Should I wait for vaccinations by September?

The first big interview was given by Denis Logunov, the creator of the Russian coronavirus vaccine

Svetlana Reuter and Alexander Ershov, "Medusa"

Denis Logunov, Deputy director for Scientific Work at the Gamalei Center, managed to become a corresponding member of the Russian Academy of Sciences at the age of 43, lead a group of developers of the first Russian coronavirus vaccine and inject it himself. Logunov refuses to talk about the feelings of this experiment – because he "does not like hype" and gives an interview for the first time in his life. His vaccine has already been administered to 76 volunteers: each of them kept a "volunteer diary" in which side effects were noted – fever, rash, redness at the injection site. Fortunately, nothing more serious. The authorities hope that the vaccine will be ready by September.

In an interview with the scientific editor of Medusa, Alexander Ershov, and special correspondent Svetlana Reuter, Logunov said that in September the vaccine can only receive temporary registration, and its mass production will not begin until the end of 2020. The researchers are talking about the details of the vaccine development for the first time – the results of their work have not yet been published in the scientific literature.

First – a summary of the interview

It was very easy to find volunteers. The vaccine that we have made belongs to the vector – this means that we use a carrier virus that delivers the genetic information of the new coronavirus to the human body and causes an immune response to it. The method is based on our work to create such a vaccine against the Ebola virus, and before the pandemic happened, we had been developing a vaccine for the Middle East respiratory syndrome MERS for three years – and we had no doubts about what to do. Work began in February, and the creation of the vaccine itself took two weeks.

Before starting human trials, it was studied in detail on several species of animals, including two species of monkeys. We monitored everything: the production of antibodies, and the reaction of cells of the immune system. Tests on two groups of volunteers, 76 people in total, are now coming to an end. This is less than stated in the same UK, but, believe me, a thousand people there will not be vaccinated for a long time. We are not the press, we cannot be responsible for what is published about us, and we are not The Ministry of Health – we cannot influence the decision on registration. There will be a broad study on thousands of people, we do not shy away from this. But right now registration on limited conditions is needed so that people from the risk group can participate in the study – we are not going to protect healthy volunteers with this vaccine. By the end of 2020, we should reach millions of vaccines per year at our institute. My goal was not to become the first in the world, but to protect my loved ones.

"People are tired of being afraid"

– Did you easily find volunteers for clinical research?

– Oh, yes, there was no problem with that. 

– Even the head Russian Direct Investment Fund Kirill Dmitriev, your investor, in all interviews proudly tells how he was given the vaccine.

– We are a federal institution of the Ministry of Health of Russia. Our investor is the state.

– Why do you think people were so willing to accept the introduction of an unknown drug? Fear of getting sick? Tired of being afraid?

– First of all, I think we are really tired of being afraid. Secondly, over time, people begin to somehow come to terms with the coronavirus, realizing that it will not go anywhere. You know, there are controlled infections, and there are unmanageable ones. And at first, this infection was uncontrollable. Now – plus or minus - there are at least means to reduce the viral load and it is clear that we need to live with this virus somehow.

– Meanwhile, one medicine or another is being declared a panacea in the world, and there is either very little or no convincing evidence of effectiveness.

– The problem is that whenever everything is done with wheels, evidence suffers. 

– And how did you feel about the coronavirus yourself? Were you afraid?

– Yes, of course. For me, the initial figures were quite convincing. I remember the figures of mathematical modeling for the flu – and people often get confused in numbers, they believe that many people die in intensive care after the flu, too. In such cases, I explain that you need to look at the overall mortality rate, and not at the statistics of deaths in intensive care. And the overall mortality rate is much higher than with the flu: with the flu – 0.04%, maximum – 0.1%, COVID-19 – several times more.

– The volunteers you vaccinated were carefully checked for the absence of the slightest signs of coronavirus and protected from contact with the outside world. Now imagine this picture: your vaccine is administered to a person who is already infected, but he has no symptoms yet. It's impossible to check everyone before vaccination and protect them from contact, right? And what happens in this case? Will the injection cause an immune response that will lead to dangerous consequences?

– It's not just about our or not our vaccine. Such complications are called the ADE effect (antibody-dependent increase in infection), it is, for example, characteristic of the Dengue fever virus.

Hundreds of articles have been written about ADE, there is no point in retelling them – it also occurs with Ebola. To avoid this effect, an inactivated vaccine cannot be administered to a person – it causes only an antibody immune response, and then, when it weakens, an ADE effect. It will not cause the formation of cellular immunity, which we need. Therefore, when creating the COVID-19 vaccine, we did not make an inactivated, but a vector vaccine.

