Claim catégorie: News

• The European Commission Approved QDENGA (TAK-003) for Use in Individuals Four Years of Age and Olderⁱ
• QDENGA Becomes the Only Dengue Vaccine Approved in the EU for Use in Individuals Regardless of Previous Dengue Exposureⁱ

Today announced that the European Commission (EC) granted marketing authorization for the company’s dengue vaccine QDENGA^® (Dengue Tetravalent Vaccine [Live, Attenuated]) (TAK-003) for the prevention of dengue disease in individuals from four years of age in the European Union (EU).ⁱ  QDENGA should be used in accordance with official recommendations. The approval follows the positive recommendation from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) in October 2022.

“With the increasing ease of travel today, our once expansive world has become that much smaller, increasing the risk of dengue disease for those living in dengue-endemic areas and for those traveling to these regions,” said Gary Dubin, M.D., president of the Global Vaccine Business Unit at Takeda. “The European Commission’s approval marks an important turning point for QDENGA as we are one step closer to achieving our aspiration to help reduce the global burden of dengue. We are proud to introduce QDENGA in many parts of the EU, offering healthcare providers a new tool in dengue prevention for their patients living in the EU and traveling to endemic regions around the world.”

The worldwide incidence of dengue has risen eight-fold in the past 20 years, and it continues to rise, fueled by climate change and urbanization.ⁱⁱ Today, dengue threatens about half the world’s population with a risk of infection in over 125 countries, and the disease is endemic in most of the European overseas countries, territories, and departments located in tropical areas.^ii,iii  These factors have led to local transmission in non-endemic areas in continental Europe, including France, Italy, Germany, and Spain.^iv Dengue is a leading cause of fever in travelers returning to Europe from endemic countries, and the incidence of dengue among European travelers is generally underestimated.^v,vi  The threat of disease is present for more than 26 million people from Europe who typically travel to endemic regions each year for holidays and visiting friends and family.^vii

“Effective dengue prevention requires a multi-faceted approach, and previous methods have been insufficient for several reasons. With the potential for dengue to cause local outbreaks as demonstrated in several European countries over recent years, and the threat for European travelers visiting dengue-endemic countries, gaps exist that may put some people at risk,” said Dr. Tomas Jelinek, Medical Director of the Berlin Centre for Travel and Tropical Medicine and Scientific Director of the CRM Centrum für Reisemedizin Dusseldorf. “As a clinician, having a new dengue vaccination tool available for a broad population of my patients is encouraging.”

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The results from Part 1 of Takeda’s Phase 3 clinical trial of TAK-003, a live-attenuated tetravalent dengue vaccine candidate, were recently published in the New England Journal of Medicine. The vaccine was found to be efficacious up to 15 months after administration of the first vaccine dose in trial participants regardless of pre-vaccination dengue infection status (i.e., serostatus) for dengue virus serotypes 1 and 2, and only in dengue seropositive participants for serotype 3. Too few DENV-4 infections were seen to draw any conclusion. TAK-003 performed especially well against serotype 2.

Takeda’s pivotal Phase 3 trial, known as the Tetravalent Immunization against Dengue Efficacy Study (TIDES) conducted in Latin America (Brazil, Colombia, Dominican Republic, Nicaragua and Panama) and Asia (The Philippines, Sri Lanka and Thailand), evaluated the efficacy and safety of two doses of TAK-003 given subcutaneously three months apart to over 20,000 children and adolescents aged 4 to 16 years. The trial is being undertaken in three stages: Part 1 evaluates vaccine efficacy up to 15 months after the first dose; Part 2 will obtain an additional 6 months of data to assess efficacy by dengue virus serotype, pre-vaccination dengue serostatus, and disease severity; Part 3 will evaluate long-term safety for an additional 3 years. The results published on November 6, 2019 are from Part 1 of the trial, with results from Part 2 to be presented later this month at the annual meeting of the American Society of Tropical Medicine and Hygiene. Takeda has stated that data from Part 1 and Part 2 will form the basis for filing for licensure.

The Global Dengue & Aedes-Transmitted Diseases Consortium (GDAC) considers the published results of Part 1 to be an important and incremental development after the results of Sanofi Pasteur’s Dengvaxia®, which was found to have an increased risk of hospitalized and severe dengue in vaccine recipients who were dengue seronegative prior to vaccination. The performance of Takeda’s TAK-003 among dengue seronegative vaccine recipients against serotypes 1 and 2 is encouraging. Although limited to a 15-month follow up of per-protocol results, the preliminary data show an overall efficacy against virologically confirmed dengue of 80.2% and a 95.4% decrease in hospitalization. The data further suggest that a single dose of TAK003 provides protection, indicating that the vaccine may be useful as an emergency response tool to control epidemics. The numbers of recipients who developed severe disease were too small to draw any conclusions about preventing severe disease. GDAC looks forward to the release of Part 2 data in the near future, especially TAK-003’s further evaluation of performance in seronegative vaccine recipients and against serotypes 3 and 4. Additional data from Parts 2 and 3 will help clarify the potential utility of TAK-003 as a public health tool.

