07/30/2025 | Aline Tavares

https://butantan.gov.br/noticias/ensaios-clinicos-no-butantan-%7C-influenza-como-o-butantan-se-tornou-o-maior-produtor-da-vacina-no-brasil-e-se-prepara-para-pandemias 

Since 2013, more than 560 million doses of influenza vaccine have been produced; the Institute helped combat H1N1 in 2010 and is developing a vaccine against avian flu.

In production by the Butantan Institute since 2013, following a technology transfer from the French pharmaceutical company Sanofi, the influenza vaccine has become the institution's flagship product and the institution's main focus of study. Today, 90 million doses are produced annually to support the National Influenza Vaccination Campaign. In addition to the seasonal trivalent version, Butantan is dedicated to studying quadrivalent vaccines, vaccines against pandemic influenza strains, and vaccines with adjuvants, aiming to prepare the country for flu epidemics and develop increasingly effective products.

All of this requires adequate infrastructure for conducting clinical trials, the stage in which the safety and efficacy of products are evaluated in humans. This work is handled by Butantan's Clinical Trials and Pharmacovigilance Division: of the more than 30 clinical studies already coordinated by this department, 10 were related to influenza.

Butantan's experience with the influenza vaccine dates back to 1999, when the technology transfer agreement was signed with Sanofi, led by then-director Isaias Raw. Highly complex, the process was carried out in stages and took over 10 years to complete. Butantan began receiving the finished vaccine from Sanofi for inspection, quality control, labeling, packaging, and delivery to the Ministry of Health. Over the years, the institution took over bottling, then vaccine formulation, and finally production of the three monovalent vaccines in its own factory.

"In the early years, the registered production site was the Sanofi factory in France. After the technology transfer was completed, the Butantan factory received certification from Anvisa [the Brazilian Health Regulatory Agency] to begin operating and produce the influenza vaccine from start to finish," says Paulo Lee Ho, Butantan's Product Development and Innovation Manager, who closely monitored this process.

While Butantan developed its production process, some of the vaccines supplied to the Ministry of Health were produced in Brazil, and the rest in France. The Institute began supplying 6.3 million doses in 2013; In just three years, production increased more than sevenfold, reaching 46 million. In 2023, Butantan reached the production capacity necessary to supply 100% of the campaign's doses – that is, 90 million doses.

How is the flu vaccine made? From the arrival of the strain to the multiplication of the virus

"Not only a manufacturing structure was established, but also a pilot and laboratory structure, and this led to the incorporation of Good Laboratory, Manufacturing, and Clinical Practices, as these concepts advanced internationally," notes Butantan's Medical Writing Coordinator, Maria da Graça Salomão, who participated in the influenza studies.

As the Sanofi vaccine had already successfully passed phase 1, 2, and 3 clinical trials, after completing the technology transfer and taking over its manufacture, Butantan conducted phase 4 studies between 2013 and 2015, as required by Anvisa. The researchers evaluated the vaccine in healthy adults, the elderly, and kidney transplant recipients.

"After this period, Anvisa understood that it was unnecessary to repeat clinical trials every year while the population was already vaccinated, and that post-marketing surveillance was the best tool for assessing the safety of strain updates," explains Maria Beatriz Lucchesi, Pharmacovigilance Manager at Butantan. With each campaign, the vaccine is updated with the most circulating strains of the influenza virus, in accordance with World Health Organization (WHO) guidelines.

Despite this decision, studies did not stop. On the contrary: as it became the main supplier of the flu vaccine in Brazil, Butantan continued investing in other research to improve the vaccine, achieving WHO prequalification in 2021 and developing vaccines against potentially pandemic strains. The Institute also participated in the fight against the H1N1 pandemic in 2009.

Learn more about the developments in studies involving the influenza vaccine at the Butantan Institute:

H1N1 Pandemic

In 2009, the world faced the H1N1 pandemic, a disease known as swine flu that affected more than 70 countries. According to the WHO, the outbreak began with the spread of a type A influenza virus originating from an animal strain and unrelated to seasonal H1N1 viruses. In Brazil, Butantan Institute was at the forefront of the fight against the disease, producing a vaccine containing the pandemic strain—as part of the technology transfer process for the Sanofi vaccine. In 2010, the National Institute of Infectious Diseases (PNI) acquired 83 million doses of the vaccine.

