Dengue vaccine begins final stage of clinical trials

Phase III trials, involving 17,000 volunteers and 14 health centers in 13 cities across all five regions of Brazil, are expected to take a year.

By Karina Toledo  |  Agência FAPESP – São Paulo State Governor Geraldo Alckmin, Health Secretary David Uip and Jorge Kalil, head of the Butantan Institute, announced on December 11 the start of Phase III clinical trials of the Brazilian dengue vaccine, developed with support from FAPESP.

The trials, which are expected to last approximately a year, will involve 17,000 volunteers and 14 health centers in 13 cities across all five regions of Brazil. The aim is to prove that the vaccine is capable of protecting the population against all four serotypes of the dengue virus.

“Dengue is a disease that threatens some 3 billion people worldwide. There’s no cure. Treatment is confined to supporting life,” Alckmin said. “With climate change and rising temperatures, the number of cases is likely to increase. The priority has always been to produce a vaccine. We’re proud that São Paulo is taking this step to help the nation and science in such an important matter.”

According to Kalil, two-thirds of the volunteers will receive the vaccine; the rest will receive only a placebo. The trials will be randomized and double-blind: the volunteers will not know which group they are in, nor will the researchers, until the end of the trial, when the two groups will be compared to determine whether the vaccine effectively protected the first group.

“The results of Phase II clinical trials justify expectations that it will prove highly effective,” Kalil said. “But the duration of Phase III will depend on how long it takes to recruit volunteers and also on the incidence of the disease in the months ahead. We need to have all four serotypes in circulation.”

Volunteers from three age groups will be included in the trials: children aged 2-6 years, children and adolescents aged 7-17, and adults aged 18-59. People who have had dengue as well as those who have not can participate.

“Phase II showed that the immune response is even better in subjects who have previously contracted dengue fever,” Kalil said.

According to Uip, vaccination will begin with the oldest age group. “Children will be left until last for safety reasons,” he explained.

The health secretary added that representatives of the Butantan Institute were to met with government officials on December 14, to discuss investment and a business model to ramp up production of the vaccine if it is approved, to meet demand nationwide and possibly worldwide.

If all goes well in the final phase of clinical trials, the state government and the Butantan Institute expect the vaccine to be available for mass campaigns by 2017.

“We consider this vaccine strategic for Brazil,” Uip said. “A group of experts will monitor the trials, and when they decide the results are conclusive, production of the vaccine will start.”

Kalil noted that another dengue vaccine, produced by Sanofi Pasteur, is available, but it is considered less effective and requires three applications because it uses modified yellow fever virus. The Butantan Institute’s vaccine, which uses attenuated dengue virus, will be administered in a single dose.

The process of strain construction, which attenuates the virus used in the quadrivalent vaccine, was performed in the United States, in partnership with the National Institutes of Health (NIH).

During the news conference, Governor Alckmin stressed that until the vaccine is available, the only ways to combat the disease are by eliminating the breeding grounds of the Aedes aegypti mosquito and training doctors to provide support for infected people.

“Everyone must help,” he said. “The state government will support the municipal authorities, and we plan to allocate police personnel to help in this effort. We won’t be transferring them from patrol duty. They’ll do this work as an extra shift, and they’ll be properly paid for it.”

Phase III clinical trials

The 14 centers will not start the work simultaneously. Individuals who wish to volunteer must wait for the invitation to be published and then apply to participate in the trial in their locality. The first city to begin its Phase III trial will be São Paulo, where it will be run by the University of São Paulo’s Medical School (FM-USP) via its teaching hospital, Hospital das Clínicas, and Santa Casa de Misericórdia.

Volunteers will be followed up for five years by the medical team responsible for the trial. To facilitate the follow-up, they must live in the area covered by the relevant health service. At least ten visits to a health clinic will be scheduled during the period so that volunteers can be examined by physicians and undergo testing, and there will be 28 telephone contacts by the research team.

“This is the first time a public producer has ever held clinical trials of this size, with so many volunteers and mobilizing all of Brazil,” Kalil said. “We’re close to having an all-native solution to a problem that is afflicting our country. We’ve had severe large-scale dengue epidemics in recent years, and all Brazilians are well aware of the threat, so we expect plenty of people to volunteer for the clinical trials.”

As already reported by Agência FAPESP, clinical trials began in 2013 with the support of Fundação Butantan and BNDES, the national development bank, under the aegis of the Development of a Quadrivalent Dengue Vaccine project, coordinated by Neuza Frazatti Gallina.

The vaccine has been tested in 900 people: 700 in Phase I clinical trials held in the US by the NIH and 300 in Phase II trials held in São Paulo by FM-USP, which is partnering with the Butantan Institute. The data available thus far from the first two phases suggest that the vaccine is safe, that it induces the organism to produce antibodies in a balanced manner against all four dengue virus serotypes, and that it is potentially effective.

The Butantan Institute has a small-scale factory ready and equipped to produce 500,000 doses of the vaccine per year. With a few industrial adaptations, it can expand capacity to 12 million doses per year. It is planning to build a large-scale plant that could produce 60 million doses per year.