A Controlled Human Infection Model of Dengue (DEN-CHIM-01)

This study aims to conduct a safe human infection challenge using an attenuated serotype DEN3 dengue virus in adult volunteers. The clinical, viral and immune response characteristics of the model will be analysed to understand the pathophysiology of dengue fever. This data will be used to inform future studies, including a planned follow up study (DEN-CHIM-02) which will investigate the efficacy of an investigational dengue vaccine at protecting against DEN3 infection.

Study conditions that result in a safe, reproducible infection in ≥80% of research participants (attack rate) with the DEN3 challenge agent have been identified during studies conducted by our collaborators in the US. This includes the inoculum dose, safety monitoring, and necessary participant pre-screening to exclude prior Orthoflavivrus infection or vaccinations.

Study objectives are to:

1. Establish in seronegative volunteers in Singapore a safe DENV controlled human infection (CHI) model, with an infection rate of ≥80%, suitable for future studies of interventions.
2. Characterise the clinical, haematological and virological response following controlled inoculation of the attenuated DEN3 challenge agent.
3. Conduct deep immunophenotyping to understand the cellular, humoral and innate immune response to dengue infection.
4. Explore the longitudinal immune response in the 3 years after challenge, including following subsequent dengue vaccination.

Study Overview

• Status: Recruiting
• Conditions: Dengue
• Intervention / Treatment: Other: GMP-produced rDEN3delta30 virus

Detailed Description

Dengue fever is a mosquito-transmitted infection, with an escalating geographic distribution and disease burden because of factors including climate change, urbanisation and globalisation. Despite ongoing and often intensive vector control efforts implemented in many endemic countries, the incidence of dengue has increased thirty-fold worldwide over the past half-century, establishing it as the most rapidly spreading vector-borne disease. The rising burden of disease from dengue is further compounded by the absence of specific antiviral treatments, and the limitations of currently available vaccines.

In light of these challenges, innovative strategies to enhance our understanding of dengue and accelerate the development of effective countermeasures are urgently needed. Controlled human infection (CHI) studies have emerged as a valuable tool in this endeavour, offering a unique platform for investigating the natural history of infectious diseases and evaluating the potential of novel interventions.

CHI studies involve the deliberate inoculation of human volunteers with an infectious agent such as a virus, bacteria, or parasite. The strength of this study design is a result of their highly controlled nature, whereby carefully selected volunteers are exposed to standardised amounts of a well-characterised infectious agent. This enables exact longitudinal measurement of challenge agent replication kinetics, infectious shedding, immunological responses and clinical features, and contrasts with what is achievable through field trials of natural infection, including household contact studies. By inoculating all study participants with the same agent at the same dose and under the same conditions, confounding by strain, dose, and exposure is controlled. Host factors associated with inter-individual differences in clinical outcome and the effect of interventions can then be robustly inferred, along with the ability to connect detailed longitudinal data to the earliest time points after exposure, including prior to the onset of symptoms.

Singapore, an equatorial city-state, is highly endemic for dengue, with the co-circulation of all four serotypes. The country boasts a well-established research infrastructure and considerable expertise in infectious diseases at institutions like NCID. Singapore also has a globally recognized vector control program and maintains extensive dengue surveillance data, providing a rich context for studying the disease. The strong research infrastructure and expertise at NCID, coupled with Singapore's commitment to public health and its history of effective disease surveillance and control, create a conducive environment for conducting high-quality and impactful dengue CHI studies.

Findings from CHI studies conducted in Singapore are likely to be highly relevant to other endemic areas in Southeast Asia and globally. The specific dengue serotype dynamics in Singapore, including recent switches involving DEN1 and DEN3, make research on these serotypes particularly timely. Furthermore, Singapore has observed a shift in the average age of dengue patients towards older adults, who may be at higher risk of severe disease, making research in this context especially important.

By developing a dengue controlled human infection model in Singapore through the DEN-CHIM-01 study we intend to enable:

1. A model of infection that can be used to assess the efficacy of new vaccines, treatments, and diagnostics in a dengue endemic setting.
2. Identification of the immune and other host factors, including ethnicity, associated with viral kinetics and dengue symptoms.
3. Provide the foundation for future development of a unique model of secondary dengue.

