Open access peer-reviewed chapter

Developing Countries Can Innovate and Produce Vaccines: The Case of Butantan in Brazil

By Isaias Raw

Submitted: September 12th 2018Reviewed: December 6th 2018Published: January 24th 2019

DOI: 10.5772/intechopen.83351

4. Butantan legacy, influenza, and adjuvants

Butantan assumed a national leadership in vaccine production in 2007, with dedicated plants for diphtheria, tetanus, pertussis, and hepatitis B [26, 27, 28, 29, 30, 31, 32]. Going from the innovation all the way to production, Butantan provided the Society’s demand to control wide spread infections, delivering vaccines free of charge to all population at risk, at acceptable cost to the resources of the Ministry of Health.

The public memoir goes back to 1918 when the “Spanish flue” reported 116.777 cases in city of São Paulo and killed 5.330 people. Those who could afford or have family elsewhere fled the country, leaving the streetcars to transport bodies to be buried in common graves. Government and Society respected the translation of “innovation” into vaccines and sera, safe, and efficient. Developing and manufacturing vaccines were different from buying bulks from large companies to formulate, fill, and label as made in the other countries. This situation was named at WHO meetings, the “coca-cola” model: buy bulk, dilute, and label made in the countries.

With the few vaccines and antisera mentioned, between 1985 to 2009, Butantan was able to produce about 720 million doses of effective and safe vaccines, representing 80% of the vaccines really made in Brazil, receiving for this about 40 honors, medals, and public grants. This was made possible by creating Butantan Foundation, a not-for-profit body that could operate as a private organism, by passing the Government rules, which would make impossible to buy reagents, supplies and equipment, maintain or built new labs and dedicated production plants, hire, and trend in service, the staff, to operate the plants, without the constrains of public rules, which were not adapted to solve public emergencies.

The next priority was flu epidemic risk. The “Spanish flu” reached Brazil in 1918 killing about 35,000 people. US-Barda realized, as pandemic spreads, that the total world production vaccine plants against flu could not supply the demand for vaccines, as the virus serotypes change each year and stocks could not survive and be used for the next epidemics.

Butantan seasonal or pandemic flu first action experience was to set a pilot laboratory to maintain and replicate influenza strains certified by WHO and CDC for production, and to train the staff for produce. A control lab to test and certify vaccines was installed. The State and Federal Government granted 10 million dollars to build the production lab, ordered when possible custom-made equipment (like the machine to destroy the infected shells that was built in Brazil). A central formulation plant was constructed and equipped with a modern automated filling line, to wash and sterilize vials, fill cap, and label vials, with filling capacity of 28,000 vials per hour, containing 10 doses each. A second automated filling system was added to cover for all the vaccines produced. Flu vaccine was cultivated in fertilized chicken eggs and, after extensive purification steps, was transferred for formulation and filling. C. Merrieux (latter Sanofi) extended its help to Butantan, following the plant construction and installation, and inspecting to be sure of our suppliers of chicken eggs comply the rules established by WHO.

The first formulated vaccines produced were taken to Merrieux’s laboratory to be inspected and tested for the demanded requirements of the European Community. Butantan transported the vaccines using cold trucks to the central stock of the Ministry of Health in charge to vaccine distribution to all the state centers, which transfer them to municipal facilities during vaccination. To attend actual Brazilian yearly demand, about 100 million flu vaccine doses are necessary and it is not an easy task to achieve. It took a few years until the regulatory agency approved Butantan’s vaccine, while Sanofi assumed an agreement to meantime supply the vaccine in bulk for formulation at Butantan. We reached, in 2017, the production of 60 million doses of flu vaccine given to children, young adults, pregnant women, and people above 60 years or with special health problems, doctors and nurses.

About 5 million Brazilians live above the equator line and, by mistake, they received the same Southern vaccine, in the same date. It was clear that they were vaccinated after the top of the flu season was over, and they were not protected [25]. The solution was to use part of the year to produce Northern flu vaccine to supply the population in the North. As the sole production plant in Latin America (other than a Sanofi plant that provides bulk to Birmex in Mexico), the excess vaccine production should be offered to PAHO rotating fund, solving the demand of vaccine influenza for Venezuela, Colombia, and Central America (some countries use North and other Southern vaccines).

We found that addition of adjuvants to influenza vaccine allowed a decrease in the usual dose of 15–3.75 μg. The adjuvant addition increased the vaccine production by 4-fold per egg, for the four split virus: A H1N1, H5N1, H3N2, and even H7N9, a new serotype spreading present in the vaccine. We also developed a whole virus vaccine technology in 2010 [35], recently being tested by several large-scale vaccine producers. Whole virus represents more than double production of vaccine/egg, as compared with split virus, and may decrease production cost by a factor of 2-to 5-fold, which would make preventive influenza vaccination affordable to developing and poor countries. In the whole virus, nucleoprotein is present, and they activate toll-3, toll-7, and toll-9 receptors of the host cell, explaining the higher immune response, but also produces antibodies that cross react with hypocretin receptor 2, which will require careful investigation before whole virus influenza vaccine is approved. There are results suggesting that the role of vaccine adjuvants like vitamin A and E increases the IgG1 response as high as squalene. Vitamin D was shown to modulate influenza immune response [35].