About Dengue

Dengue is the most common vector-borne viral disease of humans. Dengue causes an estimated 390 million infections per year in over 120 countries, threatening the health of over 50% of the global population. Comprehensive prevention and control measures are urgently needed, including safe and effective vaccines and vector control methods.

About GDAC

GDAC is an international consortium that seeks to promote the development and implementation of innovative and synergistic approaches for prevention and control of dengue and other diseases transmitted by Aedes mosquitoes. GDAC is supported in part by the Bill & Melinda Gates Foundation and unrestricted grants from industry sponsors including Takeda and Sanofi Pasteur.

Read the article in the New England Journal of Medicine

Read Takeda’s news release

Yesterday, Takeda Pharmaceutical Company Limited announced their live-attenuated tetravalent dengue vaccine candidate, designated as TAK-003, had met the primary endpoint in a pivotal Phase 3 clinical trial being conducted in Latin America (Brazil, Colombia, Dominican Republic, Nicaragua and Panama) and Asia (The Philippines, Sri Lanka and Thailand). TAK-003 was found to be efficacious among trial participants in preventing symptomatic dengue of any severity caused by any of the four dengue virus serotypes up to 15 months after administration of the first vaccine dose.

Takeda’s pivotal Phase 3 trial, known as the Tetravalent Immunization against Dengue Efficacy Study (TIDES), evaluated the efficacy and safety of two doses of TAK-003 given subcutaneously three months apart in over 20,000 children and adolescents aged 4 to 16 years. The trial is being undertaken in three stages: Part 1 evaluates vaccine efficacy up to 15 months after the first dose; Part 2 will obtain an additional 6 months of data to assess efficacy by dengue virus serotype, pre-vaccination dengue infection status (i.e., dengue serostatus), and disease severity; Part 3 will evaluate long-term safety for an additional 3 years. The results announced yesterday are from Part 1 of the trial, with results from Part 2 expected later this year. Takeda stated that data from Part 1 and Part 2 will form the basis for filing for licensure.

The Global Dengue & Aedes-Transmitted Diseases Consortium (GDAC) considers today’s announcement by Takeda to be an exciting advance in efforts to develop dengue vaccines. Takeda’s Phase 3 trial announcement comes after the only currently licensed dengue vaccine, Sanofi Pasteur’s Dengvaxia®, was found to have an increased risk of hospitalized and severe dengue in vaccine recipients who did not have evidence of dengue infection prior to vaccine administration (i.e., were dengue seronegative), leading to the World Health Organization (WHO) position in September 2018 recommending only those individuals having evidence of previous dengue infection to receive Dengvaxia®. Given the issues highlighted by the experience with Dengvaxia®, the performance of Takeda’s TAK-003 among dengue seronegative vaccine recipients will be critical. With this understanding, Takeda collected baseline blood samples from all TIDES participants to allow for evaluation of safety and efficacy based on serostatus before vaccination. GDAC looks forward to the release of more detailed analysis of Part 1 data in the near future, especially TAK-003’s performance in seronegative vaccine recipients and against different dengue virus serotypes, along with results from Part 2 of TIDES later this year. This more comprehensive analysis of TAK-003’s performance will help clarify the potential utility of TAK-003 as a public health tool.

About Dengue

Dengue is the most common vector-borne viral disease of humans. Dengue causes an estimated 390 million infections per year in over 120 countries, threatening the health of over 50% of the global population. Comprehensive prevention and control measures are urgently needed, including safe and effective vaccines and vector control methods.

About GDAC

GDAC is an international consortium that seeks to promote the development and implementation of innovative and synergistic approaches for prevention and control of dengue and other diseases transmitted by Aedes mosquitoes. GDAC is supported in part by the Bill & Melinda Gates Foundation and unrestricted grants from industry sponsors including Takeda and Sanofi Pasteur.

Read more on Takeda’s announcement

Dengue is the most frequent and rapidly spreading arboviral disease. The first dengue vaccine, CYD-TDV (Dengvaxia®) is licensed in twenty countries.

WHO issued its position on the use of CYD-TDV in July 2016 based on recommendations provided by SAGE in April 2016, principally, that countries interested in introducing the vaccine consider its use only in those aged 9 years and above, and in areas with a seroprevalence of ≥70%, and not in areas below 50%.  SAGE noted that the evidence of the absence of a safety issue in seronegatives aged 9 and above was based on the limited data set of 10%-20% of the trial population, and highlighted the urgent need to better describe the benefit-risk ratio of CYD-TDV in seronegative individuals.

On 29 November 2017, Sanofi Pasteur announced the results of additional studies to better describe the benefit-risk in seronegative individuals. This was made possible through the use of a newly developed NS1-based antibody assay applied to blood samples taken 13 months after vaccination to retrospectively infer dengue serostatus at time of first vaccination.

