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The whole world is looking forward to the end of the “non-working days”, the period of “social distancing” or “lockdown” - depending on how antiviral measures are called in a particular country. However, Mark Lipsitch, a professor at the Department of Epidemiology at Harvard University, warns that the spread of the disease will not stop until there are enough people in the population vulnerable to coronavirus. Simply put, the epidemic will not stop until most of us get sick—or until a coronavirus vaccine becomes available. But why is there still no vaccine? Let's figure it out.
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As of April 30, 2021, World Health Organization (WHO) staff are aware of 102 anti-coronavirus vaccine candidates, with eight vaccines already undergoing clinical trials on healthy people. However, the real number of vaccine candidates may be higher: not all companies that are trying to create a “magic pill” against COVID-19 are on the WHO list.
The principle of action of already existing and still being developed vaccines is based on several ways to induce an immune response in the body, and each method has its own advantages and disadvantages. It's impossible to predict which type of vaccine will work best before human clinical trials begin, so drug companies are forced to fly almost blindly, trying different methods. But maybe this is for the best: if one type of vaccine turns out to be ineffective or unsafe, there is always a chance that another type of vaccine will work better.
Chapter 1
Viral vaccines
Vaccines based on weakened virus
What is this? A vaccine that contains the SARS-CoV-2 virus, which has been very weakened (in other words, attenuated) in the laboratory. This type of vaccine has been known since the 1950s: the principle behind the measles, mumps, rubella (MMR) and chickenpox vaccines.
What is the mechanism of action? To create a vaccine, laboratory workers use a virus that is successively infected in laboratory animals. The fact is that viruses adapt to the host in whose body they find themselves. If you forcibly “relocate” a human virus into an animal cell culture, the virus will begin to mutate. Thus, after each cycle of infection, the virus will adapt better to the new host - and at the same time become less and less dangerous to humans. At the same time, the mutated “animal” virus still remains sufficiently similar to the original “human” one to cause a full-fledged immune response in the vaccinated person. If a vaccinated person becomes infected with the original “wild” virus, his immune system will already be ready to meet and quickly cope with the disease.
What's good about this vaccine? Immunity from this vaccine lasts the longest. In the case of COVID-19, this is especially important, because strong immunity to coronavirus infections is not always formed.
What's the problem with the vaccine? We know very little about how viruses mutate, so the process of creating a live vaccine is largely unpredictable. There is always a chance that a weakened virus will “regain its strength” and “learn” to cause disease again. To prevent this from happening, we have to very carefully study viruses and organize scrupulous clinical trials of the resulting vaccine, which will take several years. If a “live” vaccine can be created, it will have many advantages - but such a drug will not appear any time soon.
Who is working on the vaccine and at what stage is it? The American company Codagenix (developed jointly with the Indian Serum Institute) announced the start of development of a vaccine based on a weakened virus on February 13, 2021. According to WHO, as of April 30, 2021, the vaccine is in the preclinical testing phase - that is, it either has not yet been created or is being tested on laboratory animals.
How are medications tested?
- I was offered to participate in clinical trials. Is it worth agreeing to this?
Inactivated vaccines
What is this? A vaccine that contains inactivated viruses, that is, not capable of infecting cells. This is also an old and proven type of vaccine: the principle underlies vaccinations against polio and whooping cough.
What is the mechanism of action? To create a vaccine, viruses are inactivated - heated, treated with ionizing radiation or disinfectants. Although the proteins of “killed” viruses change shape (that is, denature), their chemical composition remains the same - and the viral particles themselves partially retain their original shape. Dead viruses can also trigger an immune response.
True, such vaccines have two drawbacks. Firstly, such vaccines usually cause too weak an immune response, so substances called “immune response enhancers” - adjuvants - have to be used. The purpose of adjuvants is to help immune cells (B lymphocytes) produce more protective antibody proteins.
