COVID vaccines: who, where, when
An exhaustive (well, almost) Medusa's guide to everything that is already known about COVID-19 vaccines – when, where and what they will be
Daniil Davydov
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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 Lipsich, professor of Epidemiology at Harvard University, warns that the spread of the disease will not stop until there are enough people vulnerable to coronavirus in the population. Simply put, the epidemic will not stop until most of us get sick – or until a coronavirus vaccine appears. But why is there still no vaccine? Let's figure it out.
As of April 30, 2020, the staff of the World Health Organization (WHO) was aware of 102 candidates for anti–coronavirus vaccines - and 8 vaccines are already undergoing clinical trials on healthy people. However, the actual number of candidate vaccines may be higher: not all companies that are trying to create a "magic pill" against COVID-19 have been included in the WHO list.
The principle of action of already existing and still being developed vaccines is based on several ways to cause an immune response in the body, and each method has its advantages and disadvantages. It is impossible to predict which type of vaccine will work better before the start of human clinical trials – so pharmaceutical companies have to act almost blindly, trying different ways. But maybe it's for the best: if one type of vaccine turns out to be ineffective or unsafe, there's always a chance that another type of vaccine will work better.
CHAPTER 1. VIRAL VACCINES
Vaccines based on a weakened virus
What's it? A vaccine that includes a very severely weakened (in other words, attenuated) SARS-CoV-2 virus in the laboratory. Vaccines of this type have been known since the 1950s: the principle underlies vaccinations against measles, mumps, rubella (MMR) and chickenpox.
What is the mechanism of action? To create a vaccine, laboratory staff use a virus that consistently infects laboratory animals. The fact is that viruses adapt to the host in whose body they find themselves. If a human virus is forcibly "relocated" 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 dangerous to humans. At the same time, the mutated "animal-like" virus still remains sufficiently similar to the original "human" to cause a full-fledged immune response in a vaccinated person. If a vaccinated person becomes infected with the original "wild" virus, his immune system will already be ready to meet, and will quickly cope with the disease.
What's good about this vaccine? Immunity from such a vaccination lasts the longest. In the case of COVID-19, this is especially important, because persistent immunity is not always formed to coronavirus infections.
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 the disease again. To prevent this from happening, it is necessary to study viruses very carefully and organize scrupulous clinical trials of the resulting vaccine, which will take several years. If it is possible to create a "live" vaccine, it will have many advantages – but such a drug will not appear soon.
Who is involved in the vaccine, and at what stage is it? The beginning of the development of a vaccine based on a weakened virus was announced by the American company Codagenix (the development is being carried out jointly with the Indian Institute of Serums) on February 13, 2020. According to WHO, as of April 30, 2020, the vaccine is in the preclinical testing phase – that is, it has either not yet been created or is being tested on laboratory animals.
Inactivated vaccines
What's it? A vaccine that includes inactivated – that is, viruses that are not able to infect cells. This is also an old and proven type of vaccine: the principle is the basis of 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 cause an immune response.
However, such vaccines have two drawbacks. Firstly, such vaccines usually cause too weak an immune response, so you have to use substances-"immune response enhancers" – adjuvants. The task of adjuvants is to help immune cells (B-lymphocytes) develop more protective proteins-antibodies.
Aluminum salts are used as a universal adjuvant in most vaccines – however, vaccines with aluminum do not help prevent viral infection. By trial and error, scientists have made sure that antiviral vaccines are able to enhance adjuvants-virosomes. These are "stuffed viruses" in the form of lipid nanoparticles – microscopic droplets of phospholipid fats, on the surface of which a viral protein-antigen is "attached". Immune cells mistake "stuffed animals" for real viruses and react to them more energetically than just to viral proteins-antigens.
Secondly, the "training material" for the immune system eventually ends, so the resulting immunity is not as stable as in the case of vaccines based on a weakened virus that can multiply in the body for some time. To maintain immunity, it is necessary to resort to repeated vaccination.
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 vaccine to SARS-CoV-2 will cause a weak immune response. In order for it to work well, it will have to select an effective adjuvant for it – that is, to look for optimal parameters of a phospholipid drop-a virosome. This will require additional time and effort.
Who is involved in the vaccine, and at what stage is it? According to WHO, as of April 30, 2020, two Chinese developers have achieved the greatest success in creating an inactivated vaccine. Sinopharm is preparing two vaccines at once. The drug, created in cooperation with the Wuhan Institute of Biological Products, is in phase 1 of clinical trials – the tolerability of the vaccine is tested on healthy people. The drug, created jointly with the Beijing Institute of Biological Products (Beijing Institute of Biological Products), is at the very beginning of development – at the stage of approval of regulatory documents.
