Butantan Institute has started producing the four types of active pharmaceutical ingredient (API) required for the vaccine’s final formulation (photo: Butantan Institute)
Published on 02/03/2025
By Fernanda Bassette | Agência FAPESP – The state of São Paulo is preparing to face yet another outbreak of dengue: Butantan Institute has already begun to produce the first batch of tetravalent vaccines, comprising 1 million doses, and on January 23 the state government announced the creation of a center for emergency operations, as well as the transfer of BRL 228 million to cities statewide to support the fight against dengue and other diseases caused by arboviruses (transmitted by arthropods, such as mosquitoes and ticks).
A cause of concern is the reappearance of dengue serotype 3 after 17 years without circulation of this viral variant, potentially leading to fresh outbreaks of the disease, as the population is not immune to this specific strain. Dengue types 1 and 2 continue to circulate in Brazil.
“We’ve begun to produce the inputs [active pharmaceutical ingredients, or APIs] for each of the four viral serotypes. Production is continuous because the composition of the vaccine includes all four APIs. It makes sense to process all these stages together so that as soon as our vaccine is approved we can rapidly have doses ready for the population,” said Gustavo Mendes, Butantan Institute’s head of regulatory affairs, quality and clinical trials.
Butantan Institute expects ANVISA, Brazil’s regulator of vaccines, medical drugs and devices, and healthcare procedures, to license its vaccine soon, having filed for approval in December 2024.
The results of the phase 3 clinical trial of the vaccine, known as Butantan-DV, were published in the New England Journal of Medicine last year, showing 79.6% overall two-year efficacy (89.5% for DENV-1 and 69.6% for DENV-2). The vaccine is designed to combat all four serotypes, but the researchers were unable to assess its efficacy against types 3 and 4 because no cases of disease caused by them were detected during the trial (read more at: agencia.fapesp.br/50764).
According to Mendes, the team responsible for conducting the clinical trial had previously done several in vitro studies and comparisons of the different viral subtypes to extrapolate the efficacy data from types 1 and 2 to types 3 and 4 in their presentation of the results.
“The extrapolation is based on the comparability of the four serotypes. This methodology is accepted by the scientific community and the regulators. We discussed this information with ANVISA before. So far we haven’t been asked by ANVISA to do a phase 3 trial focusing on types 3 and 4, but post-vaccination monitoring and testing [i.e. phase 4 trials] are part of the regulatory requirements in Brazil,” he said.
Constant monitoring after approval of a vaccine is a mandatory part of pharmacovigilance, a set of activities designed to detect and prevent unforeseen adverse effects, which can occur in mass vaccination campaigns, and to investigate possible cases of vaccine inefficacy. No phase 4 trials focusing on dengue virus serotypes 3 and 4 have been scheduled so far, however.
Mendes said Butantan Institute has put together a team to investigate these cases if they happen, but reaffirmed the technical and scientific argument that it is possible to extrapolate the efficacy results obtained so far for types 3 and 4 even though none of the participants in the trial was infected by them.
As soon as ANVISA licenses the vaccine, Butantan Institute will request approval of its price from the Drug Market Regulation Chamber (CMED). Delivery of the vaccine free of charge via the national health service (SUS) will then be considered by the National Commission for Health Technology Incorporation (CONITEC), a multisectoral agency linked to the Ministry of Health.
Production process
If Butantan-DV is approved, it will be the first single-dose dengue vaccine in the world. The institute plans to produce around 1 million doses in 2025, mostly for purchase and distribution by the Ministry of Health via the national vaccination program (PNI), and plans to produce 100 million more doses by end-2027.
“We’ve been discussing technical aspects of the production process with ANVISA for a long time, so we believe the production technique won’t be affected even if ANVISA requires changes to optimize the process,” Mendes said.
He also explained that ANVISA does not prohibit production of a vaccine before it is licensed. Doing so risks a major financial loss, as any batches produced will have to be destroyed if the regulator rejects the license application.
“If I produce a vaccine that expires a year or 18 months from now, for example, it’s risky unless I’m absolutely certain of fast-track approval. For this reason, we’re producing the APIs but not the final formulation,” he said.
The production process for Butantan-DV comprises two distinct stages. The first is production of the four serotypes separately. They are then combined in the final formulation.
ANVISA has not yet concluded its analysis of the licensing request. The procedure typically takes about 90 days. Butantan Institute’s application was filed on December 16, so a final decision by the regulator should be announced around mid-March.
A decade and a half of studies
Development of the tetravalent dengue vaccine began in 2010, with support from FAPESP. The initial inspiration was a formulation created by researchers affiliated with the U.S. National Institutes of Health (NIH). The NIH conducted the phase 1 clinical trial in 2010-12. The phase 2 trial was conducted in Brazil (2013-15). A phase 3 trial began in 2016, also in Brazil, and ended in 2024, when all 16,235 volunteers completed the five-year follow-up period.
The results attest to the safety of the vaccine for people aged 2 to 59, regardless of whether they have ever been infected by the virus. Butantan Institute is now waiting for ANVISA’s approval of a clinical trial involving the over-60s, a particularly vulnerable age group, and expects to begin in the coming months.
Challenges for 2025
São Paulo State Governor Tarcísio de Freitas stated on January 22 that combating dengue is the first challenge of the year. He highlighted the development of the vaccine by Butantan Institute, but warned that it will not be available on a large scale until next year and preventing infection must therefore remain the top priority.
“We have the current challenge from the climate, which favors vector proliferation. The second problem is that many people had dengue last year, and repetition favors the development of severe dengue. Lastly, a different serotype is circulating this year. We must combat the vector and get organized with the tools we have now. We all have to do our homework – citizens and municipal governments, which must be effective in keeping the mosquito at bay, and the state government, which will provide full support,” Freitas said.
Source: https://agencia.fapesp.br/53840
