To be vaccinated or not?
What We Know about COVID-19 vaccines
We have collected the most important questions about Russian and foreign COVID-19 vaccines and asked them to virologist Nikolai Nikitin.
Get vaccinated or just get sick?
The most obvious way to acquire immunity to a certain disease is to get over it. However, as practice shows, this is not the best strategy, since infection can lead to both serious complications and even death. Fortunately, you can do otherwise and introduce the body to the safe form of the pathogen in the form of a vaccine in advance, allowing the immune system to prepare for a meeting with a real threat.
What about COVID-19?
The purpose of the COVID-19 vaccine is to demonstrate to the body the S–protein of the coronavirus, which attaches to a special receptor on the cell surface and due to which the virus usually enters it. Studies show that it is in response to it that antibodies are produced that can bind to a viral particle (virion) and neutralize it. At the same time, the S-protein itself is not dangerous and does not lead to infection. After the introduction of the S-protein, an immune response is gradually formed in a person, thanks to which he is less likely to get infected with coronavirus in the future or will suffer the disease more easily.
SARS-CoV-2 consists of four proteins – S-protein (spike), N-protein (nucleocapsid protein), M-protein (membrane protein) and E-protein (shell protein) – and the genome of the virus, which is an RNA molecule. The virus enters the cell due to spike spikes (from the English spike – spike), which attach to targets on the cell surface – angiotensin converting enzyme 2 (APF2, English ACE2). APF2 is expressed in most tissues, including brain, lung, heart, and kidney tissues. That is why these organs may be vulnerable to infection.
In fact, antibodies are produced in response not only to the S-protein, but also to other coronavirus proteins, in particular the N-protein. However, they are not virus neutralizing, that is, they cannot protect against the disease.
Why are there several types of antibodies?
The body reacts to infection by producing antibodies of several types: immunoglobulins of classes M (IgM) and A (IgA) and immunoglobulins of class G (IgG). The first two types accompany the onset of infection and reach a maximum in the acute period of the disease. IgG appear later, after 3-4 weeks, and mean that the disease is coming to an end or has already ended. The development of immunity to the virus is associated with IgG.
What are the coronavirus vaccines?
There are several ways to deliver S-protein to the body. The traditional method is to inject a very weakened or attenuated virus into a person's blood. Vaccines of this type have been used since the middle of the last century, but the process of their creation may take more than one year. This is due to the fact that the "living" virion is unpredictable: it may at some point become active again and learn to cause the disease again. Therefore, before introducing a weakened virus into the patient's blood, scientists should make sure that it does not pose a danger, and for this you need to conduct a lot of thorough research. Today, similar coronavirus vaccines are being developed, as they allow for the formation of persistent immunity (in particular, an American company is currently engaged in the creation of a drug based on a weakened virus Codagenix), but all of them are still in the initial stages of research.
However, the virus can be "killed" – inactivated. To do this, it is treated with high temperature, ultrasound, radiation, formaldehyde or beta-propiolactone – the latter method, for example, was used at the Chumakov Center when creating the KoviVak vaccine. As a result, viral particles are chemically inactivated, that is, they lose the ability to cause infection, but S-proteins remain on their surface and can stimulate the formation of the necessary antibodies. Sinovac Biotech Sinopharm and China have developed vaccines using this technology in addition to Russia, and in India (Bharat Biotech company). They are currently approved for use in a number of countries.
Another classic technology is subunit vaccines, which use not an entire viral particle, but S–protein or its fragments. To do this, researchers first identify the necessary areas of the spike, and then using genetic engineering technologies synthesize them to create the necessary "training material" for the immune system. The Novosibirsk Vector Center, which developed the EpiVacCorona vaccine, followed this path. It consists of several small fragments of S-protein associated with a carrier protein, which is the N-protein of the same coronavirus. To increase the effectiveness, aluminum hydroxide was added to the drug, an adjuvant that helps strengthen the immune response.
Nevertheless, today there are more modern methods of creating vaccines, which began to appear about 30 years ago, but have become widespread only today. They work on the basis of nucleic acids (DNA and RNA).
The first technology – RNA vaccines – uses matrix RNA (mRNA). This molecule is actually a "template" – an instruction for creating the coronavirus S-protein. Clad in a special lipid envelope that allows it to merge with the membrane of the target cell, the mRNA penetrates inside. The cell, considering the ribonucleic acid molecule to be its own, reads the "template" and begins to synthesize the S-protein needed by the virus and us in this case, to which antibodies are then produced. Due to the fact that mRNA vaccines do not contain the virus at all, the risk of getting sick due to such a vaccination is zero. At the same time, according to the idea of the creators, they should provide the same good protection as "live" viral vaccines.