– Let's imagine that you are talking to a curious child. What is an inactivated vaccine?

– You took the virus, grew it, inactivated it – killed it. They made a vaccine with him. Introduced. A vaccine made according to this principle can only cause antibody protection.

Vector vaccines, and our coronavirus vaccine is made on this principle, also cause a cytotoxic immune response – immune cells appear that target cells infected with the virus. It is not entirely correct to transfer talk about the ADE effect to a vector vaccine - studies have shown that there is no ADE effect for vector vaccines. No one is saying that this effect does not need to be investigated further and it is not necessary to look at it, but the Oxford and Chinese [vector] vaccines [against SARS-CoV-2] studied on primates do not show any ADE effect. We also tested our vaccine for this effect on primates. And, although we cannot fully say whether humans will have the same picture as primates, now we should be wary of the possibility of the ADE effect, but nothing more.

– What does "vector" mean?

– You take a virus [vector] – a non–dangerous, non-embeddable genome that all mankind encounters during their lifetime - an adenovirus. Then you make him even safer – you cut off a piece of his genome, or rather, two. With such modifications, it is not able to reproduce in normal human cells, but it can get there and bring what you tell it to carry, what you "embed" into its genome – in our case, a gene foreign to the adenovirus, but important for the coronavirus, encoding the S-protein (the "spike" protein). The adenovirus can deliver it effectively, and after two or three weeks there will be no traces of the vector in the body. Time history: delivered – produced a foreign protein in human cells – got the result.

– Minibus.

- yes. We took the gene encoding the S-protein, translated it from RNA into DNA. We inserted this gene into the adenovirus genome and got a vector. 

– Half an hour of work, and the vaccine is ready. 

– Almost. Two weeks. 

"There were no creative torments. Copy-paste in the literal sense"

– Tell us how you made this vaccine.

– We created it in the standard way for all vector vaccines. Such vaccines did not arise out of the blue, they have been actively used since the 1990s. According to this principle, we made a vaccine against the Ebola virus, which was registered with us. 

– You have chosen a vector vaccine and it is based on adenovirus. Why? Because you've already worked with her?

– When we made the decision about the vaccine, it was clear that it should be a vaccine that induces a cytotoxic immune response. A fairly simple solution – anyone would go my way. Choosing between DNA, RNA and viral vectors for vaccine delivery - and we work with all types - we chose viral vectors because they are more effective. We conducted a lot of experiments with different carriers and compared them with vector ones, and already at the start it was clear that this was heaven and earth. 

– When did you decide – that's it, we are joining the race, we are making a vaccine and it will be exactly like this?

– I have to explain one thing here: we have been making a vaccine against [Middle East respiratory syndrome virus] MERS for three years.

– And you took the finished one?

- yes. We made a vaccine against MERS and tried different options. It was a lot of work, we have reached the second phase of clinical trials. Therefore, when another coronavirus appeared, the closest colleague from the beta-coronavirus group, we had no doubt what to do and how to do it. There were no creative torments. Copy-paste in the literal sense.

– And when did you start working? In April? In March?

– In February. The idea that we turn on and do something arose right then. In January, no one really understood what we were dealing with. In February, I participated in the WHO conference – then it became clear that we were dealing with a serious problem.

– Did the WHO understand what happened?

– On the 20th of February, yes. I will not criticize WHO, there are other people for this. They are probably right about something, but it is also difficult for WHO – it very often does not receive objective information, it is not a state body that makes decisions for everyone. Its employees are doing everything they can – they have assembled model committees, clinical and preclinical research committees, all of which are openly used all over the world. WHO is probably late in terms of speed – we are closing the borders, we are not closing them – but this is such a political decision that you will not accept quickly.

– You have copied your vector vaccine for MERS. And why didn't you use a vector that can multiply in cells – it could potentially make immunity last longer?

– I'll just say: the vector that needs to multiply will cause more pronounced side effects. If it does not multiply, then you will have standard adverse events after vaccination – fever, pain at the injection site. If you make a vaccine on a vector that multiplies, then you let the genie out of the bottle. What are we doing? We inject the vaccine in two stages – first one vector, then another. Such a scheme is known in the world – I think it is not used now for some economic reasons. But in our situation, we understand that a two-time introduction is better than a single one. We tested this on vaccines against MERS and Ebola virus.

– Recent studies by British and German scientists show that the number of antibodies to coronavirus in the blood is decreasing much faster than expected. Can this somehow interfere with vaccination?

