Coronavirus update: Gene-based vaccines have potential

We are back with a new episode of our update. The good news of the day: Christian Drosten at least has enough voice again to speak a little bit after he had to stop for a day yesterday due to illness - not due to the corona virus, very important to say that!

We want to speak about a theme of hope which at the same time often makes the laity despair: We need a vaccine. But it will still take one to one and a half years before a suitable vaccine has been sufficiently examined and tested and then approved.

We would like to talk to the virologist Professor Christian Drosten, head of the Department of Virology at the Charité hospital in Berlin, about how such a vaccine can work and whether it is possible to change anything during this long period.

Korinna Hennig: Mr Drosten, what is it like for you in the Institute - if someone is systemically relevant, then all of you in research are also relevant: do you test yourself closely? We already heard from you yesterday that you tested negative for the corona virus.

Christian Drosten: At the Charité, as in many other universities, it is actually the case that research should actually stand still, but of course: research into this disease, especially the closer to the patient, the more it is naturally systemically relevant. And exactly, we help ourselves there as well. In other words, here internally we test ourselves. We do tests of employees every day, so it is relatively simple. For example, I have been tested twice during the course of my cold, because at some point I had the feeling that it had been going on for quite a long time.

Korinna Hennig: And the test was negative in both cases?

Christian Drosten: Yes.

Korinna Hennig: Today we want to tackle the big topic of vaccines, which is a difficult and confusing one. We actually have a strange situation. Vaccine development has never been as fast as it is at present. The USA has already reported the first beginnings of tests on volunteers. And yet all of this is still too slow - in terms of the virus - because several longer phases of clinical testing are prescribed. Two weeks ago, you said here in the podcast that we need a shortcut to vaccine approval. Before we get into the big complex of "What's happening? What are the vaccine candidates aiming at?" I would still like to ask, theoretically speaking: At what point in the long process is such an abbreviation even conceivable?

Christian Drosten: This abbreviation is not only conceivable, but has long been planned. For example, what you can do is to use so-called vectors, vaccine vectors that you already know.

Korinna Hennig: So carriers.

Christian Drosten: Right, exactly. We sometimes also speak of "backbone", the backbone of this vaccine. These are often certain carrier vaccines, such as one that works well, MVA, or Modified Vaccinia Ankara. This is a vaccinia virus variant, which was used for smallpox vaccination in the past, and is an extremely well tolerated vaccine carrier. And it is now possible to clone proteins or antigens from the new coronavirus into this system, which can then be applied in humans and produce an immune response to these proteins of the new coronavirus.

Experience from MERS research

Of course, every time a vaccine like this is tried out, a lot of work has to be done in the preclinical phase. In other words, a lot of trial and error is required before the first person is treated with the vaccine. But this carrier system, and this also applies to some other carrier systems, has a lot of safety data from other diseases for whose vaccines these carrier systems have already been used. In other words, we know exactly what is happening and do not necessarily have to repeat everything in this emergency situation, such as how laboratory animals react to it. For example, how the basic solution of the vaccine is tolerated and so on. Many things, including pharmacokinetic questions. For example, how is this distributed in the muscle when the vaccine is injected into the muscle? All these things have already been clarified. It is not at all to be expected that now with this slight change of such an already known carrier system, only with the adaptation to this other virus any relevant differences at these important places can happen. Because in this case one has experience with the MVA for the MERS virus, as well as with other carrier vehicles, i.e. with other vectors, one also has experience with other vaccination targets, with other diseases. These are then always only very minor adjustments.

Korinna Hennig: Is that the principle we know from the measles vaccination? So here then: attenuated other viruses are the carrier and are genetically engineered so that the protein is exchanged, a component is replaced?

Christian Drosten: In the measles vaccination we have an attenuated live virus. That is a measles virus. What we can do, however, is - and this is also one of these carrier systems - we can actually modify the measles virus so that the information for the vaccination is also brought along for the new SARS-2 virus. This is also one of the approaches currently being discussed in vaccine development.

Korinna Hennig: If you say this abbreviation is already priced in, are there other possibilities? We have already talked in this podcast about how important clinical testing is, that you first test for safety and intolerance, that you test it in animal experiments, that you then go to small groups and only in phase three do large cohort studies with many volunteers. Is it possible to run any processes in parallel?