Most vaccines use aluminum salts as a universal adjuvant, but vaccines containing aluminum do not help prevent viral infection. Through trial and error, scientists have become convinced that antiviral vaccines can enhance virosome adjuvants. These are “stuffed viruses” in the form of lipid nanoparticles - microscopic droplets of phospholipid fats, onto the surface of which a viral antigen protein is “attached”. Immune cells mistake the dummies for real viruses and react to them more vigorously than to just viral antigen proteins.
Secondly, the “educational material” for the immune system eventually runs out, so the resulting immunity is not as durable as in the case of vaccines based on a weakened virus that can multiply in the body for some time. To maintain immunity, you have to resort to repeated vaccinations.
What's good about this vaccine? Inactivated vaccines are safer than “live” ones - because they do not contain a weakened virus that can mutate.
What's the problem with the vaccine? Most likely, an inactivated SARS-CoV-2 vaccine will cause a weak immune response. For it to work well, it will have to select an effective adjuvant - that is, look for the optimal parameters of the phospholipid virosome droplet. This will require additional time and effort.
Who is working on the vaccine and at what stage is it? According to WHO, as of April 30, 2021, two Chinese developers have achieved the greatest success in creating an inactivated vaccine. Sinopharm is preparing two vaccines at once. The drug, created in collaboration with the Wuhan Institute of Biological Products, is in the first phase of clinical trials - the tolerability of the vaccine is tested on healthy people. The drug, created jointly with the Beijing Institute of Biological Products, is at the very beginning of development - at the stage of regulatory approval.
The most information about the inactivated vaccine is from Sinovac, which is also in the first phase of clinical trials. This company cooperates with the American company Dynavax, which transferred to Sinovac an effective adjuvant that has shown itself well in the hepatitis B vaccine - so it is not surprising that the Chinese developer has taken the lead, because it saves him a lot of time.
On April 19, Sinovac published a preprint - a preliminary version of an article in which they showed that their vaccine works: it stimulates the formation of antibodies against 10 strains of SARS-CoV-2 in mice, rats and rhesus macaques. Although it’s still too early to rejoice - we don’t yet know how the vaccine will perform in humans.
Chapter 2
What are the advantages of inactivated vaccine
NUR-SULTAN.
KAZINFORM — As you know, today in Kazakhstan the Russian vaccine “Sputnik V” is widely used - a combined vector vaccine for the prevention of the new coronavirus infection COVID-19. As for our domestic vaccine, scientists note that the QazVac inactivated vaccine is developed based on reliable and time-tested vaccine manufacturing technology. Related news
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In this regard, in order to understand what advantages vector and inactivated vaccines have, a Kazinform correspondent talked with an expert in evidence-based medicine, associate professor of the Department of Epidemiology, Biostatistics and Evidence-Based Medicine at the Kazakhstan Medical University VSHO Rafail Kipshakbaev.
— Good afternoon, Rafail Kopbosynovich! Please tell us what the vaccination campaign guarantees us?
— In epidemiology there is such a concept as “herd immunity.” What it is? This is when more than 60% of the population has either recovered from the disease or been vaccinated. Therefore, when we reach this figure, naturally, we would not want to achieve the figures at the expense of those who have recovered from the disease; accordingly, we can talk about victory over the pandemic. That is, the coronavirus infection will not spread so quickly, we will be able to take a break from lockdowns and restrictions. I would like to point out right away that a vaccine is not a guarantee that a person will not get sick. The vaccine in this case guarantees that the disease will be either asymptomatic or milder. Vaccination is necessary for the population to develop collective immunity. According to the law of epidemiology, it is necessary to vaccinate 60% or more of the population in order to obtain an immune layer. Herd immunity will be formed at these numbers.
— A person is given two doses of the vaccine. Why is it necessary to gradually introduce two doses of vaccines?
— “Sputnik V”, which we are talking about now, is a vector vaccine. What does it mean. The coronavirus spike protein is inserted into an adenovirus that is known to the body, then this construct, called a vector, is introduced. Two doses are administered so that all available strains reach the cell and an immune response is generated accordingly. That is, this is achieved with two doses of the vaccine.
