QDENGA® (TAK-003) Dengue Vaccine Clinical Trials, Dosage, Indication, Side Effects
Takeda GmbH's QDENGA® (TAK-003) (Dengue Tetravalent Vaccine [Live, Attenuated]) is an approved two-dose vaccine preventing dengue fever and/or Severe Dengue caused by any of the four serotypes of the dengue virus. QDENGA is based on dengue serotype two, which provides the genetic "backbone" for all four dengue virus serotypes. The active substance of QDENGA (ATC code: J07BX04) contains live attenuated dengue viruses, which replicate locally and elicit humoral and cellular immune responses against dengue serotypes.
Takeda's clinical development program for QDENGA consists of Phase 3, Phase 1, and Phase 2. Data in children and adolescents showed that QDENGA induced immune responses against all four dengue serotypes in seropositive and seronegative participants. In addition, QDENGA was found to be generally safe and well-tolerated. In a phase 2 study published on October 17, 2024, TAK-003 elicited durable T cell responses against all four DENV serotypes irrespective of baseline serostatus in people aged 4–16 years living in dengue-endemic countries. Furthermore, TAK-003-elicited CD4 and CD8 T cells were multifunctional and persisted up to 3 years post-vaccination.
On December 8, 2022, QDENGA became the only dengue vaccine approved in Europe for use regardless of previous dengue exposure and without pre-vaccination testing. Europe's Committee for Medicinal Products for Human Use adopted a positive opinion on October 13, 2022, recommending granting marketing authorization to Takeda GmbH for QDENGA EMEA/H/C/005155.
The World Health Organization (WHO) published a paper in May 2024 focused on the second licensed dengue vaccine, TAK-003 (Qdenga, Takeda), along with WHO’s position on its use. The WHO added QDENGA® (TAK-003) to its List of Prequalified Vaccines effective May 9, 2024. On May 3, 2024, the WHO published a paper on dengue vaccines to include final guidance on using QDENGA in public vaccination programs based on the SAGE recommendation. In 2023, Brazil was the first country to integrate QDENGA into its public health system. As of October 2024, QDENGA is the only licensed dengue vaccine available in the United Kingdom.
Osaka-based Takeda Pharmaceutical Company Limited (TSE: 4502, NYSE: TAK) is a global, values-based, R&D-driven biopharmaceutical leader headquartered in Japan, committed to discovering and delivering life-transforming treatments, guided by our commitment to patients, our people, and the planet in approximately 80 countries and regions. For more information about QDENGA (TAK-003), visit www.TakedaVaccines.com. QDENGA - Trademark Details: 2019-06-04. QDENGA's FY2024 Q1 Revenue was JPY 9.5B (+1,099% growth). In FY 2023, QDENGA produced 8% of Takeda's revenues.
Qdenga (TAK-003) Vaccine Efficacy
On October 17, 2024, the journal NPJ Vaccines published results from a study that concluded TAK-003 was well tolerated and elicited durable T cell responses against all four DENV serotypes irrespective of baseline serostatus in children and adolescents aged 4–16 years living in dengue-endemic countries. TAK-003-elicited CD4 and CD8 T cells were multifunctional and persisted up to 3 years post-vaccination.
An exploratory analysis published on September 11, 2024 (December 2, 2024) demonstrated a VE of 82.1 % for the onset of protection of TAK-003 in the three months between administration of the first and second doses in the safety population. The journal Vaccine published a Short Communication on September 7, 2024, determining QDENGA's VE against disease up to 3 months after the first dose was 82.1%. On October 2, 2023, the WHO Strategic Advisory Group of Experts on Immunization (SAGE) confirmed QDENGA demonstrated efficacy against all four serotypes of the virus in baseline seropositive children (4-16 years) in endemic countries and against serotypes 1 and 2 in baseline seronegative children. The SAGE recommended that the vaccine be considered for introduction to children aged 6 to 16 years of age in settings with high dengue disease burden and high transmission intensity. Long-term efficacy results announced on June 9, 2022, supplemented previously published TIDES clinical study data, demonstrating QDENGA met its primary endpoint of overall VE against VCD, with 80.2% efficacy at 12-month follow-up, as well as all secondary endpoints for which there were a sufficient number of dengue cases at 18-months follow-up, including 90.4% VE against hospitalized Dengue. On May 20, 2021, an audio review of Three Years Efficacy of Takeda's Tetravalent Dengue Vaccine Candidate was published.