Christian Drosten: Yes, it is true that the preclinical evaluation can be shortened considerably because we already know that these vaccines are very well tolerated. And that a tolerability study is then carried out in a group of volunteers, in humans. If the vaccines are well tolerated, then the vaccines can be extended relatively quickly, i.e. after an initial efficacy study, the vaccines can be expanded relatively quickly.

You can't just use volunteers

Then, of course, there is always the question - which is also being discussed a bit at the moment, there are many commentary articles on it in the medical literature at the moment - of how to deal with a situation, for example, where people would say There is a crisis group of volunteers here, they are all healthy and they would be ready. They would basically roll up their sleeves and say: "Why don't you vaccinate me and then put the real virus in my throat so that I get infected or something, so that the vaccine can then prove that it has protected me". That simple thought, the heroic volunteer - how to deal with it, it's not that simple. A person who means well and wants to get an approved vaccine as quickly as possible cannot judge for himself, but there is an investigator, a doctor and a scientist who has many things to consider. For example, you cannot simply put a laboratory virus in someone's throat to make them infected. The question is: how much virus is there in the natural infection? These stress infections, which are known in animal experiments, where you give laboratory animals a defined dose of a laboratory virus and then see whether the vaccination carried out previously also protects them, cannot simply be transferred to humans. It is not known how the normal patient gets infected, naturally outside with the virus.

This leads to the fact that in such studies, where one would like to shorten many things, one needs another kind of parallel stress experiments in a good animal model. So there is no way around it. And one question that is currently being asked is: what is a good animal model?

Korinna Hennig: I would have asked you the same question now.

Christian Drosten: Yes, so there is now, there is newer information on this virus, where you can now say that the first animal models are emerging. But not every good animal model in which the virus simply replicates somehow in the throat of the laboratory animals, for example, or in the lungs, is also a good vaccination model. The immune system of animals is sometimes slightly different from that of humans. In many cases, the disease pattern in these experimental animals is not pronounced at all. You only see that the virus replicates, but the animals do not actually become ill. That is why you have to look very closely at this.

The alternative is then always something that you don't really want to do, that is ethically difficult, these are primate experiments. So of course you don't do ape experiments, there is no such thing in this field any more. But of course macaques, for example, rhesus monkeys - this is something that is done in a very, very limited way, because the immune system of primates is of course more similar to the human immune system. And you need something like that from a certain point of relying on a vaccine. That is when you want to see such data.

Different immune responses through vaccination

Then apart from that, there is a completely different line of argument. And that is that in this situation, which we have at the moment, with a lot of infection events taking place outside, you naturally have a situation where, in such broader studies of the effects of a vaccine in humans, you do not necessarily say that you are going to infect the vaccinated persons after the vaccination, but rather that you simply say that you are going to vaccinate persons and measure whether they get antibodies, for example. Or you can measure whether the immune cells of a person's body are activated and react against the virus in the test tube. So you take blood from people after the vaccination and then you extract immune cells from the blood and measure whether these immune cells have become sensitive to the virus in the test tube. Such tests are then done.

By the way, I have to say again, I am not a vaccine researcher, I am a general forest and meadow virologist, perhaps with special knowledge of epidemic corona viruses. But vaccine research, the development of vaccines, is increasingly becoming a science in its own right. I'm not in the middle of that. But now that I've said that..: there are vaccine researchers who know more about it than I do. They are now saying and publishing statements in which they say that, while we are actually well acquainted with the principle of these vaccines, where we actually know exactly they are well tolerated, and where we will then relatively soon, perhaps even in late summer or so, enter into large-scale studies to determine the effect of this vaccination, that is to say the test tube effect: does the patient get antibodies? Do the immune cells start up after the vaccination? We almost get information on the actual protective effect without wanting to, and of course we plan to do so. The virus will circulate until then, and of course we will also record among the vaccinated patients who will later become infected. Of course, this will also be compared with the population in which the whole thing is taking place, the whole study, in other words, the comparative population that has not been vaccinated.

Korinna Hennig: We have been talking about this antibody principle and about the immune response in this podcast as well for quite some time and in more detail. We have learned from you that there are different antibodies. Some are more effective, others less effective. And there is also the immune response at the cellular level. Is that relevant for vaccine research, what kind of immune response is generated? So if the body recognizes a protein and then starts to react?

