Dengue: Takeda’s vaccine is approved in Brazil
The granting of the registration by Anvisa allows the commercialization of the product in the country, as long as the approved conditions are maintained10/04/2023
The Brazilian National Health Surveillance Agency (Anvisa) has approved the registration of a new vaccine against dengue from the Japanese pharmaceutical company Takeda, the QDENGA® (TAK-003) for the prevention of the disease caused by any serotype in people aged four years and older. In February, the National Technical Biosafety Commission (CTNBio) approved the safety of the vaccine, which was awaiting regulatory approval. The registration had been requested in April 2021. The use of the immunizer must be in accordance with the official recommendations of Anvisa. QDENGA ® is based on a live attenuated dengue serotype 2 virus (DENV-2), which provides the genetic backbone for all four vaccine serotypes and, exposes the individual to various components of the virus that may be important in protecting against future infections. To date, this is the only vaccine approved in Brazil for use in individuals regardless of previous exposure to dengue and without the need for pre-vaccination testing.
The granting of registration by Anvisa allows the commercialization of the product in the country, provided that the approved conditions are maintained, however, QDENGA is not yet available in Brazil. The next step is the pricing definition that will be made by the Chamber of Regulation of the Medicines Market (CMED), an interministerial agency linked to Anvisa. According to Takeda, it is necessary to wait for the completion of this process to proceed with the importation of the vaccine and the commercialization for health clinics. In October 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) gave a positive recommendation for the approval of the vaccine. The decision was supported by results from rigorous clinical trials.
The communications advisory board of Takeda explained in the article “Dengue: EMA committee endorses vaccine candidate from 4 years old” published by the Brazilian Society of Tropical Medicine (SBMT) that the vaccine was evaluated in 19 clinical trials of Phase 1, 2, and 3 involving more than 28,000 children and adults, with data from four and a half years of follow-up from the Tetravalent Immunization against Dengue Efficacy Study (TIDES), consistent with the recommendations of the World Health Organization (WHO), which require follow-up data of three to five years after 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 20,000 participants), the ability to perform stratified efficacy and safety analyses, and implementation of a rigorous surveillance system.
“The TIDES study achieved its primary endpoint of overall confirmed virologically-evaluated vaccine efficacy against dengue at 80.2% after 12 months of follow-up. It also met all secondary endpoints for which there were sufficient dengue cases after 18 months of follow-up. There was a vaccine efficacy of 90.4% in preventing hospitalization due to dengue. Exploratory analyses showed that over four and a half years, TAK-003 prevented 84% of hospitalized dengue cases in the overall population, including seropositive and seronegative individuals. The vaccine has been generally well tolerated, with no evidence of disease enhancement in those who received it, and no important safety risks identified in the TIDES study to date,” said Dr. Derek Wallace, Vice President and Head of the Dengue Global Program in the Vaccines Department at Takeda Pharmaceuticals, in an article published in November 2022 by SBMT.
Dengue cases surge and government announces emergency center
In 2022, Brazil experienced an explosion of dengue cases, and the total number of deaths was higher than in the last six years. According to the epidemiological bulletin of the Ministry of Health, there were 1,016 deaths and 1,450,270 probable cases of the disease, an increase of 162.5% compared to 2021, which recorded 544,000 infected individuals.
The situation in 2023 is not looking good either. The Ministry of Health reported a surge in cases of dengue, Zika, and Chikungunya in the first three months of this year, with 210,000 probable cases, a 43.8% increase compared to the same period last year. The region with the highest incidence of dengue is the Midwest, with 254.3 cases per 100,000 inhabitants, followed by the Southeast, with 214.7 cases per 100,000 inhabitants, and the South, with 98.2 cases per 100,000 inhabitants. Espírito Santo was the state with the highest increase in incidence, with 921.7 cases per 100,000 inhabitants, followed by Mato Grosso do Sul, with 432.5 cases per 100,000 inhabitants, and Minas Gerais, with 392.1 cases per 100,000 inhabitants.
