Safety and Immunogenicity of the Live Attenuated Tetravalent Butantan-Dengue Vaccine (Butantan-DV) in Patients With Autoimmune Rheumatic Diseases Living in Dengue-Endemic Areas
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 入组人数
- 477
- 试验地点
- 4
- 主要终点
- Seroconversion Rate After Vaccination
研究概览
简要总结
The goal of this clinical trial is to evaluate whether the live attenuated tetravalent Butantan-Dengue vaccine (Butantan-DV) is safe and capable of inducing an immune response in patients aged 12 to 59 years with autoimmune rheumatic diseases (ARDs) who are clinically stable and under low-grade or no immunosuppression, as well as in healthy volunteers matched by sex and age.
The main questions it aims to answer are:
Does the vaccine induce adequate seroconversion in patients with ARDs compared to healthy controls? What is the frequency and intensity of common adverse events after vaccination in ARDs patients? Does physical activity levels and nutritional status influence vaccine-induced immune response in patients with ARDs?
Researchers will compare patients with ARDs to healthy controls to evaluate if the vaccine elicits similar immune responses and safety profiles.
All participants will:
- receive a single 0.5 mL dose of the Butantan-DV vaccine via subcutaneous injection;
- undergo blood sample collection before and after vaccination (baseline, Day 42, and Day 400) to assess antibody and cellular responses;
- attend follow-up visits on Days 7, 14, and 42 for safety monitoring and laboratory tests;
- report any symptoms or adverse events using a standardized diary for 42 days;
- be followed for up to one year for long-term safety and immunogenicity assessments.
- wear a device for 14 consecutive days to assess current and habitual physical activity levels.
- answer three non-consecutive 24-hour dietary recalls, including at least one weekend day to assess nutritional status.
- collect blood samples one-year after vaccination to access immunogenicity and cellular response.
Researcher will also perform subgroups analysis in:
A viremia subgroup (50 patients and 50 healthy controls) will provide additional samples on Days 1, 7, 14, 28, 42, and-if viremia is detected-Day 68, to evaluate post-vaccination viremia and its duration.
An immunogenicity subgroup (~20% of participants, n=96) will undergo cellular immune response testing via flow cytometry to evaluate T-cell responses.
详细描述
Dengue is hyper-endemic in Brazil, with millions of probable cases and a growing burden of hospitalisation and death each year. Patients with autoimmune rheumatic diseases (ARDs) are especially vulnerable because their underlying immune dysregulation and the use of immunosuppressive agents increase the risk of severe infection and poor outcomes. Current rheumatology guidelines recommend vaccination, yet live-attenuated products are traditionally avoided unless immunosuppression is minimal, leaving an important evidence gap for this population.
The Butantan-DV vaccine is a single-dose, tetravalent, live-attenuated formulation derived from all four dengue serotypes. Phase II-III data in the general population have demonstrated an overall efficacy of ~80 % and an acceptable safety profile, with clear operational advantages over other licensed vaccines (broader age indication and single-dose schedule). However, its immunogenicity and safety have not been prospectively examined in ARD patients under low-grade or no immunosuppression-precisely the subgroup for whom live vaccines may be permissible but still pose theoretical risks.
This open-label, Phase IIIb, prospective study will enrol 318 clinically stable ARD patients (ages 12-59 years) on low-grade or no immunosuppression and 159 age- and sex-matched healthy controls living in dengue-endemic areas. All participants receive a single 0.5 mL subcutaneous dose of Butantan-DV on Day 1. Core follow-up visits occur on Days 7, 14 and 42 for clinical assessment, laboratory safety panels and adverse-event diary review; long-term surveillance continues to Day 400 to characterise antibody persistence and late safety signals.