— Do I need to follow certain measures after the first dose of the vaccine?
— After administering the first dose of the vaccine, there is a chance of becoming infected. Just a couple of weeks ago there was a lot of noise. One of the doctors in Almaty fell ill with coronavirus after administering the first dose of the vaccine. There was a lot of hype on the Internet about how vaccines don’t save people and so on. Here I can say that a colleague forgot or did not know the basics of immunology. Immunity and protection will only develop after the second dose is administered by the third week thereafter. That is, the second dose was administered, and only after three weeks can we talk about formed immunity. Until this moment, after the administration of the first dose, immediately after the second dose, a vaccinated person is no different from an unvaccinated person. Therefore, when people, having administered the first dose, immediately take off their masks and begin to violate sanitary rules, this leads to the fact that a person can get sick. For three weeks you need to do everything you did before vaccination: use antiseptics, maintain social distance, wear a mask.
— When can you take off your mask?
“The fact is that until 60% of our population has been vaccinated, until collective immunity has been formed, it’s difficult to talk about it. You can take off your mask three weeks after your second dose of the vaccine, but does that make sense? Why put yourself at risk: even if you get a mild form of infection.
— Can you remind us about the contraindications and which categories of people do not need to receive the vaccine?
— The main contraindication is intolerance to certain components of the vaccine. The second is pregnancy and lactation. The third is a severe autoimmune disease. That is, cases when the immune system itself produces antibodies against its own body, in this case the issue of vaccination is decided on an individual basis.
— What can you say about the effectiveness of vaccines?
— Regarding efficiency, I would start talking a little later. Now it is fundamentally important to understand: we know that antibodies after coronavirus in the body last about 6-8 months. Now, after the start of vaccination, it is interesting to understand: if antibodies last 6-8 months, this is good, if more, excellent, if less, the meaning of this vaccine is lost. Therefore, we can talk about effectiveness six months later by measuring the level of antibodies in vaccinated people.
— What are the advantages of an inactivated vaccine?
— The Kazakhstani vaccine QazVac is inactivated. What is an inactivated vaccine? A virus is taken, it is killed in one way or another, a vaccine is prepared from the dead virus and accordingly injected into the body. The advantage is that this is the oldest method. Accordingly, it has been studied in the best way. Its side effect is predictable and also studied. That is, this is the method on the basis of which the vaccines that are given to us according to the vaccination calendar are made. This is a good old classic. We can talk about disadvantages or advantages when we see clinical results. An old method does not mean that it is worse than others.
— How can people overcome their fear of getting the vaccine? What is this connected with?
— I think this is due to the active activities of “anti-vaccinationists” who convey their information in modern ways. On the other hand, there is the absence or shortage of official verified information. I try to convey objective, verified information. On Instagram, I have tens, hundreds of times fewer followers than those who propagate that the vaccine means microchipping and so on. This is the nature of man. Coronavirus is a fairly new infection. We see a lot of deaths and infections. Little objective information. And when there is little information, a person begins to think, and this goes towards fairy tales about chips, 5G towers, about the fact that we will be controlled, and so on. These are beautiful science fiction stories that are more fun to read than the scientific data on immunology.
Even though I told you that there is not much data, primary data shows that there are not many serious complications. The vaccine is generally well tolerated. Those who have received the vaccine are living well. Taking this opportunity, I would like to appeal to the population: there is no need to be afraid of vaccination, which has long been proven, the vaccine is a reliable method of prevention.
- Thank you for the interview!
It should be noted that Dr. Rafail Kipshakbaev on his professional Instagram page @drrafhuan answers people’s questions absolutely free of charge and advises on issues of COVID-19 and medicine in general. “This is my personal contribution to the fight against the epidemic,” notes the evidence-based medicine expert.
