Across Europe, the incidence of tick-borne encephalitis (TBE) is increasing. This is worrying, especially as the diagnosis of tick-borne diseases is limp, and preventive vaccinations – as in Poland – are expensive and recommended only for a narrow group of particularly vulnerable people. A chance for change may be the fruit of the work of scientists from the Intercollegiate Faculty of Biotechnology of the University of Gdańsk and the MUG. Under the supervision of dr hab. Ewelina Król, they have developed an antigen that can be used as a new vaccine against TBE – highly effective, safe, easy and quick to produce, and much cheaper than existing preparations.
- Current TBE vaccines contain killed viruses. In the case of such preparations, there is always a risk of incomplete inactivation of the pathogen
- The new vaccine would be recombinant – not containing the genetic material of the virus
- Among its greatest advantages is quick and uncomplicated production and lower – perhaps even by half compared to current vaccines – cost
- Prof. Ewelina Król explains what the process of developing a new vaccine looks like, how long does it take and why the mRNA vaccine against COVID-19 was developed so quickly
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Paulina Wójtowicz / Medonet: Two vaccines against TBE are currently available in Poland. Where did the idea to develop a new one come from?
Dr hab. Ewelina Król, prof. UGExisting vaccines contain inactivated or killed viruses. Their disadvantage is inactivation, because although the vaccinated person has not been infected so far, it can potentially happen because the production of inactivated vaccines carries a risk resulting from the use of large amounts of potentially highly pathogenic viral strains and there is a possibility of incomplete inactivation. these viruses. For this reason, the TBE vaccine is not recommended for young children and people with reduced immunity. The virus is inactivated, but it’s still a virus.
Another disadvantage of these vaccines is the dosing cycle and associated costs. For full protection, we need to take three doses at regular intervals, and then booster doses every three or five years. The cost of one dose is currently about PLN 200, and since vaccination is not reimbursed, it is quite a cost overall.
How is the vaccine you are working on different from them?
It is a recombinant vaccine based on virus-like particles. These capsules are made of the structural proteins of the virus, but empty inside, without its genetic material, so the virus is unable to multiply in our body. All it can do is enter our cells through receptors.
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What is he doing in them?
It forces our immune system to produce neutralizing antibodies that are able to bind viral particles during infection and render them harmless. This is why some viral infections are only contracted once in a lifetime. Because when it comes into contact with the pathogen for the first time, our body produces a sufficient amount of antibodies that we are protected the next time we come into contact with it and the virus has no chance with our immune system. The level of these antibodies is sometimes insufficient or they are not strongly neutralizing – then we reach for vaccines.
How are these virus-like particles constructed?
By genetic engineering methods. We can produce them in a variety of expression systems as an alternative to authentic viral antigens, but not all cells are suitable for this. For example, bacterial cells are not good at producing vaccine antigens because protein modifications are not the same as in the human body. They do not even have the process of glycosylation, i.e. adding sugars at the stage of protein formation, so this system is not a choice.
We can also produce virus-like particles in mammalian cells, but the system is quite expensive – the cost is increased by the price of cell culture media. In our plant, we obtain the same virus-like particles in Leishmania tarentolae cells – a protozoan parasite of a gecko. It does not infect mammalian cells, and at the same time has all the machinery typical for them, which in practice means that all protein modifications are almost identical. Thanks to this, we can cheaply produce a large amount of virus-like particles in the flask.
What cost are we talking about?
I think it could be half, maybe even a quarter of the current price of a vaccine.
How long does it take to produce an inactivated vaccine?
We always have to produce a virus in cells first. Viruses are produced in primary chicken fibroblasts, i.e. mammalian cells. We must have the right amount of such cells – these are whole cell factories, not one bottle or flask, but large fermentors containing suspension cells. The entire process of producing a virus and then inactivating it takes roughly one and a half to two months. However, it is difficult to estimate this time precisely, because it is a controlled continuous process, i.e. when some cells grow, others are infected, and so on. The longest, however, is what happened before – the optimization of the conditions of cell production and culture. These are huge amounts of experimentation, a process that often takes months or years.
Would recombinant vaccine production be faster?
Yes, because the process itself does not require work in a specially adapted laboratory with a high level of biological safety. Moreover, we are able to obtain much more virus-like particles from the same culture volume. This is a big advantage.
Another is that the method of purifying particles is much easier and cheaper. In the protozoal system used by us, the cell culture medium is quite poor, does not contain many other components, so it is easy to separate what interests us by means of ordinary ultracentrifugation. In the case of mammalian cells, the purification process itself is much more complicated because the medium is rich in various components. The cleansing is then multi-stage and, of course, more expensive.
At what stage is work on the vaccine?
It is not that we already have a vaccine ready. We have an antigen that could be used as a potential future vaccine – and that has been patented by us.
Unfortunately, it is not possible to produce an effective vaccine antigen in a very short time from the known sequence of the genetic material of the virus. If that were the case, all scientists in the world would have new, effective vaccines every now and then. Many years of optimization and painstaking experimentation are required to obtain such recombinant virus-like particles. We started working with the potential vaccine antigen more than two years ago. Now we are at the stage of checking whether what we have managed to produce is effective in the mouse model. In short, does the administration of this preparation cause mice to produce a large amount of neutralizing antibodies? The animals have already been vaccinated, we will see if the sera are capable of neutralizing the virus. We expect the results soon.
Assume that they are positive, the antigen will be of interest to a company that will develop the composition and production. When could such a vaccine be marketed?
