The frequency and severity of AEs through day 28 and SAEs through day 180.	Evaluate the safety of the challenge strain in all groups.	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.	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.	Through Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	At Day 57

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Principal Investigator: Camila D Odio, M.D., National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Estimated): July 21, 2026
• Primary Completion (Estimated): November 3, 2028
• Study Completion (Estimated): May 3, 2029

Study Registration Dates

• First Submitted: July 15, 2026
• First Submitted That Met QC Criteria: July 15, 2026
• First Posted (Actual): July 16, 2026

Study Record Updates

• Last Update Posted (Actual): July 16, 2026
• Last Update Submitted That Met QC Criteria: July 15, 2026
• Last Verified: July 13, 2026

More Information

Terms related to this study

• Keywords: Immunology; Healthy Volunteers; Dengue; Viruses; Human challenge trial; Antibody dependent enhancement; Bone marrow examination; Host pathogen interactions; Lymph node aspiration
• Additional Relevant MeSH Terms: Vector Borne Diseases; Mosquito-Borne Diseases; Infections; RNA Virus Infections; Arbovirus Infections; Flavivirus Infections; Flaviviridae Infections; Hemorrhagic Fevers, Viral; Dengue; Virus Diseases
• Other Study ID Numbers: 10002606; 002606-I

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All collected IPD may be shared. To protect research participant identities, all direct identifiers will be stripped from datasets. Patient-level variables not needed for interpreting the data will be removed or, where appropriate, anonymized using data masking (hiding data with altered values). Indirect identifiers needed for interpreting the data will be anonymized through generalization (e.g. ranges for age, larger categories for country of birth) or perturbation (slight alteration of the data, e.g. time since last lived in a dengue-endemic region), as appropriate.
• IPD Sharing Time Frame: Scientific data will be made available no later than the time of publication, when possible. We place no restrictions on the length of time data will be made available.
• IPD Sharing Access Criteria: IPD used in publications will be de-identified, generalized, and shared as supplemental material, which can be accessed by any person reading the article. De-identified, generalized IPD will also be deposited in ImmPort. Data are available on ImmPort to qualified researchers after a brief registration and approval process. Users must accept a data sharing and access agreement before approval is granted. Genetic data will be deposited in dbGap with only the minimal associated metadata needed for interpretation to reduce any possibility of de-identification. To gain access to data on dbGap, researchers must agree to follow the NIH Genomic Data Sharing (GDS) Policy, and be approved by the NIH Data Access Committee or appropriate Data Access Committee. They must describe the proposed use of the data and ensure all researchers involved in the request will adhere to this project outline. Investigators gain access to the data for one year with the ability to extend to additional years.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No