Vector vaccines
What is this? Vaccines are based on completely different viruses (for example, adenoviruses), into which a small gene is embedded - a section of the SARS-CoV-2 genome. As a result, SARS-CoV-2 antigen proteins appear in the shells of harmless viruses (they are called “vectors,” that is, transport for delivery into cells).
What is the mechanism of action? Once in the body along with the vaccine, genetically modified auxiliary viruses provoke an immune response to SARS-CoV-2 proteins - that is, they work approximately like “live” viral vaccines.
Theoretically, it is possible to try to create two types of vector vaccines - based on viral particles that are capable of and those that are not capable of reproducing in the body. Most likely, vaccines based on viral particles that can reproduce inside the cells of the host body will protect against coronavirus longer. However, only vaccines with viruses that are not capable of reproducing have reached the stage of clinical trials on humans.
What's good about this vaccine? According to the developers' plan, vector vaccines should work as well as live ones, but at the same time they will not be able to mutate.
What's the problem with the vaccine? Vector vaccines based on attenuated genetically modified adenoviruses have not been sufficiently studied. Attempts have been made to develop vector vaccines to combat cancer, HIV, influenza and Ebola viruses, but none have yet been approved for use in humans.
Who is working on the vaccine and at what stage is it? According to WHO, as of April 30, 2021, two strong players are involved in vector viral vaccines.
The Chinese company CanSino Bio, together with the Beijing Institute of Biotechnology, is developing the Ad5-nCoV vaccine, based on a modified type 5 adenovirus. The vaccine is in the second phase of clinical trials - that is, testing of the vaccine on real patients has already begun. At the moment, CanSino Bio is the leader in the “vaccine race” - but this does not mean anything yet, because the global medical community has not yet seen the results of the first phase of trials. It is possible that there are a number of unreported problems with the vaccine.
The second strong player is the English University of Oxford, which is developing a vector vaccine based on a modified chimpanzee adenovirus ChAdOx1. The vaccine is in phases 1-2 of clinical trials - that is, it is also already being tested on real patients. Nothing much is known about ChAdOx1 yet. But another Oxford product based on the same principle—a vaccine against MERS-CoV, a “cousin” of the SARS-CoV-2 virus—appears to work and has had no safety problems.
Chapter 3
Inactivated vaccines
These are the most complex biological products in composition.
To obtain them, epizootic virulent viruses are usually used. They are subjected to gentle treatment (inactivation), which leads to an irreversible loss of the ability of the virus to multiply (reproduce), but its antigenic and immunogenic properties are preserved. Therefore, in an inactivated vaccine, the viral genome (nucleic acid) must be “killed” and the proteins, glycoproteins, and polysaccharides of the virus must not undergo changes, since the immune response is caused mainly by substances on the surface of the virus capsid. As a result, the virus loses its ability to reproduce and infect, but retains the ability to stimulate specific immune factors in animals.
The production of inactivated vaccines also begins with the selection of a production strain of the virus (taking into account its basic biological properties), cultivation and accumulation of the production strain of the virus in a sensitive biological system (animals, bird embryos, cell culture). Then the virus-containing material is purified and concentrated by various methods (low-speed centrifugation, filtration, ultracentrifugation, etc.). Purification and concentration of viral agents is an important step, since the “killed virus” does not multiply in the body, and in order to obtain a sufficiently intense immune response, a significant amount of viral material must be administered. Virus suspensions must be cleared of ballast substances (fragments of cellular structures, non-viral proteins, lipids, etc.), which put an additional burden on the body’s immune system and significantly reduce the specificity and intensity of immune reactions. The virus-containing suspension obtained after purification and concentration is subjected to inactivation. In the case of particularly dangerous viruses, inactivation precedes the purification process. It must be borne in mind that ballast substances interfere with the inactivation process.
An important condition for the effectiveness of vaccines is the choice of inactivator and optimal inactivation conditions, which make it possible to completely deprive the virus of infectivity while maximizing the preservation of antigenicity. However, the mechanism of inactivating effects has not been sufficiently studied and their use is often empirical.
