TV003 / Medigen Biotech, National Institute of Allergy and Infectious Diseases, Butantan Institute - LARVOL DELTA

Evaluation of the Protective Efficacy of TV003 or Previous Zika Infection Against Infection With ZIKV-SJRP Challenge Compared to DENV and ZIKV-naïve Controls Against Infection With ZIKV-SJRP Challenge (clinicaltrials.gov) - P1 | N=27 | Completed | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Recruiting ➔ Completed

Trial completion • Dengue Fever • Infectious Disease

Butantan-DV Vaccine in Elderly Populations (DEN-04-IB) (clinicaltrials.gov) - P3 | N=997 | Recruiting | Sponsor: Butantan Institute | Not yet recruiting ➔ Recruiting

Enrollment open • Head-to-Head • Dengue Fever

Long-term efficacy and safety of the single-dose tetravalent Butantan dengue vaccine. (PubMed, Nat Med) - P3 | "The proportions of participants with unsolicited vaccine-related AEs (including serious AEs) were comparable between intervention groups. A single dose of Butantan-DV was efficacious against symptomatic virologically confirmed dengue because of DENV-1 or DENV-2, regardless of dengue serostatus at baseline, with no safety concerns observed during the 5-year follow-up (ClinicalTrials.gov: NCT02406729 )."

Journal • Dengue Fever • Infectious Disease • Pain

Animal Models Illuminate Dengue Immunopathogenesis to Guide Vaccine and Therapeutic Developments. (PubMed, J Virol Methods) - "The protection provided by the monoclonal antibody C10 was shown to mitigate antibody-dependent enhancement (ADE) in murine models, though it is not associated with the Dengvaxia vaccine. The further development of these animal models will be necessary to expedite the safe development of next-generation dengue vaccines (TAK-003, TV003/TV005), antivirals (favipiravir, sofosbuvir), and immune modulators (IL-6 and TNF-α blockers) for use in endemic areas."

Journal • Preclinical • Review • Dengue Fever • Hematological Disorders • Infectious Disease • Obesity • IFNAR2 • IL1B • IL6

Barriers to dengue vaccine coverage in low- and middle-income countries (LMICs). (PubMed, Virology) - "Dengvaxia (CYD-TDV) and Qdenga (TAK-003) are the only two licensed dengue vaccines currently available, while Butantan-DV (TV003) is an advanced candidate with promising Phase 3 clinical trial results...We therefore identify several state and market-driven systemic factors, as well as declining vaccine confidence, as barriers to scaling up dengue vaccine access in LMICs. These barriers must be addressed through creative solutions to ensure the equitable distribution of dengue vaccines to the populations and countries that need them the most."

Journal • Review • Dengue Fever • Infectious Disease

Current status of dengue fever epidemics and vaccine development. (PubMed, Virol Sin) - "To date, two vaccines-Dengvaxia and Qdenga-have been licensed for clinical use. Six other vaccine candidates are currently in clinical trials, among which the tetravalent live-attenuated vaccines TV003/TV005 are considered the most promising. Despite considerable advances in dengue vaccine research, significant challenges remain, including the need to elicit balanced immune responses against the four serotypes and to reduce the risk of antibody-dependent enhancement (ADE). Taken together, this review systematically summarizes recent global and regional trends in dengue fever and the current progress in dengue vaccine development, collectively offering a valuable resource for informing prevention and control strategies."

