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

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

An In Silico Design of a Vaccine against All Serotypes of the Dengue Virus Based on Virtual Screening of B-Cell and T-Cell Epitopes. (PubMed, Biology (Basel)) - "Despite the urgent demand for vaccines in the control of the disease, the two approved vaccines, Dengvaxia and TV003/TV005, there are current questions regarding their effectiveness due to an increased risk of antibody-dependent enhancement (ADE) and reduced protection...Our new vaccine design offers a promising additional option for Dengue virus protection. Further experimental validations will be conducted to confirm its protective efficacy and safety."

Journal • Dengue Fever

Trends and insights in dengue virus research globally: a bibliometric analysis (1995-2023). (PubMed, J Transl Med) - "This bibliometric study underscores the critical role of interdisciplinary collaboration in advancing DENV research, identifying key trends and areas needing further exploration, including host-virus dynamics, the development and application of antiviral drugs and vaccines, and the use of artificial intelligence. It advocates for strengthened partnerships across various disciplines to effectively tackle the challenges posed by DENV."

Journal • Dengue Fever • DDX58 • IFNA1 • NFKB1 • STAT1

A pre-vaccination immune metabolic interplay determines the protective antibody response to a dengue virus vaccine. (PubMed, Cell Rep) - "Systems vaccinology identifies a multi-OMICs pre-vaccination signature and mechanisms predictive of broad antibody responses after immunization with a tetravalent live attenuated DENV vaccine candidate (Butantan-DV/TV003)...The inhibition of viral sensing by PC/PE-induced TGF-β is confirmed in vitro. Our studies show that the balance between metabolites and the pro- or anti-inflammatory state of innate immune cells drives broad and protective B cell response to a live attenuated dengue vaccine."

Journal • Dengue Fever • TGFB1

Regional Variation of the CD4 and CD8 T Cell Epitopes Conserved in Circulating Dengue Viruses and Shared with Potential Vaccine Candidates. (PubMed, Viruses) - "With these data, we catalogued epitopes conserved in circulating dengue viruses from India and matched them with each of the six vaccine candidates under consideration (TV003, TDEN, DPIV, CYD-TDV, DENVax and TVDV). Similar analyses with viruses from Thailand, Brazil and Mexico revealed regional overlaps and variations in these patterns. Thus, our study provides detailed and nuanced insights into regional variation that should be considered for itemization of T cell responses during dengue natural infection and vaccine design, testing and evaluation."

Journal • Dengue Fever • Infectious Disease • CD4 • CD8

EFFICACY AND SAFETY OF BUTANTAN-DV LIVE, ATTENUATED TETRAVALENT DENGUE VACCINE AND EPIDEMIOLOGICAL ANALYSES IN BRAZIL OVER AN AVERAGE OF 3.7 YEARS OF FOLLOW-UP (ESPID 2024) - P3 | "Background Butantan-DV is a live, attenuated tetravalent dengue vaccine analogous to TV003...Overall, different geographical regions experienced waves of VCD from DENV-1 and DENV-2 and no cases of DENV-3 or DENV-4 were observed through the follow-up. Conclusions/Learning Points A single dose of Butantan-DV was generally well tolerated and efficacious against DENV-1 and DENV-2 symptomatic VCD through an average 3.7 years of follow-up."

Clinical • Dengue Fever • Infectious Disease • Novel Coronavirus Disease

Whole genome sequencing of outbreak strains from 2017-18 reveals an endemic clade of Dengue 1 virus in Cameroon. (PubMed, Emerg Microbes Infect) - "Comparing our sequences to the vaccine strains, 19 and 15 amino acid (aa) substitutions were observed in the immuno-protective prM-E protein segments of the Dengvaxia® and TetraVax-DV-TV003 vaccines, respectively...The new DENV strains constitute a conserved genomic pool of viruses endemic to the Central African region that needs prospective monitoring to track local viral evolution. Further work is needed to ascertain the performance of emerging therapeutics in DENV strains from the African region."

IO biomarker • Journal • Dengue Fever • Infectious Disease

Molecular Evolution of Dengue Virus 3 in Senegal between 2009 and 2022: Dispersal Patterns and Implications for Prevention and Therapeutic Countermeasures. (PubMed, Vaccines (Basel)) - "Comparison of the amino acids in the CprM-E regions of genomes from the Senegalese strains against the vaccine strains revealed the presence of 22 substitutions (7 within the PrM and 15 within the E gene) when compared to CYD-3, while 23 changes were observed when compared to TV003 (6 within the PrM and 17 within the E gene)...Altogether, these data give up-to-date insight into DENV-3 genomic evolution in Senegal which needs to be taken into account in future vaccination strategies. Additionally, they highlight the importance of the genomic epidemiology of emerging pathogens in Africa and call for the implementation of a pan-African network for genomic surveillance of dengue virus."

Journal • Dengue Fever • Infectious Disease

Tracing down the Updates on Dengue Virus-Molecular Biology, Antivirals, and Vaccine Strategies. (PubMed, Vaccines (Basel)) - "There is a need to put more effort into developing effective vaccines and therapeutics for dengue, as already approved vaccines and therapeutics have limitations. DENGVAXIA is approved for use in children and teenagers who are 6-16 years of age and have confirmed dengue infection, while Takeda is approved for use in certain countries, and it has withdrawn its application for FDA approval."

Journal • Review • Dengue Fever • Infectious Disease