Qdenga (TAK-003) Time to Onset of Vaccine Efficacy
A study (DEN-301 clinical trial) published by Vaccine on September 7, 2024, found that the estimated time to onset vaccine efficacy was approximately two weeks.
Qdenga (TAK-003) Vaccination Breakthrough Case
This study, published in October 2024, examined a case involving a child who developed dengue symptoms following Qdenga vaccination. Despite initial negative diagnostic results, molecular analysis confirmed an infection with DENV4.
QDENGA (TAK-003) Vaccine Availability 2024
As of 2024, QDENGA was authorized in 40 countries and launched (or available) in 24 of those countries, such as Indonesia (approved Aug 2022, available April 2023), Brazil (approved Mar 2023, available June 2023, Thailand (approved May 2023, available Aug 2023), Argentina (approved Apr 2023, available Oct 2023), Malaysia (approved Feb 2024, available June 2024), Colombia (approved Sept 2023, available July 2024), Germany (approved Dec 2022, available Feb 2023), Finland (approved Dec 2022, available Feb 2023), Sweden (approved Dec 2022, available Feb 2023), Norway (approved Dec 2022, available Feb 2023), Denmark (approved Dec 2022, available Mar 2023), The Netherlands (approved Dec 2022, available Mar 2023), Luxembourg (approved Dec 2022, available March 2023), Czech Republic (approved Dec 2022, available April 2023), Austria (approved Dec 2022, available April 2023), Belgium (approved Dec 2022, available April 2023), Ireland (approved Dec 2022, available April 2023), Portugal (approved Dec 2022, available May 2023), Spain (approved Dec 2022, available May 2023), U.K. (approved Jan 2023, available 2024), Slovakia (approved Dec 2022, available Aug 2023), Italy (approved Dec 2022, available Oct 2023), Poland (approved Dec 2022, available Dec 2023), Israel (approved May 2024, available July 2024), Switzerland (approved Aug. 2024), Malasyia, Vietnam, and is pending in India.
QDENGA Vaccine Production 2024
Biological E. Limited committed in February 2024 to manufacturing up to 50 million QDENGA vaccine doses annually, accelerating Takeda's ability to deliver 100 million doses annually by 2030.
QDENGA and U.S. FDA
Takeda announced on July 11, 2023, that the Company voluntarily withdrew the U.S. Biologics License Application (BLA) for TAK-003 following discussions with the U.S. Food and Drug Administration (FDA) on aspects of data collection, which cannot be addressed within the current BLA review cycle. The plan for TAK-003 in the U.S. will be further evaluated, given the need for travelers and those living in dengue-endemic areas, such as Puerto Rico, Mexico, and Florida. On November 22, 2022, Takeda announced that the FDA had accepted and granted priority review of the BLA for QDENGA to prevent dengue disease caused by any dengue virus serotype in individuals four years through 60 years.
QDENGA and U.S. CDC
During the U.S. Centers for Disease Control and Prevention Advisory Committee on Immunization Practices (ACIP) meeting on October 26, 2023, Dr. Gabriela Paz-Bailey (CDC/NCEZID) led a QDENGA update. Wilbur Chen, MD, presented Updates on Dengue Vaccines. On June 22, 2023, I reviewed the following presentations: ACIP Dengue Vaccines Work Group introduction, Wilbur Chen, MD, MSc; Economic analysis and health impacts of routine vaccination with TAK-003 dengue vaccine in San Juan, Puerto Rico; Summary of two economic models for dengue vaccine TAK-003 use in Puerto Rico; Partial Evidence to Recommendations Framework for Dengue Vaccine TAK-003, presented by Joshua Wong, MD. On February 23, 2023, the ACIP met to discuss the following presentations: Introduction, Dr. W Chen; Takeda dengue vaccine (TAK-003) safety and efficacy, Dr. Shibidas Biswal; Workgroup considerations, Dr. Gabriela Paz-Bailey. Previously, Laura Adams, DVM, MPH, DACVPM, led the U.S. CDC's Dengue Epidemiology vaccine overview on October 20, 2022, during the CDC/ACIP Dengue Vaccine Workgroup presentation.
QDENGA (TAK-003) Indication
Dengue is now detected in 129 countries. In the European Union Member States, QDENGA is indicated for preventing dengue disease in individuals from four years of age. It prevents Dengue, which is caused by the four Dengue serotypes. On May 15, 2024, the WHO confirmed that Qdenga is approved for children aged 6–16 in settings with high dengue burden and transmission intensity.