Journal • Review • Dengue Fever • Infectious Disease

SAFE-BDVARD: Safety and Immunogenicity of the Live Attenuated Tetravalent Butantan-Dengue Vaccine in Autoimmune Rheumatic Diseases (clinicaltrials.gov) - P4 | N=477 | Not yet recruiting | Sponsor: University of Sao Paulo General Hospital | Phase classification: P3 ➔ P4

Phase classification • Ankylosing Spondylitis • Dengue Fever • Genetic Disorders • Hematological Disorders • Idiopathic Arthritis • Immunology • Inflammatory Arthritis • Lupus • Myositis • Psoriatic Arthritis • Rare Diseases • Rheumatoid Arthritis • Rheumatology • Scleroderma • Seronegative Spondyloarthropathies • Spondylarthritis • Systemic Lupus Erythematosus • Systemic Sclerosis • Vasculitis

Immunogenicity and safety of tetravalent dengue vaccines: a systematic review of clinical trials. (PubMed, Gac Med Mex) - "The studies evaluated outcomes such as the incidence of severe dengue, seropositivity, and immune response to the vaccines TV003 and TV005. Tetravalent vaccines show a promising outlook in reducing the incidence of severe dengue, although limitations were identified in study designs and heterogeneity in the studied populations. Further research is needed to confirm efficacy and safety in diverse populations."

Clinical • Journal • Review • Dengue Fever

Butantan-DV Vaccine in Elderly Populations (DEN-04-IB) (clinicaltrials.gov) - P3 | N=997 | Not yet recruiting | Sponsor: Butantan Institute | Initiation date: Jul 2025 ➔ Nov 2025

Head-to-Head • Trial initiation date • Dengue Fever

SAFE-BDVARD: Safety and Immunogenicity of the Live Attenuated Tetravalent Butantan-Dengue Vaccine in Autoimmune Rheumatic Diseases (clinicaltrials.gov) - P3 | N=477 | Not yet recruiting | Sponsor: University of Sao Paulo General Hospital | Initiation date: Oct 2025 ➔ Jan 2026

Trial initiation date • Ankylosing Spondylitis • Dengue Fever • Genetic Disorders • Hematological Disorders • Idiopathic Arthritis • Immunology • Inflammatory Arthritis • Lupus • Myositis • Psoriatic Arthritis • Rare Diseases • Rheumatoid Arthritis • Rheumatology • Scleroderma • Seronegative Spondyloarthropathies • Spondylarthritis • Systemic Lupus Erythematosus • Systemic Sclerosis • Vasculitis

Efficacy of the live attenuated tetravalent dengue vaccine TV003 or previous Zika infection against Zika challenge (ASTMH 2025) - "Previous ZIKV infection imparted complete protection against ZIKV challenge 9/10 volunteers. One volunteer who was enrolled based on ZIKV seropositivity was not protected against ZIKV challenge. The efficacy of TV003 against ZIKV challenge at 6 months will also be presented."

Clinical • Dengue Fever • Infectious Disease

Five-Year Efficacy and Safety of a Live, Attenuated Tetravalent Dengue Vaccine Produced by Instituto Butantan: Results from a Phase 3 Clinical Trial in Children, Adolescents, and Adults (ASTMH 2025) - P3 | "VE [95%CI] against dengue with warning signs/severe dengue was 80.5% [50.8-92.4%]. In summary, Butantan-DV remained efficacious against symptomatic VCD due to DENV-1 or DENV-2, regardless of dengue serostatus at baseline, with no safety concerns observed during the entire five-year follow-up."

Clinical • P3 data • Dengue Fever

Randomized, double-blind, placebo-controlled, phase 3 trial to demonstrate lot-to-lot consistency of 3 lots of the simplified formulation of Butantan-dengue vaccine. (PubMed, Vaccine) - P3 | "Three lots of simplified formulation were safe and achieved the endpoint of equivalence of lots."

Clinical • Journal • P3 data • Allergy • Dengue Fever • Immunology • Infectious Disease

SAFE-BDVARD: Safety and Immunogenicity of the Live Attenuated Tetravalent Butantan-Dengue Vaccine in Autoimmune Rheumatic Diseases (clinicaltrials.gov) - P3 | N=477 | Not yet recruiting | Sponsor: University of Sao Paulo General Hospital | Trial completion date: Dec 2027 ➔ Dec 2028 | Trial primary completion date: Aug 2025 ➔ Dec 2027