Christian Drosten: Yes, that is of course relevant. There are two approaches. One approach is, we try to understand the natural infection and the natural immunity in the best possible way and then reproduce them in the best possible way. But that is an approach for which we may not have time at the moment. We may not have the time to carry out very long research into immunity at the moment. That will definitely be done. It is already running in parallel. So, the groups that are planning to do vaccination studies in the near future are already studying the course of immunity in the natural infection in detail.

But at the same time, they know that these studies take a long time, including the evaluation and so on. That is why there is also a completely different approach to vaccine development, which is to say that if you take all experience about infections together, which are perhaps as similar as these infections now with the coronavirus, and there is, for example, the old SARS infection, which is already quite similar, but also other infections of the respiratory tract, which can be brought about - then you can of course consider how else to proceed. So what you want to achieve. There are two main lines of work. One is to provoke very strong neutralising antibodies, for which one can use certain vaccine antigens that are perhaps already prepared in the same way as they are created in nature in natural infections, for example the surface protein of the virus. In a natural infection, this protein has to undergo certain maturation steps. The shape of this surface protein changes in the process.

Korinna Hennig: This is the spike protein that is always talked about?

Christian Drosten: Right, exactly, that is the spike protein. Now, it is possible to produce a vaccine in such a way that the spike protein is present in the vaccine in the form as the virus really looks like shortly before the infection, so that other variants of the form of this surface protein do not occur in the vaccine at all and cannot distract the immune system at all. This is what the viruses want to do, what they do during the course of the infection: They only expose themselves at the last second, just before cell entry, when the very sensitive areas of the glycoprotein, the surface protein, are exposed. If an antibody is present, the virus can no longer enter the cell. This is one of the reasons why such viruses hide these critical epitopes until the last moment. But now, of course, it is possible to make a vaccine in which these epitopes are just exposed and released so that the immune system recognizes what is happening during the vaccination and that antibodies are then preferentially formed against this most sensitive part of the virus.

Korinna Hennig: We just talked about live vector-based vaccines. But there are also dead vaccines with viral protein. We know this from the flu vaccination, tetanus vaccination. What role does that play in this case? How fast can it happen? And how good can it be?

Christian Drosten: Yes, I think we must now go back to the previous question. We have discussed that one strategy is to produce particularly active and neutralizing antibodies by exposing the shape of the surface protein. What can also be done, however, is to provoke particularly active cellular immunity by placing certain proteins, including the main surface protein of the virus, in vector systems which are already known to stimulate the cellular immune response in a very special way. This is a parallel approach that is being pursued. And both approaches say that natural infection is a mixture of cellular and humoral activity of the immune system. Humoral means antibody production. Cellular means immune cell activation. Now in one approach you can say that we make particularly good antibodies. In the other approach, however, we can also say that we make particularly good immune cell stimulation through a carrier vector of a vaccine, which stimulates the immune cells better than the natural virus would do. This means that we pick out the strengths of the immune system and stimulate them in a very special way.

Now we can talk about what you just asked. What about inactivated vaccines? Of course, we must also say in the same breath: what about live attenuated vaccines? That's another thing.

Korinna Hennig: That is, with attenuated viruses in which the disease-causing properties have been reduced.

Christian Drosten: These inactivated vaccines are the simplest thing you can do in vaccine production. You simply take the virus and let it grow to a high concentration in the laboratory. Then you kill the virus. You can put formalin on it, for example. You can make it hot. There are several ways. Then you can just inject it into the patient's muscle. And then you will see that at least after two or three vaccinations the patient will get an immune reaction. He gets antibodies against the virus, and he also gets cellular stimulation. This simply works empirically with many pathogens. We know that, that is how vaccines were historically produced. We simply have data that say that this is a sensible vaccine, and we are not going to change that now.

Simple dead vaccines have risks

But these vaccines are often not good. These dead vaccines have two problems. One problem is that the stimulation of the cellular immune system is not complete. Only a small part of the cellular immune system is properly activated in the process, while another part remains inactive, which upsets the balance of the immune response. You get an unbalanced immune response. Then there is something else that also disturbs the balance of the immune response. We have just talked about this, if we have a virus in the natural infection, it hides certain domains that are actually particularly sensitive. In the course of the infection, there are sometimes only short points in the replication cycle where these domains are really exposed. But if you kill such a virus, there is no natural course of infection or reproduction cycle. Then it is possible, for example, that these sensitive areas are never revealed. So you simply vaccinate against a virus whose most sensitive areas are not exposed at all. This then contributes even more to an unbalanced immune response.

