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immunobiologicals

En route to self-sufficiency

Factory of anti-flu vaccine to generate savings of R$ 94 million a year

Brazil is self-sufficient in the production of vaccines against measles, diphtheria, tetanus, whooping cough, mumps, hepatitis B, meningococcal meningitis A and C and yellow fever. And, by 2007, it should be producing the 17 million doses of vaccine used in combating flu currently imported from the French laboratory Aventis, at an annual cost of R$ 94 million. The Ministry of Health, the government of the state of São Paulo and the Butantan Foundation are investing R$ 52.2 million in the construction of a factory of anti-flu vaccines, which is expected to start operating in 2005.

Besides meeting the domestic demand for this kind of medicine, the Ministry of Health also wants to produce, at the Butantan Institute itself, blood products’ such as specific immunoglobulins, albumin and coagulation factors – importing which consumes US$ 150 million a year.The correction to the national policy on immunobiologicals and vaccination, supported by heavy investments in the national production of immunoprophylactics, was one of the few points of consensus in the area of Public Health hammered out in the country in the last 20 years.

The success of the National Immunization Program is undeniable: no case of measles has been notified in the last two years, and the number of records of other immunopreventable diseases, such as poliomyelitis, diphtheria, tetanus, whooping cough, measles and mumps, is the lowest of all times. And the bet placed on self-sufficiency has yielded results. The director of the Butantan Institute Foundation, Isaias Raw, recalls that ten years ago the cost of importing the vaccine against Hepatitis B was US$ 24 for each dose, and the vaccine is administered in three doses. “Today, the vaccine is produced in Brazil, and the three doses cost around US$ 1”, Raw compares.

Another hallmark of the model for the Brazilian immunobiological policy is the strong presence of the public sector in the production of vaccines. At the beginning of the 80s, public laboratories – amongst them the Instituto de Tecnologia em Imunobiológicos ( Technology in Immunobiologicals Institute), better known as Bio-Manguinhos, and the Butantan Institute – and private ones shared the responsibility for producing vaccines. “Some of them had neither economy of scale nor technological development.

When the Ministry of Health started to demand an improvement in the quality of the production, Sintex, a private multinational company, responsible for 80% of the production of anti-snake venom serums and vaccines in Brazil, left the business, and the country had dramatic problems in meeting demand”, says Akira Homma, a director of Bio-Manguinhos. Other smaller laboratories also wound up their activities, and there were problems with the supply of vaccines.

In the case of anti-snakebite serum, there was noteven the alternative of importing it, since the serum produced in the United States, for example, does not offer protection against the bites of Brazilian snakes, due to the specificity of ophidian venom. This “disaster”, as Homma describes it, was the last straw that led the country to create the National Program for Self-Sufficiency in Immunobiology, in 1982. In its first ten years, the Program cost the public coffers something in the order of US$ 120 million, by Homma’s accounts, but it has consolidated the infrastructure for producing serums and vaccines in the country.

“We are qualified to produce vaccines with suitable technology and prices, all of them tested in human beings”, says Raw. Bio-Manguinhos, linked to the Ministry of Health, and the Butantan Institute, linked to the Secretariat for Health of the State of São Paulo, are currently responsible for 75% of the domestic production of vaccines in the country. Also part of the national system for the production of immunological products is the ‘Instituto Tecnológico do Paraná ‘(TecPar Technological Institute of Paraná ), maintained by the government of the state of Paraná, which produces a vaccine against rabies, and the Ataulfo de Paiva Foundation, a private non-profit organization that, together with the Butantan Institute, is responsible for the supply of BCG (bacillus of Calmette and Guerin), a vaccine against tuberculosis suitable for children between 0 and 4 years old.

In spite of the goods results of the policy for immunobiologicals in the country, the model of the public sector production of vaccines is becoming extinct in the rest of the world, explains Raw, who also occupies the post of president of an association of vaccine producers from developing countries. Only China and Indonesia adopt a strategy similar to the Brazilian one. The great obstacle for the public sector lies in the high fixed cost of producing vaccines, in the requirement for economy of scale, and in the constant need for incorporating new technologies.

“It takes some ten years to produce a new vaccine”, Raw reckons. “It is a risky investment. It has to have a hefty strategy”, Homma adds. He estimates that governments and private laboratories all over the world invest something like US$ 2 billion every year in research and development for new vaccines. At the same time that they engage in fantastic competition for technology – which results in investments of as much as 20% of earnings in research and development -, the major private producers have sought to centralize production on one or two countries, and from there to win over the world market.

But none of these factories is installed in developing countries, recalls the director of Bio-Manguinhos. For these countries, the way out is either to produce or to import. Besides the high cost of importing vaccines, the Brazilian option for self-sufficiency in immunobiology took into account the instability of the producers. Homma points out that the United States has had difficulty in meeting the demand for vaccines like DTP (Diphtheria-Tetanus-Pertussis vaccine) and the MMR vaccine in the last four years, since the laboratory responsible for producing them decided to take these production lines out of service, due to “economic issues”, according to Homma.

