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HEALTH 22.01.2021

“COVID-19 is also revolutionizing the way medicines and drugs will be made for the foreseeable future”

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An interview with Mariano Esteban, a researcher at the CSIC (Consejo Superior de Investigaciones Científicas — Spanish National Research Council), head of the Poxvirus and Vaccine Group of the CNB (Centro Nacional de Biotecnología — Spanish National Center for Biotechnology) and a member of the scientific committee of the World Health Organization (WHO).

Question: So where are we at now? Starting the fourth wave?

Answer: We’re still going through the third. But it’s going to take longer than expected. Let’s see how long it lasts. In actual fact, we are currently in a highly critical phase of exponential growth.

When will we be able to sit face to face and travel again? When will we get back to normal?

Mariano Estevan

By the fall of 2021, we can reasonably hope that we’ll be able to move around more freely and travel… But we will also need to maintain the control measures, most likely with masks and social distancing practices and all the other practices that are proving effective. Let’s hope it will be possible at least to have a slightly more relaxing summer—but we’ll need to continue to vaccinate the population on a large scale. That’s what we should aim for: to get to this time next year hopefully having had a much more enjoyable Christmas and New Year than we did this time round. It’s difficult, isn’t it? It’s admirable how people are dealing with it, because we have no choice. We are all in the same boat and we need to work together. That’s why we are grateful to you for publicizing the relationship between scientists and society. The thing I’m most grateful to MAPFRE for is the support they’ve given to the Spanish National Center for Biotechnology and to the CSIC right from the start, because you were the first ones who really came to the aid of the institution to work on a vaccine against COVID and control the pandemic.

…The fact is that we are in an emergency situation, with measures that seem to be constantly changing all over the world, but also with the hope brought by the vaccines. What differences would you highlight between the various vaccines available?  

Basically, the difference is in the composition of each vaccine. Depending on this composition, the method of action may have significant biological differences and, above all, differences in terms of immunity. Essentially, the ones being administered now are based on mRNA (messenger ribonucleic acid). In these, several molecules of the messenger RNA are encapsulated inside a nanoparticle that is lipidic (like a sort of nodule of fat). Upon penetrating the cells, as happens during intramuscular vaccination, they release the mRNA that creates the coronavirus’s S protein (or spike), which in turn alerts the immune system.

This mRNA vaccine is very different from AstraZeneca’s, which is a vector of a chimpanzee adenovirus that carries in its DNA genome the gene that produces the SARS-CoV-2 coronavirus S protein. This adenovirus, in itself, is not replicative, so it is highly attenuated; it simply penetrates the cells, releases its genetic material (also from the coronavirus) and alerts the immune system. By the very nature of the adenovirus vector, this intracellular and immune system activation is, in part, different from that produced by mRNA.

In the case of the [CNB-CSIC vaccine] that we use, it is based on a poxvirus vector—also DNA-based and highly attenuated (MVA) and more complex than the adenovirus—and acts differently on cells and the immune system. It has a great capacity to penetrate many cells, releases its genetic material, produces the coronavirus protein in a much larger quantity than the mRNA, and activates an immune response that is quite different from that activated by the mRNA vaccine or the adenovirus. It mainly activates both the humoral response (of antibodies) and the cellular response (of T lymphocytes), as we have demonstrated in a recent article, resulting in 100 percent protection against SARS-CoV-2 in the animal model. In vectors that are based on chemically inactivated viruses, penetration into the cells and immune activation is directed more toward the humoral response than the cellular response.

Then there is the purified S protein or pseudo-particles as vaccines, which will also have a more differentiated function and will be more targeted toward producing an antibody response.

Which vaccines have the most wide-ranging response?

All those vectors based on attenuated viruses, such as the adenovirus or (to an even greater extent) our own poxvirus vector, because they trigger multiple activations of many of the cellular signals that are necessary and important to induce broad and lasting immune responses.

“Now we will have to see what happens in people who have been vaccinated with all these different vaccines, over a longer period of time, and whether the effects they display are really different at an immunological level”.

…Let’s talk about Moderna and Pfizer.

Yes. Moderna and Pfizer’s vaccines are based on mRNA encapsulated in a lipid particle. They have a different effect than that which, as I mentioned, Astrazeneca’s adenovirus or the poxvirus that we use [at the CNB] causes. In other words, from this perspective, vectors that are based on highly attenuated viruses that penetrate the cell, that do not give rise to progeny, but which do perform their coronavirus protein production functions, are considered more comprehensive in terms of triggering an immune response of neutralizing antibodies, and of T lymphocytes, which are the cells in charge of recognizing and destroying the infected cell.

