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ACEP Now: Vol 40 – No 02 – February 2021

COVID-19 mRNA vaccine induces an immune response through the activation of T cells with antigenes obtained out of the viral spike protein (red)., which is encoded by the mRNA contained in the vaccine. APC=antigen-presenting cell. Credit: JUAN GAERTNER / SCIENCE SOURCE

Two COVID-19 vaccine candidates, one from Pfizer-BioNTech and the other from Moderna, have received emergency use authorization (EUA) from the Food and Drug Administration. For the first time outside of clinical trial environment, vaccinations began in the United States in mid-December. 

Ingredients in the Pfizer and Moderna vaccines are listed in Tables 1 and 2. Both vaccines use gene-based technology, relying on synthetic messenger RNA (mRNA).¹ In each, a synthetic strand of mRNA created for these vaccines was designed to emulate the SARS-CoV-2 mRNA strand that specifically codes for the production of the coronavirus-specific spike protein. Once inside of the cell, our own ribosomes translate the synthetic mRNA into the spike protein. That protein is then recognized as foreign, and our immune systems create antibodies. 

This spike protein was chosen because it binds and fuses with human cells, allowing entry.1 It resides on the viral capsid (envelope) of the coronavirus, a lipid bilayer that encloses the viral nuclear material.² Thus, this viral surface spike protein is visible to the human immune system and is highly antigenic during virus invasion. 

Unlike conventional vaccines, the chosen mRNA segment does not come from “live” viruses grown in eggs or cell culture. Rather, it is a hybrid mRNA synthesized in the lab.^1,3 Therefore, such vaccines can be developed rapidly in large quantities, with the potential for rapid production and delivery to large-scale recipient populations. This technology is highly attractive for the ability to produce and provide vaccine doses rapidly, both to address current needs and to address subsequent pandemics that may appear and spread rapidly in the future.

Vaccines based on mRNA represent a new approach, one that had not previously been used clinically for infectious diseases. There have been some small, early-phase trials researching mRNA vaccines for diseases such as rabies, influenza, and Zika. However, the majority of mRNA research until recently had been directed at cancer immunotherapy. This is the first time mRNA vaccines have been proposed for wide-scale clinical release and utilization. Of note, two other vaccine candidates are currently either in trials or widespread use: the University of Oxford/AstraZeneca vaccine (now in use in the United Kingdom) and the Johnson & Johnson/Janssen Pharmaceuticals vaccine (trials are under way). These use more traditional vaccine technologies based on adenoviruses.  

Table 1: Ingredients of Pfizer-BioNTech mRNA Vaccine

Source

Table 2: Ingredients of Moderna Vaccine

Source

More Detail on How mRNA Vaccines Work

These mRNA vaccine candidates are exciting in that they can be rapidly and safely produced but also have thus far demonstrated greater than 94 to 95 percent immunization success. This is a success rate far in excess of other historical vaccines. But let’s look a bit more closely at how they achieve this. 

During vaccination, the lab-generated mRNA template that codes for the spike protein is delivered, in these cases, via injection into a host’s muscle. (It has been proposed that such vaccines could potentially be delivered by other routes such as nasal spray.)⁴ As this mRNA segment is not part of an intact virion, the mRNA template has been encased, in the lab, within a lipid carrier molecule to further assist the mRNA in successfully reaching and crossing the host cell membrane to carry out its function of entering cells of the just-vaccinated host. 

Upon entering the cell’s cytoplasm, the mRNA redirects some of the cell’s protein production machinery (of which ribosomes are the workhorse) to begin producing viral spike proteins. The produced spike proteins are then incorporated into and “displayed” on the host cell’s outer membrane surface.⁵ This mRNA-directed production is, in some ways, similar to actual virus infection where the infecting virus hijacks the cell’s machinery. When a replication-competent virus infects a cell, the viral mRNA introduced contains templates for all of the proteins the virus needs to replicate. Those sequences redirect our cellular production line into making all the different virus particle proteins. A completed virion is then assembled. A viral particle either exits a cell via an established cellular pathway or is released when a dying cell ruptures. However, in this case only one virus component is produced: the spike protein. None of the other 28 proteins in a typical SARS-CoV-2 genome are manufactured, so the virus itself has not been replicated. Therefore, the host cell’s functions are not otherwise disrupted, and the cell does not die during this production process. 

