The virologist Margarita del Val has no doubts: we begin 2021 with what for her is the fourth wave – not the third – of the pandemic. The scenario is complex and the numbers of infections and hospitalizations are on the rise. However, the beginning of the vaccination program places us at “the beginning of the end”. The Pfizer and Moderna vaccines “are safe and effective, which allows us to say that many months from now this will gradually subside,” says del Val. But at the same time there are unknowns: once a person is vaccinated, how long does immunity last? Do these vaccines protect from infection or just prevent us from developing the disease? Will there be other more effective ones? While the answers arrive, del Val, who works at the Severo Ochoa Molecular Biology Center (CSIC-UAM), launches clear messages. “There will be more vaccines”, but “being able to protect now and avoid deaths in the coming months is not negotiable.” He also insists that, to train the immune system well, “you have to get both doses of the vaccine.” As coordinator of the CSIC Global Health Platform, the researcher speaks of the institution’s “unprecedented effort” to provide solutions to the health crisis.
After many months of pandemic, how would you describe the current moment from an epidemiological point of view? The start of the vaccination program is hopeful, but this Christmas several adverse factors have come together.
We are at the worst moment in terms of infections because they have been dates of many social contacts that we are not giving up. In addition, the low temperatures cause us to carry out many activities indoors, and that increases the risk of transmission of respiratory viruses. With this particular coronavirus, it has been quantified that the risk regarding the number of outbreaks and infected people is about 10 times higher in poorly ventilated interiors than outdoors. That’s a lot. Almost all interiors are poorly ventilated, except in very large rooms with few people. The gauges are calculated so that there is a distance of 1.5-2 meters between people, but ventilation has not been taken into account.
Regardless, the arrival of vaccines has shed some light.
Yes. The Pfizer and Moderna vaccines, which have just been licensed by the European Union, are very similar. Both are safe and effective, which allows us to say that many months from now the pandemic will subside. Now the first-line health workers and all the people in the nursing homes will be vaccinated. But there is only around 3% of the entire Spanish population over 65 years of age. If we are going to vaccinate 3% between now and Easter, there will be a pandemic for a while, unless Moderna manufactures many vaccines, Pfizer accelerates production and also lowers demand in the rest of the world. If not, this will go with a dropper.
What are the benefits and risks of the Pfizer and Moderna vaccines or similar ones that may arrive in the coming months?
The two are very similar in design and results. Both are based on messenger RNA [a molecule that instructs cells to make the coronavirus S protein and generate an immune response] that has to be protected because it is very unstable. This makes storage conditions difficult, especially for the Pfizer vaccine. Both have a very high safety profile because, as their development was urgent, more people were recruited for the trials, which have been carried out with 5-10 times more volunteers than in other vaccines. We have been analyzing vaccines, their safety and their adverse effects since the mid-20th century. They are drugs that are more closely monitored because they are almost the only ones for healthy people. Adverse reactions occur between 6 weeks and two months after receiving the dose. Long-term effects have not been described for practically any vaccine. In short, these are safe and do not have any serious effects, at least according to the results in the more than 20,000 and 15,000 volunteers vaccinated by Pfizer and Moderna, respectively. If there is an adverse effect that only occurs in one person in a million, obviously we still do not know it, so there is a monitoring plan in time. Now it has just been detected that very strong allergic reactions occur in one in every 100,000 vaccinated people, and for this reason it is required that the professionals who vaccinate are prepared to neutralize them.
What would you say about its effectiveness?
Both are very effective in the very short term. Efficacy is measured by comparing the 20,000 and 15,000 vaccinated people with the 20,000 and 15,000 of the control groups, made up of highly conscientious people who adopt hygiene measures, distance, ventilation, etc .; however, some, very few, are exposed to natural infection without knowing it. So the efficacy data is based on fewer people, because few have been exposed to natural infection. Even so, the two vaccines have far exceeded the figures that had to be reached to confirm that their efficacy was good. Their protection from coronavirus symptoms is very high, 95%. As time goes by, it may decrease, but to find out you have to wait.
Are these vaccines equally effective in neutralizing mild and severe symptoms?
