Dengue: EMA committee endorses vaccine candidate from age 4
If definitively approved, the vaccine manufactured by Japanese pharmaceutical Takeda will be the second in the world against dengue fever14/11/2022
The Committee for Medicinal Products for Human Use (CHMP), a Committee at the European Medicines Agency (EMA) gave a positive recommendation in mid-October for the approval of the candidate vaccine against dengue fever by Japanese pharmaceutical industry Takeda, entitled TAK-003, for the prevention of the disease caused by any serotype in people from four years or older in Europe and in countries where dengue is endemic and that joined in the EU-M4all procedure. The decision is supported by results in rigorous clinical trials including people aged between 18 months and 60 years from endemic and non-endemic regions. TAK-003 is based on a live attenuated dengue serotype 2 virus (DENV-2), which provides the main genetic structure for all four vaccine serotypes and exposes the individual to various components of the virus that could be important in protecting against future infections.
In terms of safety, Takedas communications advisory board explained that TAK-003 was evaluated in 19 Phase 1, 2 and 3 clinical trials enrolling more than 28 thousand children and adults, which includes a four-and-a-half years of follow-up data from the global Tetravalent Immunization against Dengue Efficacy Study (TIDES), consistent with the recommendations of the World Health Organization (WHO), which require three to five years of follow-up data after the completion of a primary vaccination against dengue, in order to more accurately assess safety and efficacy. According to the pharmaceutical company, the TIDES study also met other important WHO recommendations, such as a large study population (more than 20 thousand participants), ability to conduct stratified efficacy and safety analyses, and implementation of a rigorous surveillance system.
The TIDES trial achieved its primary endpoint of overall efficacy against virologically confirmed dengue vaccine with 80.2% efficacy in 12 months of follow-up. The study also met all secondary endpoints, for which there were a sufficient number of cases of the disease in 18 months of follow-up. There was 90.4% vaccine efficacy in preventing hospitalized dengue cases. Exploratory analyses showed that, over four and a half years, TAK-003 prevented 84% of hospitalized dengue cases in the general population, including seropositive and seronegative individuals. The vaccine candidate has generally been well tolerated, with no evidence of increased disease in those who received it, and no major safety risks were identified in the TIDES so far, said Derek Wallace, Vice President and Global Dengue Program Head in the Vaccine Business Unit at Takeda Pharmaceuticals.
Regulatory reviews progress
If approved definitively, the vaccine manufactured by the Japanese pharmaceutical company will be the second in the world used against dengue. According to Takeda, TAK-003 is the first dengue vaccine to have long-term follow-up data as robust as part of its filing package. We deliberately designed the Phase 3 TIDES to address the complexity of the dengue virus and its global presence, including dengue-naïve populations and also those who have already been exposed to dengue viruses in eight endemic countries in Asia and Latin America, he added.
According to the company, this positive opinion is an important moment for the global health community, European countries and dengue-endemic countries that participated in the EU-M4all procedure and symbolizes a step forward to potentially provide the global community with an important new option to complement existing disease prevention efforts. The opinion also marks the conclusion of the first-ever parallel EMA assessment of a medicinal product for use in the European Union (EU) and other countries through the EU-M4all procedure. CHMP endorsements support the quality and robustness of TAK-003 data and help inform endemic countries that participated in the study as they advance their own regulatory reviews, Derek Wallace said.
Also according to the Japanese pharmaceutical company, if the European Community (EC) grants marketing authorisation for TAK-003, it will be the only dengue vaccine approved for use in the EU for individuals regardless of previous exposure to the disease, without the need for pre-vaccination testing so far. Another good news is that regulatory reviews are progressing in endemic countries in Latin America and Asia. According to Takeda, in August the company received approval for the vaccine in Indonesia, an area that experiences almost half of the dengue burden in Southeast Asia. The first launch is scheduled for early 2023.
The pharma will continue to advance regulatory records in other endemic and non-endemic countries, however, regulatory approval and use of the vaccine depend on the assessment of the relevant local authorities and the indication they deem appropriate. When asked about the negotiations with Brazil, whose registration was requested to the National Health Surveillance Agency (ANVISA) in April 2021, the company said they could not comment specifically, as discussions and the regulatory processes are ongoing. In December, Takeda will hold an event for TAK-003 investors to provide more details on business planning and updates on regulatory progress. Before that, they will participate in the 57th Congress of the Brazilian Society of Tropical Medicine (MEDTROP), to be held in Belem (PA), between November 13 and 16.
Brazil is also developing its own dengue vaccine. The Butantan Institute is in phase 3 trials of a study that tracks 17 thousand participants over five years. The research is expected to end in July 2024. The Butantan immunizer differs by being a single-dose and should act against the four types of dengue in people between 2 and 59 years old who have had the disease or not.
Dengue is a major public health challenge, underreported and on the rise due to factors such as climate change and urbanization. There is an unmet medical need and global urgency, as prevention methods are limited and vector control has not been sufficient.
According to WHO data, there are approximately 390 million dengue infections worldwide per year, with an estimated mortality rate of 20-25 thousand people per year, mostly children. It is estimated that around 500 thousand people with severe dengue need hospitalization each year worldwide. The disease is endemic in more than 100 countries. In Brazil, until mid-October, there was an increase of 184.6% in the number of probable dengue cases compared to the same period in 2021. The occurrences went from 478.5 thousand cases last year to 1.3 million in 2022. 909 deaths were confirmed this year. This number is greater than all of 2021 alone, when 246 people died of the disease. It has also surpassed the 2020 records of deaths, when 574 people lost their lives. Experts point out that the increase in cases can be attributed to factors such as urbanization, globalization and climate change.
The dengue virus is transmitted by female mosquitoes, mainly of the species Aedes aegypti and, to a lesser extent, of the species Aedes albopictus. These vectors also transmit chikungunya and Zika fevers. Symptoms of the three arboviruses are similar and include an abrupt-onset of fever accompanied by headache, body and joint aches, prostration, weakness, pain behind the eyes, rashes and itching of the skin, red spots on the body, in addition to nausea, vomiting and abdominal pain. Recovery from infection by a serotype provides lifelong immunity only against this serotype and subsequent exposure to any of the remaining serotypes may be associated with a higher risk of severe disease. There is no specific medication available, so prevention is the most effective tool in combating the disease.