So, an antiviral vaccine is a drug consisting of a virus or its components, which is able to form a strong immunity against this virus, i.e. to build such immunological “defensive lines”, which the virus has few chances to break through. Immunological defense is deeply ‘layered’ (I will not go into details), but most vaccines used in medical practice use only one of these lines – the production of antibodies in response to the ingestion of viral antigens.
The vast majority of antiviral vaccines are designed to prevent virus infection. In other words, a person must be vaccinated (synonym: immunized) BEFORE the virus “attacks” (in the literature it is called pre-exposure vaccination). Ideally, by the time of the “attack”, the vaccinated person should already have a strong immunity. In practical terms, this means that protective antibodies must be present in a sufficiently high concentration (immunologists say ‘in high titers’) at the time of the viral ‘attack’. It is important to understand that not all antiviral antibodies are protective. Knowing which antibodies are protective is crucial in developing a vaccine. One example is that in the case of hepatitis B virus (HBV), anti-surface antigen (HBsAg) antibodies called anti-HBs are protective, and antibodies against the “internal” HBV antigen called anti-HBc are not protective. It is easy to guess that the vaccine against hepatitis B virus (by the way, a very good vaccine, such would be from coronavirus!) Consists of HBsAg antigen.
Very rarely, antiviral vaccines are used after infection (post-exposure vaccination). So usually the rabies virus vaccine is used. This type of vaccination is possible only when the incubation period is long (weeks, or even months) and the immune system has enough time to build “defensive lines” after the vaccine has been introduced. Obviously, in the case of coronavirus, this approach is not applicable. A vaccine is needed that is administered to HEALTHY PEOPLE in advance before the virus attacks them.
The “shelf” is the first – what component of the virus should the vaccine consist of (which coronavirus protein is an analogue of HBsAg, in the context of vaccine development)? In answer to this question, there is practically a consensus – it is surface protein S (glycoprotein S), a product of the viral gene S. There are a large number of modern technologies with which you can make various preparations of this protein or its ‘pieces’. Even more laboratories, institutes, firms that own such technologies. Reconfiguring these technologies to coronavirus is relatively simple and does not take much time. As a result, there are now dozens of different drugs based on Coronavirus Protein S, which can be called “vaccine prototypes” or “pre-vaccines”. But, sometimes, unreasonably, they are called vaccines. The vast majority of reports on the successful development of a prototype coronavirus vaccine can be put on this shelf. To become a vaccine, these drugs must successfully pass preclinical and clinical trials. During these tests, most of them are eliminated.
‘Shelf’ second – preclinical trials. These are tests on laboratory animals. Their relatively simple stage is a safety test – the absence of obvious toxicity or any other serious side effects. Most likely, the “pre-vaccines” this stage will pass. The next step is more difficult – an assessment of the ability to trigger the synthesis of antiviral antibodies (immunogenicity). Most likely, most vaccines and this stage will pass. Indeed, if a foreign protein is introduced to an animal, antibodies are almost always formed. But the trick is that not all antibodies are needed, but protective ones. And exactly which antibodies are protective, in the case of coronavirus, is not yet known. But there is an opportunity to get a ‘hint’. Protective antibodies are typically able to neutralize the virus in vitro i.e. they can block the ability of the virus to multiply in an in vitro cell culture. This is relatively easy to verify. When such experiments are carried out, “pre-vaccines”, in response to which neutralizing antibodies are poorly developed, will be rejected. The fact that some kind of “pre-vaccine” gives a good yield of neutralizing antibodies is encouraging, but does not give guarantees of protection against the virus in vivo. And in order to check whether there is a protective effect in vivo, not just laboratory animals are needed, a model of infection and disease on laboratory animals is needed. This is the hardest part in preclinical trials.
Virus vaccine development. Conceptual framework 2.
In “regular” conditions, clinical trials begin after the successful completion of preclinical trials. But in an emergency, “cutting the corner” is possible. This is exactly what is happening with the US mRNA-1273 candidate vaccine trial (no preclinical trial information is available, but phase 1 of the clinical trial has already begun). The same situation is possible with the Chinese vaccine Ad5-CoV, but at least it stated that preclinical trials were successful (but no data confirming this were published).
Let me remind you that in clinical trials there are three phases:
1 – safety check (no serious side effects)
2 – immunogenicity test (ability to cause the formation of antiviral antibodies)
3 – test of effectiveness (ability to protect against infection)
In the case of SARS-CoV-2 such clinical trials are, in fact, human experiments. Is it necessary to say how negative emotions the words ‘human experiments’ evoke. Immediately I recall Dr. Mengele and the like. Less lively, but also disgusting experiments on humans, such as the study of Taskigi syphilis, are also known (google or add Taskegee or Taskigi). There are other examples, moreover, not from such a distant past. But this is a separate issue. Now no one needs to be convinced that such “clinical trials / trials” are absolutely unacceptable. But there’s no way to get away from the fact that research on a person of a new medicine, vaccine, treatment method is always accompanied by the possibility of negative effects, even fatal. And without clinical trials, a new progress in medicine is impossible. Therefore, the question is not whether it is possible to “experiment on people,” but how to do it so that the risks for the subjects are minimal and that everything possible is done to maintain their psychological comfort and compensation in the event of any negative consequences. Therefore, there are many regulatory rules, international and national, that articulate how clinical trials should be conducted. In short, the main condition is to maximally inform the potential subject about the purpose of the test and the possible risks. It is extremely important that this be done in a manner that is understandable to a layman. The decision on whether to participate in the tests as a test subject or not, a person must make consciously and absolutely voluntarily. It is very important that the subject has the right, despite initial consent, to refuse to participate in the tests at any time. Finally, measures should be provided for adequate emergency medical care in case of unforeseen consequences (for example, hypersensitivity reactions) and compensation in case of negative consequences. Everything should be done to maximize the psychological comfort of the subjects. This, incidentally, involves the non-use of expressions such as ‘human experiment.’ In this text I use this bad phrase, but only in order to “expose” the meaning.
People, as you know, spoils the ‘housing problem’, in the modern version – money, in a bad sense of the word. In modern clinical trials, participants are often recruited for a fee. By the way, a clinical trial is being prepared in England in which participants will be infected with a live coronavirus. You need to dial 24 people. Payment of 3,500 pounds. Wishing a few thousand. Do not worry. This is not about SARS-CoV-2 infection. They will be infected with the usual “cold” strain of coronavirus. But this model of recruitment is widely used. There are many companies specializing in this. Are all ethical standards observed in commercial recruiting? On paper, probably yes. I don’t know in life. But this is also a separate issue, outside the scope of my professional competence.
Returning to the phases of clinical trials of coronavirus candidate vaccines. Phases 1 and 2 of such trials actually duplicate the similar stages of preclinical trials. Of course, it is better if candidate vaccines are pre-tested for safety in animals. But, the acceptable result of such a preclinical trial, even on monkeys, does not guarantee that everything will be the same in humans. In general, serious side effects from the administration of various protein S preparations are unlikely for people, and I do not see a significant increase in the risk for subjects when moving to phase 1 clinical trials directly (or with minimal preclinical trials). But, of course, the national authorities governing the conduct of clinical trials must decide this. As for phase 2 clinical trials, then in the ‘normal mode’ it must be carried out on a new group of subjects. However, preliminary immunogenicity data can be obtained already in Phase 1 trials. Indeed, a candidate vaccine is administered to these subjects.