27 March 2020

Catch up and warn

How to create a coronavirus vaccine and can it stop the pandemic

Polina Loseva, N+1

Dozens of biotech companies and scientific institutes are racing against the pandemic to create different versions of vaccines against the new coronavirus SARS-CoV-2. We understand what technologies are used for their development, how long it will take until the moment when it will be possible to vaccinate from COVID-19, and whether the future vaccine will be able to stop the pandemic.

Every time humanity faces a new infection, three races start simultaneously: for a medicine, a test system and a vaccine. We have already written about how doctors are looking for an effective medicine, sorting through all known antiviral drugs. And they told how the test systems work, and what prevents them from checking the entire population of the planet with their help. Now it's time to talk about vaccines. The previous week in Russia has begun testing the anti-coronavirus vaccine on animals, and in the United States – already on humans. Does this mean that victory over the epidemic is close?

According to WHO, about 40 laboratories in the world have announced that they are developing vaccines against coronavirus. Moderna CanSino Biologics, the Chinese company that has received permission for human trials, and the American Moderna, which has already started them, despite the fact that there are clear leaders among them – for example, it is difficult to predict which of the companies will win this race, and most importantly, whether the development of vaccines will overtake the spread of coronavirus. Success in this race depends not least on the choice of weapons, that is, on the principle on which the vaccine is built.

A dead virus is a bad virus

School textbooks usually write that a dead or weakened pathogen is used for vaccinations. But this information is somewhat outdated. "Inactivated ("killed" – N+1) and attenuated (weakened – N+1) vaccines were invented and introduced in the middle of the last century, and it is difficult to consider them modern," explains in a conversation with N+1 Olga Karpova, Head of the Department of Virology, Faculty of Biology, Lomonosov Moscow State University. – It's expensive. It is difficult to transport and store, many vaccines reach the places where they are needed (if we are talking, for example, about Africa) in such a state when they no longer protect anyone."

Besides, it's not safe. In order to get a high dose of the "killed" virus, it is necessary to first acquire large quantities of live ones, and this increases the requirements for equipping the laboratory. Then it needs to be neutralized – for this, for example, ultraviolet or formalin is used. But where is the guarantee that among the many "dead" viral particles there will not be any that can cause disease?

With a weakened pathogen, everything is even more difficult. Now, in order to weaken, the virus is forced to mutate, and then the least aggressive strains are selected. But at the same time, a virus with new properties turns out, and not all of them can be predicted in advance. Again, where is the guarantee that once inside the body, the virus will not continue to mutate and will not produce "offspring" even more "evil" than the original?


Different approaches to creating a vaccine (using the example of HIV). On the left: "killed" virus, weakened virus, synthetic viral protein. In the center is a fragmented virus. On the right is a viral vector, a bacterial vector and a DNA vaccine.

Therefore, both "killed" and "unfinished" viruses are rarely used today. For example, among modern flu vaccines, "weakened pathogens" are in the minority – only 2 out of 18 vaccines approved in Europe and the United States by 2020 are so arranged. Out of more than 40 coronavirus vaccine projects, only one is arranged according to this principle – the Indian Institute of Serums is engaged in it.

Divide and vaccinate

It is much safer to introduce the immune system not to the whole virus, but to a separate part of it. To do this, you need to select a protein by which the "internal police" of a person will be able to accurately recognize the virus. As a rule, this is a surface protein with which the pathogen penetrates into the cells. Then you need to get some cell culture to produce this protein on an industrial scale. This is done with the help of genetic engineering, so such proteins are called genetically engineered, or recombinant.

"I believe that vaccines must necessarily be recombinant, and nothing else," says Karpova. – Moreover, it must be vaccines on carriers, that is, the virus proteins must be on some carrier. The fact is that by themselves they (proteins) are not immunogenic. If low-molecular-weight proteins are used as a vaccine, immunity will not be developed on them, the body will not react to them, therefore carrier particles are absolutely necessary."

As such a carrier, researchers from Moscow State University suggest using the tobacco mosaic virus (this, by the way, is the very first virus discovered by humans). Usually it looks like a thin stick, but when heated it takes the form of a ball. "It is stable, it has unique adsorption properties, it attracts proteins to itself," says Karpova. "On its surface, you can place small proteins, the same antigens." If you cover the tobacco mosaic virus with coronavirus proteins, then for the body it turns into an imitation of the SARS-CoV-2 virus particle. "The tobacco mosaic virus," Karpova notes, "is an effective immunostimulator for the body. At the same time, since plant viruses cannot infect animals, including humans, we are making an absolutely safe product."