DNA vaccines are also being researched today. They work on a similar principle to RNA vaccines, but to trigger an immune response, viral DNA must penetrate not just into the cell (into its cytoplasm), but into its nucleus. There, a cellular enzyme (RNA polymerase) synthesizes mRNA using this DNA as a matrix (this process is called transcription). Thus, the difference between DNA and RNA vaccines is that in the case of a DNA vaccine, an additional step is required related to the formation of mRNA in the cell.
The only problem with vaccines using genetic material is that before the pandemic, none of them went through all the stages of the approval process for administration to patients, although some DNA vaccines, including for certain types of cancer, were tested on humans. The most famous mRNA-based vaccine today belongs to Pfizer and BioNTech, and the company is also engaged in research in this area Moderna. The DNA vaccine is being developed by Inovio Pharmaceuticals, the Indian company Zydus Cadila, the Japanese biotechnology company AnGes and others.
Finally, another approach, the formal leader among COVID-19 vaccines, is based on the use of a viral vector. Here, the gene (DNA sequence) of the SARS-CoV-2 S-protein is delivered to the body with the help of another, more harmless virus – adenovirus. It attaches to the cell, but since the genetic material in it is changed, instead of adenoviral copies, S-protein begins to be synthesized, to which an immune response then arises. There is no danger that the virus will mutate. The first vaccines against coronavirus infection appeared thanks to this technology. Today, CanSino, a Chinese company, Johnson & Johnson, an American AstraZeneca, and the Anglo-Swedish company, produce similar vaccines in addition to Gamalea, who created Sputnik V (or Gamalea-COVID-Vac).
How did you manage to shorten the time of vaccine development?
Traditionally, drugs go through five stages of development. First, scientists conduct preclinical tests, during which they perform a basic study of the virus, create a prototype of the vaccine and test its safety and effectiveness on laboratory animals. Then they move on to the most important stage – clinical trials on humans. Before mass administration of the vaccine to volunteers, they check whether the drug is not toxic on one or two dozen healthy people (phase I trials). If everything is fine, after the toxicity assessment, biologists proceed to check the effectiveness already on a hundred volunteers (phase II). And finally, at the final stage of clinical trials, the drug is being tested on tens of thousands of people (phase III). There is another one – phase IV. It is called post-registration, because in the case of successful phase III trials, the vaccine receives a license and begins to be used everywhere.
Previously, on average, 10-15 years passed from the creation of a vaccine in the laboratory to market entry, but COVID-19 vaccines were developed in less than six months. How did it happen?
There are several ways to reduce the development time. For example, you can immediately start a human study without waiting or without conducting preclinical tests at all. This is what happened with the Moderna RNA vaccine. This was justified, since their technology has been tested more than once on other mRNA vaccines (against influenza and respiratory syncytial virus), which have shown complete safety and effectiveness.
However, the main approach to accelerate vaccine research is to combine the phases of clinical trials, that is, parallel implementation of the first (I/II) and last (III/IV) stages. Many companies took advantage of this opportunity, including the Gamalea Center, the Novosibirsk Virological center "Vector" and the Chumakov Center. The first two stages study the safety of the new vaccine, while the third and fourth are already testing its effectiveness.
It is worth noting that coronavirus infection is not something unique. The sequence of its genome is known, it is known for which protein antibodies are produced. Therefore, scientists used long-established approaches and as a result were able to create a new vaccine in just weeks. The Gamalei Center used as a basis an existing vaccine against another severe coronavirus infection MERS, which caused an epidemic in 2012, while the Chumakov Center has been specializing in inactivated vaccines for many decades.
What vaccines are currently available in Russia?
A total of 78 vaccines are currently being tested on volunteers as part of clinical trials in the world (as of the end of March 2021), and 23 of them have reached the final stage. In addition, at least 77 vaccines are being actively tested on animals.
Three vaccines are now officially registered in Russia: Sputnik V (vector), EpiVacCorona (subunit) and KoviVak (inactivated). The latter, as it became known quite recently, will also soon enter civil circulation.
Foreign vaccines – will they come to the domestic market?
Moderna Pfizer–BioNTech CanSino Johnson & Johnson and AstraZeneca Sinopharm and Moderna based on the inactivated virus are among the foreign vaccines that have received registration. Sinopharm and Moderna are based on mRNA; Oxford-AstraZeneca, CanSino and Johnson & Johnson based on the adenovirus vector. Sinopharm and Sinovac based on the inactivated virus.
A foreign vaccine can enter the Russian market only after it passes local "simplified" clinical trials. Usually this procedure takes from six months to a year. Then the documents are submitted to The Ministry of Health of Russia, which, after consideration, can give permission for the use of the vaccine. If it is received, the drug will most likely be sold in private clinics, since foreign vaccines are not covered by mandatory medical insurance.
In reality, there are several more serious obstacles. The main one is the limited production capacity. Now there are not enough vaccines from companies such as Pfizer, even for the population of the countries in which they were developed, so there is no need to talk about exports. In addition, many countries have applied for the purchase of vaccines and are already in line for their delivery. Russia has not expressed such interest – for obvious reasons. Therefore, it is unlikely that European or American vaccines will appear on the domestic market in the near future.
