Brazilian dengue vaccine supported by FAPESP starts Phase 3 clinical trial

Agreement with Health Ministry calls for investment of R$100 million in final phase of testing.

Agência FAPESP – A Phase 3 clinical trial of the Brazilian tetravalent dengue vaccine began on February 22 at Hospital das Clínicas (HC), the teaching and general hospital of the University of São Paulo’s Medical School (FM-USP). The vaccine was developed by Butantan Institute with support from FAPESP.

On the same day, an agreement was signed between the Health Ministry and Butantan Institute, calling for investment of R$100 million in the trial over the next two years.

President Dilma Rousseff attended the ceremony alongside São Paulo State Governor Geraldo Alckmin, Health Minister Marcelo Castro, and São Paulo State Health Secretary David Uip. Butantan Institute Director Jorge Kalil, FAPESP President José Goldemberg and FAPESP Scientific Director Carlos Henrique de Brito Cruz were also present, among other government officials.

The federal government pledged to invest R$300 million in total to complete testing of the vaccine. In addition to funding from the Health Ministry, the government is analyzing an injection of R$100 million from the Science, Technology & Innovation Ministry (MCTI) via FINEP, the Brazilian Innovation Agency, and R$100 million from BNDES, the national development bank.

Alckmin also announced that over the next five years, FAPESP will invest R$100 million in applied research for the development of vaccines, serums, rapid diagnostic techniques, epidemiological cohort studies, and other subjects relating to Zika, dengue and chikungunya viruses. FAPESP will also fund research on the development of methods to control Aedes aegypti, the mosquito that transmits these viruses.

“We’ve reached a point in science where Brazil is on the front line of a question that involves a large part of the planet,” Alckmin said. “Dengue, Zika and chikungunya are tropical and subtropical diseases. These affect some 2.5 billion people. On behalf of the São Paulo state government, I would like to thank the federal government for this partnership via the Health Ministry and MCTI.”

Butantan Institute is studying the development of both a serum to neutralize the action of Zika virus in an infected person and a prophylactic vaccine, Alckmin said.

Combating Aedes aegypti

Action is necessary to eliminate the vector mosquito’s breeding grounds until the vaccine is available, President Rousseff said during the event. “We must adopt an effective attitude to make sure no more children are born with microcephaly and no more people suffer from dengue, chikungunya and Zika fever. That means exterminating the mosquito’s breeding grounds,” she said. “We have mobilization campaigns under way using the armed forces, fire brigades, and lessons in schools on the subject. There’s only one way to combat Zika virus today, and that’s not letting the mosquito breed.”

Butantan Institute’s research is “promising,” according to Health Minister Castro. “It can help us find solutions against Zika virus,” he said.

For FAPESP President Goldemberg, “this agency has been funding research in this field for eight years, developing serums and vaccines and combating Aedes and the diseases it transmits. FAPESP has already invested R$48 million in such projects over this period.”

Brito Cruz added that “it’s thanks to FAPESP’s support eight years ago for the production of experimental batches of Butantan Institute’s dengue vaccine that it has been possible to start the last phase of clinical trials today, with the aim of proving that the vaccine is effective.”

In the same week, FAPESP announced a call for proposals in partnership with FINEP to develop technologies for products, services, and processes to combat Zika virus and Aedes aegypti. Some R$10 million in funding will be allocated to the selected projects.

In addition, the Zika Network, linking researchers at several institutions in São Paulo State, is active in a large number of research projects in the field (for more about the Zika Network, see http://agencia.fapesp.br/22802/). New applications for research funding are being received all the time.

Final test

The Phase 3 clinical trial of the dengue vaccine is starting with 1,200 volunteers recruited by FM-USP’s general hospital (HC), one of 14 centers accredited by Butantan Institute. Eventually, the trial will involve 17,000 participants in 13 cities in Brazil’s five regions. Ten people were vaccinated on the first day.

Butantan Institute expects all participants to be vaccinated within a year. The results of the trial will depend on how the virus circulates, but Butantan Institute believes that it will be possible to have the vaccine available for registration by 2018.

The volunteers who have signed up for the trial so far went to the hospital directly or left their details with Butantan Institute’s Citizen Service Center (SAC), with permission to send them to the hospital’s research facility. They are between 2 and 59 years of age and live in different parts of metropolitan São Paulo, including the city itself.

More than 2,000 people have volunteered in the city alone. Only healthy individuals have been accepted, although they can have had dengue in the past. The volunteers are divided into three age groups: 2-6, 7-17, and 18-59 years. Candidates can also email Butantan Institute at [e-mail].

The participants will be monitored for a five-year period to measure how long they are protected by the vaccine, with visits to collect blood as well as telephone contacts and messages exchanged by cell phone.

Butantan Institute’s vaccine, developed in partnership with the US National Institutes of Health (NIH), is designed to protect human subjects against all four serotypes of dengue virus with a single dose. It is a live-virus vaccine built around a genetically attenuated virus. The immune system responds more vigorously to a live virus, but the attenuation ensures that the vaccine will not cause dengue fever.

Besides HC, São Paulo’s Santa Casa de Misericórdia hospital has also been accredited by Butantan Institute to participate in the Phase 3 clinical trial. The vaccination schedule for the other 13 centers will be published shortly.

The trial will also be conducted in Manaus (Amazonas), Porto Velho (Rondônia), Boa Vista (Roraima), Aracaju (Sergipe), Recife (Pernambuco), Fortaleza (Ceará), Brasília (Federal District), Cuiabá (Mato Grosso), Campo Grande (Mato Grosso do Sul), Belo Horizonte (Minas Gerais), São José do Rio Preto (São Paulo) and Porto Alegre (Rio Grande do Sul).

So far, the vaccine has been tested on 900 people: 600 in the Phase 1 trial held in the US by the NIH and 300 in the Phase 2 trial held in the city of São Paulo by FM-USP, Butantan Institute’s partner. The results of Phases 1 and 2 show that the vaccine is safe, induces balanced production of antibodies against all four dengue virus serotypes, and is potentially effective.