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Projeto S's pioneering methodology enables safe vaccination without the use of placebo in clinical trials

Publicado em: 01/01/1970

Before Projeto S, a study on the effectiveness of the CoronaVac vaccine carried out in the population of the municipality of Serrana, São Paulo, to find out if an immunizing agent was safe and effective, the clinical trial protocol used to involve only volunteers divided into a group that took the active vaccine and another that received a dose of placebo (that is, a substance with no effect on the body). These data were compared to confirm whether the first group would be more protected in comparison with the second, which remained unprotected during the research.

The innovative method chosen for the clinical trial in Serrana was a stepped-wedge research. The procedure divided the municipality into 25 areas, forming four groups, named in Projeto S as “clusters” and identified by different colors: green, yellow, gray and blue. However, the distribution was not geographical: the blue cluster, for example, involved residents from all regions of Serrana, and the same happened with the other groups. This division was possible because, a few months before the immunization, a Health Census mapped the entire city, including information on the incidence of Covid-19 among residents. Vaccination took place in a stepped-wedge fashion (hence the name of the technique): first the green cluster, then the yellow one, then the gray one, and finally the blue one. The order of colors was publicly drawn.

Before being put into practice, Projeto S underwent extensive analysis by regulatory bodies. “We submitted to an ethics committee, which evaluated and approved it, we made monthly and semi-annual reports to show the results for them and also for Anvisa [the Brazilian Health Regulatory Agency]”. Residents over 18 were able to participate in the research and, therefore, get vaccinated.

In the assessment of the director of the Serrana State Hospital, Marcos Borges, the randomized methodology proved to be quite effective for emergency vaccination during the health crisis. “From an ethical point of view, in the midst of the pandemic, it is a very appropriate model. Vaccinating each area at a different time, with a one-week interval, allows us to determine what we call indirect immunity”, he explains. “By the percentage of people immunized, it is possible to see the indirect effect of vaccination, of protecting those who did not take it”, completes Marcos, who is the main investigator of the research.

The first phase in Serrana was to implement the first and second dose vaccination, with an interval of 28 days between one and the other. The entire immunization took place in eight weeks, from February to April. The results show that symptomatic cases dropped 80% and deaths 95%. The two-dose vaccination protected not only adults, but also unvaccinated children and adolescents under 18 years of age, creating an immune barrier. Projeto S is expected to take place over a year and the population is being analyzed every three months. The evaluation protocol carried out in four periods aims to avoid biased analyses.

Marcos Borges emphasizes that for the methodology to be adopted it was essential that 95% of the population had understood and adhered to the vaccination campaign, since the study is completely voluntary. “The pioneering spirit of the methodology lies in being able to assess in the real world how the vaccine will behave, in a model that is rarely used, precisely because of the technical difficulty of application”.

The municipality of Serrana was chosen to host the project because it presents a high level of people infected with Covid-10 and has a regional hospital that could support the studies. The research was conducted by Instituto Butantan and approved by the ethical and health authorities, in partnership with the University of São Paulo at the Ribeirão Preto School of Medicine and with the support of the Serrana City Hall.


Different methods for safety assessment

To assess the effectiveness of a vaccine, several methodologies can be used. The most common is to have a group vaccinated with the immunizing agent and another without the active ingredient, and then compare the reactions of both. Another way, according to Marcos, is to carry out massive vaccinations over a weekend, as occurred in Botucatu, in the countryside of São Paulo, with a quick assessment of before and after immunization.

A third model is the stepped-wedge implementation carried out in Projeto S, dividing the city into vaccinated regions in different periods. One advantage is to offer the intervention to everyone who wants to participate, without distinction.

“There are some reports of the use of the stepped-wedge implementation methodology in Gambia in the 1980s, and the possibility of using it to fight Ebola was also studied, but it didn't happen because it was controlled before,” he says. “The stepped-wedge methodology had never been used in the world using a vaccine to find indirect immunity and fight the pandemic”, summarizes the researcher.

The director of the Serrana State Hospital, Marcos Borges, will be present at the opening of the CoronaVac Symposium, promoted by Instituto Butantan and Sinovac. At the international online event, the doctor will present the basis of the Projeto S research methodology, values of direct and indirect effectiveness in the population of Serrana and some serology data.