Safety and Immunogenicity of the Live Attenuated Tetravalent Butantan-Dengue Vaccine in Autoimmune Rheumatic Diseases

Safety and Immunogenicity of the Live Attenuated Tetravalent Butantan-Dengue Vaccine (Butantan-DV) in Patients With Autoimmune Rheumatic Diseases Living in Dengue-Endemic Areas

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.

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.

Cellular-immunity substudy: ~20 % of participants provide peripheral blood mononuclear cells at baseline, Day 42 and Day 400 for intracellular cytokine staining to define CD8+ T-cell responses against pooled dengue peptides, filling a key knowledge gap on cell-mediated protection in immunocompromised hosts.

Safety oversight is reinforced by a predefined toxicity-grading schema, 24-hour study hotline, systematic capture of solicited/unsolicited adverse events through Day 42, and independent Data and Safety Monitoring Board review at six-month intervals or ad-hoc for any serious events.

Disease-activity flares will be tracked with validated indices tailored to each ARD diagnosis (e.g., DAS-28, SLEDAI-2K, ASDAS) on Days 1 and 42 to distinguish vaccine reactogenicity from underlying disease exacerbation.

Physical activity will be assessed using validated questionnaires at D1 and objective accelerometry (D1-D14), while dietary intake will be evaluated through repeated 24-hour dietary recalls and food quality classification starting at D1.

The primary scientific contribution is to establish whether seroconversion rates (PRNT50) in low-grade immunosuppressed ARD patients are non-inferior to healthy controls at Day 42, while rigorously quantifying common and serious adverse events. Secondary analyses explore viremia kinetics, T-cell immunity, antibody durability to one year, and host- or treatment-related modifiers of vaccine response.

By integrating comprehensive immunologic endpoints with robust safety monitoring, this trial will provide the first high-quality evidence to inform dengue vaccination policy for children, adolescents and adults living with ARDs in endemic regions-potentially broadening individual protection and supporting public-health efforts to mitigate dengue's impact in Brazil and similar settings.

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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