QDENGA (TAK-003) Dosage
Under the approved dosing regimen, QDENGA should be administered subcutaneously at a two-dose (0 and 3 months) schedule, as a 0.5 mL dose. The WHO SAGE recommends administering QDENGA in a 2-dose schedule with a 3-month interval between doses. QDENGA should be administered preferably in the upper arm in the deltoid region. QDENGA must not be injected intravascularly, intradermally, or intramuscularly. In Europe, the EMA approved after reconstitution, one dose (0.5 mL) contains Dengue virus serotype 1 (live, attenuated)*: ≥ 3.3 log10 PFU/dose Dengue virus serotype 2 (live, attenuated): ≥ 2.7 log10 PFU/dose Dengue virus serotype 3 (live, attenuated): ≥ 4.0 log10 PFU/dose Dengue virus serotype 4 (live, attenuated): ≥ 4.5 log10 PFU/dose.
On September 2, 2024, Vaccine published an analysis that concluded that one dose of TAK-003 was consistent with efficacy after both doses.
QDENGA (TAK-003) Coadministraion
Co-administration with a hepatitis A vaccine has been studied without increased side effects or impaired antibody response. When co-administered with yellow fever vaccine, a lower level of neutralizing antibodies against DENV1 was seen, the clinical significance of which is unclear.
QDENGA Format
Qdenga is available as a powder and solvent for solution for injection.
QDENGA (TAK-003) Side Effects
A phase 4 study published by Science Direct (Volume 42, Issue 26) on October 4, 2024, identified anaphylaxis as a safety signal for TAK-003 vaccines in adolescents. Most anaphylaxis cases occurred 15 min after vaccination. In response, Brazil's Ministry of Health published recommendations for intensifying actions for safe vaccination, including healthcare professional training and post-vaccination observation.
The ongoing phase 3 study of TAK-003 demonstrated rates of serious adverse events were 2.9% in the TAK-003 group and 3.5% in the placebo group during the continuing long-term follow-up (i.e., the second half of the three years following vaccination), but none were related. The European Medicines Agency says there is no clear evidence of a higher risk of severe dengue disease in previously infected people.
QDENGA (TAK-003) Adverse Reactions
The most frequently reported adverse reactions post TAK-003 vaccination in subjects 4 to 60 years of age were injection site pain (50%), headache (35%), myalgia (31%), injection site erythema (27%), malaise (24%), asthenia (20%), and fever (11%). Very common (≥1/10 of subjects): upper respiratory tract infection, decreased appetite, irritability, headache, drowsiness, myalgia, injection site pain, injection site erythema, malaise, asthenia, fever.
QDENGA (TAK-003) Contraindications
Contraindications include hypersensitivity to the active substances, excipients listed, or previous QDENGA doses. Individuals with congenital or acquired immune deficiency, including immunosuppressive therapies such as chemotherapy or high doses of systemic corticosteroids (e.g., 20 mg/day or 2 mg/kg body weight/day of prednisone for two weeks or more) within four weeks before vaccination. Individuals with symptomatic HIV infection or asymptomatic HIV infection with impaired immune function and pregnant and breastfeeding women.
Dengue Outbreaks
The U.S. CDC issued Dengue-related travel advisories in 2024.
QDENGA (TAK-003) Price
Takeda indicated in a March 16, 2023, presentation that the price of QDENGA in Indonesia would be USD 40 per dose, USD 26 ex-factory). For the travel market segment, vaccine pricing will be similar to that of other innovative travel vaccines in their respective countries. For example, the retail price in Germany would be USD 115 per dose. In Brazil, reports indicate QDENGA's price is about US 171.
QDENGA Vaccine Sales
On October 31, 2024, Takeda reported Qdenga sales increased 863% in the FY2024 H1, reaching JPY 19.9 billion (~$124 million). On July 31, 2024, Takeda reported sales of QDENGA were JPY 9.5 billion (JPY +8.8 billion and +1,231.5% AER, +1,098.6% CER). The increase in sales was due to the expansion of QDENGA availability in endemic and non-endemic countries.
QDENGA (TAK-003) Vaccine News
September 7, 2024 - The journal Vaccine published a Short communication - Early onset of protection of the TAK-003 dengue vaccine: Data from the DEN-301 clinical trial - Estimated time to onset of Qdenga vaccine efficacy was approximately 2 weeks.
May 10, 2024 - The World Health Organization prequalified Takeda's QDENGA vaccine. “The prequalification of TAK-003 is an important step in the expansion of global access to dengue vaccines, as it is now eligible for procurement by UN agencies, including UNICEF and PAHO,” said Dr Rogerio Gaspar, WHO Director for Regulation and Prequalification.
