A Controlled Human Infection Model of Dengue
ConditionDengue
Trial statusRecruiting
Trial phaseNot applicable
Trial typeInterventional
Biological sexAll
Age21-45
SponsorTan Tock Seng Hospital
About this trial
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.
Eligibility criteria
This trial accepts healthy volunteersQualifiers
An informed consent form (ICF) has been signed and dated by the participant, an investigator, and a witness
Adult, aged between 21 and 45 years, inclusive (at the time of consent)
No known history of prior dengue, zika or other Orthoflavivirus infection
No history of prior dengue, yellow fever, Japanese encephalitis virus, or other Orthoflavivirus vaccination
Disqualifiers
History or evidence of any clinically significant or currently active neurologic, cardiac, pulmonary, hepatic, rheumatologic, autoimmune, or renal disease.
History of active depression and/or anxiety with associated severe psychiatric comorbidities, for example psychosis.
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.
Significant history or presence of drug or alcohol misuse
Trial design
Design model
Single group
Treatments tested in this trial
GMP-produced rDEN3delta30 virus
Other interventionThe 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).
Treatment groups
5 Participants
are divided into 1 treatment groupGroup A: Attenuated dengue virus serotype 3 (rDEN3delta30) human infection challengeExperimental treatment 1 intervention
Trial outcomes
Primary outcomes
1
Incidence of unsolicited Adverse Events (AEs) [Safety]
Number of unsolicited AEs
Time frame
From day of viral challenge (Day 0) to Day 28 follow-up visit2
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)
Time frame
From day of viral challenge (Day 0) to Day 28 follow-up visit3
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
Time frame
Day of viral challenge (Day 0) to Day 28 follow-up visit4
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
Time frame
From day of viral challenge (Day 0) to discharge from quarantine (Day 10).Secondary outcomes
1
Incidence of symptomatic DENV infection
Number of participants with lab confirmed symptomatic DENV infection
Time frame
From day of viral challenge (Day 0) to 10 days post-inoculation2
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
Time frame
Day 1 post-inoculation to Day 10 for uninfected participants or Day 14 for infected participants3
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.
Time frame
Day 1 post-inoculation to Day 10 for uninfected participants or Day 14 for infected participants4
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.
Time frame
Day 1 post-inoculation to Day 10 for uninfected participants or Day 14 for infected participantsOther outcomes
1
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.
Time frame
Day of inoculation (Day 0) to discharge from quarantine (Day 10)2
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)
Time frame
Day of inoculation (Day 0) to discharge from quarantine (Day 10)3
Incidence of concomitant medication usage
Total number of concomitant medications used after viral challenge
Time frame
Day 0 to Day 28 follow-up4
Number of participants with laboratory confirmed infection from urine
Laboratory confirmed infection is defined as occurrence of at least one quantifiable (≥LLOQ) qPCR measurement
Time frame
Day 1 post-inoculation to discharge from quarantine (Day 10)Sponsors and contacts
Click on the lead sponsor to view all of their trials.
Tan Tock Seng Hospital
Lead sponsor
A*Star
Collaborator
Duke-NUS Graduate Medical School
Collaborator
Nanyang Technological University
Collaborator
Source ClinicalTrials.gov