Mild symptoms are produced by the direct action of the virus in our cells, especially in the nasopharyngeal and pulmonary mucosa. Severe symptoms occur when the person has previous pathologies with inflammatory processes; then, in the presence of the virus, the inflammatory response persists and this causes pathologies in many organs. As they are different mechanisms, vaccines did not have to protect in both situations. Now it has begun to be seen that they do protect against serious symptoms. Pfizer’s has very few serious cases, but the protection is resounding, over 90%, similar to that of mild symptoms. Moderna has more serious cases because it adopted a different strategy when recruiting volunteers, selecting people at high risk of exposure, health workers, essential workers, etc. Within these groups there have been more people who have been infected and thus more severe cases, and the data is very convincing. Regarding deaths, there has only been one, so to say that they protect against death is very premature. The main question is the long term: How long will the protection last? For now, to those who ask me if they consent to have their father or mother vaccinated, I say: ‘Go ahead.’
According to the latest CIS barometer, a part of the Spanish population is still reluctant to get vaccinated. What risks do we expose ourselves to with these vaccines?
These messenger RNA vaccines are new and can cause unusual reactions within two days of receiving the dose. This is not considered an adverse effect of the vaccine, but rather a direct effect of the immunization. The two vaccines are quite reactogenic, they can cause a general discomfort with fatigue, headache, muscle and joint pain, chills … It does not happen to everyone and nobody has to go to the hospital for it, but you have to know it. The same thing happens with the second dose and it is not necessary to do without it to avoid discomfort.
Both vaccines consist of two doses, why?
This is how the immune system is trained. Vaccines teach you to recognize the infectious agent, of which they carry a portion (in this case, protein S) to respond. Natural infection also trains the immune system, but with great risk in the form of mild, severe symptoms, or even death. Vaccines train him in an innocuous way except for the discomfort to which I have referred. The first dose puts our lymphocytes – the cells of the immune system – on alert, and the second gives them a more powerful and lasting immune memory. In fact, the second dose produces about 50 times the neutralizing response of the virus. If we want to train the immune system well, we have to wear both. Something that I am often asked is if people who have already had covid-19 should also be vaccinated. The answer is yes’. Although they are quite protected from the next infection – when there are reinfections they are usually milder than the first – the vaccine protects them even more.
Let’s get on with the risks. So far he has talked about everything that is known about these vaccines, which is a lot, but there are also questions.
Yes. We know that it protects infected people from suffering, but we do not know if it also protects them from becoming infected. This may sound strange because many people believe that they get vaccinated to avoid getting infected. That is a false belief or an oversimplification. You get vaccinated so as not to suffer. Almost half of the vaccines we give babies do not protect them from infection, but rather from suffering, symptoms, and death. Vaccines from Pfizer and Moderna and others to come may or may not protect against infection. For now we have to rely on what has been observed in preclinical animal tests; when they were vaccinated and then infected, the vaccine did not protect against infection because the virus multiplied. This means that it may not protect vaccinated people from infection. If so, when infected without developing symptoms they can be as contagious as any asymptomatic. It may also be that the infection occurs at such a low level that they are not contagious. The unknown will be resolved as the vaccination campaigns progress and the clinical trials are completed.
In vaccination programs, are measures planned to test whether vaccinated people actually infect or not? Is this going to be controlled in any way?
First we will try to control the volunteers in the Pfizer clinical trial. In an important part it will be checked if they have been infected, even if they do not have symptoms. If so, they will have antibodies against SARS-CoV-2 proteins, but in addition, vaccinated people will have antibodies against protein S. Among the volunteers in the placebo group there must be around 30% asymptomatic, something similar to what happens in the normal population among people who are not vaccinated. The question is whether among those vaccinated there will also be 30% who show with the antibody tests that they were infected. This means that the vaccine does not protect against infection; if there is less, it means that it partially protects; if there are none, it will fully protect. All of this is being analyzed.
For now, this unknown implies that both the general population and the vaccinated population must continue to adopt the same protection measures.
Indeed. And we will have to wait months to see if the unvaccinated population is benefiting from the vaccination of people at risk, then we will confirm that they are not contagious. For this, it is necessary to have the entire population at risk vaccinated and verify that in circumstances of little control, cases do not proliferate.
Then we would be close to herd immunity … Do you dare to venture a deadline?
Herd immunity occurs when there is a group of people vaccinated with a very good vaccine, which protects against infection and therefore lowers the transmission of the virus, thus indirectly also protecting unvaccinated people. That is the unknown we are facing and it is going to be difficult to clear up. We do not yet know if these vaccines are capable of providing herd immunity, not all of them are.