Physical and chemical methods are used to inactivate viruses. Of the physical methods, the most common are γ-rays, UV rays, exposure to temperature, less often ultrasound, photodynamic exposure to certain dyes (methylene blue, acridine orange, toluidine, etc.). The most vulnerable targets for γ-rays are purine and pyrimidine bases. The protein shell is slightly damaged under the influence of radiation. This method makes it possible to simultaneously reliably inactivate and sterilize the finished drug.
The effectiveness of UV rays is determined by their permeability and adsorption by biological molecules. Proteins absorb UV rays to a lesser extent than nucleic acids and are therefore more resistant to their action. It is believed that under the influence of UV rays, dimers are formed in the nucleic acid between adjacent pyramidin bases, as well as covalent bonds between the nucleic acid and the protein shell.
In the practice of creating inactivated vaccines, the most widely used chemical inactivators are formaldehyde (the addition of formaldehyde to the amino groups of purines and pyrimidines destroys the matrix and information activity of nucleic acids), β-propiolactone, ethylenimines, hydroxylamine (the inactivating effect is determined by its interaction with the pyrimidine bases of the nucleic acid). acids, depending on the pH value) etc. The reagents that are used to inactivate viruses are mutagens, so the inactivator must either undergo self-decomposition (β-propiolactone, hydroxylamine), or be converted into an inactive form (neutralized), and the neutralization products must remain safe.
After inactivation, avirulence monitoring is carried out, aimed at identifying the remaining viable virions. The degree of safety of inactivated vaccines is inextricably linked to the sensitivity of the test system, which evaluates the completeness of virus inactivation. For this purpose, sensitive cultures of animal cells, including bird embryos, are used. In this case, there should be no reproduction of the virus.
An individual approach is determined by the properties of the virus, the characteristics of the disease, and the sensitivity of biological systems. Thus, the avirulence of vaccines against foot and mouth disease is determined in cattle (this is more reliable), in pigs, laboratory animals and cell culture; rabies vaccine - on white mice; vaccine against Aujeszky's disease - in rabbits or in cell culture, which was used to accumulate the virus; vaccine against Newcastle disease - on chicken embryos (at least three blind passages). If the production strain of the virus that is used to obtain the vaccine is cultivated in cell culture and causes characteristic cytopathic changes, then the generally accepted method is to test inactivated drugs in sensitive cell cultures (at least three blind passages). However, some vaccines use complex, multi-pronged approaches to assess the safety.
To increase the immunogenic activity of the vaccine, adjuvants are introduced into its composition - substances of various chemical natures that nonspecifically stimulate the immune response to various antigens. The following are used as adjuvants: aluminum hydroxide, aerosil, mineral oils, DEAE-dextran, saponin; in addition, synthesized substances are used - muramyl dipeptide, polyanions, polycations, etc. The mechanisms of action of adjuvants are varied and not fully understood. Some of them cause an inflammatory response, others promote the deposition of antigens and slow down their hydrolysis, and others enhance the uptake of antigens by macrophages and antigen-presenting cells.
The following requirements are imposed on adjuvants: they must be non-toxic in the doses used, not cause adverse reactions in the body, do not themselves have antigenic activity, and must stimulate the development of long-term humoral and cellular immunity.
After adding the adjuvant, the vaccine is controlled for the absence of foreign contaminants (bacteria, fungi) by inoculating on nutrient media (MPA, MPB, MPPB, Sabouraud or Chapek). There should be no growth of microorganisms. The vaccine is then packaged into vials and labeled. The final control of the vaccine for the main indicators: avirulence, sterility, harmlessness, acceptable degree of reactogenicity (on susceptible animals), antigenic and immunogenic activity (on laboratory and susceptible animals) is carried out by state inspectors in accordance with the technical specifications for this drug.
