RIO DE JANEIRO, BRAZIL – The covid-19 pandemic has exposed a weakness in Brazil: the high dependence on imported raw materials from China for vaccine production and the scrapping of laboratories and factories used to produce immunizers in the country.
While in the 1980s Brazil had at least five institutes capable of producing vaccines, today there are only two in operation: Bio-Manguinhos, of Fiocruz, and the Butantan Institute.
And of the 17 vaccines currently distributed by these two research institutes, only four are manufactured entirely in Brazil and do not depend on the import of the Active Pharmaceutical Ingredient (API), as the raw material to produce immunizers is called.
This scrapping of the human vaccine sector contrasts with the high investments in the national manufacturing of immunizers for animals, mainly cattle.
While Brazil imports the vast majority of the vaccines used by the Single Health System (SUS), over 90% of vaccines for cattle are manufactured in the country, according to the National Union of Animal Health Products Industry (SINDAN).
“The problem in Brazil is that we import everything. Over the last few years, we have reduced the national production capacity of vaccines by 50%. We have only two factories. In the veterinary sector, we have countless factories,” says Ana Paula Fernandes, researcher at the Center for Vaccine Technology and Diagnosis at the Federal University of Minas Gerais (UFMG).
In fact, there are about 30 factories for veterinary vaccine – most of them in the Southeast of the country, according to SINDAN. This is a market that guaranteed profits of R$6.5 billion to the veterinary pharmaceutical sector and that helps sustain Brazil’s global leadership in cattle exports.
“The entire manufacturing process, from the live virus working seed to the bottling and distribution, is done here. For more than 90% of vaccines for cattle, the complete production cycle occurs on Brazilian territory,” said Emílio Saldanha, SINDAN’s executive vice-president.
But when did the human vaccine industry cease to be a priority, while livestock vaccination was developing?
From self-sufficiency to dependence on China
According to the founder and first president of the Brazilian Health Regulatory Agency Gonzalo Vecina Neto, it was in the 1980s that the national vaccine research and manufacturing sector for humans experienced its peak of investments.
“During the military regime, the import substitution model was implemented. The military made an effort to expand the local productive capacity of pharmaceutical raw materials and the peak occurred in the late 1980s,” he recalls.
In 1985, the military regime launched the Program of Self-Sufficiency in Immunobiologicals (PASNI), with the goal of making Brazil self-sufficient in the production of immunizers. Resources from the Ministry of Health were transferred to four research institutions: Bio-Manguinhos, the Butatan Institute, the Ezequiel Dias Foundation, and the Vital Brasil Institute.
In a few years, Brazil started to manufacture a series of vaccines on national territory, such as triple viral vaccine, yellow fever, triple bacterial vaccine, polio, tuberculosis (BCG), and hepatitis B.
“For both the Butantan and Fiocruz, investments in the 1980s were a milestone. Brazil had a pharmochemical park for API (Active Pharmaceutical ingredient) production,” said Tiago Rocca, manager of strategic partnerships and new businesses at the Butantan.
But the tide would soon turn for the vaccine research industry. As of March 1990, the commercial opening promoted by the then president Fernando Collor allowed the massive entry of imported products and many Brazilian industries did not survive, including the immunizing sector. Meanwhile, China and India emerged as major producers of pharmaceutical raw materials.
“Brazil started importing APIs on a large scale, small molecules and other raw materials used to produce vaccines. The problem is that investments have not kept up with the competitiveness and openness. Currently, we import about 90% of immunobiological raw materials,” explains Butantan’s Rocca.
As a consequence of the economic opening, institutes and factories were closing their doors, leaving only Fiocruz and the Butantan with the capacity to produce vaccines with national technology.
“The Collor government’s economic opening was done carelessly, with no consideration on how the different segments would be affected. In the pharmaceutical industry, what we did was dry up the national production capacity and start importing everything through multinationals,” adds Vecina Neto, professor at the School of Public Health at the University of São Paulo (USP).
Tighter and necessary regulation was ‘nail in the coffin’
Another important measure in the vaccine industry’s trajectory was the creation of the Brazilian Health Regulatory Agency during the Fernando Henrique Cardoso administration, in 1999.
Brazil began to adopt a more judicious regime for releasing drugs, and rules were imposed to bring Brazil up to international standards of safety and quality in research.
The researchers say that these measures were important, but point out that they were not followed by investments so that institutes such as Fiocruz and the Butatan could update their infrastructure and continue to manufacture end-to-end vaccines in the country.
The result was that immunizers that used to be produced in Brazil began to be imported. The Butantan, for one, used to manufacture the Triple Bacterial Acellular (against diphtheria) and the Hepatitis B vaccine, but began to import these products because it is costly to upgrade the factories to meet regulatory requirements.
“We registered the patent, we own the technology, but we need a new plant to produce these vaccines according to the Brazilian Health Regulatory Agency’s best practices,” explains Tiago Rocca.
Currently, of the seven vaccines supplied by the Butantan Institute, only the influenza vaccine is manufactured entirely in Brazil, based on a technology transfer agreement. And of the 10 vaccines supplied by Fiocruz, only 4 do not depend on the import of Active Pharmaceutical Ingredients.
Gonzalo Vecina Neto believes that the governments that followed Collor, including those of Fernando Henrique Cardoso and Luiz Inácio Lula da Silva, did not have a long-term vision and also did not invest in pharmaceutical and vaccine research.
“The commodities boom encouraged governments to sail on calm waters and rely on the export of agricultural products. Why didn’t Cardoso and Lula invest in vaccine self-sufficiency? A lack of long-term vision. Neither of the two took their foot off the short term, local populism, reelection in the fourth year.”