The DEN-CHIM-01 study will use the optimised conditions established by our collaborators in the US to conduct a GMP rDEN3delta30 challenge study in seronegative volunteers. This study aims to investigate in the Singapore context the clinical, virologic and immunologic features of DEN3 infection and what immune, transcriptomic and genomic markers correlate with symptomology, viral kinetics and the immune response.

The DEN-CHIM-01 study forms part of a wider programme of work in Singapore, both in dengue fever and using CHI studies as an experimental model to advance the development of therapeutics and vaccines. Experience from the Sing-CoV controlled human infection study (PI: A/Prof Barnaby Young) has informed development of this protocol, and agreements for sharing of samples and data with our scientific collaborators are in place.

The DEN-CHIM-01 is a critical first step to conducting a follow up pilot clinical trial, DEN-CHIM-02, funded by the same grant. In DEN-CHIM-02 we plan to investigate the efficacy of a dengue vaccine at protecting against challenge with rDEN3delta30.

• Study Type: Interventional
• Enrollment (Estimated): 5
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Xuan Ying Poh, PhD; Phone Number: +65 6511 5090; Email: poh.xuan.ying@nhghealth.com.sg

Study Locations

• Singapore
  • Singapore, Singapore
    • Recruiting
    • National Centre for Infectious Diseases (NCID)
    • Contact: Xuan Ying Poh, PhD; Phone Number: +65 6511 5090; Email: poh.xuan.ying@nhghealth.com.sg
    • Principal Investigator: Barnaby E Young, MB BChir, PhD
    • Sub-Investigator: Po Ying Chia, MBBS, PhD
    • Sub-Investigator: Stephanie Sutjipto, MBBS

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. An informed consent form (ICF) has been signed and dated by the participant, an investigator, and a witness
2. Adult, aged between 21 and 45 years, inclusive (at the time of consent)
3. No known history of prior dengue, zika or other Orthoflavivirus infection
4. No history of prior dengue, yellow fever, Japanese encephalitis virus, or other Orthoflavivirus vaccination
5. Sero-suitable based on the pre-screening serology result
6. a Female participants must be willing and able to use contraception from 2 weeks before the scheduled date of viral challenge until 1 month after receipt of the final dose of study virus. Negative urine pregnancy tests will be required at screening, and on admission to the quarantine unit a negative serum beta human chorionic gonadotropin (β-hCG) is required prior to inoculation.

6b Male participants who are willing to use one of the contraception methods described in the study protocol, from the date of viral challenge, for 1 month. In addition to the contraceptive requirements above, male participants must agree not to donate sperm following discharge from quarantine until 1 month after the date of viral challenge.

7 In good health with no history of clinically significant medical conditions (as described in Exclusion criteria) that would interfere with subject safety, as defined by medical history, physical examination and routine laboratory tests, ECG, and Chest X-Ray and determined by the Investigator at an admission evaluation.

8 Willing and able to commit to participation in the study.

Exclusion Criteria:

1. History or evidence of any clinically significant or currently active neurologic, cardiac, pulmonary, hepatic, rheumatologic, autoimmune, or renal disease.
2. History of active depression and/or anxiety with associated severe psychiatric comorbidities, for example psychosis.
3. Behavioural, cognitive, or psychiatric disease that in the opinion of the investigator affects the ability of the subject to understand and cooperate with the requirements of the study protocol.
4. Significant history or presence of drug or alcohol misuse
5. History of anaphylaxis and/or a history of severe allergic reaction or significant intolerance to any food or drug, as assessed by the PI.
6. Family history of 1st degree relative aged 50 years or less with sudden cardiac or unexplained death
7. A total body weight of ≤ 45kg and a Body Mass Index (BMI) ≤18 kg/m2 and ≥30 kg/m2.
8. Venous access deemed inadequate for the phlebotomy demands of the study.
9. Any clinically significant abnormal finding on screening biochemistry, haematology and microbiology blood tests or urinalysis apart from minor deviations which are clinically acceptable and approved by the investigator.

Any of the following:

• Elevated HbA1C

• Positive HIV, active/chronic hepatitis B or hepatitis C test. 10 Twelve-lead ECG recording with clinically relevant abnormalities as judged by the study investigator.

  11 Receipt of a live vaccine within 60 days prior to the planned date of viral challenge, a non-live vaccine within 30 days prior to the planned date of viral challenge or intention to receive any vaccination(s) before the day 28 follow-up visit.

