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The promise to neutralize the virus

Instituto Butantan to conduct clinical studies of dengue fever vaccine developed in the USA

In 2008, Instituto Butantan started the clinical tests of a dengue fever vaccine whose efficacy will verified by 2010. The product has been in development for the last seven years at the National Institute of Allergy and Infectious Diseases (NIAID), one of the USA’s National Health Institutes, and is ready to be tested on human beings. Experiments with monkeys suggest that the drug is 100% efficient when it comes to dealing with the four kinds of dengue fever viruses. The technology is very similar to the one used for the manufacturing of anti-rabies and rotavirus vaccines, also produced by the Instituto Butantan.

The disease-causing agent can stimulate the production of antibodies, but is unable to cause the disease or to be transmitted by the female Aedes aegypti mosquito. During the first phase, expected to last for about two months, the vaccine will be given to thirty adults to evaluate whether it poses any hazards to human health. The safety of the antigen has already been attested to in the USA – but Brazilian health laws require replication of these results in the country. Phase 2 and 3, during which the vaccine’s efficacy will be actually evaluated, will rely on a much larger number of volunteers from regions where dengue fever is rampant. A number of institutions will take part in the effort: the University of São Paulo (USP) Medical School, through its Children’s Institute, the USP Universitário teaching hospital, the Santa Casa Medical School, and the Adolfo Lutz Institute, in charge of the laboratory tests.

Although dengue is no longer a threat to the American population, the research into a vaccine mobilized health authorities in the USA, who were concerned about the possible contagion of Americans traveling abroad and of American soldiers on foreign missions. In addition to the NIAID, two other dengue fever vaccines are being tested by the US Navy Medical Research Center and by the Walter Reed Medical Center, a research institution run by the US Army. This institute also invests heavily in research into and treatment of malaria, as this is another nightmare for the American military. At least three other immunizing agents are being developed at Thailand’s Mahidol University and by the American biotech companies Acambis and Hawaii Biotech.

Given the lack of victims in its territory, it was natural for the NIAID to look for partnerships to test its vaccine in countries where the disease is rampant. The decision to partner with the Butantan Institute is mostly due to the latter’s noteworthy expertise in this field. “This is  recognition of our competence in developing the production technology and in building facilities comparable to the best in the world”, said Isaias Raw, president of the Butantan Foundation and also technical scientific head of Butantan’s Biotechnology Center. Butantan is accredited by Unicef and by the Pan American Health Organization/PAHO as a supplier of vaccines for developing countries. The agreement with the US National Health Institutes repeats the terms of a partnership agreement signed last year for the testing and production of an anti-rotavirus antigen; this antigen is already available and is being manufactured on an industrial scale by Butantan. “In the wake of Butantan, India and China will produce the same anti-rotavirus vaccine, which is less costly and more efficient than the imported vaccines”, commented Raw.

The preparation of the clinical studies in Brazil, which will be financed by BNDES, the national development bank, will have the help of epidemiologists from the Pediatric Dengue Vaccine Initiative (PDVI), based in South Korea. The institution is funded by the Bill & Melinda Gates Foundation, which donated US$ 55 million to speed up the development of various dengue fever vaccines. The PDVI mission that came to Brazil, headed by Donald Francis, a researcher renowned for his work on Aids, Ebola and measles in Africa, signed an agreement with the Butantan Institute. “We have been saying for at least three decades that a dengue fever vaccine should be available within the next ten years. Now it finally seems that this will materialize”, Duane Gubler, a dengue fever expert from Honolulu’s University of Hawaii, Manoa campus, told the journal Science. Gubler is a member of the consulting board of the PDVI.

The vaccine tested in Brazil will be tetravalent, able to provide immunity against four dengue fever serum strains: 1, 2, 3 and 4. This production was a task that took more than fifty years to be successfully achieved. Until the nineties, the tests conducted with anti-virus vaccines faced huge obstacles. Two of the drugs were successful against the 1, 2 and 4 sub-strains, but failed in the attempt to attack the 3 strain type: as a result, volunteers, instead of becoming immune to dengue fever, were actually contaminated by it. The advent of the genetic manipulation of the virus allowed the researchers to shape the body’s immunological response to the four strains of the infectious agent. Another challenge for the dengue fever vaccine was to ensure that it would not provoke hemorrhagic dengue fever, which may lead to death. Ninety percent of the cases of hemorrhagic dengue fever occur in individuals that had already been infected with one of the sub-strains and were re-contaminated by another strain. The biggest fear was that the antigen, once it had been given to people who had already had the disease, might cause an exaggerated response that could lead to hemorrhagic shock. This risk does not exist in the case of the vaccine tested in Brazil. According to Isaias Raw, data from the NIH shows that the immunization does not produce the same contagion effect with wild viruses.

If the efficacy of the vaccine is proven within two to three years, as Isaias Raw expects, the NIH has already agreed that Butantan will be authorized to produce it for all of Latin America. The government will take part in this effort by financing the building of a plant on the plot of land on which Butantan is currently located. The Government of the State of São Paulo will be responsible for the construction and the Ministry of Health has already agreed to provide the equipment. This strategy is similar to the one used for the production of the flu vaccine.