“Valley of Death”
According to microbiologist Ana Paula Fernandes, professor at the Federal University of Minas Gerais (UFMG), the major bottleneck in the national vaccine industry is the lack of technological laboratories and manufacturing plants to enable the transformation of research into a final product.
“We have technical capacity, cutting-edge researchers, but there are bottlenecks that prevent the findings from being transformed into vaccines. We have the technical knowledge to produce covid-19 vaccines like Pfizer and Moderna’s, but we don’t have the raw material, investments, and factories to produce them,” she summarizes.
These bottlenecks are called the “valley of death” by scientists. This is because there is currently an unbridgeable chasm between scientific findings and their use.
According to USP immunology professor Jorge Kalil, there is a shortage of laboratories and manufacturing plants that would allow the university’s findings to be tested on animals and later on humans.
“What prevents this from happening is lack of investment. We have excellent science in Brazil, but we need to cross the valley of death, which is to go from scientific findings in academic laboratories to the final stage, industrialization,” says Kalil, who is also director of the Incor Laboratory of Immunology and ex-president of the Butantan Institute.
Economic Interest Fuels Veterinary Vaccines
The veterinary vaccine industry, on the other hand, managed to survive the market opening and escaped the Brazilian Health Regulatory Agency’s strict regulations.
The release of vaccines and drugs for animal use is regulated by the Ministry of Agriculture, which imposes more flexible rules, says the agency’s ex-president Gonzalo Vecina Neto.
In addition, a large and lucrative private market guarantees the purchase of cattle, swine and poultry vaccines, while the main buyer of human vaccines is the federal government.
Brazil is the largest exporter of cattle in the world and the amount of cattle on Brazilian territory is equivalent to the size of the Brazilian population. The large-scale sale of vaccines for animal use guarantees that it is more advantageous to manufacture the product in Brazil than to import from other countries, also because the manufacturing cost is lower than that of vaccines for humans, given that the rules are less strict than those imposed by the regulatory agency.
Otto Mozzer, owner of Allegro Biotecnologia, also points out that part of the animal vaccine industry grew leveraged by the federal government’s program to eradicate foot-and-mouth disease by 2026- a highly contagious disease that can cause the animal’s death and that resulted in great losses to producers.
“The large industrial technology park followed the trail of the production of foot-and-mouth disease vaccine. All of them have raised funds to manufacture this vaccine and more than R$6.2 billion in doses have been produced here in Brazil over the last 20 years,” said Mozzer, a PhD in biotechnology from USP.
Brazil totals some 220 million heads of cattle, according to the executive vice-president of SINDAN, Emilio Saldanha. Each of these animals needs be administered two doses of the foot-and-mouth disease vaccine – a requirement of the Ministry of Agriculture for all cattle producers in the country.
“For 30 years we have been self-sufficient in the main vaccines for Brazilian cattle. Vaccination is synonymous with competitiveness,” notes Saldanha.
And why invest in a Brazilian vaccine for humans?
The main argument against investing in national vaccines is that it is currently cheaper to import products from India or China than to build laboratories and factories to ensure self-sufficiency. Currently, the deficit in the Brazilian trade balance of pharmaceutical inputs stands at R$2.1 billion (2019 data), according to the Brazilian Association of Pharmaceutical Inputs Industry (ABIQUIFI).
Since Brazil has experienced over 30 years of disinvestment in the sector, it would take a heavy investment from public authorities to reverse this scenario.
On the other hand, the coronavirus pandemic has exposed the risks of relying entirely on imported supplies. Delayed delivery of raw materials from China could represent months of delay in vaccinating the population against covid-19.
In addition, there are diseases in Brazil that do not arouse research interest from large foreign pharmaceutical companies, because they are a regional problem.
For specialists, investing in national vaccines is strategic to protect the population from regional diseases and reduce foreign dependence, particularly in times of crisis, such as pandemics.
“For example, you have a type of malaria that is common in Brazil, but not in other countries. We have dengue, zika, chikungunya… Producing effective vaccines against diseases that are prevalent here is important to protect the population,” says Ana Paula Fernandes, who is currently involved in a national covid-19 vaccine project.
The Butantan’s manager of partnerships Tiago Rocca, also advocates investments in national technology. “It’s not just a matter of profit, cost and sales. It is a strategic issue not to depend almost entirely on imports,” he says.
“Today, we have a partnership with a foreign company to continue supplying the Hepatitis B vaccine. But it is a strategic issue to have national production, because everyone in Brazil needs to take it and needs a booster dose every ten years. This disease is here.”
Brazilian scientists also argue that investing in national vaccine production infrastructures is important to tackle the coronavirus, particularly due to evidence that vaccines against covid-19 will have to be constantly updated to address the variants of the virus.
The Butantan signed a technology transfer agreement to produce the CoronaVac in the country. And Fiocruz is negotiating a similar contract with Oxford-AstraZeneca. Both institutes have invested in upgrading their factories and laboratories to make these agreements feasible.
Meanwhile, Brazilian researchers are trying to raise funds to supply the market with vaccines made with 100% national technology.
The research group of microbiologist Ana Paula Fernandes, from UFMG, has already completed the pre-clinical trial phase to produce a Brazilian vaccine against covid-19. “We had an excellent response. We used mice and they responded very well.”
Professor Jorge Kalil, from USP, is trying to develop a nasal spray vaccine against covid-19. He has also used the product in mice and is trying to cross the “valley of death” to be able to test the product in humans.
“If we get funds for the most crucial phase of the finding, it is difficult to go down the path that leads to the development of the industrialized product. We are now negotiating partnerships with Brazilian companies.”
Source: BBC Brasil