The safety of various methods related to recombinant proteins has made them the most popular – at least a dozen companies are now trying to obtain such a protein for coronavirus. In addition, many use other carrier viruses - for example, adenovirus vectors or even modified "live" measles and smallpox viruses that infect human cells and multiply there along with coronavirus proteins. However, these methods are not the fastest, because it is necessary to establish the in-line production of proteins and viruses in cell cultures.

Naked genes

The stage of protein production in cell culture can be shortened and the process can be accelerated if the cells of the body are forced to produce viral proteins on their own. According to this principle, gene therapy vaccines work – "naked" genetic material – viral DNA or RNA can be embedded in human cells. DNA is usually injected into cells by electroporation, that is, together with the injection, a person receives a light discharge, as a result, the permeability of cell membranes increases, and DNA strands get inside. RNA is delivered using lipid vesicles. One way or another, the cells begin to produce a viral protein and demonstrate it to the immune system, and it unfolds an immune response even in the absence of a virus.

This method is quite new, there are still no vaccines in the world that would work on this principle. Nevertheless, seven companies, according to WHO, are trying to make a coronavirus vaccine based on it. Moderna Therapeutics, the American leader in the race for a vaccine, is following this path. He was also chosen for himself by three more participants of the race from Russia: the Vector Research Center in Novosibirsk (according to Rospotrebnadzor, it checks as many as six vaccine designs at the same time, and one of them is based on RNA), the Biocad company and the Scientific and Clinical Center for Precision and Regenerative Medicine in Kazan.

"In principle, it is not so difficult to create a vaccine," says Albert Rizvanov, director of the Center, Professor of the Department of Genetics at the Institute of Fundamental Medicine and Biology of KFU. "Gene–therapeutic vaccines are the fastest in terms of development speed, because it is enough to create a genetic construct." The vaccine, which is being worked on at the Center, should shoot at several targets at once: a DNA strand with several viral genes is injected into the cells simultaneously. As a result, the cells will produce not one viral protein, but several at once.

In addition, according to Rizvanov, DNA vaccines may be cheaper than others in production. "We are essentially like Space X," the scientist jokes. – Our prototype development costs only a few million rubles. However, creating a prototype is only the tip of the iceberg, and testing with a live virus is a completely different order."

Vicissitudes and tricks

As soon as vaccines turn from theoretical developments into an object of research, obstacles and restrictions begin to grow like mushrooms. And financing is only one of the problems. According to Karpova, MSU already has a sample of the vaccine, but further testing will require cooperation with other organizations. At the next stage, they plan to check the safety and immunogenicity, and this can be done within the walls of the university. But as soon as it is necessary to evaluate the effectiveness of the vaccine, you will have to work with the pathogen, and this is prohibited in an educational institution.

In addition, special animals will be required. The fact is that ordinary laboratory mice do not suffer from all human viruses, and the picture of the disease can also be very different. Therefore, vaccines are often tested on ferrets. If the goal is to work with mice, then genetically modified mice are needed, which carry on their cells exactly the same receptors that the coronavirus "clings to" in the patient's body. These mice are not cheap (ten or two thousand dollars per line). True, sometimes you can save money – buy only a few individuals and breed them in the laboratory – but this lengthens the stage of preclinical testing.

And if we are still able to solve the problem of financing, then time remains an insurmountable difficulty. According to Rizvanov, the development of vaccines usually takes months and years. "Rarely less than a year, usually more," he clarifies. Veronika Skvortsova, the head of the Federal Biomedical Agency (they are developing a vaccine based on a recombinant protein), suggested that a ready-made vaccine could appear in 11 months.

There are several stages at which the process can be accelerated. The most obvious one is development. The American company Moderna has taken the lead because it has been creating mRNA vaccines for a long time. And to make another one, the decoded genome of the new virus was enough for them. Russian teams from Moscow and Kazan have also been working on their technology for several years and rely on the results of tests of their previous vaccines against other diseases.