The new analyses from the long-term safety follow-up indicated that:

While overall population level benefit of vaccination is favourable, the vaccine performs differently in seropositive versus seronegative individuals. Vaccine efficacy (VE) against virologically confirmed symptomatic dengue was high among inferred baseline seropositive participants ≥9 years of age: 76% (95%CI: 63.9, to 84.0), but much lower among baseline seronegative participants: 38.8% (95%CI: –0.9 to 62.9%) in the first 25 months after the first dose of vaccine.

An increased risk of hospitalized and severe dengue in seronegative individuals was noted from year 3 onwards throughout the trial observation time of 66 months

These findings translate into the following: In areas of 70% dengue seroprevalence, over a 5-year follow-up, for every 4 severe cases prevented in seropositives there would be one excess severe case in seronegatives per 1,000 vaccinees; for every 13 hospitalizations prevented in seropositive vaccinees, there would be 1 excess hospitalization in seronegative vaccinees.

In light of the new evidence on the long-term safety issue in seronegative individuals, balanced against the documented efficacy and safety in seropositive individuals, SAGE carefully considered two strategies: population seroprevalence criteria versus pre-vaccination screening. SAGE weighed up the feasibility of population seroprevalence studies and individual pre-vaccination screening, heterogeneity of seroprevalence between and within countries, potential vaccine coverage rates, public confidence in national vaccination programmes, perceptions of ethical considerations with regard to population level benefit versus individual level risk, and communication issues.

SAGE concluded that for countries considering vaccination as part of their dengue control program, a “pre-vaccination screening strategy” would be the preferred option, in which only dengue-seropositive persons are vaccinated.

SAGE highlighted that important research and implementation questions remain for CYD-TDV, in particular the development of a highly sensitive and specific rapid diagnostic test to determine serostatus, simplified immunization schedules, and assessment of the need for boosters.

The Strategic Advisory Group of Experts (SAGE) on Immunizations, an independent panel of experts that advises the World Health Organization (WHO), issued updated recommendations on 19 April 2018 regarding the use of Sanofi Pasteur’s dengue vaccine, Dengvaxia®.

The update was based on supplemental evidence announced by Sanofi Pasteur on 29 November 2017 which showed Dengvaxia® can increase the risk of severe dengue in people of all ages who have not had prior dengue infection (i.e., are seronegative). SAGE recommended that, in order to maximize public health impact and minimize harm, pre-vaccination screening should ideally be performed on prospective Dengvaxia® recipients, and that only those individuals having evidence of previous dengue infection (i.e., are seropositive) should be vaccinated. SAGE acknowledged that Dengvaxia® could still have an overall public health benefit in populations with high seroprevalence.

Given the current lack of optimal assays to use for widespread dengue serostatus screening, SAGE recommended that dengue IgG ELISAs could be used to test for evidence of prior dengue infection, if evaluated in the local epidemiological context. SAGE also noted that, in the absence of better assays, currently available rapid diagnostic tests (RDTs) that include an IgG component could be used to determine serostatus in settings with very high transmission.

The Global Dengue & Aedes-Transmitted Diseases Consortium (GDAC) believes SAGE’s updated recommendations are a prudent approach to implementing Dengvaxia®, while minimizing the likelihood of harm in an identifiable group of seronegative individuals. However, GDAC also recognizes that these recommendations are hampered by the current lack of accurate point-of-care serological assays. This situation may result in a large number of seropositive individuals not receiving Dengvaxia® due to lack of testing, who would otherwise benefit from the vaccine.

The SAGE recommendations underscore the critical need to address scientific and technical gaps in dengue vaccine development. An immediate priority, as pointed out by SAGE, is the need to improve point-of-care dengue serological assays, which is further complicated by co-circulating flaviviruses such as yellow fever and Zika. Additionally, there is an urgent need to better understand the mechanisms for the increased risk induced by Dengvaxia® in seronegative individuals. This will require improved coordination of ongoing efforts to define correlates of protection and enhancement of dengue vaccines, taking advantage of the increasing availability of biological samples from vaccine recipients with both positive and negative clinical outcomes.

The two other dengue vaccines currently in phase 3 trials, Butantan’s Butantan-DV and Takeda’s TDV, utilize different vaccine designs than Dengvaxia®, and may or may not have the same issues as Sanofi Pasteur’s product. Nevertheless, efficacy and long-term safety of these and other dengue vaccines in people without prior dengue infection need to be assessed carefully.

Finally, effective communication will be crucial to manage expectations about Dengvaxia®’s effectiveness and safety, and to reinforce the public’s confidence in dengue vaccines more generally. And as always, vaccination should be considered as part of an integrated effort to prevent and control dengue, which includes effective vector control strategies, robust surveillance systems, evidence-based clinical care, and strong community outreach.