Two exploratory components will be evaluated:
Viremia substudy: 50 patients and 50 controls undergo additional sampling on Days 1, 7, 14, 28, 42 (and Day 68 if viraemic) to quantify the incidence, magnitude and duration of post-vaccination viremia by multiplex RT-PCR.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 年龄范围
- 12 Years 至 59 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Age between 12 and 59 years
- •Male or female
- •Clinical diagnosis of an autoimmune rheumatic disease (ARD) based on internationally accepted criteria (e.g., rheumatoid arthritis, systemic lupus erythematosus, juvenile idiopathic arthritis, Sjögren's syndrome, vasculitis)
- •Healthy control matched by age and sex
- •ARD patients with clinically stable disease for at least 3 months
- •ARD patients under low-grade immunosuppression or no immunosuppression
- •Acceptable immunosuppressive treatments include:
- •Hydroxychloroquine Sulfasalazine Prednisone ≤ 20 mg/day Methotrexate ≤ 0.4 mg/kg/week (maximum 20 mg/week) Leflunomide 20 mg/day Azathioprine < 3 mg/kg/day Combination therapy with low-dose prednisone (≤ 7.5 mg/day), hydroxychloroquine, or sulfasalazine
- •Healthy controls with no history of autoimmune or chronic infectious diseases
- •Healthy controls not taking immunosuppressive medications Willing and able to comply with study procedures and follow-up
- •Female participants of reproductive potential with negative pregnancy test at baseline
- •Female participants of reproductive potential agreeing to use effective contraception for at least 90 days after vaccination
排除标准
- •Prior receipt of any dengue vaccine
- •Receipt of a live attenuated vaccine within 4 weeks prior to enrollment
- •Receipt of an inactivated vaccine within 2 weeks prior to enrollment
- •Known allergy to any component of the vaccine
- •Febrile illness (≥ 37.8°C) within 72 hours prior to vaccination
- •History of immunodeficiency syndromes
- •History of asplenia
- •History of cancer
- •History of HIV infection
- •History of primary immunodeficiencies
- •Immunosuppression due to organ transplant
- •Chronic uncontrolled comorbidities (e.g., heart failure, renal failure, hepatic insufficiency, diabetes mellitus)
- •Hospitalization or acute illness at screening
- •Receipt of blood transfusion within 3 months prior to enrollment
- •Current pregnancy or breastfeeding
- •Intention to become pregnant within 90 days post-vaccination
- •Participation in another clinical trial within 30 days prior to enrollment
研究组 & 干预措施
ARDs
Patients with ARDs will receive 0.5 mL subcutaneous dose of Butantan-DV
干预措施: Dengue 1,2,3,4 (attenuated) vaccine (Biological)
Control
Healthy subjects will receive 0.5 mL subcutaneous dose of Butantan-DV
干预措施: Dengue 1,2,3,4 (attenuated) vaccine (Biological)
结局指标
主要结局
Seroconversion Rate After Vaccination
时间窗: From enrollment to day 42 after vaccination
Proportion of participants who achieve seroconversion (defined by PRNT50 neutralizing antibody titers) for any dengue serotype at Day 42 following a single dose of the Butantan-DV vaccine. Comparisons will be made between patients with autoimmune rheumatic diseases (ARDs) and healthy controls.
Frequency and Intensity of Common Adverse Events
时间窗: Baseline through Day 42.
Frequency and intensity of solicited local and systemic adverse events (e.g., pain at injection site, fever, headache, fatigue) with frequency up to 1/100, up to Day 42 post-vaccination, classified according to severity grading. Comparisons will be made between ARD patients and healthy controls.
次要结局
- Disease Activity Flares After Vaccination(Day 1 to Day 42)
- Frequency of Serious Adverse Events (SAEs)(Day 1 through Day 400)
- Frequency of Adverse Events of Special Interest (AESIs)(Day 1 through Day 400)
- Intensity of Viremia Post-Vaccination(Days 1, 7, 14, 28, 42, and 68 (if viremia is detected))
- Duration of Viremia Post-Vaccination(Days 1, 7, 14, 28, 42, and 68 (if viremia is detected))
- Frequency of Grade 3 or 4 Adverse Events(Day 1 to Day 42)
- Geometric Mean Titers Against Dengue Serotypes(Day 1 and Day 42)
- Factors Associated With Vaccine Immunogenicity(Day 1 and Day 42)
- Persistence of Antibody Response(Day 400)
- Disease Activity Flares After Vaccination(Day 1 to Day 42)
- Frequency of Serious Adverse Events (SAEs)(Day 1 through Day 400)
- Frequency of Adverse Events of Special Interest (AESIs)(Day 1 through Day 400)
- Intensity of Viremia Post-Vaccination(Days 1, 7, 14, 28, 42, and 68 (if viremia is detected))
- Geometric Mean Titers Against Dengue Serotypes(Day 1 and Day 42)
- Duration of Viremia Post-Vaccination(Days 1, 7, 14, 28, 42, and 68 (if viremia is detected))
- Factors Associated With Vaccine Immunogenicity(Day 1 and Day 42)
- Persistence of Antibody Response(Day 400)
- Frequency of Grade 3 or 4 Adverse Events(Day 1 to Day 42)
- Influence of Physical Activity Levels on Vaccine-Induced Humoral Immune Response(Day 1 to 14)
- Influence of dietary intake on Vaccine-Induced Humoral Immune Response(Day 1)