– These works prove the obvious thing – immunity decreases over time. It is important that no one knows how things will go from here. Firstly, why do we consider a decrease in antibodies in the blood to be a marker that immunity has disappeared? Antibodies in the blood always decrease – we cannot reach the peak of the immune response for one infection and immediately for the second, third, fourth – in this case, all the forces of the body will be spent. About two months after the rise in the level of antibodies to infection, you have a strong drop in it.

And here the main question arises: will such a sick person be protected? There are vaccines that form effective immunity, but then it falls, the pathogen changes, enters the body again, and the person gets sick again – but it is easier to tolerate the disease, does not die. Such a situation, for example, with the flu. And it happens, as with yellow fever – immunity rises, then falls to fairly low values, but its protective effectiveness persists for up to 20 years. And now if there is a person who will say that a decrease in antibodies to COVID-19 means that immunity will not work, it will be a bold, but unsubstantiated and absurd statement.

– In developing the vaccine, did you decide from the very beginning to follow one path and not turn anywhere? And why, for example, are there not 13 variants of different vaccines? After all, it happens like this – you invest entirely in one option, and in the end suddenly something breaks. 

– We weren't scared, we've been through this story many times. I repeat, we have already made a two-vector vaccine against MERS and administered it to volunteers.

– But there are different options in the world, and now everything has been shared so that what kind of science the country has – this is what it will have a vaccine. Your vaccine has analogues – the Oxford vaccine and the Chinese vaccine.

– Moreover, Johson & Johnson are also making an adenovirus vaccine, they are just a little behind. That is, the three closest analogues.

– Can you name the main differences between your vaccine and the design of the study?

– The design of the study is about the same everywhere – first a limited group is investigated, then full-scale studies, which will definitely be. 

– But you have two vectors, and they don't.

– I'll tell you why we have a two-vector vaccine. If you prick one vector and it does not reproduce, you need to prick a second time. You cannot inject the same vector – your immune response to it is in an acute phase. And the person did not respond to the first injection, this happens, for example, with elderly people. You are not working with white mice with intact immunity, who react to everything the same way as twins. No. You have different situations in your population. And very often in this case you can get a good immune response, but for this it needs to be boosted [strengthened] and a second injection is administered.

We have tested this story well – both on mice and primates. We had a clinical study of two-factor administration of the same vector in humans. We know that re–introducing the same vector is not a good story. After the first injection, a response was observed in all volunteers, but with repeated administration, a significant gain was achieved only in those who were injected with a second component based on a different vector, and the introduction of the same vector gave an extremely weak gain. That is, if someone introduces the same vector, he risks creating a weak immune system, which can critically decrease within three to six months. 

– Is this your main difference from the Oxford vaccine?

– Here you are looking for a difference, and I am looking for a similarity. We [all] do not act according to the principle when we want to prick something once, and then suddenly something will work. We need to be sure that different people will respond to the vaccine.

"And in America, and in Russia now has the opportunity to cut corners"

– Did the volunteers have unpredictable reactions?

– No, fortunately. Everything is predictable – temperature, pain at the injection site. The rash is small. Everything is standard. 

– What is ready to work with the vaccine, and what is planned?

– Preclinical studies have been conducted on mice, monkeys and hamsters. Safety has been additionally tested on rats, rabbits, and two types of monkeys – rhesus monkeys and marmosets. 

– And everything is fine?

– Yes, otherwise we would not have been allowed to go to clinical trials with volunteers.

– There are antibodies, and there are no side effects?

– You know, it's not the most problematic part – to get antibodies from Rhesus and marmosets.

– And T-cells?

– Also. Everything is simple with them, the animals respond quite well. 

– And they protect against the virus itself, have you checked it somehow?

– Yes, there was a study on hamsters and rhesus monkeys. 

– You haven't published it yet?

– Not yet, we will.

– Accordingly, then - studies on 38 people?

– Two times 38.

– Some are given the usual vaccine, others are "dried"?

– It is.

– Is this phase over?

– It's ending. Everything has already been entered and tracked. 

– And what is the day after the introduction now?

– 28th.

– And what are the results?

– We will see the final results, while we have looked at the preliminary ones – safety, immune response. We will announce the full data a little later.

– You check antibodies, neutralizing antibodies, T-cells, and probably everything – nothing else can be checked?

– You can. We test different antibodies on different test systems - IgG, ELISA for a full–size S-protein and for an S-protein fragment (RBD domain), the titer of virus neutralizing antibodies, T-cell immune response in two variants - lymphoproliferation [population increase] of CD4 and CD8 cells and their production of gamma interferon. When there are few patients, they should be examined from all sides – we do this, first of all, for ourselves – we need to know as much as possible about our vaccine.

