The History, Emergence, and Future of Revolutionizing mRNA Vaccines
The History, Emergence, and Future of Revolutionizing mRNA Vaccines
Karena Peterson, 8/14/24
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4 years ago, amidst the mad rush to develop vaccines to treat the rapidly spreading SARS-CoV-2 (commonly known as COVID-19), the first mRNA vaccine to reach full approval of the U.S. Food and Drug Admissions (FDA) emerged. This vaccine was produced by a company called Pfizer- a familiar name to most. Now, it has been administered to countless individuals and was a huge milestone in the development of mRNA vaccinations. However, this process did not begin at Pfizer, or even within this century. MRNA research into its applications in vaccinology has been ongoing since the 1990s and will continue as this new era of vaccination progresses. This revolutionary step was not the first, and will certainly not be the last in regards to mRNA vaccines.
March 23rd, 1990, an article titled, “Direct Gene Transfer into Mouse Muscle in Vivo,” documented a radical discovery. Injecting mice with DNA and mRNA can result in protein production that continues for up to multiple weeks. Expanding on this, two years later an experiment found that injecting mice with mRNA coding for vasopressin (more commonly known as Antidiuretic Hormone, ADH) resolves symptoms in mice with diabetes insipidus. These were huge steps and opened scientific minds up to more uses of mRNA. Research on this topic expanded, yet the emphasis shifted more towards DNA instead of RNA, owing to the challenges associated with RNA.
To understand the issues of mRNA and its applications, it is important to understand the workings of genetic vaccinations first. There are both DNA and RNA-based vaccinations - consisting of, not surprisingly, DNA and RNA respectively. Because of the mentioned roadblocks with RNA, DNA was focused on first and is much more commonly used as of the present. These vaccinations consist of circular DNA molecules called plasmids taken from bacterial cells. These plasmids- when injected into the bloodstream of an animal- travel through a cell's cytoplasm and nuclear membrane to enter a cell’s nucleus. When inside animal cells, the code is read, translated into mRNA, moved into the cytoplasm, and then translated into a protein. This protein is recognized as foreign to the organism and triggers the production of antibodies by the immune system. Now, immune memory cells are formed that allow the immune system to quickly recognize the virus by the protein that was previously produced. In contrast, using a mRNA vaccine does not require crossing into the nucleus. The strands of mRNA only have to pass into the cytoplasm to trigger the same series of effects. This distinction may seem trivial, but, in actuality, has significant implications.
DNA vaccinations have an additional step in comparison to RNA-based. Consequently, DNA vaccines don’t produce as potent of an immune response as RNA, which could be considered problematic and lower the effectiveness of a given vaccine. On the flip side, RNA-based vaccines may be too immunostimulatory. This can cause inflammation within the muscles, as well as other side effects as a result of the immune system’s higher reactivity. Many experienced side effects of the Phfizer vaccine, likely for this reason. Although these irksome side effects were tolerated in order to prevent the spread of SARS-CoV-2, they may not be well received for future implications against non-infectious diseases. This may limit the use of mRNA vaccines. It is also important to note that while the DNA may have an additional step involved, a single plasmid DNA can create numerous mRNA. It is apparent that stating one is “better” for this reason is challenging; superiority may depend on the case.
The differences between these two vaccines pose another challenge. The inherent nature of DNA is different from RNA in terms of stability. While DNA vaccines can be stable at room temperature for months, RNA molecules are infamously fragile and require extraordinary cold temperatures. This issue was well discussed during the SARS-CoV-2 pandemic- many heard of the challenges with transporting and storing the vaccines. RNA as a molecule struggles outside of the cell.
Finally, RNA is quickly degraded by the body’s enzymes before it is able to deliver its information into the cell. This is in contrast to DNA, which can take weeks to degrade. This can cause inefficient in vivo delivery.
Because of the main struggles with RNA vaccinations pertaining to immunogenicity, stability and delivery, DNA vaccines were focused on and developed earlier. However, with the SARS-CoV-2 pandemic, government funding and pressure on the development of RNA vaccines were prioritized. It must be noted that these vaccines were not completely new by the time SARS-CoV-2 rolled around, many companies were in the process of finalizing their RNA-based vaccines and technology. Furthermore, the technology that helped overcome the issues was not brand new but has been in the making since the realization of RNA potential in the 1990s. Still, the pandemic gave a surge of funding to companies such as Pfizer and Moderna, allowing them to release their vaccines.
The road to modern technology that enables the use of mRNA vaccines is long and full of many technical and scientific advances. Many aspects come into play for the utilization of mRNA. One significant revelation is the use of lipid-based nanoparticles and polyplexes/polymeric nanoparticles as delivery systems or carriers. These- especially lipid-based, are popular as they protect the mRNA strands from degradation. They also stabilize the mRNA. Chemical modifications before the injection have also shown to somewhat help with stability. This helped overcome significant struggles with the earlier tests of mRNA vaccinations. However, RNA has plenty of benefits that make the challenging process worth it, and make the future trials worth the potential results.
As alluded to before, mRNA vaccines have more uses than just for the SARS-CoV-2 pandemic. A very popular potential is the potential for cancer vaccines. Ideas of this have been considered and tested for around a decade by the time of the pandemic. There are currently dozens of clinical trials testing the uses of mRNA vaccines to boost the immune response against tumors in subjects. Still, these vaccines have yet to prove themselves or be approved by the FDA. While this prospect is exciting, most studies have been conducted with small subject group sizes, and there are issues involved- such as the slow development of personalized cancer vaccines. This issue is a consequential one; cancer often develops fast, and treatment must be fast. However, a carefully optimistic attitude is held by many experts- this may be a way to teach the body to recognize cancer cells as different from the rest of the body. This impressive potential is just one of the many ideas for mRNA.
While the public was on lockdown, scientists were busy finalizing and improving the work of decades. MRNA vaccines are unique and useful, yet problematic, reflected by the only recent approval and administration of the first mRNA vaccine. Overcoming the challenges of mRNA was surely difficult and troublesome, yet millions now have the Phfizer vaccine today. Looking forward, mRNA strands could be utilized for many more diseases- including non-infectious. While it is not a simple or straightforward journey, it is a hopeful one.
References:
How mRNA Vaccines Might Help Treat Cancer - NCI
Cancer mRNA vaccines: clinical advances and future opportunities | Nature Reviews Clinical Oncology
The Long History of mRNA Vaccines | Johns Hopkins | Bloomberg School of Public Health (jhu.edu)
How do mRNA vaccines work? (medicalnewstoday.com)
mRNA vaccines — a new era in vaccinology | Nature Reviews Drug Discovery
Advances in mRNA Vaccines for Infectious Diseases - PMC (nih.gov)
The History of the mRNA Vaccines | History of Vaccines
Direct gene transfer into mouse muscle in vivo - PubMed (nih.gov)
mRNA Vaccines: What They Are & How They Work (clevelandclinic.org)
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