The vaccine\u2019s efficacy was tested on two rodent species (mice and hamsters) at USP in Ribeir\u00e3o Preto in collaboration with a team led by immunologist Jo\u00e3o Santana da Silva and virologist Luiz Tadeu Figueiredo. In all the animals, the SpiN protein\u2013based vaccine triggered a powerful immune response. According to results published in the journal Nature Communications<\/em> in August, SpiN-Tec stimulated both the activation of T lymphocytes, which directly combat the virus and infected cells, and B lymphocytes, which are responsible for producing antibodies. Administered in two doses, SpiN-Tec prevented illness in one type of rodent used as a model for mild disease and in another used to simulate severe disease, against the original SARS-CoV-2 virus and against the Delta and Omicron variants.<\/p>\n \u201cThe SpiN protein\u2013based vaccine does not, by itself, induce the production of neutralizing antibodies,\u201d explains Gazzinelli, who also works at the Oswaldo Cruz Foundation (FIOCRUZ) in Minas Gerais and is a visiting professor at USP in Ribeir\u00e3o Preto, where he has received funding from FAPESP. \u201cBut as a booster dose, it stimulates the production of antibodies generated by previous vaccinations, as well as cellular immunity, providing double protection.\u201d<\/p>\n The Cimatec-HDT vaccine, which is already being tested on human volunteers, uses RNA technology, but not the same technique adopted by the Pfizer-BioNTech and Moderna vaccines. Instead of using messenger RNA to carry the S protein recipe to the host\u2019s cells, the Cimatec-HDT formulation uses self-replicating RNA, which multiplies inside cells several times before it starts spike protein production. The self-replicating RNA and lipid nanoparticles that surround it were developed in Seattle, with the participation of infectious disease specialist Roberto Badar\u00f3 and biochemist Bruna Machado, both from SENAI-CIMATEC. \u201cThey have been collaborating with HDT on this platform to target diseases like Zika since before the pandemic,\u201d says Valdir Gomes Barbosa, business manager at the Bahia-based research center. \u201cIn preclinical trials against the coronavirus carried out in the USA, the technology generated an immune response consistent with very low doses,\u201d he reports. The technology has already been incorporated by SENAI-CIMATEC, which can now produce it on a laboratory scale.<\/p>\n In the first phase of the clinical trial, funded by the MCTI and conducted in Salvador at the beginning of the year, the vaccine was given to 90 adult volunteers who had previously been immunized against COVID-19 with other vaccines. They were divided into three groups that each received two doses of 1 microgram (\u00b5g), 5 \u00b5g, or 25 \u00b5g. According to Barbosa, the results, which have already been submitted to ANVISA, showed that the compound is safe and does not cause serious adverse effects, leading to approval of phase 2 trials. In this phase, scheduled to begin in the coming months, half of the 330 volunteers will receive two 5 \u00b5g or 10 \u00b5g doses\u2014the dose size will be based on clinical trials already in progress in the USA, India, and South Korea. The other half will be given two doses of the Pfizer-BioNTech vaccine.<\/p>\n Nalini Vasconcelos\u2009\/\u2009Senai-Cimatec<\/span>Scientist performs a visual inspection of a vial of Cimatec-HDTNalini Vasconcelos\u2009\/\u2009Senai-Cimatec<\/span><\/p><\/div>\n ButanVac, meanwhile, uses the Newcastle disease virus, which is practically harmless to humans, to introduce a more stable version of the S protein into the body (see<\/em> Pesquisa FAPESP issue nos. 302<\/a> and 303<\/a><\/em>). It was designed at the Icahn School of Medicine at Mount Sinai in New York with the aim of providing a cheap alternative that can be synthesized in flu vaccine factories. Authorized by ANVISA in July 2021, phase 1 trials evaluated the performance of the compound in 318 participants in Ribeir\u00e3o Preto, in the interior of S\u00e3o Paulo State. The volunteers were separated into groups and given two doses of 1 \u00b5g, 3 \u00b5g, or 10 \u00b5g. \u201cWe observed a marked humoral response [production of antibodies], especially with the highest dose,\u201d says \u00c9rique Miranda, clinical development manager of the Butantan Institute\u2019s clinical trials division.<\/p>\n Two weeks after the second dose, ButanVac increased antibody production more than fourfold in 98.7% of participants. There were no serious adverse effects. The most common problems were pain on the injection site, reported in 89% of cases, headache (67%), fatigue (65%), body aches (58%), and fever (17%). \u201cThe results were very similar to the clinical trial of the same formulation carried out in Thailand,\u201d says Miranda. The data from the Asian study were published as a preprint in September 2021 and suggest that the vaccine also triggers a cellular response. Once authorized, Butantan plans to start another trial with 400 volunteers from S\u00e3o Paulo and Rio de Janeiro.