Rafael Simões / Butantan Communication Eggs used to produce experimental batches of ButanVacRafael Simões / Butantan Communication
On August 23, the Butantan Institute announced that it was stopping all clinical trials and development of ButanVac, the COVID-19 candidate vaccine it has been working on for the last three years. The decision was based on the results of phase 2 trials involving 400 participants. At this stage, ButanVac’s safety and ability to generate an immune response were compared to the Pfizer vaccine, which is available through Brazil’s public health system (SUS). The Butantan Institute’s vaccine candidate was intended to be used as a booster dose, but it did not perform as well as hoped.
“Before testing began, it was agreed that there would be an analysis to assess whether the immunity produced by ButanVac was able to match that generated by the comparison vaccine,” said infectologist and immunologist Esper Kallás, director of the Butantan Institute. “In terms of safety, there was no problem. Tolerability to ButanVac and the side effects associated with it were similar to the Pfizer vaccine, but the immunogenicity results were inferior,” he explains.
The development of ButanVac started in 2021, at the height of the pandemic, as part of an international project that adopted a technology created by the Icahn School of Medicine at Mount Sinai Hospital in New York, USA. The approach uses an inactivated version of the Newcastle disease virus—which causes respiratory problems in birds—that has been genetically altered to incorporate the spike protein of SARS-CoV-2, the virus that causes COVID-19. It is this protein that allows the SARS-CoV-2 virus to bind to the surface receptors of human cells and invade them (see Pesquisa FAPESP issue n° 302).
The vaccine, known as NDV-HXP-S, was designed to be cheap to produce and manufacturable in developing countries using the same embryonated-egg-based production lines as influenza vaccines. During the pandemic, several nations entered the race to produce a vaccine against the disease. Only five vaccines—manufactured by AstraZeneca, Pfizer/BioNTech, Sinovac, Moderna, and Sinopharm—have been developed, approved by the health authorities, and distributed in time to reduce the number of deaths.
After analyzing the performance of 32 vaccines developed during the pandemic, chemical engineer Michael L. King of the University of Virginia, USA, concluded that the five successful candidates were produced by pharmaceutical companies that had the ability to develop the vaccines and scale up production quickly. “The critical success factors include prior experience with commercialization and approval, robust quality systems, rigorous process development strategies, flexible manufacturing facilities with a skilled workforce, collaboration, access to consumables, reagents, and adjuvants, and an equitable distribution of the global vaccine manufacturing network,” he wrote in an article published in the journal Vaccine in February.
These five vaccines, however, require specialized factories and ingredients, and they are costly to import. Some developing countries thus decided to invest in NDV-HXP-S, which can be stored in conventional refrigeration systems (see Pesquisa FAPESP issue n° 303).
Marilia Ruberti / Butantan CommunicationVials of the vaccine candidateMarilia Ruberti / Butantan Communication
Through an international consortium, Mount Sinai provided access to the viral vector technology free of royalties to research centers in Brazil, Thailand, Vietnam, and Mexico. To be approved for use, any vaccine would need to go through three phases of clinical trials: the first to assess safety, the second to measure the ability to generate an immune response (immunogenicity), and the third to verify efficacy—meaning the ability to prevent infection or illness.
ButanVac’s phase 1 results, with 318 participants, were promising. They showed that the vaccine was well tolerated, safe, and at the highest dose, induced a significant immune response. In the next phase, 400 volunteers were randomly allocated into two groups: one was given ButanVac and the other was given the Pfizer vaccine. A specific criterion was established for this stage in advance: Butantan’s vaccine candidate must not have a lower immunogenicity than Pfizer’s. In this regard, ButanVac failed.
Despite the Brazilian institution’s decision to stop clinical trials, other countries using the Mount Sinai technology are continuing to develop their vaccines. Versions produced in Thailand and Mexico have already been authorized for emergency use. The Government Pharmaceutical Organization (GPO) of Thailand, where the vaccine is called HXP-GPOVac, approved its emergency use as a booster dose for adults in September 2023.
On June 6 of this year, Mexico’s Federal Commission for Protection against Health Risks followed Thailand’s decision and approved emergency use of the Mexican version of the vaccine, called Patria. Data from the phase 2/3 clinical trial, carried out with 4,056 volunteers, indicated that Patria’s immunogenicity was able to match the AstraZeneca vaccine, according to an article shared on the preprint server medRxiv in February this year. The AstraZeneca vaccine uses a different technology to Pfizer’s and is slightly less effective at preventing symptomatic cases. In Vietnam, the results of phase 2 trials—which also used AstraZeneca as a point of comparison—were presented in a paper uploaded to medRxiv, showing a similar outcome to the Mexican vaccine.
Although ButanVac testing has been halted, Butantan is not stopping its search for a Brazilian vaccine. “Even before these results, Butantan had begun looking at potential new platforms for a COVID-19 vaccine,” says Kallás. In 2023, the institution signed an agreement with Brazil’s Ministry of Health that will include R$72 million in funding to build an mRNA vaccine factory. The institute is currently analyzing which line of technological development will be used to produce these vaccines.
The story above was published with the title “Goodbye, ButanVac” in issue 344 of October/2024.
Scientific articles
KING, M. L. How manufacturing won or lost the Covid-19 vaccine race. Vaccine. Feb. 15, 2024.
LÓPEZ-MACÍAS, C. et al. Phase II/III double-blind study evaluating safety and immunogenicity of a single intramuscular booster dose of the recombinant Sars-CoV-2 vaccine “Patria” (AVX/Covid-12) using an active Newcastle disease viral vector (NDV) during the omicron outbreak in healthy adults with elevated baseline antibody titers from prior Covid-19 and/or Sars-CoV-2 vaccination. medRxiv. Feb. 14, 2024.
THIEM, V. D. et al. Safety and immunogenicity of an inactivated recombinant Newcastle disease virus vaccine expressing Sars-CoV-2 spike: A randomised, comparator-controlled, phase 2 trial. medRxiv. Dec. 1, 2023.
