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The São Paulo government announced on Monday the 19th that the Coronavac vaccine, developed by the Butantã Institute in partnership with the Chinese pharmaceutical company Sinovac, was also safe in tests with 9,000 Brazilian volunteers, reaffirming the results of previous research with 50,000 Chinese participants. However, efficacy data should only be released between November and December, which should delay Governor João Doria’s (PSDB) prediction of starting immunization later this year.
According to Dimas Covas, director of Butantã, the tests with the 13,000 volunteers have not been completed and the effectiveness analysis cannot yet be carried out. The researcher said that this week only concluded the first stage of the study, with 9 thousand people. Even in this group, not everyone has taken both doses yet, which should happen by the end of the month. “We already have the safety data for this stage, they are very similar to the Chinese (a study in which more than 90% of the volunteers had no adverse events).
“It is these data that I will detail in the second. It is not yet possible to speak of effectiveness because we have to wait for people to come into contact with the virus. From my impression, I think we will have conclusive data later in the year, between November and December ”, he told Estadão.
Vaccine effectiveness
Covas explained that conclusions on efficacy depend on the occurrence of a minimal number of COVID-19 infections among volunteers. This index, defined by statistical calculations, is necessary for researchers to compare how many of the contaminants were in the vaccinated group and how many were in the group that received the placebo. If the total in the second group is significantly higher than the first, there will be evidence that the vaccine was able to protect against covid.
In the case of the Coronavac study, the minimum number for a first analysis is 61 contaminated, which, according to the director of Butantã, has not yet been reached. “This is the number necessary for us to perform the intermediate analysis (type of evaluation carried out before the conclusion of the investigation). If with 61 cases it is not possible to demonstrate effectiveness, we will expect to have 151 cases.
With the efficacy results expected only for November or December, it is unlikely that vaccination will begin in 2020 not only because of the time left to complete the tests, but also because of the deadline for the National Sanitary Surveillance Agency (Anvisa) analyze the information and issue the product registration.
Vaccine analysis
Although the agency has created a new analysis flow, allowing researchers to continually submit research data as soon as it is produced, only information from Coronavac’s preclinical phases (tests performed in the laboratory or on animals) is already available. agency, as stated by Estadão Gustavo Mendes, Anvisa’s general manager of medicines. “We have not yet received the data for phases 1 and 2, for example, but some researchers prefer to send data for all clinical phases at once,” he said.
He says that, even in a time of emergency such as the pandemic, the analysis of the studies must follow some procedures and highlights that the intermediate analyzes do not always present enough data to make the registry known. “The big question of the interim analysis is that depending on the percentage of infected volunteers, it may not have the statistical power to confirm effectiveness. To subsidize the registry, the interim analysis must have very strong evidence,” he explains.
Mendes points out that the maximum period for the agency to evaluate a request for registration of a drug or vaccine against covid is shorter than that adopted for normal situations: two months, compared to one year. But the analysis is not easy. “An application for registration includes approximately 10,000 pages of documents. We evaluate information on efficacy and safety, but also on production quality. We need to issue a certification for the factory in China that will produce the doses ”, he details.
Due to the pandemic, the agency also revised its rules regarding the minimum effectiveness required to grant the vaccine registration. Immunizers are generally only approved if they receive greater than 70% protection. For vaccines against covid, Anvisa already admits that it can license with 50%.
If Coronavac is approved, there is already an agreement between the São Paulo government and the Chinese pharmaceutical company to supply 46 million doses by the end of this year.
The president of the Brazilian Society of Immunology, Ricardo Gazzinelli, argues that there should be a longer follow-up period for volunteers before registration is requested. “Ideally, it should take at least ten months to measure effectiveness,” he says.
The test will also measure the action of the vaccine to reduce severe cases.
Efficacy tests in a vaccine study can measure not only how much the product is capable of reducing infections, but also other outcomes associated with disease prevention. “Researchers may want to measure the number of infections, but they can also check if there has been a reduction in mortality, if there has been a reduction in severe cases,” explains Gustavo Mendes, general director of medicines at Anvisa.
