How a coronavirus vaccine is being created and can it stop a pandemic

Dozens of biotechnology companies and scientific institutes are racing against the pandemic to create different vaccine options for the new SARS ‑ CoV ‑ 2 coronavirus. We are examining what technologies are used to develop them, how long it will take until the moment when vaccines against COVID-19 can be given, and whether a future vaccine will be able to stop the pandemic.

Every time humanity is faced with a new infection, three races start simultaneously: for a medicine, a test system and a vaccine. Last week, the Scientific Center of Rospotrebnadzor began testing a vaccine against the new coronavirus, testing an anti-coronavirus vaccine in animals, and in the United States, an NIH clinical trial of investigational vaccine for COVID-19 begins in humans. Does this mean that the victory over the epidemic is near?

According to WHO, about 40 laboratories around the world have announced the DRAFT landscape of COVID-19 candidate vaccines - March 20, 2020 that they are developing vaccines against coronavirus. And despite the fact that there are clear leaders among them - for example, the Chinese company CanSino Biologics, which received RECOMBINANT NOVEL CORONAVIRUS VACCINE (ADENOVIRUS TYPE 5 VECTOR) APPROVED FOR CLINICAL TRIAL permission for human trials, and the American Moderna, which has already begun them, - Now 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 weapon, that is, on the principle on which the vaccine is built.

A dead virus is a bad virus

In school textbooks, they usually write that a killed or weakened pathogen is used for vaccinations. But this information is somewhat outdated. “Inactivated (“killed”. - Approx. N + 1.) And attenuated (weakened. - Approx. 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 is 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 a state where they no longer protect anyone."

Moreover, it is not secure. In order to get a high dose of the "killed" virus, you must first acquire large quantities of live, and this increases the requirements for laboratory equipment. Then it needs to be neutralized - for this they use, for example, ultraviolet light or formalin.

But where is the guarantee that among the multitude of "dead" viral particles there will not be a number of those capable of causing disease?

It is even more difficult with a weakened pathogen. Now, in order to weaken, the virus is forced to mutate, and then the least aggressive strains are selected. But this produces a virus with new properties, 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 produce "offspring" even more "evil" than the original?

Different approaches to creating a vaccine (for example, HIV)

Therefore, both "killed" and "not killed" viruses are rarely used today. For example, among modern influenza vaccines, “attenuated pathogens” are in the minority - Next ‑ generation influenza vaccines: opportunities and challenges are in the minority - only 2 of 18 vaccines approved in Europe and the United States by 2020. Of more than 40 projects of vaccines against coronavirus, only one is organized according to this principle - the Indian Institute of Serum 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 the help of 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, which is why such proteins are called genetically engineered, or recombinant.

“I believe that vaccines must be recombinant, and nothing else,” says Karpova. - Moreover, these must be vaccines on carriers, that is, the proteins of the virus must be on some kind of carrier. The fact is that by themselves they (proteins) are not immunogenic. If low-molecular-weight proteins are used as a vaccine, they will not develop immunity, the body will not react to them, so carrier particles are absolutely necessary.”

As such a carrier, researchers from Moscow State University propose to use the tobacco mosaic virus. Tobacco mosaic virus - "Wikipedia" (this, by the way, is the very first virus discovered by humans). It usually looks like a thin stick, but when heated, it takes the shape 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 very 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 viral particle. “The tobacco mosaic virus,” notes Karpova, “is an effective immunostimulant for the body. At the same time, since plant viruses cannot infect animals, including humans, we make an absolutely safe product."

The safety of various methods associated with recombinant proteins has made them the most popular - at least a dozen companies are now trying to obtain such a protein for the coronavirus. In addition, many use other carrier viruses - for example, adenoviral 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 in-line production of proteins and viruses in cell cultures.

Naked genes

The protein production step in cell culture can be shortened and accelerated by making the body's cells produce viral proteins on their own. Gene therapy vaccines work according to this principle - “naked” genetic material - viral DNA or RNA - can be inserted into human cells. DNA is usually injected into cells using electroporation, that is, along 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, cells begin to produce 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 no vaccines in the world that would work on this principle.

Nevertheless, according to the WHO, seven companies at once are trying to make a vaccine against coronavirus based on it. This is the path taken by Moderna Therapeutics, the American leader in the vaccine race. He was also chosen for themselves by three more participants in the race from Russia: the Vector Research Center in Novosibirsk (according to Rospotrebnadzor, he tests as many as six vaccine designs at the same time, and one of them is based on RNA), Biocad and the Scientific and Clinical Center for Precision and regenerative medicine price 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 the Kazan Federal University. "Gene therapy vaccines are the fastest in terms of development, 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 at the same time. As a result, 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. True, prototyping is just the tip of the iceberg, and testing with a live virus is a completely different order.”