Brazil also had difficulties in importing the viral concentrate used in the production of the anti-polio vaccine, when the Melinda and Bill Gates Foundation injected US$ 700 million into the Global Alliance for Vaccines and Immunization (GAVI), to purchase and to supply vaccines for poor populations. “Brazil was forced to invest in the public laboratories. We can’t keep remain dependent on importing enormous volumes of inputs so strategic as vaccines, which would leave the National Immunization Program more vulnerable to the humors of the market”, Homma argues.

Efficient production
The two largest vaccine producing centers in the country date back to the beginning of the century. Bio-Manguinhos had its origin in the Federal Serotherapic Institute – nowadays the Oswaldo Cruz Foundation (Fiocruz) – created in 1900 with the objective of developing serums and viral and bacterial vaccines, besides supporting the public health campaigns commanded by Oswaldo Cruz. Every year, it produces 30 million doses of vaccine against yellow fever, which, besides supplying the domestic market, meets the international demand from the World Health Organization (WHO), the Pan American Health Organization (PAHO) and UNICEF. This is not to mention its support for public programs in Latin American countries.

Using technology from the Biken Institute, through a technical cooperation agreement with the Japanese government, Bio-Manguinhos also produces 10 million doses of vaccine against measles, which will shortly be replaced by the MMR vaccine, which also combats mumps and rubella. And it carries on processing imported viral concentrates to distribute annually around 47 million doses of vaccine against poliomyelitis. Since 1976, thanks to a cooperation agreement with the Merieux Institute, of France, Bio-Manguinhos has been making vaccines against meningococcal meningitis A and C. Another agreement for the transfer of technology, this time with SmithKline Beecham, has made possible the production of 2.5 million doses against Haemophilus influenzae type b. This vaccine will be incorporated into the triple vaccine (DTP), against diphtheria, tetanus and pertussis, produced by the Butantan Institute.

The Butantan Institute was created in 1901, with the name of Serotherapic Institute, after an outbreak of the bubonic plague spread over the port of Santos. Today, it produces 200 million doses of vaccine a year, including the triple vaccine (whooping cough, diphtheria and tetanus), and a double vaccine, against diphtheria and tetanus, used to immunize children and as a booster dose for the adult population.

“In the last three years, we have made 60 million doses of this vaccine, for people over the age of 60”, Raw says. They also make the vaccine against hepatitis B and part of the BCG produced at the Ataulfo de Paiva Foundation. “We will shortly also have vaccines against meningitis B, meningitis B and C, pneumococci and schistosomiasis, produced jointly with Fiocruz”, Raw reveals.

Other projects that are at an advanced stage include a whole-cell pertussis vaccine, a recombinant vaccine against pneumococci, and a combined hepatitis B and BCG vaccine for the newly-born and for people aged over 60. Not to forget the anti-flu vaccine, which will start being distributed within two years. He reveals that, five years hence, when all the youngsters have been vaccinated against type B hepatitis, the institute will begin production of vaccines against HPV, or the human papilloma virus, which is the main cause of cervical cancer. “The two vaccines are very similar”, he notes.

But the institute’s plans go further. Raw says that an American group is interested in developing a vaccine against leishmaniasis and would be prepared, as he says, to finance the clinical tests that would be done under the Butantan’s responsibility. Moreover, he reveals that “We are negotiating with theNational Institutes of Health of the United States, which wants to transfer to Brazil technology for producing rotavirus vaccines”, he reveals. The institute also wants to take part in a tender for Unicef, in the amount of US$ 9 million, for the period from 2004 to 2006.

Malaria and dengue
Brazil has already proved that it is qualified to produce vaccines, in a production model centered on the public sector. However, the great challenge is to keep the ability for incorporating new technologies. In the assessment of the director of Bio-Manguinhos, there has to be an investment in technological development with a focus on a few products (please see the box)”, Homma suggest. He insists that it is fundamental for the country to invest heavily in research that generates knowledge for the development of new technologies. “We need critical mass in technological development”, he says. He reveals that Bio-Manguinhos, after creating a professional master’s degree course in immunobiological technology, is going to implant a doctoral course in the area. “New products are not developed without this”, Homma concludes.

Gene vaccines
The incorporation of new technologies is making it possible for Brazil to take big steps forward in the direction of gene vaccines as well. Researchers from Fiocruz are testing on mice a gene vaccine against dengue. This method consists of copying a stretch of the genetic material of the virus and inserting it into a plasmid – a fragment of DNA that does not hook up with the chromosomes, but which is capable of setting off the production of a protein that – when incorporated into the cell – will induce the production of a protein of the virus, which will activate the organism’s defense system.

Tests are also advanced of a gene vaccine against tuberculosis, which is being developed at the School of Medicine in Ribeirão Preto. And the sequences have now been isolated of the proteins of the bacterium responsible for a reaction of the organism that unleashes rheumatic fever. They will be the basis for developing a vaccine against throat infections caused by this microorganism. The project brings together researchers from the Heart Institute (Incor) of the University of São Paulo, the Teuto-Brazilian Laboratory and FAPESP, in the ambit of the Program for Technological Innovation (PITE).

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