A Controlled Human Infection Model of Dengue
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 5
- 试验地点
- 1
- 主要终点
- Incidence of unsolicited Adverse Events (AEs) [Safety]
研究概览
简要总结
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:
- 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.
- Characterise the clinical, haematological and virological response following controlled inoculation of the attenuated DEN3 challenge agent.
- Conduct deep immunophenotyping to understand the cellular, humoral and innate immune response to dengue infection.
- Explore the longitudinal immune response in the 3 years after challenge, including following subsequent dengue vaccination.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 21 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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
排除标准
- •) 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.
- •Exclusion Criteria:
- •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/m
- •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.
研究组 & 干预措施
Attenuated dengue virus serotype 3 (rDEN3delta30) human infection challenge
GMP-produced rDEN3delta30 virus will be administered to participants via subcutaneous injection.
干预措施: GMP-produced rDEN3delta30 virus (Other)
结局指标
主要结局
Incidence of unsolicited Adverse Events (AEs) [Safety]
时间窗: From day of viral challenge (Day 0) to Day 28 follow-up visit
Number of unsolicited AEs
Severity of unsolicited AEs [Safety]
时间窗: From day of viral challenge (Day 0) to Day 28 follow-up visit
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)
Incidence of Serious Adverse Events (SAEs) related to the viral challenge [Safety]
时间窗: Day of viral challenge (Day 0) to Day 28 follow-up visit
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
Number of participants with lab confirmed infection [Infectivity]
时间窗: From day of viral challenge (Day 0) to discharge from quarantine (Day 10).
Laboratory confirmed infection is defined as at least one quantifiable (greater than lower limit of quantification, ≥LLOQ) qPCR measurement of DENV from blood
次要结局
- Incidence of symptomatic DENV infection(From day of viral challenge (Day 0) to 10 days post-inoculation)
- Peak viral load in serum samples measured by qPCR(Day 1 post-inoculation to Day 10 for uninfected participants or Day 14 for infected participants)
- Duration of DENV viraemia measured by qCPR(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(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(Day 1 post-inoculation to Day 10 for uninfected participants or Day 14 for infected participants)
- Duration of DENV viraemia measured using viral culture(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(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(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(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(Day 1 post-inoculation to Day 10 for uninfected participants or Day 14 for infected participants)
- Severity of DENV-induced symptoms during quarantine period(Day 1 post-viral challenge to Day 10.)
- Incidence of DENV illness(Day of inoculation (Day 0) to Day 14)