QDENGA® (TAK-003) Dengue Vaccine Clinical Trials, Dosage, Indication, News, Side Effects
Takeda'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 the 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 November 2019 study, QDENGA demonstrated protection against virologically confirmed dengue in children ages 4 to 16. The vaccine efficacy (VE) was 80.2% in the 12 months after the second vaccine dose, administered three months after the 1st dose. On July 13, 2020, the long-term safety and immunogenicity of a tetravalent dengue vaccine (QDENGA) in children and adults: a randomized, placebo-controlled, phase 2 study, found at Month 36, seropositivity rates were 97.3%, 98.7%, 88%, and 56% for DENV-1, -2, -3 and -4, respectively. Seropositivity rates varied significantly for DENV-4 according to serostatus at baseline (89.5% in seropositive versus 21.6% in seronegative).
On March 25, 2021, Takeda announced it was participating in the European Medicines Agency's (EMA) first-ever parallel assessment of a medicinal product for use in the European Union (EU) and through the EU-M4all (Article 58) procedure for countries outside of the EU. In addition, on May 20, 2021, an audio review of Three Years Efficacy of Takeda's Tetravalent Dengue Vaccine Candidate was published. 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. While the long-term follow-up for the primary two-dose series has been completed, the TIDES trial remains ongoing to evaluate the safety and efficacy of a booster dose. A clinical trial program demonstrated QDENGA (TAK-003) efficacy and safety profiles, including a 4.5-year Phase 3 study of over 20,000 children and adolescents living in eight dengue-endemic areas. 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.
On October 2, 2023, the WHO's 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.
As of March 2024, QDENGA was launched in 21 countries (Argentina April 2023, Thailand May 2023, Colombia September 2023), is available in 17 European countries. Qdenga produced 8% of Takeda's revenues in FY 2023.
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 Availability 2024
Biological E. Limited committed in February 2024 to manufacturing up to 50 million QDENGA doses annually, accelerating Takeda's ability to deliver 100 million doses per year by 2030.
On August 22, 2022, Takeda confirmed that QDENGA had been authorized in Indonesia. 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. Previously, 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. On February 6, 2023, the U.K. Medicines and Healthcare Products Regulatory Agency (MHRA) confirmed marketing authorization for QDENGA, followed by Argentina, Denmark, Germany, Portugal, and Thailand. Brazil approved QDENGA on March 13, 2023, without needing pre-vaccination testing. On December 22, 2023, Brazil's Ministry of Health announced it was the first country to incorporate QDENGA into the Unified Health System. In January 2023, Brazil launched a QDENGA vaccination program for about 720,000 people. Brazil forecasts that 5.2 million doses will be delivered between February and November 2024. Another 1.2 million donated by Takeda are in negotiations to make the donation process viable. Argentina authorized QDENGA in April 2023. In February 2024, Malaysia conditionally authorized QDENGA.
Takeda UK Ltd. has submitted regulatory filings in Colombia, Mexico, Singapore, and Sri Lanka in 2024.
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 Price 2023
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 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 Indication
In the European Union Member States, QDENGA is indicated for preventing dengue disease in individuals from four years of age. Qdenga prevents Dengue caused by the four Dengue serotypes. Dengue is the fastest-spreading mosquito-borne viral disease and is one of the World Health Organization's top 10 global health threats in 2019. Dengue is pandemic-prone, and outbreaks are observed in tropical and sub-tropical areas. It has recently caused outbreaks in parts of the continental United States and Europe. Approximately half of the world lives under the threat of, estimated to generate 390 million infections, 500,000 hospitalizations, and 20,000 deaths globally each year. Severe Dengue accounts for about 5% of dengue cases and is a leading cause of severe illness and death among children and adults in Latin America and Asia. In addition, Dengue is the second most diagnosed cause of fever in travelers returning to Europe from endemic countries.
QDENGA 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.
QDENGA 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 Side Effects
The ongoing phase 3 study 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 Adverse Reactions
The most frequently reported adverse reactions 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 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.
QDENGA News
October 3, 2023 – Takeda announced that the WHO Strategic Advisory Group of Experts on Immunization shared recommendations for using QDENGA. In the coming months, the WHO will consider the SAGE recommendation and update its position paper on dengue vaccines to include final guidance on using QDENGA in public vaccination programs.
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 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.
April 20, 2023 - Pan American Health Organisation director Jarbas Barbosa told a news conference it is in preliminary talks with Takeda over potential orders of its Qdenga vaccine.
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.
September 29, 2022 - What Clinicians Need to Know about Dengue in the United States: Clinician Outreach and Communication Activity Call presentation.
September 8, 2022 - The peer-reviewed International Journal of Infections Disease published a Review article: Epidemiology and costs of Dengue in Malaysia: a systematic literature review. Conclusion: To appropriately mitigate and control Dengue, it is critical to implement integrated strategies, including vaccination, to reduce the burden of Dengue.
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."
December 16, 2021 - The JAMA Network published a Viewpoint: Vaccination for Dengue Prevention. Physicians practicing in dengue-endemic areas of US territories and affiliated states can promote health equity by implementing screen-and-vaccinate programs among children 9 to 16.
July 30, 2021 - Takeda said the European Medicines Agency had converted a previous accelerated review of Takeda's dengue vaccine, TAK-003, to standard assessment. As a result, the Company expects a decision next year instead of a potential approval by the end of 2022.
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.
October 31, 2018 - About Dengue and Takeda's dengue vaccine candidate (TAK-003).
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 TIDES trial met its primary endpoint of overall vaccine efficacy (VE) by preventing 80.2% of symptomatic dengue cases 12 months after vaccination.4 In addition, TAK-003 met its critical secondary endpoint by preventing 90.4% of hospitalizations 18 months after vaccination.5 Efficacy varied by serotype (DENV-1 – 4).
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.
