In a matter of a few days, several press releases have been published announcing the effectiveness of the first vaccines against covid-19. First came the Pfizer / BioNTech vaccine, 90% effective. A few days later the Russian Sputnik V followed, with 92%. Now that of Moderna, with 94.5%. This is very good news and excellent results: efficacy of more than 90% for a vaccine is extraordinary and, in principle, it should lead us to optimism. However, it seems more like a commercial war that has aroused suspicion in part of the citizenry.
Most vaccines are given when you are healthy. That is why they are one of the most regulated, monitored and safe medicines that exist. We should not forget that a press release is advertising and that it is not the manufacturing companies that authorize its use, but the regulatory agencies. The results are still preliminary and we are still waiting for detailed scientific reports that should be made public as soon as possible.
Vaccination programs have contributed to a significant decline in the number of cases and deaths from infectious diseases in the last century. Vaccines have saved millions of human lives. In general, vaccination coverage or childhood vaccination rates continue to grow worldwide, which indicates that it is an accepted public health measure.
However, anti-vaccine movements have been responsible for declining vaccine acceptance rates and increasing preventable infectious disease outbreaks. Between this extreme and the enthusiasts there are more and more people who doubt and who feel insecure about vaccination. In a recent survey carried out for the newspaper El País, 24% of the Spanish population would be vaccinated as soon as possible against covid-19, but 37% would choose to wait a while before doing so, 21% would only do it if strictly necessary and 13% do not even consider it.
The way this vaccine process is being communicated is very worrying. If you do not act with absolute transparency, people can lose confidence in vaccines in general and then we will have a very serious problem. Many of those who doubt vaccines are not reactionary extremist deniers. They are normal people who have doubts or do not trust what they see in the media. They are legitimate questions that must be addressed with respect. Nor do some politicians who present themselves as vaccine advocates help. Some have made lying a political tool, which reduces their credibility on this important issue.
This increase in distrust of vaccines is very worrying because for the success of vaccination campaigns, high vaccination coverage must be maintained. It should be achieved that it is normal for a person to be vaccinated. Vaccination is an individual measure but one that benefits the community. Unlike other preventive interventions, if a person refuses vaccines not only puts his own life at risk but also that of those around him, the weakest, the sick and the elderly. Fighting opposition or doubt about vaccines is a community problem.
How do we know that a vaccine is safe and works?
Before human clinical trials can begin, the vaccine is tested in the laboratory to be non-toxic and has no side effects in cell cultures and animal models. Typically, doses higher than those that would be used in humans are applied and possible adverse effects are checked.
It is also studied in animal models if the vaccine induces the production of antibodies – if it activates the defenses – and if it is capable of protecting against an experimental infection. Since humans are very different from a laboratory mouse, sometimes a vaccine that works very well in animals does not work in humans. If the results of this preclinical development are satisfactory, permission is requested from the health authorities to begin the clinical phases of experimentation with human beings.
Human clinical trials are divided into several phases.
Phase I consists of evaluating the safety of the vaccine (which is not toxic or has serious side effects in people) and immunogenicity (its ability to induce an immune response, antibody production, and cellular immunity). It is usually done with a few healthy volunteers (between twenty and one hundred).
If the results are satisfactory, you can proceed to phase II, in which the safety and immunogenicity of the vaccine is re-evaluated but with a greater number of volunteers (between one hundred and two hundred). It also takes into account how it can affect the age and sex of the person, and several doses are usually tried. But we still don’t really know if the vaccine works. We can already know if it has any toxic or secondary effect and even if it stimulates the defenses, but we do not know if this stimulation is really enough to protect us against infection.
If the results continue to be satisfactory, it is authorized to advance to phase III, in which the efficacy of the vaccine is already tested. In this phase III, a good group of volunteers are already involved (in some cases several thousand) and the efficacy of the vaccine is tested and compared with controls of unvaccinated people who have been inoculated with a placebo. Apart from verifying its effectiveness, it is also determined if there are any previously undetected toxicity or side effect. To avoid bias, the trials are conducted without knowing until the end who has been vaccinated and who has not (the control group): this is what are called ‘double blind’ trials.
Obviously, volunteers are not deliberately infected at this stage, but are allowed to continue with their lives and some of them are expected to become infected naturally. When this happens, it is checked who was vaccinated and who was not, and from there the efficacy of the vaccine is estimated.