  12 Previous receipt of a flavivirus vaccine (licensed or experimental). 13 Receipt of blood or blood products, or loss (including blood donations) of 550 mL or more of blood during the 3 months prior to the planned date of viral challenge or planned during the 3 months after the final visit.

  14 Medications:

  1. Receipt of any investigational drug within 3 months prior to the planned date of viral challenge
  2. Receipt of systemic (intravenous and/or oral) glucocorticoids or systemic antiviral drugs within 6 months prior to the planned date of viral challenge.
  3. Over the counter medications (e.g., paracetamol or ibuprofen) where the dose taken over the preceding 7 days prior to the planned date of viral challenge had exceeded the maximum permissible 24-hour dose (e.g., >4g per day of paracetamol over the preceding week).
  4. Participants who have received any systemic chemotherapy agent, immunoglobulins, or other cytotoxic or immunosuppressive drugs at any time.

  15 Participant is mentally or legally incapacitated in the opinion of the Investigator.

  16 Females who:

  1. Are breastfeeding within 6 months of study commencement, or
  2. Had been pregnant within 6 months prior to the study, or
  3. Had a positive pregnancy test at any point during screening or prior to inoculation with challenge virus 17 Anyone who is first degree related to anyone who is a delegated member of the research team.

  18 Any other reason that the Investigator considered made the participant unsuitable to participate.

  19 Presence of symptoms and/or fever (defined as participant presenting with a temperature reading of >37.9ºC) suggesting an infection at pre-challenge on Day 0.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Attenuated dengue virus serotype 3 (rDEN3delta30) human infection challenge; GMP-produced rDEN3delta30 virus will be administered to participants via subcutaneous injection.