At the time, the Institute investigated the safety and immunogenicity of the H1N1 vaccine with different adjuvants (substances used to enhance the immune response). Studies were also conducted to evaluate the vaccine in vulnerable populations, such as patients with chronic diseases, immunosuppressed individuals, the elderly, and pregnant women—groups that accounted for the majority of deaths from the disease.

Vaccination helped contain swine flu cases and led the WHO to declare the end of the pandemic in August 2010. During the health emergency, 18,500 deaths from H1N1 were officially confirmed worldwide, but a study by the United States Centers for Disease Control and Prevention (CDC) estimates that there may have been between 151,700 and 575,400 deaths. In Brazil, nearly 60,000 cases and more than 2,000 deaths were recorded.

WHO Recognition

In 2016, Butantan submitted a request to the WHO for inclusion of the influenza vaccine on its list of prequalified vaccines. The organization requested a non-inferiority study between the Butantan and Sanofi versions. The Clinical Trials and Pharmacovigilance team spent years working to meet the agency's requirements and earn this international recognition. The WHO approved the vaccine's prequalification in 2021 – validating Butantan's best practices across all product manufacturing processes.

"Three major departments of the Institute worked for years to improve production processes, pharmacovigilance structure, and production quality. We had support from international consultants to adapt all these areas," says Maria Beatriz. "We also conducted an active pharmacovigilance study to assess the vaccine's safety in the elderly, children, healthcare professionals, pregnant women, and postpartum women."

The inclusion of the influenza vaccine on the WHO prequalification list allowed Butantan to begin exporting the product to Latin American countries through the Pan American Health Organization (PAHO). Between 2022 and 2024, 14 million doses were exported to countries such as Colombia, Bolivia, Uruguay, Cuba, and Nicaragua.

Tetravalent Vaccine

To expand population protection against influenza and enhance the effectiveness of the influenza vaccine, Butantan has been working on developing a tetravalent version, composed of two type A influenza virus strains (H1N1 and H3N2) and two type B strains (Victoria and Yamagata lineages). This is because two type B strains may co-circulate during an influenza season. Typically, the trivalent vaccine is composed of only one B strain and two A strains.

Because it is produced in the same way as the trivalent influenza vaccine, with the addition of a monovalent vaccine, Anvisa authorized the study of the vaccine to begin directly with phase 3 clinical trials, in a non-inferiority assessment. This means that the candidate vaccine must prove to be as effective as the trivalent version or even more effective.

Preparing for Future Emergencies

The decision to build a dedicated flu vaccine factory was strategic for the Butantan Institute – both to help control the disease in Brazil and to assist the country in combating epidemics and pandemics. According to Paulo Lee Ho, the facility can be easily adapted to produce other strains of the virus, as new emergencies arise.

Proof of this is that Butantan has been mobilizing to combat a potential avian flu pandemic: in July 2025, the Institute obtained approval from Anvisa (Brazilian Health Regulatory Agency) to begin clinical trials of a human vaccine against the disease. Development of the vaccine began in January 2023, given the spread of the virus in wild birds and mammals worldwide. New human infections began to be recorded last year, raising alarm among authorities. From 2003 to 2024, 904 human cases of avian flu were reported, with a fatality rate of 51%, according to the WHO.

The vaccine candidate must pass phases 1 and 2, which demonstrate its safety and ensure it produces antibodies. From there, it will be kept in strategic batches for phase 3 testing in the event of an epidemic—the virus must be circulating to assess its efficacy. This means that if there is indeed an avian flu emergency in Brazil, the Institute will be ready to supply a vaccine.

Another vaccine with pandemic potential already developed and tested by Butantan is the H7N9 influenza vaccine, which underwent a phase 1 clinical trial between 2017 and 2018. The product was formulated with an adjuvant produced by the institution itself, IB160. Published in the journal PLOS One, the research showed that the use of the adjuvant doubles the dose yield, in addition to enhancing the immune response.

According to the WHO, history teaches us that it is only a matter of time before a new global emergency occurs. Therefore, in conjunction with the Coalition for Epidemic Preparedness Innovations (CEPI), the organization reinforced in August of last year the call for scientists and governments to strengthen global research to prepare for the next pandemic.

For Maria da Graça, this preparation must be continuous, and fighting for Brazil's self-sufficiency in the pharmaceutical sector is essential. "Butantan has made decisions on several fronts, such as producing cells to serve as substrate for antigen production, improving factories, and investing in new technologies so that we can become self-sufficient. The biggest bottleneck in pandemics is time: you must contain the virus as quickly as possible."