But in Russia may receive the Chinese adenovirus vaccine CanSino, which is planned to be produced under the brand name "Convidezia". Clinical trials of the drug conducted by Petrovax have demonstrated its safety and high efficacy. Now the vaccine is awaiting registration by the Ministry of Health. However, most likely, it will be poorly represented on the domestic market, at least it will not be free. The main focus is planned to be on exports to the CIS countries, since Petrovax has exclusive rights to supply.
How effective are the new coronavirus vaccines?
The effectiveness of the vaccine is evaluated in a double-blind study. One group of volunteers receives a vaccine, and the other receives a placebo, that is, a saline solution that is very similar to the vaccine in all its external characteristics. Patients do not know which of them is in the control group, and doctors who participate in clinical trials are not informed of this information either. After some time, researchers compare the number of coronavirus cases in two groups and determine how effective the drug is based on the difference.
It is important to pay attention to the fact that the percentage of effectiveness calculated in clinical trials was obtained in a fairly short period. It will approach the real value during mass vaccination, when there will be available data on patients after vaccination. At the moment, most information is available about the results of studies of the Sputnik V vaccine. In February 2021, the Lancet medical journal published an article with the results of phase III clinical trials of this vaccine, where the effectiveness of more than 90% was demonstrated on 20 thousand volunteers. In other words, out of a hundred people after vaccination, only ten can potentially become infected and get sick.
At the end of March 2021, the results of clinical trials of the EpiVacCorona vaccine were published. The results of the studies demonstrated low reactogenicity (the ability to cause an organism's reaction to the vaccine), immunogenicity (the ability to cause an immune response) and the safety of the vaccine. Initially, the figure of "immunological effectiveness" of 100% was called for the EpiVacCorona vaccine. However, it is worth mentioning that here we mean the ability of the vaccine to stimulate the formation of antibodies to its components, and not the ability to protect against future infection (the presence of antibodies does not mean protection from infection, since, as mentioned above, not all of them neutralize the virus). As for the KoviVak vaccine, the third (the largest in terms of the number of volunteers) phase of clinical trials is currently starting, so it's too early to talk about its effectiveness.
Side effects – how are they detected (and have they been detected in new vaccines)?
Side effects are recorded during clinical trials. At the first stage, doctors monitor the health of volunteers around the clock and detect the presence of adverse reactions immediately. If the vaccine is safe, then further monitoring takes place in a simplified mode. After vaccination, the subjects install an application on their mobile phone, where they report on their health status every day, and also periodically donate blood. If the analysis is bad or there are some complications, the person comes to the hospital, where he is additionally examined. In different organizations, the procedure may vary slightly, but the general mechanics are about the same.
Side effects of COVID-19 vaccines are usually mild or moderate. These include headache, muscle aches, lethargy, fever, chills, diarrhea and pain at the injection site. The frequency depends on the specific drug. For example, for "Sputnik V" the most popular symptoms turned out to be similar to those that appear after a flu shot. However, in general, these reactions are characteristic of many vaccines, since a foreign substance is introduced into the body, which causes a natural response.
Does the vaccine save from transmission of the virus to an unvaccinated person?
Hypothetically, a vaccinated person can transmit the virus to another, but such a scenario is unlikely, since this usually happens with a large viral load, that is, with a large number of viral particles in the body. If a strain of coronavirus gets into the body, from which the vaccination is made, the immune system will quickly deal with the pathogen and will not allow it to multiply significantly. However, it may happen that the patient becomes infected with coronavirus in the interval between the first and second dose of the drug or before acquiring full immune protection (or he simply did not develop enough antibodies for some reason). Then the transmission of the virus is quite likely. However, this requires suitable conditions, namely close contact.
Is it possible to get sick with a new strain if there is already a vaccine against the old one?
Unfortunately, there is accumulating evidence that the immunity that a person receives after a disease or vaccination may not protect against the disease with new COVID-19 strains. Moreover, there are statistics on seasonal coronaviruses, which suggests that immunity from even one strain does not always protect against it, and after six months you can easily get sick again. And since SARS-CoV-2 belongs to the same family, the prognosis is disappointing.
What can this lead to? To the fact that it will be necessary to create new vaccines. Moreover, it is not very clear how often this will have to be done. On the other hand, this will no longer be a big problem, and clinical trials will not be required. Researchers will simply replace the S-protein sequence with a mutant one – a vaccine against new flu strains is being manufactured in a similar way today. This significantly reduces time costs. The only difficulty that may have to be faced is a sufficient amount of production capacity for the potential production of a seasonal vaccine.
About the author: Nikolay Nikitin – Doctor of Biological Sciences, Head of the Department of Virology, Faculty of Biology, Lomonosov Moscow State University.
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