This is, for example, what Pfizer / BioNTech and Moderna have announced (90 and 95 volunteers were infected with covid-19, respectively, of which the majority were unvaccinated). Throughout the process, the results are evaluated by external agents, who give their approval and authorization to move from one phase to the next. Any adverse outcome on the safety or efficacy of the vaccine leads to discontinuation of the trials. In addition, the results are published before their commercialization so that the scientific community can review them.
If the vaccine has finally passed all the “filters” and is authorized to be marketed, we must not forget that a fourth phase of epidemiological monitoring begins.
No drug is 100% safe, because none of us are 100% identical. For example, a vaccine that causes some type of serious side effect with a very low frequency of one per million vaccinated will only be detected in this surveillance phase. It is, therefore, a matter of detecting possible side effects that may have previously gone unnoticed.
These studies that are carried out after the vaccine has been approved also aim to evaluate its effectiveness: how it works in the “real world”, to see if it works to control the disease. Therefore, in addition to being safe, a vaccine must be efficient and effective.
The term efficacy refers to the protection provided by the vaccine in clinical trials under optimal conditions (storage and distribution) in a group of generally healthy volunteers and under close surveillance. This is what is studied in phase III. But efficacy is not the same as effectiveness, which refers to the protection generated by the vaccine in real conditions, when it has already been approved and is distributed in the population, in phase IV. It could happen that a vaccine is effective in clinical trials, but then when it is used in real conditions, its effectiveness in controlling the disease is less.
With all this it is achieved, as I have said, that vaccines are the safest drugs that exist. This also implies that it should not be surprising that a vaccine that is already on the market could be withdrawn if a problem is detected during this phase IV. This would show that the surveillance system works.
Why have COVID-19 vaccines gone so fast?
Because we are in a situation of maximum alert, immersed in a global pandemic and, probably, to return to a “normal” normality as soon as possible we need vaccines. Most of the research groups that are preparing vaccine prototypes have been working and testing them for several years. For example, messenger RNA-based vaccines (like Pfizer / BioNTech and Moderna) haven’t been out of their sleeves or invented the technology in a few months. It is true that it is the first time that this technology has reached a phase III clinical trial, but they had been working on this type of vaccine for years.
We also have to take into account that never in history has so much money been invested in the manufacture of vaccines, and there has been an unprecedented international collaboration between research centers, universities, pharmaceutical companies and governments. Procedures and authorizations have been streamlined, but without skipping any phase, although in some cases overlapping clinical phases has been allowed.
In addition, they have been working on the large-scale manufacture of these vaccines for months. A risky bet if we take into account that we still do not know what its efficiency and effectiveness will be. But, I insist, it is not the vaccine manufacturers that authorize their use, but the regulatory agencies.
Do we have to make vaccination mandatory?
The debate has already started. When we ask if we should force vaccination, we usually find answers such as “If the rabies vaccine is mandatory for dogs, why vaccinate children is not?”, “If wearing a seat belt in the car is mandatory, why not vaccinations? ”,“ If smoking is prohibited in many places because it is bad for health, why are vaccines not mandatory if they are good for health? ”,“ If an unvaccinated person can put my health at risk, why don’t you oblige to be vaccinated? “,” If it is mandatory to wear a mask, why not vaccination? “…
In Spain vaccination is voluntary, our legal system does not explicitly incorporate the duty of vaccination and no one can, in principle, be forced to be vaccinated. However, there are certain situations, such as an epidemic outbreak or a pandemic, that allow the competent public authorities to impose forced vaccination. To control and even eradicate an infectious disease, it is recommended that vaccination coverage for that disease be at least 95% (it depends on the pathogen in question).
It also seems logical that if we force healthy people to be vaccinated we should also have a compensation system for possible serious effects that may arise. We have already said that the probability is very small, but when we vaccinate millions of people, a case of serious side effect could occur. An independent commission should be charged with demonstrating whether there is a cause-and-effect relationship between vaccination and that particular serious side effect.
Advancing regulatory changes that coercively impose vaccination could generate a rebound effect contrary to that intended. Forcing may not be the solution for now. Although there are subtle ways: it is not mandatory but to access a certain service (nursery, school) you must have the “vaccination card” up to date. I personally am more in favor of convincing people of the benefits of vaccination. AND Yes, I would get vaccinated with the covid-19 vaccines that have been authorized by the competent regulatory agencies.
Ignacio López-Goñi, Professor of Microbiology, University of Navarra
This article was originally published on The Conversation. Read the original.