Inactivated vaccines are more stable and safer. They are used for animals of any age and in reproductive herds. Such vaccines are used mainly for preventive purposes in safe farms and threatened areas. However, these vaccines have some disadvantages:
- the technology for their production is much more complex, which is associated with the need to obtain a large amount of virus-containing material, purification, concentration of the antigen, inactivation of the viral genome and the inclusion of adjuvants in the vaccine;
- it is necessary to vaccinate repeatedly and in significant doses;
- they induce less intense and long-lasting immunity than when using live vaccines;
- they can only be used parenterally;
- they stimulate the T-system of immunity and the local immune response less strongly, therefore the resistance of the mucous membranes of the upper respiratory tract and digestive tract is less pronounced than after the use of live vaccines;
- can sometimes cause an allergic condition after repeated vaccination.
The production technology of inactivated vaccines is more complex than live vaccines and consists of the following steps:
- selection of production strain;
- cultivating the virus in a biological system;
- determination of virus (antigen) concentration;
- inactivation, purification and concentration of viral material;
- adding an adjuvant;
- in-shop control;
- packaging, labeling;
- final control for sterility, avirulence, harmlessness, reactogenicity, antigenic and immunogenic activity.
In addition to traditional whole-virion vaccines (live, inactivated), methods for creating new generations of vaccines have been developed: subunit, synthetic, and obtained by genetic engineering. The improvement of vaccines went in the direction of reducing the number of ballast components, reducing reactogenicity and increasing the immunogenicity of the drug.
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Nucleic acid vaccines
DNA vaccines
What is this? A vaccine that contains a circular DNA molecule (plasmid) that contains the “instructions” for creating a viral protein.
What is the mechanism of action? Once in the cells of the grafted person, the circular DNA will become part of their genome. As a result, the cells of the host body will receive new instructions, according to which they will begin to “stamp” viral proteins-antigens - and an immune response will be formed to them.
To ensure that a piece of DNA with information about viral proteins penetrates cells, it can be inserted into the genome of a harmless carrier virus. This virus works like an “intracellular syringe” - it throws its modified genome into the cell, which is then integrated into the nucleus (unlike vector vaccines, here only the shell is used from a harmless virus).
What's good about this vaccine? The advantages are the same as those of vector vaccines: immunity is as durable as that of “live” viral vaccines, but without their inherent disadvantages. Since SARS-CoV-2 is not taken as the “carrier virus” for the plasmid, there is no danger that the weakened virus will mutate and cause the disease again.
What's the problem with the vaccine? DNA vaccines are poorly studied. So far, only one vaccine of this type is used - the Zika virus vaccine for horses. No DNA vaccine has yet been approved for use in humans.
Who is working on the vaccine and at what stage is it? According to WHO, as of April 30, 2021, Inovio Pharmaceuticals (Pennsylvania, USA) is creating a DNA vaccine INO-4800 - only based on DNA plasmids, without modified carrier viruses. INO-4800 is a so-called electroporation DNA vaccine. To “drive” the plasmid into muscle or skin cells, they will need to be exposed to an electric field, which will temporarily make the cell membranes more permeable. To make such a vaccination, a simple syringe will not be enough - you will need a special electroporator device. This vaccine is in phase 1 clinical trials, with trial results expected in June.
RNA vaccines
What is this? A vaccine that contains a viral molecule similar in structure to DNA - messenger RNA (mRNA). This molecule is a “template” from which the viral protein is directly read. mRNA is not integrated into the cellular genome.
What is the mechanism of action? The mRNA enclosed in a lipid nanoparticle enters the body along with the vaccine. Then the lipid particle will merge with the membrane of the target cell, and its contents will enter the cell and turn into a “template” for the synthesis of viral antigen proteins. As a result, the body’s own cells will begin to synthesize viral proteins, although the viral DNA will not be integrated into the cellular genome.
