Dengue viral infection and dengue hemorrhagic fever (DHF) are important emerging health problems worldwide. Several candidate dengue vaccines are currently in different stages of development but CYD is the only licensed vaccine currently available. Although this vaccine can induce neutralizing antibodies against all four DENV serotypes, the vaccine showed enhanced hospitalization in recipients who were dengue-naïve before vaccination. The long-term safety assessment of the vaccine in endemic regions demonstrated that the risk of hospitalization in year 3 of vaccination was higher in the vaccine group especially among recipients under 9 years of age with a relative risk of 1.58 \[95% CI, 0.83 to 3.02\]. Surrogate animal models are not good models to see whether the vaccine or therapeutic is able to be tested in clinical trials since animals do not develop symptoms of infection as in humans. The ADE phenomenon and the lack of known correlates of protection in animal models are still the major problems and challenges in the development of an effective dengue vaccine and make it difficult to identify candidate vaccines. The efficacy and safety situation of CYD also highlights the requirement of verification of candidate vaccines before performing clinical trials with a large number of participants. The controlled human infection model, therefore, has been proposed to pre-evaluate candidate vaccines before moving into larger clinical trials. It has been previously used for several infectious diseases i.e., malaria, norovirus, influenza, cholera, Campylobacter, and Shigella, to accelerate vaccine or therapeutic development. For dengue, two controlled dengue human infection models (DHIM) have been established for vaccine testing and evaluation of therapeutics in a dengue naïve population in the USA. Although it has been proved useful for studies of dengue in naïve individuals, it is necessary to set up DHIM in endemic regions like Thailand as more than 90% of the population has been previously exposed to the virus and, importantly, host immune status prior to the introduction of viruses can influence clinical outcomes and vaccine efficacy. It will also be very challenging in terms of safety concerns since having pre-existing immune responses to natural DENV infection is a risk factor for severe dengue. The establishment of DHIM will not only allow a small-scale demonstration for safety and efficacy of vaccines or therapeutics which can appropriately guide the design of phase III to be more cost-effective but it will also allow the investigation of immune correlates of protection and determination of factors correlated with disease protection and pathogenesis as clinical endpoints can be closely followed up in all participants. Safety, Virological and Immunological Assessment of the Controlled Dengue Human Infection Model in Thailand (DHIT) is proposed to challenge the live attenuated dengue virus serotype 2, rDEN2Δ30-7169, in 5 flavivirus naïve participants recruited from Bangkok, Thailand, and aims to assess the safety, viremia, NS1 antigenemia profile, and immunogenicity of the challenge virus in the volunteers. In addition, this DHIT project will vaccinated all 5 participants with Dengvaxia® after inoculation with the challenge virus to reduce the risk of severe disease of dengue in the future. Blood collection will be obtained after each vaccination to assess virological and immunological profiles. Active and passive surveillance will be set up to monitor for dengue infection after vaccination. The overall study period from administration of live attenuated virus until last follow-up visit is 38 months.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
OTHER
Masking
NONE
Enrollment
5
rDEN2Δ30-7169 will be inoculated at Study Day 0. After 6 months of the inoculation, the participants will be vaccinated with Dengvaxia® until completion of 3 doses with 6-month interval between each dose.
Siriraj Hospital
Bangkok Noi, Bangkok, Thailand
The safety of rDEN2Δ30-7169 in flavivirus naïve participants
Occurrence of local and general adverse events (AEs) and serious adverse events (SAEs)
Time frame: 21 Days
The frequency of viremia following administration with rDEN2Δ30-7169 in flavivirus naïve participants
Proportion of number of volunteer with detectable virus genome assessed by nested RT-PCR, real time RT-PCR and virus culture after administration of DENV2Δ30-7169
Time frame: 180 Days
The quantity of viral genome following administration with rDEN2Δ30-7169 in flavivirus naïve participants
The quantity of viral genome (copies/mL) assessed by nested RT-PCR, real time RT-PCR and virus culture after administration of DENV2Δ30-7169
Time frame: 180 Days
The duration of viremia following administration with rDEN2Δ30-7169 in flavivirus naïve participants
Days of detectable virus genome assessed by nested RT-PCR, real time RT-PCR and virus culture after administration of DENV2Δ30-7169
Time frame: 180 Days
The frequency of viremia following administration with rDEN2Δ30-7169 in flavivirus naïve participants
Proportion of number of volunteer with detectable infectious activity assessed by nested RT-PCR, real time RT-PCR and virus culture after administration of DENV2Δ30-7169
Time frame: 180 Days
The quantity of infectious activity following administration with rDEN2Δ30-7169 in flavivirus naïve participants
The quantity of infectious activity (FFU/mL) assessed by nested RT-PCR, real time RT-PCR and virus culture after administration of DENV2Δ30-7169
Time frame: 180 Days
The duration of infectious activity following administration with rDEN2Δ30-7169 in flavivirus naïve participants
Days of detectable infectious activity assessed by nested RT-PCR, real time RT-PCR and virus culture after administration of DENV2Δ30-7169
Time frame: 180 Days
The frequency of NS1 antigenemia following administration with rDEN2Δ30-7169 in flavivirus naïve participants
Proportion of number of volunteer with detectable NS1 antigen after administration of DENV2Δ30-7169
Time frame: 180 Days
The quantity of NS1 antigenemia following administration with rDEN2Δ30-7169 in flavivirus naïve participants
The quantity of NS1 antigenemia (ng/mL) after administration of DENV2Δ30-7169
Time frame: 180 Days
The duration of NS1 antigenemia following administration with rDEN2Δ30-7169 in flavivirus naïve participants
Days of detectable NS1 antigen after administration of DENV2Δ30-7169
Time frame: 180 Days
The immunogenicity of rDEN2Δ30-7169 in Thai flavivirus naïve participants
Levels of neutralizing antibodies (NT50) as measured by PRNT to dengue virus after administration with rDEN2Δ30-7169
Time frame: 180 Days
Measurement of levels of anti-dengue virion-IgM/IgG antibodies following administration with rDEN2Δ30-7169 in flavivirus naïve participants
Levels of anti-dengue virion-IgM/IgG antibodies (titer) as measured by ELISA following administration with rDEN2Δ30-7169 in flavivirus naïve participants
Time frame: 180 Days
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