On the weekend the alarms went off after stop the most advanced Spanish vaccine. The drug developed by the National Center for Biotechnology (CNB-CSIC) and the company Biofabri was about to start the human trials phase, but the Spanish Medicines Agency (AEMPS) has not authorized them. Since it came to light last Saturday, official information has been scant and theories have not stopped surfacing. This is what is known about the vaccine that was closer to becoming a real option just as Spain struggles to get more doses from foreign ones.
The only thing that the CSIC has spoken for has been to deny one of those theories. “It is totally false that the administration of the vaccine has caused the death by lung lesions of one of the macaques used in preclinical trials,” they point out in their press release, referring to a news of The Spanish who took that hypothesis for granted.
Both the CSIC and Biofabri assure that “all the usual international protocols have been followed in the development of preclinical vaccine trials and that, based on the safety and efficacy results, it has been considered appropriate to request the clinical phase trial” . Therefore, “if the death of a macaque by lung injury had occurred after administration of the vaccine, the clinical trial would not have been requested.” The denial of the research center does not provide the real reasons for the “postponement” – since they rule out talking about suspension or cancellation – and give the floor to the Spanish regulatory agency.
Mariano Esteban, virologist and head of the Poxvirus Group of the CSIC, in charge of this vaccine, also avoids pronouncing before the AEMPS. “Until we have that report, we cannot define the causes and respond adequately,” the researcher apologized. For its part, the agency has informed this newspaper that the technicians are finalizing the dossier and that “in the next few days” they will send it to the promoters of the trial. “Out of absolute respect for their decision, additional information will be provided once said response is received,” they promise from the CSIC.
Still not known. The Hospital La Paz, the designated place to carry out the tests in people, was informed of the stoppage on Friday afternoon, “with no scheduled date” to resume them, and when they had already summoned a series of candidates, as reported to elDiario.es . The Madrid health center was recruiting volunteers between 18 and 39 years old, healthy and who had not passed COVID or were vaccinated. This stage is known as Phase I of the clinical trial, in which the vaccine is administered to a small group, of between 50 and 100 adults, to initially check that the drug is safe. As it is the most delicate phase, it is also the most scrupulously monitored by regulatory agencies.
The vaccine developed by Mariano Esteban’s team had concluded Phase III of the preclinical trials, which is recorded in studies in vitro (performed in a laboratory) and in vivo (in animals). “We have shown in two animal models, mice and hamsters, that the vaccine meets the basic requirements. That is, it produces neutralizing antibodies and T lymphocytes, which are the cells responsible for recognizing and destroying the coronavirus infected cell. In both tests, with 100% efficiency “, Esteban revealed in an interview with this newspaper in April. At that time, his team was waiting to receive the result of the preclinical Phase III, carried out in macaques.
With all this, the research groups prepared a clinical dossier to present it to the AEMPS. “As soon as they give us the go-ahead, we would like to start the clinical trial before the summer. Phase I, with about 112 volunteers, serves to demonstrate safety, and Phase II, with a larger number of people, about 500, to confirm safety and demonstrate immunogenicity. If all goes well, we would reach III with 20,000 or 30,000 healthy people to demonstrate effectiveness, but it all depends on the data obtained, “he revealed then.
Far from being just another bureaucratic process, the exchange of information with the agencies is the most complicated stage. “The AEMPS asks us questions and asks us to incorporate more data. We make a document, but then that document is reviewed and that is what we have been completing,” said Mariano Esteban. when asked about the general reasons delaying the clinical phase in humans. “We are in the phase of filing the details with them. They put a lot of effort into you, but that is very good and I am very in favor. We have no complaints about it, but quite the opposite. The relationship is great,” said then the scientific.
The details with which the AEMPS is most demanding, according to Esteban, are those related to “safety and proven efficacy in the preclinical phase”. “They review all the bibliography, what has been published in this regard and they let you know if there is any reference that you have missed. They are very strict when ordering, but it is part of our daily assets,” explained the scientist before adding that there is “not a single request that has gone forward without comment, which is very positive.” The person in charge of the CSIC also assured that “the regulatory agencies are there to help, not to create problems.”
It is not the first time that a trial of COVID vaccines or the administration of the doses itself has been paralyzed. AstraZeneca did so in September 2020 after one of the volunteers developed a rare disease after receiving the vaccine. After verifying that it was not a side effect, the trials continued their course. “It is a routine decision that must be made whenever there is a potentially unexplained disease,” said those in charge of the development of the study.
In the spring of this year, vaccinations with Janssen and AstraZeneca were also halted pending study of a series of related thrombotic events. It should be noted that on that occasion they had already been approved and reviewed by the EMA (European Medicines Agency) and the FDA (the US agency). “All trials have to be very perfect, well structured and have all kinds of details,” understood Esteban, who a few months ago considered the continuous surveillance protocol of the regulatory agencies “very positive”.
The CSIC and Biofabri vaccine does not use any of the technologies known so far: neither messenger RNA (Pfizer or Moderna) nor adenovirus (AstraZeneca and Janssen). It is a viral vector that is already used in seven vaccines against diseases other than COVID.
“We use a more complex structure than these. The vaccine is based on a variant that was used against smallpox and, on this vehicle, we have incorporated the gene for the protein S of the coronavirus, from the spicule. It is an attenuated virus, which which means that the transport vehicle has the advantage of penetrating many types of cells and discharging them. These viruses have been designed by nature to easily penetrate cells, unlike an RNA molecule embedded in a fat particle. that it is not something physiological “, expressed Mariano Esteban.
The scientist argued that the immune response would be “much more extensive and lasting.” The reason is that “it gives the immune system greater scope to activate many populations of memory cells and T lymphocytes, which is what needs lasting protection.” On the other hand, in April they proposed that the clinical trial consist of two punctures, although in the preclinical trial they obtained data of 100% effectiveness with a single dose.
Absolutely. Everything discovered so far, and especially in the case of a new “more complex and durable” technology against COVID, is very useful for the future. In addition, that of the National Center for Biotechnology was only one of the three vaccines that are being carried out in Spain, all of them in different departments of the CSIC.
The acclaimed CSIC virologist, Luis Enjuanes, prepares a single-dose, intranasal administration vaccine that would not only prevent the disease, but also the transmission of SARS-CoV-2. In turn, the one of Vicente Larraga is underway, which is based on DNA, an “extremely stable” molecule producing “a protein recognized as foreign” and generating a response from the immune system.