– Will this vaccine be mandatory?

– This is not a question for me. I can say my opinion: obliging people is not quite right, they are able to make a decision themselves. The Ministry of Health is likely to identify some risk groups to whom vaccination may be recommended due to the large number of contacts. Doctors, teachers. Recommendations for these specialties are likely to be accepted.

– The press writes: everyone, the vaccine trials have been completed at the Gamalei Institute. Everything has been proven, everything works, get ready for vaccinations.

– I'm not the press, I can't be responsible for it. The news falls on us unexpectedly. We are as open as possible, we tell everything – we do not have 20 spare options, there is only one, it did not appear by chance, there is all the information, everything will be published in foreign magazines. The clinical bases actually administered all doses to the volunteers. And the press probably meant it when they wrote that the study was over. But it has not ended, the observation of volunteers will go on for another six months. But also in America, and in Russia has special regulations that allow…

– Cut corners.

– Yes, to simplify regulatory procedures. But this does not mean that the volunteers were vaccinated, and no one will be responsible for them. Information about them will be collected 42 days after the introduction of the vaccine, then three months later, then six months later. But the stage of cutting corners will be completed after the first phase of vaccination. And in 42 days we will post all the information. 

– Then what do the statements mean that the vaccine will be available in September? How to understand them?

– It means that if it is…

– And maybe not?

– Understand, this is an objective study – we do not decide whether the vaccine will be registered or not, we do not influence this decision. From a regulatory point of view, it works like this: the developer, who is also the sponsor, gives the vaccine to the clinical base [where the study is being conducted] and then she will do everything. They won't ask us anything. The clinical base will prepare documents: observations, diaries of volunteers, etc. All this will be collected in a data package – on tests, on immunogenicity. All this will be submitted to the center of expertise of the Ministry of Health, and it will be he who will make a decision – based on a package of preclinical and clinical studies – whether this vaccine is suitable, whether it is effective enough, how good is the ratio of safety and efficacy parameters, and whether it is possible to release such a vaccine on limited terms into circulation. 

What does "on limited terms" mean? This means that if we do not repeat [the results] on a large sample, the registration will end. Therefore, there will definitely be an extended study (the third phase, as is customary in the international classification) and all observations of volunteers (both these 76 and those who will only participate) will not be carried out for 42 days – they will be carried out for six months. And only when this happens, when efficiency and safety are proven, we will receive a permanent registration certificate, if the expert body decides that this is enough. And now [what we are talking about] is only registration on "limited conditions", which will allow, for example, vaccination of at–risk groups. That's all. 

"I have no desire to be the first in the world. The first task is to protect your inner circle"

– Are you saying that the tests on these two groups of 38 people are enough to get registered? But that's very little!

– They are enough to get registration on "limited conditions" – it, for example, does not allow vaccinating children, the elderly, but will allow you to do research on a larger sample. You will have risk groups, they will receive a drug that will pass a quality examination in Roszdravnadzor. Then a thousand people will still need to be vaccinated in order to pass the third phase. In this sense, practically nothing will change – except that it will be possible to use it in a slightly wider circle of people, not only in healthy volunteers, but also in people from risk groups. We don't want to protect volunteers with a vaccine, do we?

– Do you think it is right to release the vaccine according to such a registration scheme?

– America has now come to exactly the same thing – their vaccines have gone according to a simplified scheme. If we are talking about precedents, then more or less everyone followed the same path. And the British, including – now after the first phase, they will still go to simplified registration, you'll see. 

– But they have 1000 people in the study, not 78, and they will come out after a thousand volunteers?

– They won't explore a thousand for a long time anyway. There will be no full investigation in either America, not anywhere else.

– Is it possible to give such a very rough arithmetic: if the lethality of the disease is about 1%, then in order to prove that the vaccine is safe enough, that it really gives a win when used, you need to observe at least 100 people to be able to see some serious, but rare side effect - I don't know, ADE reaction or something else. Just to claim that the risks of vaccination are lower than the risks of the disease itself. Isn't that right?

– Of course, that's what we're going to do. The protocol for the large third phase of the study with the participation of two thousand volunteers has already been developed, but has not yet been approved, so nothing has been published about it. But he is. We are not just not shying away from this big study, we are doing everything to make it happen right now, in the very near future – in August.

– And if you imagine such a fantastic situation: you put a drug on the market, and then, God forbid, something very bad happens, just like in the movies. What happens then – everything is called back?