Trial completion date • Trial primary completion date • Ankylosing Spondylitis • Dengue Fever • Genetic Disorders • Hematological Disorders • Idiopathic Arthritis • Immunology • Inflammatory Arthritis • Lupus • Myositis • Psoriatic Arthritis • Rare Diseases • Rheumatoid Arthritis • Rheumatology • Scleroderma • Seronegative Spondyloarthropathies • Spondylarthritis • Systemic Lupus Erythematosus • Systemic Sclerosis • Vasculitis

State of the Art on Vaccine Development Against Dengue Infection: Scoping Review of the Literature. (PubMed, Infect Dis Rep) - "Vaccines were categorized into licensed (CYD-TDV and TAK-003), late-stage (TV003/TV005), and early-stage candidates (TDEN, DPIV, V180, TVDV)...TAK-003 (Qdenga®) demonstrated high efficacy against virologically confirmed dengue (VCD) and dengue-related hospitalization...Currently, TAK-003 is regarded as the best option for broad implementation, while TV003 and TV005 remain promising candidates due to their shorter schedule and robust immunogenicity. Further research is needed to optimize vaccine strategies in seronegative populations, immunocompromised subjects, older adults, and travelers."

Journal • Review • Dengue Fever • Infectious Disease

Advancing dengue vaccine development: Challenges, innovations, and the path toward global protection. (PubMed, Pediatr Investig) - "This review provides a comprehensive analysis of the historical and current landscape of dengue vaccine development, focusing on CYD-TDV, TAK-003, and Butantan-DV...Additionally, this review highlights key areas for future research, including the impact of ADE, advancements in vaccine platforms, the need for region-specific vaccine formulations, and the integration of vaccination into broader dengue prevention strategies. Ultimately, sustained investment and global collaboration are crucial for achieving the goal of a dengue-free world."

Journal • Review • Dengue Fever

Dengue Vaccines. (PubMed, Curr Top Microbiol Immunol) - "The chapter reviews the historical trajectory and current landscape of vaccine candidates, such as Dengvaxia®, Qdenga®, and Butantan-DV, analyzing their efficacy, safety profiles, and the lessons learned from their clinical trials. It also discusses other hurdles like suitable animal models and viral interference. Ultimately, the chapter highlights the advancements made and outlines future research directions crucial for a universally effective dengue vaccine."

Journal • Dengue Fever

SAFE-BDVARD: Safety and Immunogenicity of the Live Attenuated Tetravalent Butantan-Dengue Vaccine in Autoimmune Rheumatic Diseases (clinicaltrials.gov) - P3 | N=477 | Not yet recruiting | Sponsor: University of Sao Paulo General Hospital

New P3 trial • Ankylosing Spondylitis • Dengue Fever • Genetic Disorders • Hematological Disorders • Idiopathic Arthritis • Immunology • Inflammatory Arthritis • Lupus • Myositis • Psoriatic Arthritis • Rare Diseases • Rheumatoid Arthritis • Rheumatology • Scleroderma • Seronegative Spondyloarthropathies • Spondylarthritis • Systemic Lupus Erythematosus • Systemic Sclerosis • Vasculitis

From controversy to confidence: Strengthening dengue vaccines safety reporting. (PubMed, Vaccine) - "Dengue vaccines-Dengvaxia, Qdenga, and TV003/TV005 (NIH dengue vaccine) -offer potential for control, yet their implementation has been challenged by safety issues, including heightened risks in seronegative individuals, presumably due to antibody-dependent enhancement, though the precise mechanisms remain under investigation...The erosion of public trust following past vaccine controversies highlights the urgent need for transparency to bolster acceptance and inform policy. By integrating advanced surveillance with international cooperation, these measures can refine risk-benefit assessments, rebuild confidence in immunization programs, and maximize the protective impact of dengue vaccines, ultimately reducing the burden on vulnerable populations worldwide."