With the newly manufactured spike protein now situated on the outer membrane of the host cell, it is visible to antibody and T-cell systems. This triggers the body to develop an immunological response, just as it would if the real virus were present. Thus, the body’s immune system has now been “immunized” to attack the SARS-CoV-2 virus if it subsequently invades. In addition, the cell breaks down the existing mRNA after it translates its message into the spike protein, meaning that it can continue to function normally and with no long-term changes.^4,5 It is also important to note that while the synthetic mRNA remains in the cell cytoplasm until broken down, it never enters the nucleus of the cell where the cell’s DNA resides.⁵ Therefore, mRNA vaccines cannot introduce any changes into our own genomes.

Are There Concerns?

With any new technology come concerns, especially with ones like mRNA vaccines, which were developed rapidly and previously had never been delivered to millions of humans. Already, there are multiple myths circulating online and elsewhere, at least two of which relate to the function of mRNA vaccines.^6,7 One myth is that mRNA vaccines use a “live” version of the coronavirus. This is false. As described above, the mRNA for these vaccines was synthetically generated in laboratories; mRNA vaccines are not grown in eggs or cell cultures, though some other established vaccines in use for other diseases are. A second myth is that mRNA vaccines can alter the human cell’s DNA. As also noted previously, the synthetic mRNA remains in the cell’s cytoplasm until broken down and never enters the nucleus of the cell.

Several other hypothetical problems have been suggested. One of the chief hypothetical concerns is the possibility of the vaccine inducing an autoimmune state and/or heightened inflammatory state in the vaccinated host.⁷ Some have suggested that, by the human cell installing the virus spike protein on its cell membrane, certain immune systems could become hyperreactive and identify the whole cell as “foreign” and develop autoantibodies to all cells in its “lineage” all over the human body. This would in effect create a temporary or permanent autoimmune disease state. Others have proposed autoimmune reactions could occur if there are spike protein homologues elsewhere in the body.⁸ Autoimmune induction like this has previously occurred in medical therapies, most recently in some cases of cancer immunotherapy. However, many Pfizer clinical trial vaccine recipients are now over nine months out from their initial injections. So far, no reports have been released on any type of autoimmune or other ongoing or evolving debilitating symptoms related to vaccination. 

As with any new medical technology, all of the answers we need will not be available until a very large number of people have received it. However, with the information available to us currently, a risk-benefit assessment strongly favors mRNA vaccination. This is especially true for those at increased risk of COVID-19 exposure or those at increased risk of developing more severe disease.

Dr. Severance is adjunct assistant professor in the department of medicine at Duke University School of Medicine in Durham, North Carolina, and attending physician in the division of hyperbaric medicine, department of emergency medicine at Erlanger Baroness Medical Center/Erlanger Health System and UT College of Medicine/UT Health Science Center in Chattanooga, Tennessee. Contact him via Linked in.

References

1. Abbasi J. COVID-19 and mRNA vaccines—first large test for a new approach. JAMA. 2020;324(12):1125-1127. 
2. Coronavirus. Wikipedia website. Accessed Jan. 10, 2020.
3. Garde D, Saltzman J. The story of mRNA: how a once-dismissed idea became a leading technology in the COVID vaccine race. Stat website. Accessed Jan. 10, 2020.
4. RNA vaccines: an introduction. PHG Foundation website. Accessed Jan. 10, 2020.
5. Understanding mRNA COVID-19 vaccines. Centers for Disease Control and Prevention website. Accessed Jan. 10, 2020. 
6. Nania R. 7 myths about coronavirus vaccines. AARP website. Accessed Jan. 10, 2020.
7. Adams M. mRNA vaccines, a primer: How they work, why they’re “cleaner” than traditional vaccines, and why they might prove catastrophic in a rushed coronavirus response. Natural News website. Accessed Jan. 10, 2020.
8. No proof of Pfizer’s COVID-19 vaccine causing female sterilisation. Boom website. Accessed Jan. 10, 2020.