<\/p>\n The three candidates\u2014SpiNTec, Cimatec-HDT, and ButanVac\u2014are the survivors of a long obstacle course that leaves many competitors at the wayside. Federal and state research-funding agencies in Brazil began investing in the development of potential COVID-19 vaccines back in 2020. The MCTI funded the initial development of 16 compounds whose active ingredients were developed by scientists from Brazilian institutes or international partnerships that allowed the technology to be transferred to the country. \u201cWe are good at using foreign technology to produce vaccines in Brazil, but we have never made one ourselves from start to finish. We decided to encourage the development of a domestic capacity to produce immunizers,\u201d says Marcelo Morales, Secretary of Scientific Research and Education at the MCTI, the department responsible for stimulating the development of COVID-19 vaccine candidates in the country.<\/p>\n Of the 16 compounds, five have completed animal testing and applied to share the R$115 million set aside for phase 1 and 2 trials, including the HDT-Cimatec and UFMG formulations. Two others are eligible to receive funding for clinical trials as soon as they receive approval from ANVISA for human testing: MultiCovax, created by Kalil’s team at InCor; and Versamune-CoV-2F, formulated by immunologist C\u00e9lio Lopes Silva of USP in Ribeir\u00e3o Preto, in partnership with S\u00e3o Paulo\u2013based company Farmacore and American laboratory PDS Biotechnology. \u201cIn testing on animals, we showed that our compound generates high levels of antibodies and cellular response in the nasal mucosa,\u201d says Kalil. His group now faces the challenge of obtaining an initial pilot batch to administer to human volunteers, which will have to be manufactured abroad at a cost of US$4 million due to the lack of options in Brazil. At the Federal University of Rio de Janeiro (UFRJ), a team led by biochemical engineer Leda Castilho is pushing to complete the animal testing phase of its UFRJVac vaccine later this year.<\/p>\n Project<\/strong>![\"\"](\"https:\/\/revistapesquisa.fapesp.br\/wp-content\/uploads\/2023\/02\/040-043_covid_321-1-1140.jpg\")
\nBivalent intranasal vaccine using influenza virus expressing the S protein (spike) of SARS-CoV-2: mechanisms of protection and lung injury<\/em> (n\u00ba 20\/05527-0<\/a>); Grant Mechanism <\/strong>Regular Research Grant; Principal Investigator<\/strong> Ricardo Tostes Gazzinelli (USP); Investment<\/strong> R$283,052.33.<\/p>\n
![\"\"](\"https:\/\/revistapesquisa.fapesp.br\/wp-content\/uploads\/2023\/02\/040-043_covid_321-2-1140.jpg\")
CTVacina\u2009\/\u2009UFMG<\/span>A batch of UFMG\u2019s SpiN-Tec vaccines destined for clinical trialsCTVacina\u2009\/\u2009UFMG<\/span><\/p><\/div>\n The attempt to develop a vaccine entirely or partially in Brazil is part of a national effort to control all stages of the extensive and complex manufacturing chain of immunobiological products. Several research groups in the country carry out the initial stages of vaccine production, from formulating the active ingredient to conducting experiments on animals. This, however, is not enough to arrive at a product ready to be injected into people’s arms. Some of the links in the chain are missing. One is the absence of facilities with the capacity to increase vaccine production while following good manufacturing practices, which are needed to start clinical trials. \u201cWe do not have industrial development expertise in Brazil,\u201d says Jorge Kalil, an immunologist from the Heart Institute (InCor) at the Hospital das Cl\u00ednicas of the University of S\u00e3o Paulo (USP) School of Medicine who led the development of a nasal anti-COVID-19 formula that has already been tested on animals.<\/p>\n Since the beginning of 2020, the novel coronavirus has infected 620 million people worldwide and killed 6.5 million, according to figures from the World Health Organization (WHO). Experts have stated that the virus is here to stay, and after the initial phase during which the global population was completely unprotected, it is now likely to behave more like the flu virus, causing outbreaks in the winter months. This pattern will require the use of regular booster doses, which still need to be made more effective to generate more lasting protection.<\/p>\n Risk of dependency The three candidates undergoing human trials to which Brazil contributed all use different technologies to trigger the immune system.<\/p>\n Developed with funding from FAPESP, the Brazilian Ministry of Science, Technology, and Innovation (MCTI), and the Minas Gerais State Research Foundation (FAPEMIG), SpiN-Tec stimulates the production of antibodies against the SARS-CoV-2 spike protein, like most vaccines currently available on the market. Where it differs, however, is that as well as targeting the spike protein, which is on the surface of the virus exposed to attack by antibodies and undergoes frequent alterations, the team from Minas also added the nucleocapsid (N) protein\u2014the envelope that protects the virus\u2019s DNA and rarely changes from one strain to another. Synthesized by bacteria, the hybrid protein\u2014known as SpiN\u2014is then purified and mixed with an emulsion of oily compounds that encourage the activation of immune cells and amplify the immune response.<\/a><\/p>\n<\/div>
\n<\/strong>It is for this reason that despite almost 50 vaccines already having been approved for human use worldwide, the WHO registered another 371 COVID-19 vaccine candidates under development in October (see chart<\/em><\/a>). Experts in the field point out that the pandemic has revolutionized vaccine production technologies and countries not able to master them could become dependent on imports.<\/p>\n![](\"\/wp-content\/uploads\/2023\/02\/040-043_covid_321-0-desktop-true.png\")
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