What's good about this vaccine? In addition to the benefits they share with DNA vaccines, the lipid particles with the mRNA inside are virus-like, so they can trigger an immune response on their own. There is a chance that due to the “double action”, immunity from RNA vaccines will occur earlier and last longer. In addition, short mRNA is a very simple molecule, so it can be created relatively quickly and inexpensively using special synthesizers.
What's the problem with the vaccine? This is a completely new vaccine - so we have no idea how it will behave in the human body. In principle, older vaccines of this type do not exist.
Who is working on the vaccine and at what stage is it? According to WHO, as of April 30, 2021, two companies were the furthest along in creating RNA vaccines. The American company BioNTech has signed a contract with the pharmaceutical giant Pfizer. However, other than the fact that the company received permission to begin phase 1-2 clinical trials in Germany, little is known about the vaccine. However, representatives reported that their vaccine could be ready by the fall of 2021.
More information about the vaccine from the American company Moderna, which is collaborating with the National Vaccine Research Center (NIAID). The vaccine is called mRNA-1273. The first phase of trials recently ended, which involved three vaccine options with mRNA concentrations of 25, 100 and 250 micrograms. The company has now submitted an application for a second phase of testing, which will involve the vaccine in dosages of 50 and 250 micrograms - perhaps these are the dosages that have proven to be the most effective.
In addition, in mid-March the Russian biotechnology company BIOCAD announced the start of development of an RNA vaccine. Three vaccine options with different mRNA dosages will be developed. The first animal trials were planned to begin at the end of April.
Chapter 4
Sinopharm inactivated vaccines protect against severe COVID-19
In JAMA
Interim results of phase 3 clinical trials of two inactivated vaccines against COVID-19 developed by the Chinese company Sinopharm have been published.
The vaccines are codenamed WIV04 and HB02. WIV04 is developed based on the SARS-CoV-2 strain WIV04 isolated from a patient at Jinyintan Hospital in Wuhan. To create HB02, the 19nCoV-CDC-Tan-HB02 strain was used. Both strains were propagated in Vero cells, inactivated by beta-propiolactone, and produced in a liquid formula including aluminum hydroxide as an adjuvant.
Clinical trials took place in the United Arab Emirates, Bahrain, Egypt and Jordan. They involved a total of 40,411 volunteers at least 18 years of age with no history of SARS-CoV, SARS-CoV-2, or MERS-CoV infection. Participants were randomly assigned to WIV04 (13,470 people, 5 μg per dose), HB02 (13,470 people, 4 μg per dose), or adjuvant-only control (13,471 people). Two doses of the vaccine were administered intramuscularly at an interval of 21 days. 38,206 participants completed the scheme. They will be monitored for at least one year. (Observation time starts 14 days after the second injection.) Based on the observation results, an analysis of the effectiveness of vaccines was carried out.
Testing began on July 16, 2021. On December 20, the median follow-up time was 77 days. At this time point, there were 255 cases of symptomatic COVID-19 among participants, 142 of which occurred during the follow-up period. Of the 142 cases, 26 were in the WIV04 group (incidence rate 12.1 per 1000 person-years), 21 in the HB02 group (9.8 per 1000 person-years) and 95 in the control group (44.7 per 1000 person-years). ). Vaccine efficacy compared to control was therefore 72.8% and 78.1% for WIV04 and HB02, respectively. At the same time, severe cases of COVID-19 were recorded only in the control group. This means that both vaccines provided 100% protection against severe infection, but the authors stress that these results should be interpreted with caution. The efficacy rates including asymptomatic COVID-19 cases for WIV04 and HB02 were 64.0% and 73.5%.
Seroconversion occurred in 99.3% of participants in the WIV04 group, 100% of participants in the HB02 group, and 2.3% of participants in the control group. Both vaccines induced neutralizing antibodies to SARS-CoV-2.
Post-injection side effects were reported by 44.2% of participants in the WIV04 group, 41.7% of participants in the HB02 group, and 46.5% of participants in the control group. The most commonly reported pain was at the injection site. Side effects were generally mild, temporary and resolved without treatment. Serious side effects occurred at a rate of less than one percent in each of the three groups and were mostly not related to vaccination.
