NCT07412483

A Controlled Human Infection Model of Dengue

• Status: Recruiting
• Phase: N/A
• Study type: Interventional
• Enrollment: 5 (estimated)
• Sponsor: Tan Tock Seng Hospital · Academic / Other
• Sex: All
• Age: 21 Years – 45 Years
• Healthy volunteers: Accepted

Summary

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.

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.

Conditions

• Dengue

Interventions

Type	Name	Description
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).

Timeline

• Start date: 2026-03-01
• Primary completion: 2026-05-01
• Completion: 2029-04-01
• First posted: 2026-02-17
• Last updated: 2026-02-17

Locations

1 site across 1 country: Singapore