The ideal option would be a platform that allows you to quickly create a new vaccine from a template. Similar plans are being hatched, among others, by researchers from Moscow State University. "On the surface of our particle," says Karpova, "we can place proteins of several viruses and protect against Covid–19, SARS and MERS at the same time. We even think that it is possible to prevent such outbreaks in the future. There are 39 coronaviruses, some of them are close to human coronaviruses, and it is quite clear what overcoming the species barrier is (the "jumping" of the virus from bats to humans is N+1). But if there is a vaccine like lego, we can put a protein of some virus that originated somewhere on it. We will do this within two months – we will replace or add these proteins. If such a vaccine had been in December 2019, and people had been vaccinated at least in China, it would not have spread further."

The next stage is preclinical testing, that is, working with laboratory animals. This is not the longest process, but it can be won at its expense if you combine them with clinical trials on humans. That's exactly what Moderna did – they limited themselves to a quick safety check and immediately moved on to human research. However, it is worth remembering that the drug they are trying is among the safest. Since they do not use either viruses or recombinant proteins, there is a very small chance that the volunteers will have side effects – the immune system simply has nothing to react aggressively to. The worst that can happen is that the vaccine will be ineffective. But this has yet to be verified.

But the production of vaccines, apparently, is not a limiting stage. "This is no more complicated than the usual biotechnological production of recombinant proteins," explains Rizvanov. According to him, the plant can produce a million doses of such a vaccine in a few months. Olga Karpova gives a similar estimate: three months for a million doses.

Do I need a vaccine?

Whether it is worth reducing clinical trials is a moot point. Firstly, this is not a fast process in itself. In many cases, the vaccine must be administered in several stages: if the virus does not multiply by itself inside the body, it is quickly eliminated, and its concentration is insufficient to cause a serious immune response. Therefore, even a simple check of effectiveness will take at least several months, and doctors are going to monitor the safety of the vaccine for the health of volunteers for a whole year.

Secondly, COVID-19 is the very case when it seems impractical for many to accelerate human trials. Mortality from the disease is now estimated at units of percent, and this value is likely to be further reduced as soon as it becomes clear how many people have suffered from the disease asymptomatically. But the vaccine, if it is invented now, will have to be administered to millions of people, and even small side effects can result in a number of diseases and deaths comparable to the infection itself. And the new coronavirus is far from being so "evil" that, in Rizvanov's words, "all security considerations are completely thrown aside." The scientist believes that quarantine is the most effective in the current situation.

However, according to Karpova, there is no urgent need for a vaccine in the near future. "It is not necessary to vaccinate people during a pandemic, it does not comply with epidemic rules," she explains.

Galina Kozhevnikova, Head of the Department of Infectious Diseases of the RUDN, agrees with her. "During the epidemic, no vaccination is recommended at all, even planned, which is included in the vaccination calendar. Because there is no guarantee that a person is not in the incubation period, and if a vaccine is applied at this moment, undesirable phenomena and reduced effectiveness of vaccination are possible," Kozhevnikova said, answering the question N+1.

There are cases, she added, when emergency vaccination is needed for vital indications, in a situation where life and death are at stake. For example, during an anthrax outbreak in In Sverdlovsk in 1979, everyone was vaccinated in a row, thousands of people were urgently vaccinated in 1959 in Moscow during an outbreak of smallpox brought from India by the artist Alexey Kokorekin.

"But coronavirus is absolutely not such a story. According to what is happening, we see that this epidemic is developing according to the classical laws of acute respiratory disease," says Kozhevnikova.

Thus, vaccine developers are always in an uncomfortable situation. While there is no virus, it is almost impossible to create a vaccine. As soon as the virus appeared, it turns out that it had to be done the day before yesterday. And when it recedes, manufacturers lose their customers.

However, a vaccine needs to be made. This did not happen during previous outbreaks of coronavirus infections – both MERS and SARS ended too quickly, and research lost funding. But if there have been no SARS cases in the world since 2004, then the last case of MERS is dated 2019, and no one can guarantee that the outbreak will not happen again. In addition, a vaccine against previous infections can become a strategic platform for the development of future vaccines.

Karpova notes that even after the attenuation of this COVID-19 outbreak, another one is possible. And in this case, the state should have a vaccine ready. "This is not the vaccine that all people will be vaccinated with, as against the flu," she clarifies. "But in an emergency situation with a new outbreak, the state should have such a vaccine, as well as a test system."

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