The race of their lives to create a Spanish COVID-19 vaccine: "This makes us very sad, but we cannot do more"

In these weeks, many eyes are on the CSIC, and specifically, on the National Center for Biotechnology, from where Mariano Esteban, one of its members and former director, leads one of the teams of researchers looking for a coronavirus vaccine, the hope of a confined society to be able to return to normality.

This team, which has experience dealing with the flu, smallpox or HIV, is now one of those working to make the coronavirus visible, bridging the gap, more similar to a common flu than to the macabre threat it poses today.

Still in the first phase

The first step towards a vaccine for a new virus is to know the genetic sequence of the virus, which was published in January after studies in China. Mariano's team began working on it, having already worked on vaccines for other emerging viruses, such as Ebola or Zika. At that time, Spain seemed totally oblivious to the coronavirus, without infected cases, but they already saw that its transmission and transmission capacity were very harmful. More even than in variants of the coronavirus such as the SARS of 2002 or the MERS of 2016.

After analyzing the sequence, they chose the genes they considered important from the point of view of vaccination to induce immune responses by the organism. "We designed a vector, a plasmid (a circular structure of DNA) that can be inserted in specific places and thus insert genes there. Then we identified the sequences, the nucleotides that encode the known proteins in coronaviruses. We chose the important areas and incorporated the sequences using the plasmid, "explains Mariano.

Once that laboratory design is achieved, it is sent to a German company that synthesizes DNA forms in the specific format that the team requests.

This team continues to search for the vaccine candidate for an attenuated virus that allows them to start experimenting with it.

That process lasted about two weeks, and by February the next step was taken: determining how to generate the vaccine. There is a common approach, which is to generate the complete virus, in this case SARS-CoV-2, in an attenuated variant. This is what is done with vaccines such as measles. In this case, it was decided to use a different virus, also attenuated, as a vector as a transport vehicle to which the coronavirus gene is incorporated.

By infecting cells with the viral vector, DNA is crossed between them and a particle is incorporated into the assigned place. The result is a virus in which 99.99% is the original virus, and 0.001% is the recombinant virus. In this step, they use a colored fluorescent marking to be able to trace which is recombinant, that is, the one that becomes a candidate to be used as a vaccine. According to Mariano, "it is a long process because you have to keep making continuous infections until you find something valid and identify it as a vaccine candidate."

Right now, this team is in this phase, I. With more than 100,000 infected and 10,000 dead in Spain, and more than one million and fifty thousand respectively in the world, the self-imposed pressure by the researchers themselves intensifies. "There is pressure, of course, but on the other hand we cannot do more, we follow the rhythm that we have established. Seeing the new figures every day produces tremendous distress, but neither can we do more despite the emergency situation that we have reached, deadlines are what they are. "

Beyond that, as he explains, they are not receiving special external pressure, and their role and possibilities are usually well understood, despite the collective desire to advance in this faster than ever. However, the reports they send to the CSIC are weekly, something that is not usual: this period is usually much longer.

The next phases: animal experimentation and first tests on humans

This phase can last for months and is the same one that China concluded a few weeks ago and, contrary to what some messages suggested, it is far from the end. Rather, it is the step prior to Phase II of the study: demonstrating that this gene is stable. That is, it remains inserted into the virus chromosome, something that is verified by analyzing the expression of the corresponding protein.

The next step will be to check if the obtained vaccine candidate produces neutralizing antibodies in mice.

"Once we see that the vaccine candidate is correct, we move on to the next phase: grow it in sufficient quantity to be able to carry out animal experiments. We usually grow it in chicken embryonic cells, which are free of pathogens and are authorized to experiment for human use purposes, "says the researcher. With this step done, you begin to experiment with animals. In the world it is mainly experimented with mice and with macaques, but in the case of Spain, the use of macaques is strongly limited, so the mice will be used for those first experiments.

"By inoculating it in a mouse we have to see if it produces antibodies and if it activates leukocytes, which are important for the destruction of infected cells. If this occurs, if it generates neutralizing antibodies, we go to the next step: use humanized mice, which contain an enzyme as a human receptor. If the vaccine continues to do what it should and does not alter the body, we move on to the next phase. "

That is Phase III, the clinic, in which the vaccine needs to be produced in a sufficient number of vials (individual vaccines) to apply to healthy volunteers. If the success obtained with animals is replicated, the number of tests is increased to 200 or 300 people, and in that case they are looked for exposed to the infected, such as health personnel or close relatives of those infected who have lived together.

"It won't take less than a year or a year and a half to have a vaccine ready"

"This phase would show us if the vaccine produces a beneficial effect, that is, if the percentage of infected is lower in vaccinated than in unvaccinated. And if it is achieved with a significant statistical value, we would go on to vaccinate thousands of healthy people who can be exposed to the virus, and see if the rate of infection is reduced compared to those vaccinated with placebos.

The impact of the virus and the virus itself may be different based on the region, something that makes research from different countries even more necessary

Even if another country such as China or the United States announced the obtaining of a vaccine in the coming months, the work done in Spain would not be ruled out: on the one hand, the genome of the virus may vary geographically (in fact, Chinese is different from Spanish) . "And also, each country, each region, has a population with connotations and differences between them regarding the impact of the virus. The sum of all efforts is what will give an adequate response."

A response that, according to Mariano predicts, will not come to an end, that is, to mass vaccination for the population, for a year or a year and a half. "I don't think it will take us less time to get a vaccine ready. I am convinced that there will be several prototypes, with various formulas such as the attenuated virus or with specific proteins. We will see which one works."

The future raises many more unknowns than certainties. For example, Mariano is not even clear that the immunity obtained by those who have passed the virus will be eternal. "We do not know how long that protection lasts, we will know that as we study the effects of the virus on the population. Those who survive will serve as a reference to study their immune system: see to what degree it is activated, its antibodies, their P cells, their macrophages ... I mean, their biological baggage. "

Something that does not alleviate the future panorama of those who have passed the coronavirus and hope to have facilities to resume their normal lives in the form of immunity certificates. At least, the virus is not mutating rapidly, something that gives hope that this process will not be further prolonged. Meanwhile, Mariano's team continues to work to reach phase II.

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