November 2020 will possibly be remembered for being part of the year of the pandemic. However, on a scientific level during that month one of the great milestones of the 21st century passed. For the first time in history an RNA vaccine was approved for human use. Until that moment, technology and knowledge about them had been developed, but the fragility of the molecule among other factors had meant that they were not seriously considered despite being a revolutionary idea when it comes to treating diseases. The use of messenger RNA vaccines was proposed for the first time in 1990. To put a bit of context, there were still 10 years left for the human genome project to be completed, and the thermocyclers -with which PCRs are used to multiply molecules of genetic material- they only had 7 years of history. At that time, the foundations of genetic manipulation were about to enter a stage of exponential knowledge that 30 years later would lead us to a world in which the entire genome of a living being can be made in just one year - that of a viruses in a few months-, or PCRs are so common that laboratories use them routinely and are hardly ever mentioned in the scientific literature taken for granted.
An RNA vaccine contains a large number of copies of a sequence present in the virus. For this, a sequence of a protein essential for the virus is chosen. In addition, this sequence is accompanied by sequences and protective elements to prevent the immune system from quickly killing the foreign RNA when entering the bloodstream. In fact, the recognition of foreign RNA or DNA is one of the oldest and most powerful mechanisms of protection against infection. Many years of basic research have been necessary for us to acquire the knowledge necessary to overcome this great obstacle. In reality, a part of the RNA of the vaccine will be degraded by these defense mechanisms, but a small part will manage to enter the cells and replicate. RNA is an unstable molecule compared to DNA, so it will also be degraded if it fails to replicate. Furthermore, since it is a created sequence, it works so that it cannot be incorporated into the host genome. This is a double advantage since we avoid altering the genome and on the other hand we avoid long-term side effects since the molecule will be eliminated by the normal processes of the body in a short period of time.
In this way, a protein will be generated that the cell will expel into the intercellular space. There it will be recognized by the immune system and, now, it will cause a defense reaction that will generate immunity against the virus that presents that protein when it appears. By inoculating the RNA of only one protein that has been selected, we avoid problems associated with other types of vaccines, such as those with attenuated viruses, which could occasionally cause disease. To this must be added that thanks to modern cloning techniques and manipulation of genetic material -thanks to thermocyclers- these vaccines can be generated very quickly and can be rapidly altered to adapt them to new variations of the native virus. Protein-based vaccines, for example, need to integrate this same RNA into a bacterium or other organism that synthesizes the protein; it has to be purified; and then it can be inoculated. RNA vaccines simply bypass the generation of modified organisms to produce the specific protein, since they will use human machinery to do so. The time it takes to manufacture them has undoubtedly been one of the incentives for two of the large companies to use this technology.
The BioNTech-Pfizer vaccine (left) created thanks to an international collaboration and a box of the Moderna vaccine (right) ready for delivery
Against SARS-CoV-2, the pharmaceutical company BioNTech in collaboration with Pfizer developed several RNA-type vaccines. The BNT162b2 being the one that offered the best results in the preliminary tests, which we will commercially know as Tozinamerán. Another of the candidates also went through several phases but in the end all efforts have focused only on this one. This vaccine contains the messenger RNA of the viral spike protein, the protein that the virus uses to interact with host cells. The mRNA of the virus has been altered in order to carry out its mission. Furthermore, it is known to be encapsulated in a lipid envelope to be able to penetrate the cell membrane. This vaccine has been carried out thanks to private funds from several American and Chinese companies and public funds, both German - the country where BioNTech is based - and Europeans, with the amount that the company of public funds is more than 560 million dollars. On December 2, the United Kingdom is the first country to approve its use. By the end of 2020, multiple countries had authorized the use of this revolutionary vaccine for the immunization of their population.
Another of the vaccines that have used this type of technology has been the Modern pharmaceutical company, called mRNA1273. It also uses the sequence of the spicule protein and has been analyzed against the various variations that are currently known, the English, the Brazilian and the South African. Although for the latter it has shown a decrease in its effectiveness, the numbers that the company manages in January 2021 are very encouraging. Auqne assure that they are already working on new variations of the vaccine to make it even more effective. The psychological barrier against this type of vaccines has already been broken. We may very well see how new treatments against very diverse diseases flourish. Some of the projects that are being developed in this regard are: a vaccine against Zika disease, against AIDS, against the flu and several against different types of cancer.
Jackson LA, Anderson EJ, Rouphael NG, Roberts PC, Makhene M, Coler RN, McCullough MP, Chappell JD, Denison MR, Stevens LJ, Pruijssers AJ, McDermott A, Flach B, Doria-Rose NA, Corbett KS, Morabito KM, O'Dell S, Schmidt SD, Swanson PA 2nd, Padilla M, Mascola JR, Neuzil KM, Bennett H, Sun W, Peters E, Makowski M, Albert J, Cross K, Buchanan W, Pikaart-Tautges R, Ledgerwood JE, Graham BS, Beigel JH; mRNA-1273 Study Group. An mRNA Vaccine against SARS-CoV-2 - Preliminary Report. N Engl J Med. 2020 Nov 12;383(20):1920-1931.
Pardi N, Hogan MJ, Weissman D. Recent advances in mRNA vaccine technology. Curr Opin Immunol. 2020 Aug;65:14-20.
Reichmuth AM, Oberli MA, Jaklenec A, Langer R, Blankschtein D. mRNA vaccine delivery using lipid nanoparticles. Ther Deliv. 2016;7(5):319-34.
Schlake T, Thess A, Fotin-Mleczek M, Kallen KJ. Developing mRNA-vaccine technologies. RNA Biol. 2012 Nov;9(11):1319-30.
Zhang NN, Li XF, Deng YQ, Zhao H, Huang YJ, Yang G, Huang WJ, Gao P, Zhou C, Zhang RR, Guo Y, Sun SH, Fan H, Zu SL, Chen Q, He Q, Cao TS, Huang XY, Qiu HY, Nie JH, Jiang Y, Yan HY, Ye Q, Zhong X, Xue XL, Zha ZY, Zhou D, Yang X, Wang YC, Ying B, Qin CF. A Thermostable mRNA Vaccine against COVID-19. Cell. 2020 Sep 3;182(5):1271-1283.e16