Korinna Hennig: What does that mean?

Christian Drosten: It means that although antibodies can be measured in the laboratory, that's just one example. But these antibodies may not be the right antibodies. We have already said in an episode discussed earlier that there are neutralizing antibodies and there are antibodies in general. And we actually want the neutralizing antibodies in particular, because they interfere with the infection process.

Once the antibodies pave the way for the virus

But we can also have adverse immune reactions to a vaccine through non-neutralising antibodies, if you think of it like this, for example: There are certain cells of the immune system that are very common. They have a receptor for a part of the human antibody. Antibodies are completely variable at the front and fit exactly to the pathogen against which these antibodies have been produced in the immune reaction.

But the end piece of the antibody is always the same. And these immune cells, they have the task of recognizing pathogens that are already covered with antibodies and then eating them up. So this is often an immune reaction, for example against bacteria. And these monocytes are then attracted and they bind to such a pathogen and try to eat it up and let it in, they actively take it in.

But if such a virus is now occupied with an antibody and this antibody does not block the virus at all, but only sticks to the surface of the virus, it is not a neutralizing antibody, but only a generally binding antibody, then it can happen that this virus is now taken up in monocytes and starts to replicate there.

Under normal circumstances, the virus would not have gotten into monocytes at all, because these monocytes do not have an actual virus receptor. But now the virus uses the receptor that these immune cells have for antibodies in general. This means that the immune cell actually means well. The immune cell wants to recognise an antibody on the surface of a pathogen and then wants to eat the pathogen. In the case of a virus, however, it is possible that this antibody leads to the virus being absorbed by the immune cell. And the virus then starts not to be eaten up in the immune cell, but to replicate and to kill this immune cell, to disturb it. So the whole immune reaction can be disturbed. This can ultimately lead to a situation in which a vaccine of this kind, which makes an unbalanced antibody response - which makes antibodies, but they are the wrong ones, they are not neutralising antibodies or too few neutralising antibodies - then something happens that looks like the disease is made worse by the vaccination. So you are vaccinated, then you have contact with the virus and the disease becomes worse, as if you had not been vaccinated, because immune cells, which are actually needed to ward off the disease, have now become the target cell of the virus and the disease can then develop even more severely. This is, of course, pure theory.

In this phenomenon we speak of antibody-dependent enhancement, i.e. antibody-dependent exacerbation of the disease. All these things are examples that I can mention here of the many imponderables that lead to the fact that you can't just quickly say: "Volunteers, roll up your sleeves, we'll vaccinate you all now and then it will be fine. No, it's not that simple.

Korinna Hennig: From your point of view, is one of these two lines, as far as you can judge, the more promising one, especially with regard to such imponderables?

Christian Drosten: Many people I talk to about vaccine development for this virus, who say that the probability of such interference effects is actually not very high. But one can only speculate at the moment. You also have to rule out such things. It is simply important to carry out investigations. Much of this can be answered in animal experiments, for example. There is no getting around it. On the other hand, however, it is also possible to anticipate such effects, which I have just described here, through tests in the test tube. You don't necessarily have to do stress infections in humans for that. But it all takes a little time.

And to your question that you asked, which of the two ways, strengthening cellular immunity or antibody immunity, is the better one? It's hard to say at the moment. There are actually quite hopeful starting dates for both approaches. However, the fact is that vaccine development is an incredibly big project. At a certain point in time, a company, which actually always works with academic groups, will have to get involved in one of the approaches. At that point, it is no longer possible to simply compare the two approaches. One cannot expect to carry out vaccine studies where both approaches are simply compared. This simply exceeds all the work that needs to be done and all the affordable, financial and organisational costs. At a certain point in time, the research groups have to carry out their own studies for their own vaccines and collect the data in such a way that they are reliable. And then, afterwards, the data can be compared.