Now we will have to see what happens in people who have been vaccinated with all these different vaccines, over a longer period of time, and whether the effects they display are really different at an immunological level.

So do we still need to analyze the results then, rather than crying victory?

We’ve made tremendous progress. In just one year, we already have vaccines that are being administered to the population. Showing that vaccines reduce infection in 90 percent of vaccinated people is a milestone in clinical phases. Extensive monitoring is now underway and we are seeing that people who have been vaccinated with these mRNA or adenovirus vaccines are maintaining antibodies. These antibodies have now been under observation for between six and eight months, and the durability will logically continue for longer, for between one to two years.

How many doses and what elements need to be given to be safe? 

The most desirable scenario is one dose: you get your shot and move on and forget about it, as is the case with some vaccines we have, like the smallpox vaccine, for example. What we have at the moment are more sophisticated vaccines, and they are still being given in two doses. However, there are others that are moving forward with the goal of creating immunity with just one dose, such as the Janssen vaccine, which is also based on an adenovirus. But the important thing is that protection is induced and that it is lasting: if it is with one dose, then even better, as it is easier and cheaper than two doses.

What criteria are being applied to storage and distribution?

The most fundamental thing is for the vaccine to be stable while in storage; this aspect varies greatly from one vaccine to another. We are seeing that the mRNA vaccines from Pfizer-BioNTech require storage at -80ºC. I think they will start to reduce this gradually, but it’s because they don’t want the RNA molecule to suffer, since it’s a molecule that’s very sensitive to the action of ribonucleases, which are present everywhere around us. They are very prevalent enzymes that are responsible for destroying an RNA molecule as soon as they see it. This is a limitation, especially in developing countries, because they do not have the -80ºC storage facilities required to conserve the vaccine. With regard to the Moderna vaccine, it is kept at a higher temperature of -20ºC, which means that we will see vaccines stored in a traditional refrigerator/freezer. Iran is developing vaccines with different requirements. It is important for the vaccine to be stable and to perform the function it should, therefore the proper storage and other restrictions on the use of vaccines are required conditions for the best possible distribution of each one.

“We should all be vaccinated, because minors can also transmit the disease and we have to achieve immunity for the entire population and the whole world. And this is the problem we have: reaching every corner of the planet, and in the shortest time possible”.

Is it possible to get vaccinated if you’re recovering from the virus or have already had it?

Yes, it is possible. What an infection does, by nature, is to activate an immune response that provides protection against the pathogen. In other words, it is rare for a person to become infected again; or if they do, they may not even notice or may have only minimal symptoms. Should we also vaccinate people who have been infected? If we have enough doses, it’s the best option. If we are limited in doses – and in Spain, we consider that about 10 percent of the population has probably already been infected – then four million people could be cut from the total awaiting vaccination, leaving room for those who do not have immunity and who need the vaccine. But the best thing is to vaccinate everyone, because this way we know that everyone has the same degree of immunity. A person who is currently taking part in a clinical process will not, of course, be vaccinated until the process has been completed.

Which groups should receive the vaccine as a priority?

The groups most at risk, i.e., elderly people in nursing homes and health care workers, as is already being done. They are the number one priority. Then come other elderly people, because they account for more than 50 percent of all the deceased and need to receive due care. They play a significant social role, and continue to be a very important part of families and society. And then come those with more or less critical illnesses and so on, moving down gradually to more resistant, younger people.

Children too? Are there any groups that cannot be vaccinated?

With children, clinical trials are now being carried out to see if this is feasible. So far, only people over 16 years of age have been vaccinated and clinical trials are now underway to see if, for example, the dose now being administered to adults can be lowered and if one dose is enough instead of two. Care must be taken with people with allergies to vaccines or with various illnesses. I believe that we should all be vaccinated, because minors can also transmit the disease and we have to achieve immunity for the entire population and the whole world. And this is the problem we have: reaching every corner of the planet, and in the shortest time possible.

Vacunas a niños sin recursos

How much longer until the virus is defeated?

We still have quite some time until the global population is immunized. We are seeing that the more developed countries are accelerating the process, but it is slow, as the plant has a population of over seven billion and this will take time. This is the limitation that we have to work with: getting enough vaccines produced and sending them everywhere, which means obtaining the funding to send these vaccines everywhere.

The vaccine is the most effective way of fighting the pandemic

It is undoubtedly the most effective remedy we have, because antivirals only work over a limited period of time and we need to act as soon as there are symptoms of infection. That is, once the infection has progressed, they have little effect. This is why vaccinations, which save millions of lives each year, are the most effective and long-lasting control remedy against the SARS-CoV-2 coronavirus and other pathogens, as demonstrated by the vaccination campaigns already being implemented in all countries.