What vaccines provide herd immunity?
Those with which we are eradicating infections from the entire planet. For example, the smallpox vaccine did protect against contagion and produced herd immunity, which is why the disease was eradicated 40 years ago. The attenuated polio vaccine also protects against contagion and with it has cornered this disease, which only persists in an area between Afghanistan and Pakistan. With the measles vaccine, a herd immunity has been achieved in Spain. However, we do not have it for diseases that we know less like diphtheria. The existing vaccine does not protect against the bacteria that produce it, but it neutralizes the disease by specifically targeting the toxin that causes it. For this reason (and for hygiene) there is no diphtheria here. Neither does the tetanus vaccine provide us with herd immunity, but there are very few cases because infections only occur in serious accidents with many wounds.
The UK is already using the Oxford-AstraZeneca vaccine against COVID-19. One of its advantages is that it can be kept in the refrigerator, compared to those of Pfizer and Moderna, which require lower temperatures. What are its other characteristics?
If licensed by the European Union, the Oxford vaccine will also be safe. Instead, it seems that it is somewhat less effective, that means that not all vaccinated people are protected. Those of Pfizer and Moderna are 95% effective: if 100 people are vaccinated, 5 will not be protected and no one knows who they will be. With the Oxford one, that amount may rise to 20 or 30. However, it is an easy vaccine to maintain and will be able to reach countries with fewer resources in health personnel, technologies and infrastructure. That is good. In a pandemic, it is not useful for a country to be vaccinated, the rest of the world must also be vaccinated out of solidarity and so that we can regain mobility. On the other hand, it is a vaccine that is based on a different vector but that has been highly studied, specifically in a chimpanzee adenovirus.
Other vaccines will continue to be developed in the coming months. In an interview with Lluís Montoliu, he pointed out that the first ones we receive will not necessarily be the best.
The Pfizer and Moderna vaccines will not necessarily be the best, but they are the fastest because they are highly synthetic. I must say that an efficiency of 95% is difficult to improve, although, as I have explained, this may only be in the short term. But being able to protect now and avoid deaths in the coming months is non-negotiable. In any case, there will be more vaccines because for now there are few doses available. If we are going to vaccinate 3% of the older population at risk in three months, completing the process would take years. In addition, there may be logistical problems that delay the arrival of vaccines. On the other hand, there will be countries that only want their own vaccines; In Europe, for example, there is a lot of rejection of the vaccines from Russia and China. Trade agreements or geopolitical issues may also favor some vaccines over others. There will be vaccines that are more or less appropriate for different populations. (Here we need them to be suitable for an aging population with a weakening immune system.) There will be vaccines with a more or less lasting effect … Many needs have to be covered, so it is good to have several.
In the CSIC there are three projects for vaccines against covid. What are their characteristics?
At the CSIC we have a group that had already investigated coronavirus in animals and humans, and specifically in vaccines against the latter. Previously developed vaccines against severe human coronaviruses, in particular SARS-1 and MERS, were sterilizing, that is, they protect against infection and contagion as well as avoid suffering and disease. This is the type of vaccine that researcher Luis Enjuanes is developing against SARS-CoV-2. It may be difficult to produce, but it is the best. The vaccine that Vicente Larraga develops is made of DNA and remains stable at room temperature, that is a great advantage. And the vaccine in which Mariano Esteban works is based on the smallpox vaccine vector, which is the best ever made, the only one that has managed to eradicate a disease from the face of the earth. The basic framework of Esteban’s vaccine is already authorized for human use, it is even known that it can be applied to people with HIV who lack a strong immune system. Each has its advantages and its development speeds. The one that goes faster is Esteban’s, in fact, it is already being produced on a large scale and the clinical trial is being prepared.
What is required of a vaccine to be second or third generation?
Make it more complete and instead of stimulating a single part of our immune system, stimulate all its tools. We need to have the immune system ready to recognize the infectious viruses that are circulating – those that spread from one person to another – and destroy them; that is what the antibodies do. But we also need an immune system that eliminates the factories of new viruses, which are our own infected cells. The virus infects our body to multiply, otherwise it would disappear, because outside it is absolutely inert. A state-of-the-art vaccine stimulates the immune response in both directions: destruction of infected cells by T lymphocytes – cellular immunity – and destruction of extracellular infectious microorganisms through the release of antibodies – humoral immunity. It’s like using two armies at the same time, the aviation and the ground infantry. The Enjuanes vaccine would go in that direction.
