100 years ago a strain of virus emerged that killed between 50 and 100 million people around the world. It was called the Spanish flu because in Spain it received more attention in the media, given that other affected countries were in the middle of the world war. Adolfo García-Sastre (Burgos, 1964) -Director of the Institute of Global Health and Emerging Pathogens and of the Icahn School of Medicine at Mount Sinai in New York (USA) – is one of the researchers who revived the virus, years later, to try to find out what made it one of the most lethal pathogens (in absolute numbers) in history. On the occasion of the centenary of the pandemic, Matter interview with García-Sastre during his visit to Madrid for a symposium on the Spanish flu organized by the Ramón Areces Foundation.
Question. Why was the Spanish flu so lethal?
Answer. We do not know all the details. Some of what we know, why it was more virulent, is because the virus was rebuilt by my research team, from the sequence [genética] We obtained from tissues that were still preserved from people who died in 1918. From the sequencing of the genome of the virus we were able to reconstruct it with cloning techniques. In biocontainment laboratories we characterize it and it is one of the most virulent viruses known in the flu in animal models. Virulence map to more than one gene: it is the combination of different domains that cause the virus to replicate more and to do more damage to the respiratory epithelial cells. The influenza virus of 1918 caused about 2% mortality, much lower than Ebola, which causes between 50% and 90% mortality, but infected half the people in the world during 1919 and 1920, while the Ebola virus has not infected half the people of the world. Hence the disaster that caused the 1918 virus: many people died in a very short time, during the spread of the virus that was only a few months. This caused a very large excess mortality throughout the world and many disorders not only personal but also economic and social.
P. Could something like this happen again with a current flu strain?
The success of a virus is measured in transmission, not in the number of people who kill
R. The generation of a strain similar to that of 1918 is difficult because several factors coincided. The success of a virus is measured in transmission, not in the number of people it kills. Pandemics infect many people because there is no immunity against the pandemic virus, because it is completely new. [Un virus pandémico de gripe] it has determinants, genes, that come not from human viruses, but from animal viruses, to which humans have not been exposed. Because of that it infects many more people, but from there to being more virulent or less virulent, everything depends on what factors have been put together when it has been generated.
P. Are we prepared for a pandemic?
R. We are more prepared than in 1918 but we are not sufficiently prepared. What measures are there? The vaccines take time to generate, but at least they can generate vaccines, and although they are not generated so fast as to be managed during the first phase of the pandemic, they can at least be prepared for the second phase and, with that, save lifes. We have antivirals. Not everyone can be put on antivirals, because right now the manufacture of antivirals is not so large as to be able to treat everyone, but there are antivirals with which people with more severe disease can be treated. And then we have antibiotics. One of the major causes of mortality with respect to influenza infections is secondary infection with bacteria. Antibiotics can also give a reduction in mortality. Now, saying that, if you lower the mortality from 2% to 1%, it is still a very, very large mortality, much larger than what is seen during normal epidemics.
P. Your group is working to achieve a universal flu vaccine. How is it possible, if the strains change by new mutations every year?
One of the major causes of mortality with respect to influenza infections is secondary infection with bacteria
R. With my group, the Peter Palese group and the Florian Krammer group, we are designing strategies to achieve a universal vaccine. Although the flu virus is always changing, there are regions that do not change. Vaccines usually work by stimulating the production of antibodies in the body that are able to bind to the virus and stop the infection, because they prevent the virus from being able to infect. Antibodies generated by vaccines that currently exist or by infection with influenza viruses are generated against non-conserved areas [durante la evolución] of the virus; they are areas that we call immunodominants. They have immunodominance because they dominate the response of antibodies that are produced, and they are very good antibodies to stop the strain that has induced them. But they are against regions that are not conserved and that will change. Now, the conserved regions [evolutivamente] of the virus do not induce a good antibody response. They induce very few antibodies, so that most people do not have antibodies against them. If we had antibodies in a high amount against those conserved regions, we would be protected against any type of flu. Or that is, at least, what we try to verify if this happens in humans.
P. Can a virus be completely eradicated?
R. A virus can be eradicated, a virus has been eradicated. The smallpox virus is eradicated. There is another that is eradicated, which is an animal virus, rinderpest, which is very similar to measles but animal. It was due to the use of vaccines. Today, in theory, a virus could be eradicated with the vaccines that exist. Two circumstances must be met: one is that the vaccine works in the right number of people to be able to break the cycle of transmission and the other condition is that the virus is found only in the organism that you want to eradicate. In the case of humans, in humans.