According to information on the website Clinicaltrials.gov, the US government portal that collects information from clinical trials, the two main outcomes to be measured in the Coronavac study are the incidence of covid in volunteers two weeks later. of the application of the two doses and the appearance of adverse events. But the research also plans to monitor seven other secondary outcomes, including the incidence of severe covid cases, the incidence of the disease with just one dose of the immunizing agent, the rate of seroconversion (when antibodies to the disease become detectable through tests ) , among others.
Coronavac is now the most advanced research vaccine in Brazil, with 9,000 volunteers already immunized. The immunizer developed by Oxford in association with Astrazeneca is in a similar stage, with 6,000 of the 10,000 volunteers already vaccinated with at least one dose.
‘Extra duty’ in the volunteer career
In the race for the vaccine against covid-19, the Butantã Institute encourages the 16 Coronavac study centers throughout the country to accelerate the recruitment of volunteers. At the Emílio Ribas Institute of Infectious Diseases, one of the hospitals participating in the research, a working group was created to reach the expected number of participants this month.
The unit, which began immunizing volunteers at the end of July, also began operating on Saturdays in September. At the same time, the team working on the study was expanded from 24 to 40 professionals. Even the director of Emílio Ribas, Luiz Carlos Pereira Júnior, entered the scale to make screenings and consult with subscribers. In particular, I was very motivated because I am a doctor and I could not avoid contributing to the team in this project that has such a noble purpose.
After the loss of more than 1 million people in the world, being 150 thousand Brazilians, helping to stop this tragic statistic is what gives us all this enthusiasm, not only for me, but for the whole team ”, said Pereira Júnior .
For six weeks, the director, who is also an infectious disease specialist, reconciles administrative activities from Monday to Friday with the assistance of volunteers on weekends.
The effort is repeated among other professionals, who canceled vacations and work up to 14 hours a day to serve as many volunteers as possible. Estadão was at the center on Friday and followed the routine of researchers and volunteers, from the first visit to the actual immunization.
According to Ana Paula Rocha Veiga, infectologist and coordinator of the Coronavac field study in Emílio Ribas, the working group had results. “In the first two months of care (July and August) we immunized 190 volunteers. With the expansion of care in September we reached 550 and now we have 750 participants with at least one dose taken, ”she says excitedly. One thousand volunteers will participate in Emílio. Adding up all the centers, there will be 13,000, half will receive the vaccine and the other half, placebo.
Each enrolled participant, before taking the immunizer or placebo, must undergo medical consultation, blood tests, urinalysis and PCR, to rule out a coronavirus infection. After the results of the tests, the participant is discharged to be vaccinated. All of these procedures are performed on the first visit to the center. Fourteen days later, the participant returns to Emílio Ribas to take the second dose of the immunizer or placebo. Sometimes he again undergoes consultations and examinations. After two visits to apply the product, the patient goes through six more monthly face-to-face consultations and a weekly follow-up by phone or message.
Secret
Both doses of Coronavac and placebo are kept in the secret room or in the secret room. Only two nurses have access to the site. After receiving the first dose, the participant receives a diary in which they must note the temperature of the following days and other symptoms that may appear, such as pain, nausea, swelling at the application site, among others. The first dose is always applied to the right arm. The second, on the left arm.
Among volunteers, the greatest anxiety is knowing when they will be told whether they have taken a placebo or the vaccine. “I signed up because I wanted to help with the research, but also because I hope I have the real vaccine and it is effective,” says dentist Elizabeth Paisana Yshay, 50, who has already taken both doses.
Nurse Silvana Morais, 53, took her first dose this week after being stimulated by a medical colleague. “He said the vaccine was safe and I signed up out of solidarity. The more people available, the faster we will have a vaccine for everyone, including SUS.”
The information is from the newspaper O Estado de S. Paulo.
