Safety, Virological and Immunological Assessment of Live Attenuated Dengue Serotype 2 rDEN2delta30-7169. (DHIT)

Safety, Virological and Immunological Assessment of the Controlled Dengue Human Infection Model in Thailand

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 Overview

• Status: Not yet recruiting
• Conditions: Dengue
• Intervention / Treatment: Biological: rDEN2Δ30-7169

• Study Type: Interventional
• Enrollment (Anticipated): 5
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Panisadee Avirutnan, M.D., Ph.D.; Phone Number: +6624196667-70; Email: panisadee.avi@mahidol.edu

Study Locations

• Thailand
  • Bangkok
    • Bangkok Noi, Bangkok, Thailand, 10700
      • Siriraj Hospital
      • Contact: Panisadee Avirutnan, M.D., Ph.D.; Phone Number: +6624196667-70; Email: panisadee.avi@mahidol.edu
      • Principal Investigator: Panisadee Avirutnan, M.D., Ph.D.
      • Principal Investigator: Oranich Navanukroh, M.D.
      • Sub-Investigator: Nasikarn Angkasekwinai, M.D.
      • Sub-Investigator: Kobporn Boonnak, Ph.D.
      • Sub-Investigator: Woraphat Ratta-apha, M.D., Ph.D.
      • Sub-Investigator: Thaneeya Roytrakul, DPhil (Oxon)
      • Sub-Investigator: Sansanee Noisakran, Ph.D.
      • Sub-Investigator: Nuntaya Pornmun, Ph.D.
      • Sub-Investigator: Chunya Puttikhunt, Ph.D.
      • Sub-Investigator: Dumrong Mairiang, Ph.D.
      • Sub-Investigator: Sanhapon Ketklao, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 28 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Thai healthy volunteers, aged between 18 to 30 years old and weight is greater than or equal to 45 kg and have Thai language literacy.
2. Don't have any history of previous dengue, zika or Japanese encephalitis virus infection
3. Have not given blood donation in the past 3 months
4. Education: higher than high school

5. Display flavivirus immunity profile defined by the standard PRNT 50% (PRNT50) as follows: flavivirus naïve is defined as the PRNT50 titer against

   • DENV1 < 1:5
   • DENV2 < 1:5
   • DENV3 < 1:5
   • DENV4 < 1:5
   • ZIKV < 1:5
   • JEV < 1:5
6. Willingness to participate in the study as evidenced by signing the informed consent document.
7. Female participants of childbearing potential should be agreed to either abstinence or use at least one primary form of contraception from the time of screening for rDEN2Δ30-7169 administration until 1 month after complete course of Dengvaxia® vaccination (Study Day 568).

Exclusion Criteria:

1. For female participants: Currently pregnant, as determined by positive β-human choriogonadotropin (HCG) test or breast-feeding, and given birth or abortion within 6 months.
2. History of previous acute undifferentiated febrile illness leading to hospitalization in the past 3 months
3. Behavioral, cognitive, or psychiatric disease that, in the opinion of the investigator, affects the subject's ability to understand and cooperate with the requirements of the study protocol.
4. Any significant alcohol or drug abuse in the past 12 months that has caused medical, occupational, or family problems, as indicated by subject history.
5. History of a severe allergic reaction or anaphylaxis
6. Severe asthma (emergency room visit or hospitalization within the last 6 months).
7. Any known immunodeficiency syndrome.
8. Having any pre-existing medical conditions consist of thrombocytopenia, autoimmune disease and cancer based on history, physical examination, and/or laboratory studies.
9. Current use of anticoagulant medications (this includes anti-platelet medication such as aspirin or non-steroidal anti-inflammatory medications).
10. Use of corticosteroids (excluding topical or nasal) or immunosuppressive drugs within 28 days prior to or following vaccination. An immunosuppressive dose of corticosteroids is defined as ≥ 10 mg of a prednisone equivalent per day for ≥ 14 days.
11. Asplenia
12. Receipt of any vaccine within 28 days or a killed vaccine within 14 days prior to receive virus administration, or anticipated receipt of any vaccine during the 28 days following rDEN2∆30-7169 administration.
13. Receipt of blood products within the past 6 months, including transfusions or immunoglobulin, or anticipated receipt of any blood products or immunoglobulin during the 28 days following rDEN2∆30-7169 administration.
14. Previous receipt of a flavivirus vaccine (licensed or experimental).
15. Screening laboratory values of Grade 1 or above (as defined in this protocol) for ANC (<750 /mm3), Platelet (<100,000 /mm3), PT (> 1.25 x ULN), APTT (> 1.66 x ULN), ALT (>2.5 x ULN) and serum creatinine (> 1.3 x ULN OR Increase to >1.3 x participant's baseline)
16. Body temperature higher than 37.5 °C
17. HIV infection, as indicated by anti-HIV screening assays.
18. Hepatitis C virus (HCV) infection, as indicated by anti-HCV screening assays.
19. Hepatitis B virus (HBV) infection, as indicated by hepatitis B surface antigen (HBsAg) and/or anti-HBc screening.
20. Any other condition that, in the opinion of the investigator, would jeopardize the safety or rights of a subject participating in the trial, or would render the subject unable to comply with the protocol.