To eradicate a virus two circumstances have to be given: one is that the vaccine works in the right number of people to break the cycle of transmission and the other condition is that the virus is found only in the organism that you want to eradicate
Influenza B viruses are only in humans. So, in theory, a good vaccine that was used by most people against the B virus would eradicate it in humans. Flu A can not be eradicated. You can eradicate it from humans, but it will continue to exist in animals, and if it exists in animals, the possibility that one of those viruses adapts to human transmission again and we have a transmission cycle again can always occur.
P. Will we see the eradication of influenza that only occurs in people, type B?
R. If we have a good vaccine and if it is distributed all over the world and if it is used properly, it can be eradicated.
P. Many conditions.
R. They are many, yes. For polio we have a good vaccine and it is not eradicated. For measles we have a vaccine and it is not eradicated. Not only do you have to have a good vaccine, it has to be used by a sufficient number of people to break the virus transmission cycle.
P. But there are people who refuse to get vaccinated, or to vaccinate their children.
R. It is better to get vaccinated and yes, there is a lot of controversy. For example, there are many people now who do not get vaccinated against measles. If we all stop vaccinating against measles, many of those who oppose getting vaccinated, would be vaccinated against measles. Why? Because many people would start to die of measles, many children. I believe that people who are anti-vaccinal, if Ebola becomes transmissible, would want an Ebola vaccine. You do not want to have the possibility of your children dying of Ebola. Right now, the possibility of someone, a child, dying of measles if not vaccines is minimal because there is not much transmission: everyone else is vaccinated. So, the anti-vaccinal movement works only when there are other people vaccinated. When people stop vaccinating is when there are deaths.
P. Do you also investigate in your laboratory how to use viruses for therapeutic purposes?
We use a chicken virus that does not cause disease in humans but, when injected into tumor cells, results in an immune response
R. My laboratory works with antitumor viruses. We use a chicken virus that does not cause disease in humans but that when injected into tumor cells, results in an immune response. It causes the body to be able to develop a response against the tumor that is beneficial. It leads to better therapy than simply using the immune cell stimulator. [Los virus antitumorales] They are like anti-cancer agents.
Viruses can also be used as vaccine agents. There are viruses that do not cause disease but are capable of inducing an immune response when put in a person: if you do express an adequate antigen against another virus or another infectious agent, it induces an immune response not only against itself, against the virus, but against this new antigen, this new gene from another virus or from another infectious agent that you have put on it. If that answer is protective against the other virus [o agente infeccioso], that would lead to a vaccine. This is what has been done, for example, with Ebola. Ebola vaccines are based on the use of viral vectors that express an Ebola antigen, which do not cause disease but give rise to an immune response against that antigen and protect against the disease.
P. Talk about using viruses to create vaccines against other infectious agents. Does this method work against pathogens that are not viruses?
R. Sure, against malaria, against bacteria. Yes.
P. Do you see the emergence of bioterrorism that uses synthetic or reanimated viruses, such as the Spanish flu that cloned its own equipment?
For the virus to be used as a biological weapon, it has to be transmissible and must lead to disease, both. It is not so easy
R. Smallpox there are places where it still exists, then theoretically you can steal smallpox. It's a bit harder to synthesize, because it's big, but theoretically it could. It is known that it is a formidable pathogen in humans and that people have stopped vaccinating, so a smallpox attack would lead to something really dangerous and serious. Other viruses are a bit more complicated to use as biological agents: Ebola, for example, can be used, but it is very difficult to spread very well. Of the flu viruses, we have the Spanish flu virus, which could be used as a terrorist agent, but right now with the new 2009 pandemic [gripe porcina A H1N1], which has cross immunity with the 1918 virus, would not be the same anymore. You would have to make a virus similar to that of 1918 but different antigenically, for which we did not have immunity. And that's not so easy either: it requires a lot of research, because normally when you start to touch a virus and change things, the first thing that happens is that, just like if you try to generate something new, it does not work well. For the virus to be used as a biological weapon, it has to be transmissible and must lead to disease, both. Changing a virus so that more disease and at the same time is equally transmissible, is not so easy.
P. What attracted you to this field?
R. I am a biologist, I have always liked to discover, make scientific discoveries: how life works and how organisms work. We have 30,000 genes in each cell. There is a virus like the flu that has eight genes. Eight against 30,000. It gets inside the cell and somehow manipulates the 30,000 genes to turn the cell into a virus-making factory. How can a program of 30,000 genes reprogram eight genes? It is an extremely interesting question. And then, well … it has implications because, if you know that, you can try to get treatments. What stimulates me the most is not getting a treatment. It would be great if, through my research, we get better vaccines, or get better treatments, but what I find most interesting is how it works, how it is possible.