Vicissitudes and tricks

Once vaccines are transformed from theoretical developments into research objects, obstacles and restrictions begin to grow like mushrooms. And funding is just one of the problems. According to Karpova, Moscow State University already has a sample of the vaccine, but further testing will require cooperation with other organizations. In the next step, they plan to test safety and immunogenicity, and this can be done within the walls of the university. But as soon as you need to evaluate the effectiveness of the vaccine, you will have to work with the pathogen, and this is prohibited in the educational institution.

In addition, special animals will be required. The fact is that ordinary laboratory mice do not get sick with all human viruses, and the picture of the disease can also be very different. Therefore, vaccines are often tested in ferrets. If the goal is to work with mice, then genetically modified mice are needed, which carry on their cells exactly the same receptors to which the coronavirus "clings" in the patient's body. These mice are not cheap Ace2 CONSTITUTIVE KNOCKOUT (tens or twenty thousand dollars per line). True, sometimes you can save money - buy just a few individuals and breed them in the laboratory - but this lengthens the preclinical testing stage.

The existence of the influenza virus was proven precisely in experiments on ferrets, and they still serve as a model for many viral diseases

And if we are still able to solve the problem of financing, then time remains an insurmountable difficulty. According to Rizvanov, vaccines usually take months and years to develop. “Rarely less than a year, usually more,” he says. The head of the Federal Biomedical Agency (they are developing a vaccine based on a recombinant protein) Veronika Skvortsova suggested that the FMBA of Russia will receive the first test results of prototypes of a coronavirus vaccine in June 2020, that a finished vaccine may 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 developing mRNA vaccines for a long time. And to make another one, they had enough of the decoded genome of the new virus. 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 would be a platform that allows you to quickly create a new vaccine from a template. Researchers from Moscow State University are hatching such plans.

“On the surface of our particle,” says Karpova, “we can place the proteins of several viruses and simultaneously protect against COVID-19, SARS and MERS. We even think that we can prevent such outbreaks in the future. There are 39 coronaviruses, some of them are close to human coronaviruses, and it is completely clear what it is to overcome the species barrier (“jumping” a virus from bats to humans. - Note N + 1.). But if there is a vaccine like Lego, we can put on it the protein of some virus that originated somewhere. We will do this within two months - we will replace or add these proteins. If such a vaccine had been available in December 2019, and people had been vaccinated at least in China, this would not have spread further."

The next stage is preclinical testing, that is, work with laboratory animals. It is not the longest process, but it can be won at its expense when combined with clinical trials in humans. Moderna did just that - the company limited itself to a quick safety check and went straight to human research. However, it is worth remembering that the drug she is trying is one of the safest. Since Moderna does not use viruses or recombinant proteins, there is very little chance that the volunteers will have side effects - the immune system simply has nothing to aggressively react to. The worst that can happen is that the vaccine is ineffective. But this remains 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,” Rizvanov explains. According to him, the plant can produce a million doses of such a vaccine in a matter of months. Olga Karpova gives a similar estimate: three months for a million doses.

Do you need a vaccine?

Whether it is worth cutting back on clinical trials is a moot point. First, it is a slow 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, then it is quickly eliminated, and its concentration is insufficient Avian Influenza A Virus Pandemic Preparedness and Vaccine Development to induce a serious immune response. Therefore, even a simple test of the 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 where accelerating human trials seems impractical for many.

Mortality from the disease today is estimated at a few percent, and this value is likely to be further reduced as soon as it becomes clear how many people have suffered 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 the number of diseases and deaths comparable to the infection itself. And the new coronavirus is far from being "angry" enough to, in the words of Rizvanov, "completely throw aside all security considerations." 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. “There is no need to vaccinate people during a pandemic, this is not in line with epidemic rules,” she explains.

Galina Kozhevnikova, head of the Department of Infectious Diseases of the RUDN University, agrees with her. “During an epidemic, no vaccination is recommended at all, even a routine one, which is included in the vaccination schedule. Because there is no guarantee that a person is not in the incubation period, and if a vaccine is applied at this moment, adverse events and reduced vaccination efficiency are possible,”Kozhevnikova said, answering the N + 1 question.

There are cases, she added, when an emergency vaccination is necessary for health reasons, in a situation when it comes to life and death. For example, during the anthrax outbreak in Sverdlovsk in 1979, everyone was vaccinated, thousands of people were urgently vaccinated, and in 1959 in Moscow during an outbreak of smallpox brought by Kokorekin, Alexei Alekseevich - "Wikipedia" from India by artist Alexei Kokorekin.

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

Thus, vaccine developers are always in an awkward situation. As long as there is no virus, it is almost impossible to create a vaccine. As soon as the virus appeared, it turns out that it should have been done the day before yesterday. And when it backs down, manufacturers lose their customers.

However, a vaccine must be given. This has not happened during previous outbreaks of coronavirus infections - both MERS and SARS ended too quickly, and research has lost funding. But if there have been no cases of SARS 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 could provide a strategic platform for the development of future vaccines.

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