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Combat front against tuberculosis

Network-TB brings together 170 specialists in search of new vaccines, medicines and tests for identifying the illness

GABRIELLA ZAUITHFor eleven years Lopes Silva has been researching the relationship between the bacillus and its hostGABRIELLA ZAUITH

Tuberculosis is still a serious public heath problem throughout the world. During decades, it was believed that the illness had been under control and the majority of countries ended up reducing their investments in public policies of combating the bacillus. However, tuberculosis has been growing in various regions, together with the rates of population aging and Aids spreading, growing with migratory movements, so much so that in 1993 it was considered by the World Health Organization (WHO) to be a global emergency. Today it is estimated that something in the order of 2 billion people host the bacillus Mycobacterium tuberculosis in their cells.

Every year, 6.8 million individuals develop the illness and 3 million die from it. The situation is particularly grave in twenty two countries that concentrate 80% of the tuberculosis cases on the planet. And Brazil is amongst them, in 13th position with a total of 50 million infected. Or that is to say, almost one third of the population hosts the bacillus without, in the meantime, developing the illness. The incidence of tuberculosis in the country is of 129,000 cases per year, of which only 90,000 are notified, and the mortality rate is 3.5 per 1,000 cases. Close to 80% of tuberculosis victims are between fifteen and twenty years of age.

The only weapon against the illness – whose efficiency for a lot of people is doubtful – is still the old BCG (Bacillus Calmette-Guérin), a living vaccine based on Mycobacterium bovinus weakened for human use, developed in 1921, whose level of protection varies from zero to 75%. Today, the first real challenge of the researchers is to develop forms of immunization that are safer against the illness. Efforts to this end have been multiplying throughout the world: at least 170 vaccines are in a test phase, the majority of them genic or from DNA, considered to be of third generation.

Among them is the one that is being developed by the Research Center into Tuberculosis of the Medical School of Ribeirão Preto (FMRP-SP), of the São Paulo University (USP), with the support of FAPESP. The second challenge is to find new medicines to treat individuals who develop tuberculosis, since the current treatment – a cocktail formed by six toxic drugs – lasts six months and registers indices of giving up of 30%. The World Health Organization (WHO) would like this period of time to be shortened to two months.

New diagnostics
These two tariffs are mobilizing research communities throughout the world. In Brazil, the Brazilian Network for Tuberculosis Research has just recently been set up – the TB-Network is being coordinated by Célio Lopes Silva, of the Biochemistry and Immunology Department of the Medical School of Ribeirão Preto of USP. The Network is made up by 170 researchers and 47 research institutions throughout the country, including those of the Health Departments of nine Brazilian States. Its goal is to bring together scientific knowledge, researchers’ experiences and the products developed by work groups throughout the country in search of new vaccines, new medicines and tests for illness identification.

For example, the diagnosis of tuberculosis is fifty years old and based on the direct bacilloscopy of phlegm and presents a sensitivity of around 50%. The growing of the bacillus on the other hand presents greater sensibility, but the results are only available until after four to six weeks, slowing down the start of the treatment and making the transmission of the bacillus easier. “Technical advances over the last few decades have given origin to various promising tests, but there is little progress on the understanding of how to make these techniques operational”, observes Lopes Silva.

The biology of the bacillus
In the search for the effective prevention and cure of the illness, information exchange is a strategic tool. “The TB-Network is bringing together researchers prepared to carry out epidemiological studies and clinical operations, using post-genome techniques, and to develop research in basic areas directed towards the understanding of the biology of bacillus and the immunopathology of tuberculosis. We have qualified and competent professionals to carry out not only basic research but also to do clinical testing, testing on humans, to develop products, to manufacture them and place them on the market”, guarantees the researcher.

The goal of this work group is ambitious. “We’re going to attempt to solve the problem of tuberculosis in Brazil”, he says. And he justifies: the bacillus of tuberculosis kills more than any other infectious agent and the deaths represent 25% of all of the avoidable mortality in developing countries. Together with the HIV virus, it forms a type of “lethal duet”, since one accelerates the progress of the other. “Tuberculosis is the main death cause in people who are HIV positive”, points out Lopes Silva. Besides, the high rate of treatment abandonment ends up making the bacillus resistant to medicines.