Chikungunya had the biggest jump (97%), with 43,000 probable cases. Meanwhile, Zika totaled 1,194 probable cases, compared to 883 in the same period last year, an increase of 35.2%. In light of this scenario, the Ministry of Health has set up an Arboviruses Emergency Operations Center (COE Arboviruses), which aims to develop strategies for controlling and reducing severe cases and deaths. With the activation of the Center, the ministry will monitor the situation, with emphasis on dengue and Chikungunya, in order to guide the implementation of actions aimed at epidemiological surveillance and vector control. The planning of actions and coordinated response will be done in conjunction with states and municipalities. The director of the Department of Transmissible Diseases, Dr. Alda Maria da Cruz, emphasized that the priority is to raise awareness among the population, so that it is possible to control the spread of these arboviruses.
Dengue is a major public health challenge that continues to rise. According to WHO data, there are approximately 390 million global dengue infections per year, with an estimated mortality rate of 20,000 to 25,000 people per year, mostly children. It is estimated that around the world, about 500,000 people with severe dengue require hospitalization each year. The disease is endemic in more than 100 countries. There is no specific medication available, so prevention is the most effective tool in combating the disease.
Virus in Aedes aegypti amplifies dengue transmission
A study titled “Mosquito vector competence for dengue is modulated by insect-specific viruses“, published in the scientific journal Nature Microbiology, identified two insect-specific viruses, the Humaita-Tubiacanga virus (HTV) and the Phasi Charoen-like virus (PCLV), which commonly circulate in field populations of the main mosquito species, Aedes aegypti and Aedes albopictus, and make Aedes aegypti more prone to transmit dengue and Zika. In the analysis, the presence of HTV and PCLV was associated with a 3-fold higher chance of the mosquitoes carrying the dengue virus (DENV), suggesting a positive association between these viruses. For the study, researchers analyzed viromes from 815 urban Aedes mosquitoes collected in 12 countries worldwide.
Dr. João Trindade Marques, a professor at the Department of Biochemistry and Immunology at the Institute of Biological Sciences (ICB) at the Federal University of Minas Gerais (UFMG), who led the research, explains that the presence of HTV and PCLV accelerates the incubation period of the dengue virus in the mosquito, making it capable of transmitting DENV more rapidly. According to him, the presence and circulation of these two viruses in natural populations of mosquitoes should be evaluated, as their presence indicates a higher risk of dengue or Zika outbreaks. According to the researcher, these two viruses have a significant impact on the natural epidemiology of the disease, and this knowledge can be used in various ways, including in the analysis of dengue outbreak risk, which is currently done solely based on the presence and density of the mosquito (infestation indices). “Our research suggests that the presence of the vector is just one factor, and that the presence of HTV and PCLV should be considered, as it represents an impact on transmission, of 10 to 50 times, meaning it can compensate for a mosquito density 10 or 50 times lower for the same type of transmission,” he notes.
Regarding Aedes albopictus, no massive circulation of these insect-specific viruses was observed, and therefore, no correlation analysis was performed between arbovirus transmission and the presence of HTV and PCLV. “Apparently, A. albopictus seems to be less permissive to the circulation of these viruses. Another interesting factor is that in general, it is considered a worse vector than A. aegypti, which may suggest that this permissiveness to insect-specific viruses is generally indicative of arboviruses, but this still needs to be tested in the laboratory,” says Dr. Marques.
Chikungunya virus, which belongs to the Togaviridae family, genus Alphavirus, was not tested in this study, and according to Dr. Marques, it is possible that this interaction does not exist. The next step in the research is to understand how the presence of HTV and PCLV modifies the mosquito’s physiology to become more permissive to dengue and Zika viruses. “With this understanding, it is possible to design control strategies based on this mechanism,” concludes the professor.
About the insect-specific viroses
The Humaita-Tubiacanga virus (HTV) was named after the two regions where it was found in Rio de Janeiro, in 2015. The Phasi Charoen-like virus (PCLV) was partially identified a few years ago in Thailand and fully characterized in 2015 in a study conducted by the same laboratory at ICB/UFMG.