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

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.