– For any medicine – it does not matter whether it is ours or some other - there is a special procedure by which this happens: the trial begins, all the steps are prescribed. In general, we have to submit a report to the Ministry of Health about all the things that happen to volunteers. We actually have a pretty strict regulatory system.

– In connection with media reports about hackers who were going to steal the secrets of vaccine production, I would like to ask – what part of the information is super secret when developing a vaccine? What should be especially well protected? Such a "Koshcheev's death" that you will never willingly give to anyone? 

– When you live in some technology, whether you want it or not, you have a lot of your own developments, which you often do not even take out in a patent. But it is very difficult to steal them – you need to live 15-20 years to really master this technology perfectly and reproduce it in any conditions. Well, how can it be stolen? Only together with the development team itself. And when the vaccine enters the market, in any case, everyone will be able to see what is in its composition, there will be no secret.

– Do you have a desire to be the first in the world?

– From me? No. Probably it should be, but no. I have always set a different goal for myself: the first task is to protect my inner circle. Because it was all pretty scary, in fact – and the desire to protect and save loved ones, it's pretty strong. And then, you know, defeating Americans, defeating Europeans are financial goals to conquer the market, and I'm not conquering markets, I'm developing drugs. And I need my drug to be good and for it to work. And who and how will move it, it is important, but secondary.

"By the end of this year, we should reach millions of vaccines a year"

– After all, in your research you are looking only at indirect signs of a protective effect: antibodies and T-cells. But you don't collect the statistics that vaccinated people get sick less often than unvaccinated ones yet. Is it possible that the vaccine will be ineffective in real life even when laboratory tests say that everything should work?

– Of course, all this will be observed, and we will all see it. Animals after vaccination are protected [from infection] – both ferrets, hamsters, and primates. Therefore, there is no reason to believe that the vaccine will not work. The only concern in this regard – if you ask my personal opinion – is the duration of immunity. Whether it will last a year, two, or three – we do not know. What will a repeat infection look like in a year? Neither we nor anyone else know this yet, because the disease is only six months old. 

– How many doses of vaccines are you going to produce?

– In order to release this, production must be scaled up. And here the Ministry of Health is making every effort to ensure that the vaccines that will be broadcast to [production] sites as much as possible, so that these sites are included in the game as quickly as possible, enter the market as quickly as possible, so that there is quality, so that it can be scaled quickly. Of course, this is one of the priority tasks that will also be solved in parallel. 

– Let's say today you have a permit and they say to you: "That's it, go ahead, we need 146 million doses of vaccine." 

– I can answer [only] what will happen at the Gamalei Institute, what capacities we will reach. What capacities our colleagues will reach – and these will really be our colleagues and assistants, not enemies – how quickly they will come out, we need to ask them. 

– And you?

– By the end of this year, we should reach millions of vaccines per year. From three to five million doses per year. Our production will be increased in three stages – equipment and consumables have already been ordered. 

– Even with a culture medium for growing cells, there can be problems – everyone needs the same medium. These environments, they are not made here, they are imported. Will there be any problems with this?

– So far, there is no such thing that Russia is being cut off and something is not being sold to it just because it is Russia. In theory, probably, this can happen, but so far I have not encountered it. On the contrary, manufacturers ask to speed up the order to indicate that the medium will be used to create funds against COVID-19.

– Aren't you afraid of some kind of unrest if it suddenly turns out that officials, for example, will get the opportunity to be vaccinated as a priority?

– Why should I worry about it? No, I'm not afraid. That's not my question. My question is to make a good product, this is the end of my field of activity. State priorities that need to be set – this should be handled by the government and the Ministry of Health. If the government sends appropriate orders to our institute, then we will act according to them, and nothing more. There are no other options, we are a subordinate institution. To whom to give, which cohorts to protect first of all – this will be considered and is already considered. I am sure that there will be no such thing – we will protect these ones, but not these ones. 

– At which sites will your vaccine still be produced?

– "R-pharm", "Generium", "Binnopharm" are the main sites. The companies themselves came out to us, they wanted to participate.

– Financially profitable?

– Probably. But for many people, I think it's also an opportunity to participate in something big.

– This is a strong ambition.

– Sure. Participation in a big deal, not in some nonsense.

– Maybe this is a stupid question, but still: do you feel any special responsibility to the population of Russia for what you are doing?

– Sure. You can't sit in a trench and watch everything that is happening now with detachment. For us, this is a really big challenge that we need to meet. It just so happens that this is my specialty, you can't be a microbiologist, a virologist and not participate – this is a challenge and we have to work it out.

– I'm sorry for the tactlessness, but have your closest people been sick with coronavirus? 

– My relatives were ill. Those who are older even ended up in the hospital.

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