May 9, 2024 - Takeda announced financial results for fiscal year 2023 (period ended March 31, 2024).
October 3, 2023 – Takeda announced that the WHO Strategic Advisory Group of Experts on Immunization shared recommendations for using QDENGA.
July 11, 2023 - "Our clinical program was designed to account for the complex global nature of dengue, and data from our 4.5-year trial has built confidence in TAK-003's ability to help provide long-term protection against dengue, with a positive benefit and risk profile regardless of baseline serostatus," said Gary Dubin, M.D., president of Takeda's Vaccines Business Unit.
June 22, 2023 - The U.S. CDC's Advisory Committee on Immunization Practices reviewed various dengue vaccine presentations.
May 23, 2023 - Filomeno Fortes, Director of Portugal's Institute of Hygiene and Tropical Medicine, confirmed Qdenga vaccine authorization.
May 11, 2023 - Takeda announced Brazil's National Health Surveillance Agency. In March 2023, the approval of QDENGA was the first in Latin America.
March 13, 2023 - José Manuel Caamaño, president of Takeda in Brazil, stated in a press release, "We are proud to make our vaccine available to the Brazilian government and health care providers with the hope that it may become an important tool to help combat dengue as part of an integrated dengue management program along with vector control."
February 6, 2023 - Takeda UK Ltd. announced that the Medicines and Healthcare products Regulatory Agency had granted marketing authorization for Qdenga. The following approval step involves seeking recommendations from the Joint Committee on Vaccination and Immunisation, which is expected in summer 2023.
October 20, 2022 - The U.S. CDC vaccine committee presented Dengue Epidemiology: Globally and in the U.S.; ACIP dengue vaccine recommendations.
October 14, 2022 - The EMA's human medicines committee recommended granting marketing authorization for the QDENGA Dengue Tetravalent Vaccine (Live, Attenuated) to prevent dengue virus serotypes 1, 2, 3, and 4 in people from four years of age.
August 22, 2022 - Gary Dubin, president of Takeda's Vaccine Business Unit, announced, "We're proud to introduce QDENGA as a new dengue prevention tool to the people of Indonesia, and we will continue to work with additional regulatory agencies to make QDENGA available globally."
March 17, 2020 - The Lancet published the 'Safety and immunogenicity of a tetravalent dengue vaccine in children aged 2–17.
November 6, 2019 - Takeda's Dengue Vaccine Candidate Demonstrates Protection in Children Ages Four to 16 Years, Regardless of Previous Dengue Exposure.
November 5, 2019 – Takeda Pharmaceutical Company announced its new manufacturing plant in Singen, Germany, for TAK-003.
January 29, 2019 - Takeda announced that TAK-003, which is in a pivotal Phase 3 trial, met the primary efficacy endpoint.
September 7, 2016 - Takeda Initiated the Global Phase 3 Clinical Trial (TIDES) of the Dengue Vaccine Candidate (TAK-003).
QDENGA TAK-003 Clinical Trials
The approval of QDENGA is based on results across 19 Phase 1, 2, and 3 trials with more than 28,000 children and adults, including four and a half years of follow-up data from the global, pivotal Phase 3 Tetravalent Immunization against Dengue Efficacy Study (TIDES) trial. The study was designed per World Health Organization (WHO) guidance for a second-generation dengue vaccine. A study published in the journal Vaccine on August 22, 2023, revealed that QDENGA showed around 80.2% (95 % CI, 73.3–85.3) efficacy caused by any serotype during primary analysis. QDENGA's effectiveness declined over time, with 62% (95% CI, 56.6–66.7) efficacy at three years and 61.2% (95 % CI, 56.0–65.8) at 4.5 years.
As of June 9, 2022, through four and a half years, TAK-003 demonstrated 84.1% vaccine efficacy (VE) (95% CI: 77.8, 88.6) against hospitalized Dengue, with 85.9% VE (78.7, 90.7) in seropositive individuals and 79.3% VE (63.5, 88.2) in seronegative individuals. TAK-003 also demonstrated an overall VE of 61.2% (95% CI: 56.0, 65.8) against virologically-confirmed dengue (VCD), with 64.2% VE (58.4, 69.2) in seropositive individuals and 53.5% VE (41.6, 62.9) in seronegative individuals. Observations of VE varied by serotype and remained consistent with previously reported results. TAK-003 was generally well tolerated, and critical safety risks were identified. No evidence of disease enhancement was observed over the 54-month follow-up exploratory analysis.