Most of the information about the inactivated vaccine is from Sinovac, which is also in phase 1 clinical trials. This company cooperates with the American company Dynavax, which has transferred an effective adjuvant to Sinovac, which has performed well in the hepatitis B vaccine – so it's not surprising that the Chinese developer has pulled ahead, because it saves him a lot of time.
On April 19, Sinovac published a preprint – a preliminary version of an article in which it showed that their vaccine works: it stimulates the formation of antibodies against 10 strains of SARS-CoV-2 in mice, rats and rhesus monkeys. Although it's still too early to rejoice - we still don't know how the vaccine will show itself in humans.
CHAPTER 2 VECTOR VACCINES
What's it? Vaccines based on completely different viruses (for example, adenoviruses), in 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 a "vector", that is, a transport for delivery to cells).
What is the mechanism of action? Once in the body together with the vaccine, genetically modified auxiliary viruses provoke an immune response to SARS-CoV-2 proteins – that is, they work roughly like "live" viral vaccines.
Theoretically, it is possible to try to create vector vaccines of two types – based on virus particles that can and cannot multiply in the body. Most likely, vaccines based on viral particles capable of multiplying inside the cells of the host organism will protect against coronavirus for longer. However, only vaccines with viruses that are not capable of reproduction have so far reached the stage of clinical trials on humans.
What's good about this vaccine? According to the developers, vector vaccines should work as well as live ones – but they will not be able to mutate.
What's the problem with the vaccine? Vector vaccines based on weakened genetically modified adenoviruses are insufficiently studied. Attempts to develop vector vaccines to fight cancer, HIV, influenza and Ebola viruses have already been made, but so far none has been approved for humans.
Who is involved in the vaccine, and at what stage is it? According to WHO, as of April 30, 2020, two strong "players" are engaged in vector viral vaccines.
The Chinese company CanSino Bio, together with the Beijing Institute of Biotechnology, is developing an Ad5-nCoV vaccine based on a modified type 5 adenovirus. The vaccine is in phase 2 of clinical trials – that is, trials of the vaccine on real patients have already begun. At the moment, CanSino Bio is leading in the "vaccine race" – but this does not mean anything yet, because the results of the first phase of trials have not yet been seen by the world medical community. It is possible that there are a number of undeclared problems with the vaccine.
The second strong player is the English University of Oxford, which is developing a vector vaccine based on the modified chimpanzee adenovirus ChAdOx1. The vaccine is in phase 1-2 of clinical trials – that is, it is also already being tested on real patients. Nothing is particularly known about ChAdOx1 yet. But another Oxford product based on the same principle – a vaccine against MERS-CoV, the "cousin" of the SARS-CoV-2 virus – seems to work, and it had no safety problems.
CHAPTER 3 VACCINES BASED ON NUCLEIC ACIDS
DNA vaccines
What's it? A vaccine that contains a ring DNA molecule (plasmid), which contains "instructions" for creating a viral protein.
What is the mechanism of action? Once in the cells of a vaccinated person, the ring DNA will become part of their genome. As a result, the host cells will receive a new instruction, according to which they will begin to "stamp" viral proteins-antigens - and an immune response will be formed on them.
In order for a piece of DNA with information about viral proteins to surely penetrate into cells, it can be embedded in the genome of a harmless carrier virus. This virus works like an "intracellular syringe" – throws its modified genome into the cell, which is then embedded in the nucleus (unlike vector vaccines, only the shell is used here from a harmless virus).
What's good about this vaccine? The advantages are the same as those of vector vaccines: immunity is as stable as that of "live" viral vaccines, but without their inherent disadvantages. Since SARS-CoV-2 is not taken as a "carrier virus" for the plasmid at all, 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 understood. So far, only one vaccine of this type is being used – a vaccination against the Zika virus for horses. No DNA vaccine has yet been approved for use in humans.
Who is involved in the vaccine, and at what stage is it? According to WHO, as of April 30, 2020, Inovio Pharmaceuticals (USA, Pennsylvania) is creating a DNA vaccine INO-4800 - only based on DNA plasmids, without modified carrier viruses. INO-4800 is a so-called "DNA vaccine with electroporation". In order to "drive" the plasmid into muscle or skin cells, they will need to be affected by an electric field, which will temporarily make their cell membranes more permeable. To make such a vaccination, a simple syringe will not be enough – you will need a special device-an electroporator. This vaccine is in phase 1 clinical trials – trial results are expected in June.
RNA vaccines
What's it? A vaccine that contains a viral molecule similar in structure to DNA matrix RNA (mRNA). This molecule is a "template" from which the viral protein is directly read. mRNA is not embedded in the cellular genome.