Therefore, one must simply say that it is not the case at the moment that one can say that one way is already the more promising way. One can certainly say that with the very simple method of the simple inactivated vaccine, one must look very carefully and be very careful because of the dangers. And what I described earlier, this antibody-mediated exacerbation, is only one of the dangers, the nasty surprises that can be experienced with such simple vaccines.

Simpler, more mass - but not necessarily faster

That is why it is right to focus on the more technically advanced vaccines. There is a perception where you can already say a little bit of direction. And that is that these vaccines, which aim to make particularly high neutralising antibodies, often use only a simple protein as a vaccine substance. In the biotechnological industry, this protein can be produced more strongly and better in less time than very expensive modified live vaccines, i.e. vector vaccines that are mainly aimed at stimulating the cellular response particularly well.

Here, the production of this vector vaccine is often simply not that easy in terms of quantity. In order to achieve a high yield of these vaccines, a lot of production material has to be set in motion, i.e. many cell cultures have to be infected in fermenters. While the production of such proteins is simply biotechnological, you could say: more straightforward, you know exactly how it works. There are fewer parameters to optimise in the pharmaceutical industry and the purification processes are often simpler. This is also the point, because we want to have particularly clean vaccine preparations. Therefore, there are reasons to think that these might be vaccines that would enable the vaccination of a broad range of patients.

Korinna Hennig: What would be particularly important here.

Christian Drosten: Correct. But it's not so easy to say that these are the faster ones. They need some lead time and can then be produced in large quantities, whereas the more modern concepts have some interesting concepts that are particularly fast because pure genetic information is inoculated, the RNA or DNA vaccines. There are very promising new technologies in the field of RNA vaccines. These often come from the field of anti-cancer vaccine development, which rely on the fact that the vaccine is actually produced by the vaccine recipient's own body cells, i.e. the vaccine recipient's own body cells, which produce the protein of the vaccine.

So these are vaccines, they are neither a protein produced from the outset, nor are they a vector system that, for example, is now derived from a vaccinia virus or something like that, but they are also a protein. But this protein is produced in the inoculated cells of the body after the infection. We will have to wait and see how the trials progress, because this cuts off an entire production phase in the biotechnological industry. In the biotech industry, the only thing that needs to be done is the production of RNA, which can be done chemically in a very straightforward way. These are interesting vaccine candidates that are currently being tested. These might also be vaccines that are available very quickly, but which might not be able to be vaccinated in such large quantities. Where would one then consider, are there certain target groups in the population that would be supplied with such vaccines?

Korinna Hennig: In other words, risk groups or, for example, hospital staff who could be exposed to high virus concentrations.

Christian Drosten: Something like that, for example, hospital staff where we have people who are basically healthy and are basically able to make a good immune response.

Older people need more vaccine

Exactly, this could be one of those preferred inoculation groups. And, of course, you think the same way, no matter whether it's these vaccines or something else - so wherever you would think, no matter what we have, the first vaccine we have, we must of course immediately give it to the risk groups. This consideration is perhaps a bit too simple in parts, because: At the beginning, when the first vaccines are available, we may have to try to achieve a high impact in the population with a small amount of vaccine. So, vaccinating medical staff has the greatest effect if you prevent all of them from failing. Sure, that is important, everyone understands that immediately. When vaccinating elderly people, for example, in many cases there is a big problem with many vaccines. They need more vaccine for the same immune response.

Korinna Hennig: A higher dose.

Christian Drosten: Correct. But if this dose is limited, if the production of the vaccine is limited and you know that there is a group of patients who need five times more vaccine than the normal patient - then you will soon come to the point where you say that it is practically impossible to produce five times more vaccine. So you have to think, do you want to make five times more vaccine and vaccinate the people who are at risk? Or do we want to make five times more vaccine and thus vaccinate five times more normal patients, thereby significantly increasing civil protection and thus stopping the pandemic earlier?

These are all considerations that have to be made separately for each specific vaccine. You can't generalize. In this podcast, we can only really discuss it in this superficial initial level. I can only indicate where these very difficult problems lie. Then you have to say: I have only discussed examples here. For every example that I discuss, there are three or four other major problems in addition. And in almost all cases, these must always be dealt with specifically for each individual vaccine.