Other: GMP-produced rDEN3delta30 virus; The challenge virus used in DEN-CHIM-01 study (rDEN3delta30) is produced by the National Institutes of Health (NIH). The rDEN3delta30 strain has been tested in seronegative participants in two challenge studies and with two inoculum doses: 10^3 and 10^4 PFU. The wildtype parent (wildtype DEN3 strain) of the rDEN3Δ30 challenge agent was originally obtained from an infected patient in 1978, in Sleman, Yogyakarta, Indonesia. The Sleman/78 strain was a naturally occurring, partially attenuated dengue virus (DENV) suitable for development as a challenge agent. The NIH team made a contiguous 30-nucleotide deletion in the 3' untranslated region of the wildtype DENV genome and produced recombinant DENV via cDNA clone (rDEN3delta30).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of unsolicited Adverse Events (AEs) [Safety]	Number of unsolicited AEs	From day of viral challenge (Day 0) to Day 28 follow-up visit
Severity of unsolicited AEs [Safety]	Grading severity of AEs is guided by the FDA Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials: Grade 1 (Mild), Grade 2 (Moderate), Grade 3 (Severe), Grade 4 (Potentially life threatening)	From day of viral challenge (Day 0) to Day 28 follow-up visit
Incidence of Serious Adverse Events (SAEs) related to the viral challenge [Safety]	Number of SAEs. Whether an adverse event is serious is determined by the outcome resulting from the event. An SAE is any untoward medical occurrence that: Results in death; Is life-threatening (immediate risk of death); Requires inpatient hospitalization or prolongation of existing hospitalization; Results in persistent or significant disability/incapacity; Results in congenital anomaly/birth defect; Is a medically important event	Day of viral challenge (Day 0) to Day 28 follow-up visit
Number of participants with lab confirmed infection [Infectivity]	Laboratory confirmed infection is defined as at least one quantifiable (greater than lower limit of quantification, ≥LLOQ) qPCR measurement of DENV from blood	From day of viral challenge (Day 0) to discharge from quarantine (Day 10).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of symptomatic DENV infection	Number of participants with lab confirmed symptomatic DENV infection	From day of viral challenge (Day 0) to 10 days post-inoculation
Peak viral load in serum samples measured by qPCR	Peak viral load of DENV as defined by the maximum viral load determined by qPCR measurements	Day 1 post-inoculation to Day 10 for uninfected participants or Day 14 for infected participants
Duration of DENV viraemia measured by qCPR	Duration is defined as the day of first quantifiable viral detection until first confirmed undetectable assessment after their peak measure and after which no further virus is detected.	Day 1 post-inoculation to Day 10 for uninfected participants or Day 14 for infected participants
Incubation period of DENV in serum samples measured by qPCR	Incubation period is defined as the time from inoculation to the first quantifiable viral detection, and up to discharge from quarantine.	Day 1 post-inoculation to Day 10 for uninfected participants or Day 14 for infected participants
Peak viral load in serum samples measured using viral culture	Peak viral load of DENV as defined by the maximum viral load determined by plaque assay	Day 1 post-inoculation to Day 10 for uninfected participants or Day 14 for infected participants
Duration of DENV viraemia measured using viral culture	Duration is defined as the day of first quantifiable viral detection until first confirmed undetectable assessment after their peak measure and after which no further virus is detected.	Day 1 post-inoculation to Day 10 for uninfected participants or Day 14 for infected participants
Incubation period of DENV in serum samples measured using viral culture	Incubation period is defined as the time from inoculation to the first quantifiable viral detection, and up to discharge from quarantine.	Day 1 post-inoculation to Day 10 for uninfected participants or Day 14 for infected participants
Peak viral load in serum samples measured using quantitative NS1 antigen	Peak viral load of DENV as defined by the maximum NS1 antigen measurement	Day 1 post-inoculation to Day 10 for uninfected participants or Day 14 for infected participants
Duration of DENV viraemia measured using quantitative NS1 antigen	Duration is defined as the day of first quantifiable viral detection using quantitative NS1 antigen measurement until first confirmed undetectable assessment after their peak measure and after which no further virus is detected.	Day 1 post-inoculation to Day 10 for uninfected participants or Day 14 for infected participants
Incubation period of DENV in serum samples measured using quantitative NS1 antigen	Incubation period is defined as the time from inoculation to the first quantifiable viral detection using quantitative NS1 antigen measurements, and up to discharge from quarantine.	Day 1 post-inoculation to Day 10 for uninfected participants or Day 14 for infected participants
Severity of DENV-induced symptoms during quarantine period	Severity of DENV-related symptoms are reported and assessed by participants three times daily during quarantine using the Symptom Diary Card. Symptoms are graded on a scale of 0-3: Grade 0: No symptoms.; Grade 1: Just noticeable.; Grade 2: Clearly bothersome from time to time but does not interfere with me doing my normal daily activities.; Grade 3: Quite bothersome most or all the time, and it stops me participating in activities. The sum total symptoms diary card score, peak symptoms diary card score and peak daily symptom score can be calculated.	Day 1 post-viral challenge to Day 10.
Incidence of DENV illness	The incidence of: Febrile illness (FI); Symptomatic illness (SI); Rash; Proportion of participants with Grade 3 symptoms on any occasion at any time from Day 0 to Day 14.; Proportion of participants with Grade 2 or higher symptoms on any occasion at any time from Day 0 to Day 14.; Proportion of participants with Grade 2 or higher Symptoms on two separate occasions at any time from Day 0 to Day 14.; Proportion of participants with any symptom (grade >=1) on any occasion at any time from Day 0 to Day 14.; Proportion of participants with any symptom (grade >=1) on two separate occasions at any time from Day 0 to Day 14.	Day of inoculation (Day 0) to Day 14

