A Controlled Human Infection Model of Dengue

Обзор

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.

Подробное описание

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.

Вмешательства

• Другое 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 den

Первичные конечные точки

• Incidence of unsolicited Adverse Events (AEs) [Safety] [Срок оценки: From day of viral challenge (Day 0) to Day 28 follow-up visit]
• Severity of unsolicited AEs [Safety] [Срок оценки: 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] [Срок оценки: Day of viral challenge (Day 0) to Day 28 follow-up visit]
• Number of participants with lab confirmed infection [Infectivity] [Срок оценки: From day of viral challenge (Day 0) to discharge from quarantine (Day 10).]

Вторичные конечные точки (12)

• Incidence of symptomatic DENV infection [Срок оценки: From day of viral challenge (Day 0) to 10 days post-inoculation]
• Peak viral load in serum samples measured by qPCR [Срок оценки: Day 1 post-inoculation to Day 10 for uninfected participants or Day 14 for infected participants]
• Duration of DENV viraemia measured by qCPR [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: Day 1 post-inoculation to Day 10 for uninfected participants or Day 14 for infected participants]
• Duration of DENV viraemia measured using viral culture [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: Day 1 post-inoculation to Day 10 for uninfected participants or Day 14 for infected participants]
• Severity of DENV-induced symptoms during quarantine period [Срок оценки: Day 1 post-viral challenge to Day 10.]
• Incidence of DENV illness [Срок оценки: Day of inoculation (Day 0) to Day 14]

Критерии участия

Критерии включения

• 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
• Sero-suitable based on the pre-screening serology result
• 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.

Критерии исключения

• 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
• History of anaphylaxis and/or a history of severe allergic reaction or significant intolerance to any food or drug, as assessed by the PI.
• Family history of 1st degree relative aged 50 years or less with sudden cardiac or unexplained death
• A total body weight of ≤ 45kg and a Body Mass Index (BMI) ≤18 kg/m2 and ≥30 kg/m2.
• Venous access deemed inadequate for the phlebotomy demands of the study.
• 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:

• Receipt of any investigational drug within 3 months prior to the planned date of viral challenge
• Receipt of systemic (intravenous and/or oral) glucocorticoids or systemic antiviral drugs within 6 months prior to the planned date of viral challenge.
• 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).
• 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:

• Are breastfeeding within 6 months of study commencement, or
• Had been pregnant within 6 months prior to the study, or
• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Другое

Центры проведения

Сингапур · 1 центр

• National Centre for Infectious Diseases (NCID) — Singapore

Публикации

• Blaney JE Jr, Hanson CT, Firestone CY, Hanley KA, Murphy BR, Whitehead SS. Genetically modified, live attenuated dengue virus type 3 vaccine candidates. Am J Trop Med Hyg. 2004 Dec;71(6):811-21. PMID 15642976
• 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 MR, Carmolli M, Sabundayo BP, Dickson DM, Diehl SA, Whitehead SS, Kirkpatrick BD. TV005 dengue vaccine protects against dengue serotypes 2 and 3 in two controlled human infection studies. J Clin Invest. 2024 Feb 1;134(3):e173328. doi: 10.1172/JCI173328. PMID 37971871

Идентификаторы

NCT: NCT07412483 · 2025/0743

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