In summary, the two inactivated vaccines significantly reduce the risk of symptomatic COVID-19 in adults. The authors note that the trials did not include pregnant women and children, and therefore the effectiveness and safety of the drugs in these groups is unknown.
As of June 1, 2021, the WIV04 vaccine is only available in China; the HB02 vaccine is authorized in 42 countries.
Protein vaccines
What is this? A vaccine based on antigen proteins, that is, “pieces” of the virus.
What is the mechanism of action? When a mixture of viral antigen proteins enters the body along with the vaccine, it provokes an immune response.
What's good about this vaccine? This vaccine is safe for the body, so it can be quickly tested and put into use.
What's the problem with the vaccine? It is very difficult to obtain enough viral proteins to make a vaccine. In addition, immunity to such vaccines is likely to be unstable - much like in the case of inactivated vaccines.
Who is working on the vaccine and at what stage is it? According to WHO, as of April 30, 2021, no protein vaccine has yet crossed the threshold of preclinical trials. And if it does, it is unlikely that such vaccines will become widespread. Although, in theory, the possibility of producing viral proteins in large quantities exists - for example, Sanofi has a technology that allows them to “stamp” the proteins of influenza viruses in the cells of caterpillars. But making vaccines this way is very expensive and difficult.
Chapter 5
Why do vaccines take so long to develop?
Creating vaccines is very difficult and expensive . The creation of vaccines requires not only highly qualified personnel and large financial investments in research; the problem is also in establishing production. To bring a vaccine to market, small development companies will have to reach an agreement with large pharmaceutical companies, which will be able to produce components for the drug in large quantities. At the same time, the production of a completely effective vaccine may turn out to be too difficult to become widespread - we have already seen this with the example of protein vaccines. Due to production difficulties, 95% of vaccines that have successfully completed clinical trials do not reach consumers.
Clinical trials of vaccines take a long time . A successful vaccine is one that will be used in tens of thousands, perhaps millions, of people. Therefore, all vaccine candidates must be thoroughly tested not only for effectiveness, but also for safety - because with such huge volumes, even rare side effects become very likely.
A good example is the risk of antibody-dependent enhancement (ADE), in which there is a theoretical risk that antibodies from a vaccine designed to fight one strain of coronavirus will facilitate infection by another strain of coronavirus. Scientists do not fully understand what properties of vaccines provoke ADE - so they just have to experiment and see whether this effect exists or not. Checking for ADE also takes time.
And although developers of vaccines (especially new ones - vector and vaccines based on RNA and DNA) are doing everything to speed up the development process, the stage of testing vaccines in humans - clinical trials - should not be skipped under any circumstances.
Clinical trials (even accelerated ones) take at least several months. It is required to recruit several dozen (or better yet hundreds) participants, randomly (this is called randomization) divide them into an experimental group that will receive the vaccine and a control group that will receive a placebo, and observe these people for at least 3-4 months so that they have time possible side effects may occur.
Chapter 6
When can we expect a vaccine to appear?
In the “pre-coronavirus era,” the development of one vaccine took on average more than 10 years. The only exception is the vaccine against the Ebola virus: Merck completed the development of this drug in a record five years. But in the midst of the COVID-19 pandemic, no country in the world has that much time, so government regulators and pharmaceutical companies are accelerating the development and testing of vaccine candidates - for example, the US government hopes to have a ready-made drug by early 2021.
If this really works out, it will be an unprecedented step forward for all of humanity. However, this is still not very likely. Considering all of the above, it makes no sense to wait for a vaccine against COVID-19 earlier than in 12-18 months.
By the way, a special website has recently appeared that aggregates information from the WHO, the American Centers for Disease Control and Prevention (CDC) and other sources: COVID-19 Vaccine & Therapeutics Tracker. The site is convenient for monitoring the development of vaccines in real time.