What is the mechanism of action? The mRNA enclosed in a lipid nanoparticle enters the body together 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 – despite the fact that viral DNA will not be embedded in the cellular genome.
What's good about this vaccine? In addition to the benefits shared with DNA vaccines, lipid particles with mRNA inside are similar to a virus, so they themselves can trigger an immune response. So there is a chance that due to the "double action", immunity from RNA vaccines will arise earlier and hold on tighter. In addition, short mRNA is a very simple molecule, so it can be created relatively quickly and inexpensively – with the help of 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. Older vaccines of this type do not exist in principle.
Who is involved in the vaccine, and at what stage is it? According to WHO, as of April 30, 2020, two companies have made the furthest progress in creating RNA vaccines. The American company BioNTech has signed a contract with the pharmaceutical giant Pfizer. However, apart from the fact that the company has received permission to start 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 2020.
More information about the vaccine from the American company Moderna, which cooperates with the Vaccine Research Center (NIAID). The vaccine is called mRNA-1273. Recently, phase 1 of the trials ended, in which three variants of mRNA dosage participated: 25, 100 and 250 micrograms. Now the company has submitted an application for phase 2 trials, in which the vaccine will participate in dosages of 50 and 250 micrograms – perhaps these dosages were the most effective.
In addition, in mid-March, the Russian biotech company BIOCAD announced the start of RNA vaccine development. Three vaccine variants with different mRNA dosages will be developed. The first animal trials were scheduled to begin at the end of April.
CHAPTER 4 PROTEIN VACCINES
What's it? A vaccine based on antigen proteins, that is, "pieces" of the virus.
What is the mechanism of action? Getting into the body together with the vaccine, a mixture of viral proteins-antigens provokes an immune response.
What's good about this vaccine? Such a vaccine is safe for the body – therefore, it can be quickly tested and put into use.
What's the problem with the vaccine? It is very difficult to get enough viral proteins to make enough for a vaccine. In addition, immunity to such vaccines is likely to be unstable – approximately as in the case of inactivated vaccines.
Who is involved in the vaccine, and at what stage is it? According to WHO, as of April 30, 2020, no protein vaccine has yet crossed the threshold of preclinical trials. And if it does, it is unlikely that such vaccines will become mass-produced. Although, in theory, the possibility of producing viral proteins in large quantities exists – for example, Sanofi has a technology that allows "stamping" influenza virus proteins in caterpillar cells. But making vaccines this way is very expensive and difficult.
CHAPTER 5 WHY 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 the establishment of production. In order to bring the vaccine to market, small development companies will have to negotiate with large pharmaceutical companies that will be able to produce components for the drug in large batches. At the same time, the production of a completely effective vaccine may be too complicated to become mass – we have already seen this with the example of protein vaccines. Due to production difficulties, 95% of vaccines that have successfully passed clinical trials do not reach consumers.
Clinical trials of vaccines take a long time. A successful vaccine is a drug that will be used in tens of thousands, and possibly millions of people. Therefore, all vaccine candidates should undergo a thorough check not only for efficacy, 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 infection enhancement (ADE), in which there is a theoretical risk that antibodies from a vaccine designed to fight one strain of coronavirus will facilitate infection with another strain of coronavirus. Scientists do not fully understand exactly what properties of vaccines provoke ADE – so you just have to experiment and see if there is this effect or not. Checking for ADE also takes time.
And although the developers of vaccines (especially new ones: vector and RNA and DNA-based vaccines) are doing everything to speed up the development process, the stage of testing vaccines on humans – clinical trials – should not be skipped in any case.
Clinical trials (even accelerated ones) take at least several months. It is required to recruit several dozen (or better 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 possible side effects can manifest themselves.
CHAPTER 6 WHEN TO WAIT FOR THE VACCINE TO APPEAR
In the "pre-coronavirus era", the development of a single vaccine took more than 10 years on average. The only exception is the Ebola virus vaccine: Merck has managed to develop this drug in a record 5 years. But in the midst of the COVID-19 pandemic, no country in the world has such time, so regulatory authorities and pharmaceutical companies are accelerating the development and testing of vaccine candidates – for example, the US government hopes to get a ready-made medicine by early 2021.
If this really happens, it will be an unprecedented step forward for all mankind. However, this is still not too likely. Considering all of the above, it does not make sense to wait for the COVID-19 vaccine earlier than in 12-18 months.
By the way, a special website has recently appeared that aggregates information from WHO, the American Centers for Disease Control and Prevention CDC and from other sources: COVID-19 Vaccine & Therapeutics Tracker. The site is convenient to follow the development of vaccines in real time.
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