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: Flavivirus naïve	Biological: rDEN2Δ30-7169; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The safety of rDEN2Δ30-7169 in flavivirus naïve participants	Occurrence of local and general adverse events (AEs) and serious adverse events (SAEs)	21 Days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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	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	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	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	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	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	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	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	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	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	180 Days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The cellular immune responses including dengue virus specific B cells and NS3 peptides specific T cells to all four DENV serotypes following administration of rDEN2Δ30-7169 in Thai flavivirus naïve participants	The frequency of dengue virus specific B cells and NS3 peptides specific T cells (percentage of cells/total lymphocytes) to all four DENV serotypes following administration of rDEN2Δ30-7169 in Thai flavivirus naïve participants	Study Day 0-60
To measure anti-dengue virion-IgM/IgG antibodies following vaccination with Dengvaxia®	Levels of anti-dengue virion-IgM/IgG antibodies (titer) as measured by ELISA following vaccination with Dengvaxia®	Study Day 194-1140
The immunogenicity following vaccination with Dengvaxia®	Levels of neutralizing antibodies (NT50) as measured by PRNT to dengue virus following vaccination with Dengvaxia®	Study Day 194-1140
The frequency of viremia in oral fluid specimens following administration with rDEN2Δ30-7169	Proportion of number of volunteer with viremia as assessed by RT-PCR oral fluid specimens following administration with rDEN2Δ30-7169 and vaccination with Dengvaxia®	Study Day 0-600
The quantity of viremia in oral fluid specimens following administration with rDEN2Δ30-7169	The quantity of viremia (copies/mL) as assessed by RT-PCR oral fluid specimens following administration with rDEN2Δ30-7169 and vaccination with Dengvaxia®	Study Day 0-600
The duration (days) of viremia in oral fluid specimens following administration with rDEN2Δ30-7169	Days of viremia as assessed by RT-PCR oral fluid specimens following administration with rDEN2Δ30-7169 and vaccination with Dengvaxia®	Study Day 0-600
Anti-NS1 antibodies and anti-dengue IgM, IgG, IgG1, IgA antibodies levels in oral fluid specimens following administration with rDEN2Δ30-7169 and vaccination with Dengvaxia® in Thai flavivirus naïve participants	Levels of anti-NS1 antibodies and anti-dengue IgM, IgG, IgG1, IgA antibodies (unit) as measured by ELISA in oral fluid specimens following administration with rDEN2Δ30-7169 and vaccination with Dengvaxia® in Thai flavivirus naïve participants	Study Day 0-600

Collaborators and Investigators

• Sponsor: Mahidol University

Study record dates

Study Major Dates

• Study Start (Anticipated): August 1, 2022
• Primary Completion (Anticipated): January 1, 2023
• Study Completion (Anticipated): March 1, 2026

Study Registration Dates

• First Submitted: July 11, 2022
• First Submitted That Met QC Criteria: July 25, 2022
• First Posted (Actual): July 27, 2022

Study Record Updates

• Last Update Posted (Actual): July 27, 2022
• Last Update Submitted That Met QC Criteria: July 25, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Controlled Human Infection Model; Flavivirus naïve
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Arbovirus Infections; Vector Borne Diseases; Flavivirus Infections; Flaviviridae Infections; Hemorrhagic Fevers, Viral; Dengue
• Other Study ID Numbers: 022/2565(IRB1)

Drug and device information, study documents

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