May 14, 2021

The revolutionary and safe RNA vaccines

Never before in the history of science have so many different vaccines against the same pathogen as against SARS-CoV-2. So far they are about 120 prototypes, from a diversity of approaches and strategies huge. This is probably what has led to the development of a new type of vaccine, messenger RNA (mRNA), which has been carried out in parallel by two companies: Pfizer and Modern. A vaccine is a drug whose action consists of teaching the body a sample from the virus or bacteria against which we want to defend ourselves (called antigen), which provokes a response from the immune system so that it can recognize the pathogen in case of an active infection and eliminate it or, at least, attenuate the progression of the disease or generating only a mild pathology. The classic vaccines They consist of the injection of a weakened, attenuated or inactivated pathogen (virus or bacteria), that is, incapable of infecting or incapable of causing a severe infection. The oldest vaccine in existence was developed by a process called variolation, for the prevention of smallpox. This process consisted of collecting scabs from the sick, or other remains of an ongoing smallpox, and administering small amounts subcutaneously to a healthy subject who had not suffered from the disease. This provoked the reaction of the immune system against those agents that were identified as foreign to the organism and the generation of specific defenses against them. Although this method was not without risks, it laid the foundations for what would later become the development of modern vaccines.

Among the weakened or attenuated virus vaccines we find measles, mumps and rubella. Among the “killed vaccines” (with the inactivated pathogen), which are made with fragments taken from a virus or bacteria, is, for example, that of pertussis. Regarding the flu shots there are both types. In synthetic vaccines, a protein of the infectious agent is artificially generated; This is what happens with hepatitis B. Some bacteria act against the body by producing toxins, such as tetanus or diphtheria. In that case we can teach the body to recognize these toxins in an attenuated form (toxoids). Although these vaccines do not train the body to eliminate the pathogen, they prevent the harmful action of its toxins and, therefore, the development of the disease.

In recent years, a new concept of vaccine, messenger RNA (mRNA) vaccines, molecules that contain the information necessary to be translated into proteins. An attempt has been made to develop a vaccine of this type against viruses such as AIDS (HIV) or herpes simplex, although they have not yet worked. The mRNA vaccines are also being tested against influenza, with good prospects, but its development is being relatively slow. Attempts are even being made to develop a similar system to induce the immune system to specifically destroy tumor cells in cancer patients. However, none of the previous attempts to use mRNA vaccines have had a success as overwhelming as, in principle, it is having and it seems that it will have this type of vaccine in the fight against the coronavirus. Although there are viruses against which it was relatively easy to develop vaccines, as in the case of mumps or measles, there are other viruses that resist, such as HIV. With the coronavirus, the situation is quite favorable for the generation of an effective vaccine. In addition, there are viruses that are so variable that they require a change of vaccine every year, as is the well-known case of the flu. And it seems that we have been lucky in this as well, since SARS-CoV-2 does not seem to mutate too much. What is clear is that the global urgency to develop a remedy against Covid-19 has provided the levels of investment necessary to achieve, in record time, advances that were very promising but required powerful scientific and technological development.

He action mode One of these vaccines consists of introducing into the body the instructions, in the form of mRNA molecules, for our own body to generate copies of a protein of the pathogen. Despite being produced by their own cells, the pathogen’s protein (viral in this case) is recognized as a foreign agent (called antigen). This recognition stimulates the production of specific defenses against it, the known antibodies, and thus the antigen will be eliminated from the body. During this process of recognizing a viral protein, which we have actually synthesized ourselves, the body will generate immune memory against it. When the virus enters the body, the immune system will recognize that protein that it already recognized as a foreign agent at the time and will attack the virus that carries it, interfering with its infection and eliminating the virus without having previously come into direct contact with it. In the case of SARS-CoV-2, the mRNA used is the one that generates the protein Spike (Figure 1), present on the surface of the coronavirus and that is responsible for the entry of the virus into our cells and its strong infectivity.

Although told like this it may sound logical and even simple, the details of this process present enormous technical difficulties. First, mRNA is a tremendously labile molecule and it breaks down very easily. There are enzymes called ribonucleases (or RNases) present everywhere (in the air, in our breath, our skin, in any bacteria) that break down RNA at full speed. At room temperature, mRNA degrades rapidly. The only way to keep the mRNA intact is to preserve it in total sterility and at very low temperatures, at which ribonucleases do not act. Certain products that promote mRNA stability can also be used. In the laboratory, RNA is stored at -80ºC. It is because of that Pfizer’s Covid-19 vaccine needs to be stored in deep freezers that can keep those temperatures so low. Of course there will be strategies and reagents that favor the stability of the mRNA at higher temperatures, and that is precisely one of the limiting points in the development of an RNA vaccine. In fact, Moderna has managed to preserve its vaccine at -20ºC, apparently tripling the mRNA concentrationSo if one part is degraded it will still contain enough whole molecules to function. Although this makes its production and marketing more expensive, it facilitates its subsequent handling and distribution. Once thawed, both vaccines last for a limited and specific time.

The second technical difficulty is to get that mRNA into the cells in an intramuscular injection without being eliminated before by our immune system. You have to get it to enter the cells and reach the region of the cytoplasm where it can be translated into proteins, that is, it reaches the ribosomes, and that is not easy. This difficulty It seems to have been solved by carrying out a series of sophisticated modifications of the mRNA chains and introducing the resulting molecules into fat nanoparticles, which favor their arrival and release inside cells. Here it is necessary to clearly clarify that mRNA present in vaccines does not travel from the cell’s cytoplasm to the nucleus, where DNA is found, is translated into protein on ribosomes and degraded immediately. It is because of that there is no possibility of modifying our genome. The natural flow of mRNA is always from the nucleus to the cytoplasm, not the other way around. In other words: the vaccine cannot “make us transgenic” nor modify our DNA. Like the rest of endogenous mRNAs, or those generated by our cells, once it has fulfilled its mission and generated a certain amount of protein Spike, is eliminated.

To determine if a vaccine is efficient, the immune response generated in the trial participants by different methods. Both vaccines (Pfizer and Moderna) appear to generate immunity in the people participating in the phase III trial with an efficacy greater than 90% (see here and here). This indicates that, regardless of the different strategies followed by the two companies, the mRNA vaccine generates a specific and effective immune response against this particular pathogen. However, to achieve this level of effectiveness it is necessary to perform two injections 3-4 weeks apart and wait a few more days for them to complete their effect. That moment is when it can be said that immunity has been achieved. As for an aspect as important as the duration of this immunity in time, little can be said with just a few months of clinical trials. We can only wait and see, but, even if individual immunity lasts only a few months, it would already have very favorable effects to drastically reduce infections and the spread of the virus at the population and collective level.

The main advantage of this type of vaccine is the speed with which it can be produced, since we only need to know the RNA or DNA sequence of the pathogen in question. Furthermore, they promise to be even safer than classic vaccines. Instead of synthetically producing proteins and injecting them into individuals or developing and inoculating attenuated viruses, we directly inject mRNA, which is easier and cheaper to produce, and it is the vaccinated people who produce the pathogen protein that will induce the virus. immune response. This greatly speeds up the process, as well as decreasing the risk of the vaccine having major side effects. This is a milestone in the history of vaccine development and opens the door to the possibility of tackling other diseases much more quickly and efficiently in the future. Which is equivalent to facing the pandemics that are to come much better. No more no less.


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