Last March the CSIC Global Health Platform was created, which you coordinate. What role are you playing in finding solutions to this epidemic?
In this emergency context, it was necessary to move almost simultaneously from the research phase to the vaccine development phase. For this reason, in mid-April we began to look for candidates for their production and to define how they were going to be manufactured. The CSIC, with a very intense and decisive involvement of the Vice Presidency for Scientific and Technological Research, has made an unprecedented effort. We have created a consortium with the manufacturing companies and we are supporting the production phase of the doses at the same time that the research trials are developed. In addition, as we have seen that there were no incidents in the research and development part, clinical trials have been planned. This progresses, but it is necessary that previously batches of vaccines have been produced with sufficient and homogeneous quality standards so that when there is a trial all volunteers receive exactly the same product. In the platform, the collaboration and involvement of the Deputy Vice Presidency for Knowledge Transfer has been key, because it has been necessary to immediately patent, carry out market studies and negotiate with companies.
Although we do not yet have all the necessary doses, the scientific community highlights the speed with which the covid vaccine has been developed. Why was it possible?
Because it had been previously investigated. Research is not improvised. With a virus like SARS-1, whose epidemic was contained with drastic quarantine measures in China in 2003, work continued, that is, research continued on how to make vaccines for something that did not exist. Thanks to this, as soon as the pandemic began, we knew that it was a coronavirus and we knew its sequence. And we also knew that protein S had to be used in the vaccine against him. That knowledge comes from basic research.
For days the numbers of infections have increased and hospital pressure grows. Are we already in the middle of the third wave of the pandemic?
In fact I call it the fourth wave, because from a mathematical point of view there have clearly been four different waves separated by valleys: first we suffered the spring wave, then the summer wave, and before it got very low, autumn began and with the cold rose again. The descent that occurred was actually the overlap of two mountains, the summer with the autumn. Now there has been another valley, but we have not lowered the incidence so much and another wave is already beginning. For me it is the fourth without a doubt. We are raising the winter wave, launched by the pre-Christmas shopping and the Christmas Eve, New Year’s Eve and Three Kings gatherings. These are separated by a week, the time in which, if you have been infected, the virus is multiplying to spread more easily. The confinement of a few days due to the storm and the snowfall of the century perhaps attenuates the contagions a bit, to see if we are lucky.
We have just said goodbye to 2020, a year marked by a global pandemic that has altered our lives and that still generates uncertainty and risks. What message would you send to society?
We cannot relax. We will continue with the protective measures for months. I believe that the arrival of good weather will coincide with sufficient progress in vaccination campaigns and the existence of more information on whether vaccines protect against infection and therefore prevent vaccinated people from being contagious. In just 10 months of research we have come a long way, it has been an epic feat, science has faced a huge challenge and has responded in a spectacular way. I did not expect that there would be a vaccine available so soon, the usual thing is that many vaccines fall into the clinical phases due to some failure. This has been a race against the virus. I do not know how we will be in six months, but if the collaboration at a global level continues, solutions may appear that we did not even imagine. Maybe we already have antivirals [drugs used to treat infections caused by viruses] for those who cannot get vaccinated in time.
Beyond all the accumulated knowledge regarding this coronavirus and covid-19, what lessons have we learned from this pandemic?
It has been a cure for humility, we are more vulnerable than we thought. We were very focused on precision medicine and did not pay much attention to infectious diseases. It is not by chance that the three people who lead the CSIC vaccine projects are retired; it has been very difficult to obtain support and funding for research in this area. We have also found that it is good to get out of your specialty a bit. In the Global Health Platform we collaborate researchers from very diverse fields: demography, sociology, engineering, artificial intelligence, medical chemistry, mathematics and of course virology and immunology. That wealth is lost if you are only specializing in your field. Another positive aspect is the harmony that has existed between the media, society and the scientific community. We have dared to communicate to society, communicators have dared to ask ourselves and we have learned from each other. That has to stay; When another challenge arises, it will be good for citizens to know that science has answers, but also uncertainties, how things are communicated and how progress is being made. That will allow society to become much more knowledge-based.