“Unfortunately, we have no options of other vaccines and new drugs.” The cost of treating a case of tuberculosis is R$ 78.00. But in the case of a multi-resistant tuberculosis, it can jump as high as R$ 8,500.00 without taking into account hospital costs. “The TB-Network represents an innovative challenge for national scientific and technological development, and consequently for public health, with a huge social extension”, he forecasts.

Beginning in April, the TB-Network will launch a site to assist in the formation of human resources. “The research tests need to be coordinated and sponsored, right from the collection of the exam material until the description of the bacterium”, explaines Lopes Silva.

Last year the TB-network began to be part of , through the FMRP-USP, the group formed by seventeen Millennium Institutes, a program by the Ministry of Science and Technology (MCT) and the National Council of Scientific and Technological Development (CNPq), which has as its objective the stimulation of the development of multi-disciplinary research at the cutting edge of knowledge. Over a three year period, it will be able to draw on R$ 6 million for investments in research.

Genic vaccine
The idea for the formation of a national research network into tuberculosis advanced along with the study of the illness at the Research Center into Tuberculosis at the FMRP-USP, coordinated by Lopes da Silva. For eleven years he has been researching the relationship between the tuberculosis bacillus and its host. In a thematic project financed by FAPESP, he developed a DNA vaccine with the potential of being applied in the control of tuberculosis. The DNA vaccine is based on a piece of genetic coding of the agent that causes the illness, in this case the Mycobacterium tuberculosis .

Injected through an intramuscular shot, it has been proven that this DNA can create conditions for the production of antigenic protein form the own cells of the infected individual. In the initial studies Lopes Silva introduced the gene named hsp65, an antigenic protein into two plasmids that have the quality to direct the expression of mycobacterium genes in mammal cells. Inoculated in mice, the DNA hsp65 stimulated the production of antibodies. The same experiments were carried out on guinea pigs and the results were equally satisfactory.

The research changed direction in the third phase of the investigation, even before the vaccine was tested on humans. “In Brazil we have one third of the population infected and consequently it was difficult to think about prevention. We decided to look for something more practical: to develop a vaccine that also had therapeutic properties, or that is to say, also cures the disease”, recalls Lopes Silva.

Another aspect that weighed heavily in the redirecting of the research was the time necessary for the testing of a vaccine and of a therapeutic product. A vaccine is tested in three phases, for a period beyond twenty years and the costs are extremely high. A therapeutic product – even through it also takes on the job of a vaccine – has the advantage of being tested as though it were a drug for an one-year period before being placed on the market as a medicine. “We decided to test the use of the DNA vaccine in the direct treatment of already established infections, as an anti-microbacterium drug”, he says .

New tests were done on animals previously infected with the Mycobacterium tuberculosis, and the results indicated that the genetic hsp65 prevented the development of the illness, eliminated the infection and even showed healing properties. During 2000, Lopes da Silva, the FMRP-USP and FAPESP patented hsp65 through the Brazilian Industrial Property Office – INPI as a therapeutic genetic agent.

Side effects
The research is continuing. In a new thematic project, recently approved by FAPESP, Lopes Silva and his team at the Research Center into Tuberculosis are going to evaluate, over a four year period, the side effects, and mainly auto-immunity of organisms to hsp65. Also, they are going to adjust the product in order to obtain specific prescriptions for the presentation of the medicine, and then afterwards to move towards tests on monkeys. The big problem, at this moment with the research, is to find a laboratory with biological security for the tests. “There is only one laboratory in the country with these characteristics, which is located at Fiocruz. We’re negotiating the possibility of using it. However, we intend to set up a laboratory of safety level P3”, he says.

The project
Preclinical gene therapy tests against Tuberculosis which could shorten the duration of treatment, improve the treatment of latent infection and could be effective against MDR-TB (nº 00/09663-2); Modality Thematic project; Coordinator Celio Lopes Silva – Medical School of Ribeirão Preto – USP; Investment R$ 865,918.36 and US$ 846,938.75

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