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of AEs as defined by clinically significant abnormal laboratory measurements during the quarantine period	Total number of clinically significant laboratory abnormalities during the quarantine period. Laboratory abnormalities associated with dengue fever (e.g.: elevated ALT, AST; decreased platelets) will be expected and will not be additionally captured as an AE unless deemed by an Investigator to be clinically significant.	Day of inoculation (Day 0) to discharge from quarantine (Day 10)
Severity of AEs as defined by clinically significant abnormal laboratory measurements during the quarantine period	Severity of clinically significant laboratory abnormalities during the quarantine period. Grading severity of AEs is guided by the FDA Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials: Grade 1 (Mild), Grade 2 (Moderate), Grade 3 (Severe), Grade 4 (Potentially life threatening)	Day of inoculation (Day 0) to discharge from quarantine (Day 10)
Incidence of concomitant medication usage	Total number of concomitant medications used after viral challenge	Day 0 to Day 28 follow-up
Number of participants with laboratory confirmed infection from urine	Laboratory confirmed infection is defined as occurrence of at least one quantifiable (≥LLOQ) qPCR measurement	Day 1 post-inoculation to discharge from quarantine (Day 10)
Peak viral load in urine measured by qPCR	Peak viral load of DENV as defined by the maximum viral load determined by qPCR measurements in urine	Day 1 post-inoculation to Day 10 for uninfected participants or Day 14 for infected participants
Duration of detectable virus in urine measured by qPCR	Duration is defined as the time from first quantifiable viral detection until first confirmed undetectable assessment after their peak measure after which no further virus is detected or Day 14.	Day 1 post-inoculation to Day 10 for uninfected participants or Day 14 for infected participants
Incubation period of DENV in urine measured by qPCR	Incubation period is defined as the time from inoculation to the first quantifiable viral detection from inoculation and up to Day 10.	Day 1 post-inoculation to Day 10 for uninfected participants or Day 14 for infected participants
Changes in antibody levels after rDEN3delta30 challenge	Assays performed on blood samples to assess humoral immunity / systems serology (for example: DENV neutralizing titres, ELISAs to DENV IgG, IgM, IgA, ADCC)	Up to month 36 post-inoculation
Changes in protein levels after rDEN3delta30 challenge	Assays performed on blood samples to assess proteomic levels and changes (for example, cytokine and chemokines).	Up to month 36 post-inoculation
Changes in cellular immunity after rDEN3delta30 challenge	Assays performed on blood samples include cellular cell quantification and quality of immunity (for example T and B cell frequencies, phenotypes, and functionality assays, ELISPOTS, ICS, cytokine/chemokine responses).	Up to month 36 post-inoculation
Changes in transcriptome levels after rDEN3delta30 challenge	Assays performed on blood samples to measure transcriptome levels and changes (for example, RNAseq, single cell RNAseq, microarray, PCR)	Up to month 36 post-inoculation
Changes in microbiome after rDEN3delta30 challenge	Assays performed on stool samples for microbiome analysis in relation to viral infection, disease, and susceptibility (e.g., PCR, NGS, 16s rRNA)	Up to month 36 post-inoculation
Changes in levels of endothelial derived mediators after rDEN3delta30 challenge	Levels of endothelial derived mediators (e.g., prostacyclin, endothelin-1, nitric oxide) in the plasma will be measured.	Up to month 24 post-inoculation

Collaborators and Investigators

• Sponsor: Tan Tock Seng Hospital
• Collaborators: Duke-NUS Graduate Medical School; A*Star; Lee Kong Chian School of Medicine, Nanyang Technological University
• Investigators: Principal Investigator: Barnaby E Young, MB BChir, PhD, National Centre for Infectious Diseases (NCID)

Publications and helpful links

General Publications

• Blaney JE, Hanson CT, Firestone C-Y, Hanley KA, Murphy BR, Whitehead SS. Genetically modified, live attenuated dengue virus type 3 vaccine candidates. Am J Trop Med Hyg 2004; 71: 811-21.
• Pierce KK, Whitehead SS, Diehl SA, et al. Evaluation of a new dengue 3 controlled human infection model for use in the evaluation of candidate dengue vaccines. MedRxiv Prepr Serv Health Sci 2024; : 2023.06.07.23291100.
• Pierce KK, Durbin AP, Walsh M-CR, et al. TV005 dengue vaccine protects against dengue serotypes 2 and 3 in two controlled human infection studies. J Clin Invest 2024; 134: e173328.

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2026
• Primary Completion (Estimated): May 1, 2026
• Study Completion (Estimated): April 1, 2029

Study Registration Dates

• First Submitted: December 25, 2025
• First Submitted That Met QC Criteria: February 11, 2026
• First Posted (Actual): February 17, 2026

Study Record Updates

• Last Update Posted (Actual): February 17, 2026
• Last Update Submitted That Met QC Criteria: February 11, 2026
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: controlled human infection model; Human challenge study; dengue virus serotype 3; rDEN3delta30; dengue infection; dengue viremia; haematological response to dengue infection; neutralising antibodies to DEN-3
• Additional Relevant MeSH Terms: Vector Borne Diseases; Mosquito-Borne Diseases; Infections; RNA Virus Infections; Virus Diseases; Arbovirus Infections; Flavivirus Infections; Flaviviridae Infections; Hemorrhagic Fevers, Viral; Dengue
• Other Study ID Numbers: 2025/0743

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: All study findings and documents will be regarded as confidential. The investigators and other study personnel must not disclose such information without prior written approval from the PI. Participant confidentiality will be strictly maintained to the extent possible under the law and local hospital policy. Identifiable information will be removed from any published data.

Drug and device information, study documents

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