Cooperation has limits

Korinna Hennig: So also ethically complicated and delicate questions! Mr Drosten, we've already strained your voice a lot. However, I would like to ask you one final question again. If you look at how many vaccine projects there are worldwide; there is an international vaccine alliance, the CEPI, which provides better financing than we often knew before for the development of vaccines. In your opinion, how good is the cooperation between different research institutes? You would think that it helps to start cooperations, especially when you have to look at each individual vaccine. Does everybody do their own thing? This is not only a national question.

Christian Drosten: Starting at the level of clinical trials, there is cooperation in the sense that, for example, a clinical trial site, i.e. a hospital or a group of hospitals, can test several different vaccines against each other. That is what is done. In other areas, however, there are also trade secrets. These are industrial companies that produce such a vaccine. So the idea that a university hospital makes a vaccine is wrong. There is no such thing. Vaccines are only produced by industry. Of course, there are extremely high investments that have to be made. Certain things have to be protected. So when I say secrets, I am not saying that we have our patent remedy here and we will not give it away, that is not the problem. Those are not necessarily the secrets that rule. The companies already know each other roughly, or even quite precisely, how the other company produces its vaccine.

It is rather the case that the contents of the studies must be protected from misinterpretation up to a certain point in time. This is very important, otherwise the development of a vaccine runs the risk of being stopped at some point, at an early stage, at a time when it should have been continued and where investments made up to that point have been made for nothing. And the idea that all this is just taxpayers' money, that is to say, the CEPI, is research funding from various countries, which is put into a large pot. That is true, it is taxpayers' money. But it is only complementary to the basic investment of important pharmaceutical companies, and also of high-risk biotechnological start-up companies whose fate depends on such things. So that is rather why this whole vaccine area is not completely open, at least until a certain point in the development, but must also be subject to a certain protection.

Korinna Hennig: When we talked about these biotechnological variants, biotechnologically produced protein: Does that already take into account the period of twelve to eighteen months until we are even ready? Or is there still time to be gained through this very process?

Christian Drosten: Exactly, Exactly, one hears twelve to 18 months now. In this time range, which has always been said that if everything really goes well, if it goes very quickly, then depending on the vaccine concept, you can expect to have an approved vaccine within one or one and a half years. In other words: next year at this time or next year in the summer. The way things are going at the moment, I can assure you that everyone is working extremely hard and everyone is sitting and talking to each other until the very end, where there is still time to gain - because it is clear that the real relief from this situation comes from a vaccine. One can only say that somehow one does not come to the golden realisation that a shortcut can be taken here after all.

The last test phase can already be useful for many

We will always have press releases, we will always have messages that sound as if this is the big shortcut here and as if this is the breakthrough. But in the end, unfortunately, there is probably no way to speed it up. We will certainly have a staggered process. We will certainly have a situation where small quantities of a very first vaccine will already be available. Where we also have grey areas, where we then say that the vaccine has not yet been approved, that is still part of the approval procedure, that is still part of the clinical trial, that is, an efficacy study. But there are already so many patients involved that they will benefit from it. Such things will of course happen.

However, if we now think about it, we will probably still be able to reach the general population: a vaccine is available, available in sufficient quantities, the entire logistics are in place, it is also filled in ampoules, it is already being inoculated by doctors. Then we have to say that this time next year at the earliest, and then by the summer of 2021 it should start on a larger scale.

There is one thing, I am completely at a loss at the moment, even for myself. Even though I am talking to colleagues who also say that there is simply nothing to say at the moment: that is this news, which is now slowly becoming more widespread in the media, that a simple inactivated vaccine has already been produced in China and that clinical trials are already under way there. Of course, people will then say that this could perhaps be done more quickly with such a simple vaccine. Here, too, one must first of all say that one must be sceptical as to whether it is really so much faster to produce a simple vaccine. Because it has to be produced in production plants that have to be specially configured for this purpose. And secondly, is it really that simple, or does it ultimately lead to certain complications?

Note from the editors:

We are receiving more and more mails about voices in online media and social networks that, in short, consider everything to be exaggerated and the danger of the corona virus for a construction of media, politicians and virologists like Christian Drosten. The arguments of these critics are often repeated, and they aim at many contexts that we have already discussed in detail here in other episodes, such as the flu comparison, especially in the early episodes. We try to take this up from time to time - until then we would like to refer you to episode 16, in which we discussed the arguments of one of the critics.

Translated Version - Original here