What does the WHO suggest to facilitate vaccine administration in countries with fewer resources?

This depends on the purchasing power of countries. We are seeing clearly that, for example, Israel, which has a high purchasing power, has vaccinated more than two million people (26 percent of the population) and they believe they will have 70 percent immunized before the summer. That’s because they’ve obtained a large number of doses of the vaccine. The European Union has also acquired a large number of doses, but they are arriving in limited quantities. How are we going to be able to reach everyone? The United States wants to vaccinate its more than three hundred million inhabitants as quickly as possible. The same applies to China, Russia and other producer countries. We are limited by manufacturers’ ability to produce sufficient quantities and to distribute them to all countries.
What about the countries most in need and with least resources? There is a global effort by non-profits that have already secured funding – though not enough – to purchase vaccines and administer them in the countries most in need. Even Spain has already stated on several occasions that it is purchasing more doses of vaccines than required for its general population, also with the idea of being able to help other countries that need it. Because if they don’t get vaccinated, the virus will circulate among us continuously with spikes every so often. In China, for example, they still have sporadic cases and take forceful action when required.

“In essence, there is a collaboration between all stakeholders, scientists, health workers, managers and politicians—who have no choice but to come together. It is an important lesson for humanity and for our planet in general: we have no other choice. If there is no collaboration, there is no progress, and if there is no progress, there is no future. This pandemic is uniting us all for a common cause: health”.

Any other recommendations that you consider to be a priority? 

I think the important thing is that there is a general agreement on the production of a sufficient number of vaccines to inoculate the entire population. What is needed is for the more economically powerful countries to contribute quickly in order to have enough doses. We need to buy from companies – as we depend on them – so as to have a sufficient quantity of vaccines to inoculate the entire population. And that requires a lot of collaboration. That is one aspect that this pandemic is highlighting: countries are collaborating. In fact, Germany is vaccinating fewer people than other EU countries, such as Spain, despite producing the Pfizer-BioNTech and CureVac vaccine. There is a generous approach being shown by countries that this pandemic is highlighting.

We cannot fight with one another, even though we may compete. This is healthy, as can be seen on a sporting level. The mission of scientists has been to try to progress quickly in the development of new vaccines and to establish all the procedures to get them from the laboratory to the clinics, to the production companies and available for general distribution. I believe that we all play a part here. Regulatory agencies have a very important role, both in Spain, with the Agencia Española del Medicamento y Productos Sanitarios (Spanish Medicines and Health Products Agency), and internationally with the EMA (European Medicines Agency) or the FDA (U.S. Food & Drug Administration). They are all collaborating intensively and receive reports on how clinical trials are going.

In essence, there is a collaboration between all stakeholders, scientists, health workers, managers and politicians—who have no choice but to come together. It is an important lesson for humanity and for our planet in general: we have no other choice. If there is no collaboration, there is no progress, and if there is no progress, there is no future. This pandemic is uniting us all for a common cause: health.

 

You have been at the forefront as a researcher, looking for vaccines for viruses that have launched a direct attack on all mankind. Is this the great scientific test-case? Is this the greatest challenge researchers have faced?

It is indeed an interesting and hopeful historic moment for the scientific community, because it has shown that a pandemic has paralyzed everything globally. Today we are talking about more than 95 million people infected and more than 2 million people killed. We have the highest mortality rates ever caused by an infectious agent. We scientists play a tremendously important role here in attacking an invader as soon as it appears, and in developing procedures for controlling it.

It is worth noting that in 1981, the first cases of infection by an unknown agent appeared; in 1983, it was identified as the human immunodeficiency virus (HIV, AIDS). It wreaked havoc. I was in New York; at the time I was a professor at the Medical School of the State University of New York. We are in fact still dealing with this pandemic, which we have not yet controlled. We have done so in terms of therapeutic agents, but not in terms of a vaccine. Then on top of it all, this pandemic comes along with its airborne transmission, which makes it enormously difficult to control. So science is producing studies and developing solutions as it has never done so before. Never in such a short time have so many articles been published from the point of view of the disease, molecular biology, epidemiology, its structure—all the areas you can think of. This pandemic has put to work all the available actors throughout the globe – in other words, the entire scientific community of the planet.

In the case of HIV, research was more limited to specific groups. In 1918, with the Spanish flu, there was none of the infrastructure, technology or communications we enjoy today. This is a very important lesson in terms of how to act globally and how to establish rapid procedures from a production point of view and in terms of clinical trials, which traditionally took many years from the time there was a vaccine candidate to the time it arrived in the clinic and finally reached the market. COVID-19 is also revolutionizing the way medicine and drugs will be made for the foreseeable future.