It’s a matter of the next few years. Let us remember what the process of introducing a new vaccine to the market looks like. We have basic research that lasts five to ten years. Then there are the so-called preclinical studies – another four to eight years. Then there are clinical trials of different phases, of which three are the most important. The first is a safety phase, carried out on a small group of healthy volunteers, usually lasting around two years.
The second phase is activity tests – we are already talking about hundreds of healthy volunteers, but the duration of the research is analogous to the first phase. Finally, we have research in natural conditions – another two, maybe three years.
The clinical trials themselves, with really good organization and efficient course, last about five to six years. Taking into account the fact that we are at the stage of preliminary preclinical tests, which will probably have to be repeated, and then we will cooperate with the company and conduct the entire “clinic”, we still have a few more years of work to do.
The question is …
… why then the mRNA vaccine appeared so quickly?
Yes. There is a huge group of people who doubt the effectiveness of COVID-19 vaccines precisely because of their immediate – in the context of what you say – their introduction to the market.
What I said are the longest assumed periods. They all cover the situation where we do something ourselves from the beginning, without any help. We must remember that if a biotechnology company has very advanced research on a preparation and can use the same platform to develop another, this time will be very much shortened. If someone – such as Pfizer – has used such a platform to produce another vaccine and has already started clinical trials with this platform, very often he does not have to repeat the safety phases. This is one point.
The second is the circumstances and context of the pandemic. In such extreme conditions, each stage is kept to an absolute minimum. Most – formal issues. The commission that receives research conclusions usually takes months to gather and analyze them. In a pandemic, this is done as quickly as possible. Again, it takes almost a decade to launch a completely new vaccine on a completely new platform. But when I was already working on a vaccine for five years, for example mRNA, and this mRNA contained a gene for another protein, for me now replacing another gene is a matter of a few weeks, because the whole optimization – the longest and most arduous part of the work – is behind me.
What should the TBE vaccination program look like in Poland? Should such vaccinations be compulsory?
It must be remembered that there is a significant increase in the incidence of TBE in the whole of Europe. There are more and more ticks, as are endemic regions where infected arachnids are concentrated. In addition, new outbreaks are constantly appearing in various parts of Europe, even in places as “exotic” for ticks as Siberia, and the regions of the two most common species transmitting TBE are almost overlapping.
This means that there may be a phenomenon of recombination, i.e. a change in the genetic material between viruses. Unfortunately, the new variants are in most cases more virulent strains. Symptoms of infection with them are worse, more difficult to treat, and the death rate is greater.
So today ticks are not only a problem of foresters or other people who often and long stay in wooded areas. They are in the park, by the playground, everywhere, so it’s not like we don’t go to the forest, we don’t have to be careful and vaccinate. Answering the question: if vaccines were cheaper, recombinant, safer, they should be included in the vaccination schedule for all adults. We would feel safer.
Poles are divided on vaccination. It is difficult to persuade them to vaccinate themselves against a disease that has turned our lives upside down. So how do you convince them to protect themselves against conditions such as TBE, which are not talked about as much and do not occur as often as flu or COVID-19?
Not much is said, although more and more. Recently, there was even a government advertising spot encouraging people to get vaccinated against TBE. This means that the Ministry of Health already sees the problem and the increase in the incidence is clear. If we observe an increase of 20% in the course of 400 years, this is a significant increase. We should be so worried that it is estimated that only 20-30 percent. sick people is diagnosed correctly.
What it comes from?
Symptoms are often ambiguous. Someone walks a lot in the forest, for example, picks mushrooms, and is used to the fact that he brings a lot of ticks on himself. But some of them may be infected with the virus. Very often, at the beginning, nothing really happens, the infected person has a fever, fatigue, joint or muscle pain, but thinks that it is a common cold.
Only later this virus can attack the nervous system. Inflammation of the meninges or the brain does not always appear, but various types of neurological disorders are common. We rarely associate them with a tick bite. Meanwhile, TBE is a dangerous neurological disease that causes numerous complications, often lasting for many years. Almost every second patient leaves the hospital with permanent consequences that require many years of treatment and rehabilitation.
All this makes TBE a serious public health problem both in Europe and other parts of the world, and the most important viral tick-borne disease in Europe.
- You can buy a mail-order genetic test for tick-borne infections at Medonet Market
You are the author of two patents relating to the action of new antiviral compounds and a patent application relating to Zika virus vaccine antigens. The aim of this research is to develop a new generation of vaccines against these pathogens. Why exactly viruses?
When, as a student, I started my individual practice at the Department of Recombinant Vaccines at the Intercollegiate Faculty of Biotechnology of the University of Gdańsk and the Medical University of Gdańsk, viruses simply fascinated me. I was delighted to see how they can be genetically engineered, electron microscopy or confocal microscopy, which allows us to look at particles that, unlike bacteria, aren’t so easily seen which techniques need to be used to make this possible.
While doing my doctoral thesis at the plant, I started a completely new subject – I was looking for new antivirus compounds, which involved the need to work with live viruses. Once a person becomes interested in a given virus, has a developed methodology of multiplication of this virus in cells, needed to study the activity of antiviral compounds, but he also knows that there is no vaccine available on the market, and he has these tools in his hand, it is tempting to use this experience .
Unfortunately, there is an epidemic of some new virus every few years. Today’s times show that it is not easy, but we must remember that pandemics will happen and we must be prepared for them. We must be able to use today’s lessons, the mistakes we make, learn from the experiences we have now, learn and use this knowledge in the future. We will be surprised more than once, but the dynamically developing science and biotechnology give us hope that we will deal with every pathogen. It is only a matter of time before we develop either an effective drug or an effective vaccine for a disease that is overwhelming us today
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