Journal • Dengue Fever

Advances in the Epidemiology, Pathogenesis, Diagnostic Methods, and Vaccine Development of Dengue Fever: A Comprehensive Review. (PubMed, Viral Immunol) - "In this review, we provide an updated and more in-depth overview of dengue epidemiology and pathogenesis, along with recent progress in diagnostic approaches (including methods to address cross-reactivity with other flaviviruses) and an expanded discussion of current dengue vaccine development, such as CYD-TDV (Dengvaxia), TV003/TV005, and the new TAK-003. This comprehensive perspective aims to offer references for the prevention, clinical diagnosis, and control of the disease."

Journal • Review • Dengue Fever • Infectious Disease

Evaluation of the Protective Efficacy of TV003 or Previous Zika Infection Against Infection With ZIKV-SJRP Challenge Compared to DENV and ZIKV-naïve Controls Against Infection With ZIKV-SJRP Challenge (clinicaltrials.gov) - P1 | N=26 | Recruiting | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

New P1 trial • Dengue Fever • Infectious Disease

Localized inflammation in dengue vaccine-induced skin rash is not associated with continuous presence of dengue virus genome. (PubMed, J Invest Dermatol) - "Vaccination with the tetravalent live attenuated dengue virus (DENV) vaccines TV003 and TV005 causes a mild, relatively localized erythematous maculopapular skin rash in most dengue-naïve vaccinees. Incidence and severity of lymphocytic infiltration were highest in rash biopsy samples compared to those from non-involved areas in participants experiencing a rash or from those taken from participants not experiencing a rash. These results indicate that the rash associated with infection with live attenuated dengue vaccines or challenge strains is predominantly lymphocyte-driven perivascular dermal inflammation without local concomitant active viral replication."

Journal • Dengue Fever • Dermatology • Infectious Disease • Inflammation

Dengue and severe dengue with neurological complications: a challenge for prevention and control. (PubMed, Arq Neuropsiquiatr) - "The CYD-TDV/Dengvaxia and TAK-003/DENVax vaccines, licensed for use by the Brazilian National Health Regulatory Agency (Agência Nacional de Vigilância Sanitária, ANVISA, in Portuguese), show efficacy against hospitalizations of 72.7% (95% confidence interval [95%CI]: 62.3-80.3%) and of 90.4% (95%CI: 82.6-94.7%) respectively. The TV003/TV005 vaccine, which is being studied by Intituto Butantan in Brazil, shows promising results, with an efficacy of 79.6% for symptomatic dengue...The main individual protection measure is the use of topical repellents (icaridin). All of these actions represent important tools for the prevention of dengue fever and its neurological complications."

Journal • Review • CNS Disorders • Dengue Fever • Pain

Deletions in the 3' untranslated region compromised translation initiation to attenuate a dengue virus 3 vaccine strain (ASTMH 2024) - "Phases I-III clinical trials of TV003, a live attenuated dengue vaccine, have demonstrated favorable safety, immunogenicity, and efficacy profiles...Similarly, replacement of the DENV-3 open reading frame with enhanced green fluorescent protein (eGFP) showed lowest eGFP expression with Sleman/78Δ30/31, compared to the other two DENV-3s. Our results suggest that, beyond forming the pan-handle structure of the DENV genome, the 3’UTR through the DBI and DBII secondary structures contribute to recruiting factors involved in translation, reduced efficiency of which attenuated Sleman/78Δ30/31."

Dengue Fever

Deletions in the 3' untranslated region compromised translation initiation to attenuate a dengue virus 3 vaccine strain (ASTMH 2024) - "Phases I-III clinical trials of TV003, a live attenuated dengue vaccine, have demonstrated favorable safety, immunogenicity, and efficacy profiles...Similarly, replacement of the DENV-3 open reading frame with enhanced green fluorescent protein (eGFP) showed lowest eGFP expression with Sleman/78Δ30/31, compared to the other two DENV-3s. Our results suggest that, beyond forming the pan-handle structure of the DENV genome, the 3’UTR through the DBI and DBII secondary structures contribute to recruiting factors involved in translation, reduced efficiency of which attenuated Sleman/78Δ30/31."

Dengue Fever