How COVID Vaccines Started and Where Are We Heading in the Future?
Although the main breakthrough happened only with Pfizer-BioNTech and Moderna vaccines, it was the result of many exceptional scientists and their work. In this article, we will focus on the history with many turning points, basic COVID vaccine structures, and prospects for the future.
Many of us can still remember the COVID-19 pandemic, all the restrictions, deaths of people, and the feeling of uncertainty, even despair regarding the future, and what else it will bring for us. Many believed and predicted that the pandemic would end soon but new variants with better transmissibility stole this hope of everything going back to normal. Then the vaccines with more than 90% efficacy. Many believed that this would be the light in the tunnel. On the other hand, some people brought so much hatred and distrust, dividing the whole world into two poles — people who follow science and those who follow controversy. Nevertheless, few people know the full timeline of covid vaccine history from a scientific standpoint.
Everything started in the 90s. But for the comprehensible history overview and especially for me one of the most remarkable science stories, I need to remind you or explain to you the main components of covid vaccine. In general, vaccines are divided into several types — those that contain a deactivated virus, only a part of a virus, for example, a protein, DNA sequence, or mRNA sequence. Pfizer-BioNTech and Moderna COVID vaccines contain mRNA sequences. The main advantage of mRNA is that this sequence is not incorporated into the nucleus of the cell and the genome, this creates better safety measures. The second advantage is the faster and simpler production of mRNA vaccines.
However, mRNA also comes with some disadvantages that scientists had to focus on before COVID vaccines were distributed around the world. As a molecule mRNA is very unstable and can be easily degraded by nucleases in the cell such as the enzyme RNase. Therefore, liposome nanoparticles have been used safely transport mRNA into the cell. Emphasizing one significant factor — these lipid nanoparticles must be positively charged. For this idea we have to mention these scientists — Philip Felgner, who developed these positively charged nanoparticles, and Robert Malone, who included this new type of liposomes in his experiment with in vitro synthesized mRNA. He found that positively charged liposomal nanoparticles can engage with the negatively charged mRNA molecule and form a more stable particle.
The other drawback would be strong immunogenicity, which triggers a strong immune response. This problem was solved by two scientists Katalin Karikó and Drew Weissman, who incorporated a significant modification, they changed uridine nucleotide to pseudouridine. The sequence with uridine stimulated a strong immune response by activating Toll-like receptors (TLRs). On the contrary, a sequence with pseudouridine did not. In this way, high levels of neutralizing antibodies and T cell-mediated immunity were elicited without adverse drug reactions. This scientific breakthrough is the main reason why we have mRNA vaccines today.
Moreover, this experiment has an interesting story behind it. It is the story of a passionate and persistent scientist, who, despite all the obstacles facing her, made mRNA vaccines a reality. Katalin Karikó emigrated with her husband and daughter from Hungary. After numerous grant funding rejections, she was given a choice of leaving the University of Pennsylvania or accepting a demotion and pay cut. Besides that, she was battling cancer and her husband was unable to return to America for six months due to a visa issue. Despite all these obstacles, she refused to quit and continued her work on mRNA. In 1997, immunologist Drew Weissman moved to the University of Pennsylvania. With all the support, and result comparison Drew and Katalin became good partners, leading to the experiment with nucleosides and immune response and a scientific paper in 2005 that started the era of mRNA vaccines. This is just a brief review of the experiments, and stories of the scientists. Many more people, intellectual and talented scientists have contributed to mRNA vaccines. Ingmar Hoerr created CureVac, Uğur Şahin founded BioNTech, and Eli Gilboa founded the first therapeutic mRNA company, now called Colmmune — these are just a few scientists among many others.
Let us now focus on the perspectives. Without the obvious answer that mRNA vaccines could be used for other viral infections like HIV-1, influenza, Zika, and rabies virus, many scientists emphasize the possibility of application for personalized cancer treatment, protein replacement therapy, and regenerative medicine.
First of all, mRNA can be used to elicit immune responses to mutated oncogenes or regulatory cancer genes, such as p53. The approach would be to focus on creating personalized medicine. The individual cancer mutations and the sequence would be identified and custom mRNA vaccines would be developed to activate the immune system to recognise cancer cells. Not to mention the immunotherapy drugs such as immune checkpoint inhibitors, and chimeric antigen receptor (CAR) T cells. What if we could combine personalized mRNA vaccines and CAR-T cells for individual cancer therapy? One clinical trial in Arizona Cancer Center led by Dr. Julie Bauman with 10 participants showed that 2 patients had all signs of their tumours disappear, and another 5 participants had their tumours shrink.
In addition, mRNA vaccines could be used for protein replacement therapy. Imagine that due to a mutation, a person cannot make a certain protein that is essential for healthy living, or that this protein is dysfunctional. This could be phenylalanine hydroxylase, which plays a major role in phenylalanine metabolism (accumulation of phenylalanine in plasma results in irreversible intellectual disabilities), or arginase, which catalyses the final step in the urea cycle, converting ammonia to urea for excretion, people that have this condition suffer from progressive loss of psychomotor functions, seizures, and lethal hepatic diseases. Protein replacement therapy has emerged as a potential treatment for many rare metabolic disorders, blood disorders, and monogenic diseases.
Finally, regenerative medicine. In 2017 Shinya Yamanaka received the Nobel Prize in Physiology for induced pluripotent stem cells. He used four factors (Oct3/4, Sox2, Klf4, c-Myc) to convert mouse and human somatic cells (differentiated cells with function) into stem cells (undifferentiated cells that can differentiate into different cell types). Stem cells could be used for neurodegenerative and ocular diseases, implications of diabetes mellitus, dental tissue degradation, and cardiovascular or severe skin disorders. Thus, incorporating mRNA encoding growth or transcription factors allows signaling molecules to be introduced into the tissue of interest. This would lead to a direct cell differentiation towards the desired cell type.
In summary, new modifications have led to a new era of mRNA vaccines with a major focus on personalized cancer therapy, protein replacement, regenerative medicine, and different viral infections. We still have a long way to go, considering the fact how new vaccines are, but with all the potential, and many people’s work this will revolutionise the approach to many treatments.
Read more:
Chabanovska O, Galow AM, David R, Lemcke H. mRNA — A game changer in regenerative medicine, cell-based therapy, and reprogramming strategies. Adv Drug Deliv Rev. 2021;179:114002. doi:10.1016/j.addr.2021.114002
Theofanis V., Eleni S. et al. mRNA in the Context of Protein Replacement Therapy. Pharmaceutics 2023, 15(1), 166; https://doi.org/10.3390/pharmaceutics15010166
Vishweshwaraiah YL and Dokholyan NV (2022) mRNA vaccines for cancer immunotherapy. Front. Immunol. 13:1029069. doi:10.3389/fimmu.2022.1029069
Deng Z, Tian Y, Song J, An G and Yang P (2022) mRNA Vaccines: The Dawn of a New Era of Cancer Immunotherapy. Front. Immunol. 13:887125.
doi: 10.3389/fimmu.2022.887125
Elie Dolgin. The tangled history of mRNA vaccines. Nature 2021, Vol 597 323
Norbert Pardi et al.mRNA vaccines — a new era in vaccinology. Nature Reviews Drug Discovery 2018 17 261–279 doi:10.1038/nrd.2017.243