VaccineAgeProduced by
Hepatitis Bbirth: 1, 6 monthsButantan
[BCG-S1pertussis]
birthAtaulfo Paiva
Butantan
DTwP + HiB
[DTwPlow + HiB]
2, 4, 6 monthsImported
Butantan
Oral polio2, 4, 6, 15 monthsBiomanguinhos/GSK
[Rotavirus]2, 4 monthsImported
Butantan-NIH
Pneumococcal conj
10 valente
2, 4, 6, 10 monthsImported
Butantan
Meningitis C conj3, 6, 15 monthsImported
Yellow fever9 monthsBiomanguinhos

Brazilian vaccination schedule.

[vaccine]: under development.

5. New vaccines under development at Butantan

5.1 Haemophilus influenza B

Vaccines against Haemophilus influenza Bare based on polysaccharides. The technologies for the production and the conjugation of the polysaccharides with the carrier protein were developed by Butantan, from 2007 to 2012. It is ready to move to full-scale production [36, 37, 38]. This product will allow to simplify vaccination of newborns, by combining in a single vial a pentavalent vaccine, DTwPlow, Hepatitis B and H. influenza B, all produced with our own technology, which depends on building a GMP-dedicated lab for Haemophilusproduction, evaluating trials and registration.

5.2 Rotavirus vaccine

An agreement NIH-Butantan authorized Butantan to produce the pentavalent rotavirus vaccine. Butantan was the first to produce experimental lots for a clinical trial phase I, which was conducted with good results [39]. The phases II and III trials were not yet authorized by Anvisa, but opened for the GSK tetravalent vaccine, using Biomanguinhos as an importer. This occupied the Brazilian public market for about six years. A new vaccine trial comparing with the GSK vaccine was planned with NHI, but the previous Butantan board of directors and management did not act.

5.3 Dengue vaccine

An agreement with NIH allowed Butantan to start a pilot production of dengue vaccine. Trials at School of Public Health of Pennsylvania were successful, but the clinical trial of Butantan vaccine was delayed 2 years by ANVISA, while allowed Sanofi to test their tetravalent vaccine in Brazil. After two years delay, Butantan is conducting the clinical tests in different regions of Brazil, using pilot-scale vaccines produced by Butantan. Clinical tests about to finish slowed down by an unusual decrease in the incidence due to unexpected weather changes. Production plant building is about to be completed by 2019. Meantime, Sanofi vaccine tested in Brazil will not be used and was not approved by any other countries due to serious adverse reactions. Even so, the Brazilian State of Paraná purchased the Sanofi dengue vaccine, while Philippines sued Sanofi for its adverse events.

5.4 DTwPlow and MPLA

The production plants developing antigens diphtheria and tetanus were supposed to be renovated to comply with WHO recommendations and requirements by ANVISA. Thus, at the moment, the production has been stopped. Meantime, we invested in the development of large-scale technology for MPLA from B. pertussis, expected to be used as an adjuvant for influenza and hepatitis B vaccines.

5.5 Pneumococcal vaccine

To replace a mix of 13 to 20 serotypes of pneumococcus, Butantan developed a vaccine based on recombinant pneumococcal surface protein A (PspA) from three different strains, making production easier and less expensive [40, 41, 42].

5.6 Modified BCG

By genetic engineering, a BCG expressing pertussis S1 protein was obtained. It was shown to be more immunogenic than the regular BCG and more effective in a mouse model of bladder papilloma. With this, new BCG Butantan intends to perform proper human trials and return to produce BCG to take place at Ataulfo Paiva Institute that is closing its operation [43, 44, 45, 46, 47].

5.7 Rabies vaccine for human use

Rabies vaccine was produced by Butantan for many years, using basic Pasteur process and using suckling mice to isolate brains [48, 49]. The rabies virus inactivation used an ultraviolet lamp. This type of production was abandoned as the Ministry of Health requirement was to immunize each year about 42,000 domestic dogs. A new process was developed using Vero Cell in a serum-free media, followed by inactivation, to be used in human who had been bitten by suspected dogs [48, 49, 50]. The production and control of this vaccine limit the production to a few producers, being an expensive vaccine. Butantan invested in a large plant to where production is expected to be transferred in 2019.

6. Other process and products under development at Butantan

6.1 Plasma fractionation

According to the Brazilian Constitution, blood cannot be purchased from donor, nor its fractions sold; thus, plasma fractionation must be a public not-for-profit operation. Butantan did not have access to the plasma, but developed a process for hemoderivatives obtaining from human placenta extracts, establishing technologies to separate a series of proteins at high purity. The process allowed to isolate and purify albumin, immunoglobulin G, and some enzymes of potential interest for medical use [50, 51, 52, 53, 54]. When we got access to bags of human blood, we developed the purification process of factor VIII [55].

Butantan has worked in the development of a modern plant, replacing the Cohn method by sequential chromatographic steps, thus avoiding denaturation of fractions with potential clinical use caused by ethanol precipitation. The State of São Paulo with a few other states collected a large part of the human plasma collected in Brazil.

More

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite and reference

Cite this chapter Copy to clipboard

Isaias Raw (January 24th 2019). Developing Countries Can Innovate and Produce Vaccines: The Case of Butantan in Brazil, Vaccines - the History and Future, Vijay Kumar, IntechOpen, DOI: 10.5772/intechopen.83351. Available from:

Related Content

Next chapter

Vaccine Types

By Xiaoxia Dai, Yongmin Xiong, Na Li and Can Jian

First chapter