I was shocked to learn that the newly-developed COVID-19 vaccines are mRNA-based.
As an undergraduate researcher, I can never forget the pain RNA extractions have inflicted upon me. mRNAs are extremely vulnerable molecules that can be easily degraded by almost anything. Therefore, it was particularly difficult for me to imagine how mRNAs could make effective vaccines. Yet, as a budding scientist, it would be extremely irresponsible of me to doubt the effectiveness of the mRNA vaccines without first finding out more about them.
What are mRNA vaccines, and why did we choose them?
I had many initial doubts about the use of the Moderna and Pfizer-BioNTech mRNA vaccines. Of all, my greatest concern and confusion was: why mRNA vaccines? There are so many kinds of well-established vaccines. The inactivated vaccines used for flu and live-attenuated vaccines used for diseases like smallpox and measles are all known to work well. So, given these traditional vaccine methods, why is it that we are trying out this new mRNA vaccine that we know nothing about during a state of emergency?
Well, mRNA vaccines turn out to be the only kind of vaccines that may buy us some time to win the race against this deadly virus. With 300,000 to 400,000 new cases of COVID-19 being reported daily worldwide at the time of writing, it is simply impossible to keep up with the spread of the pandemic by using traditional inactivated, live-attenuated, or protein subunit vaccines. These traditional vaccines require either proliferation of the virus, a weakened version of the virus in large tissue cultures, or mass production and purification of the protein, all of which take a tremendous amount of time. mRNA vaccines, on the other hand, can be easily produced via an in vitro transcription experiment. In this simple reaction, the RNA polymerase enzyme transcribes template DNA into mRNAs that encode for the vaccine antigen. Both the Pfizer-BioNTech BNT162b2 mRNA vaccine and the Moderna mRNA-1273 vaccine are made this way, allowing for the production of roughly 800,000 doses of vaccine per day.
Contrary to common belief, mRNA vaccines also have a surprisingly long history. The idea of exploring mRNAs as potential therapeutics can be dated back to 1978, when scientists began introducing rabbit globin mRNA into mouse lymphocytes using liposomes. The first mRNA vaccine encoding cancer antigens was developed as early as 1995. Many mRNA vaccines against infectious diseases have also entered clinical trials in 2017. The primary reason why mRNA vaccines have never been officially introduced was that there was not a sense of urgency—not until the COVID-19 pandemic.
How do the Pfizer-BioNtech and Moderna mRNA vaccines work?
Both the Pfizer-BioNtech and Moderna vaccine mRNAs encode for the Spike (S) protein of the SARS-CoV2 virus. The S protein interacts with ACE receptors on the surface of our cells, acting as a key to unlock entry. Therefore, one obvious way to fight the virus is to ruin these “keys.” Our antibodies are particularly good at doing this job. These defense molecules are able to bind to complementary surfaces on the viral protein and block the S protein from associating with the ACE receptors. By introducing the viral S protein using mRNA, we are introducing the S protein as an antigen to elicit an immune response.
Effectively, we are giving our cells a glimpse of the devil prior to the arrival of the actual devil so that they can recognize what to fend off. Following translation of the vaccine mRNA into protein, the mature S protein is chopped up by intracellular proteases and released to the exterior of the cell. Some of these pieces become antigenic peptide epitopes when taken up by neighbouring cells and loaded onto surface display complexes called MHCs. These displays are then recognized by immune cells, specifically helper T cells and B cells, which ultimately results in the mass production of antibodies.
How does the mRNA survive in our bodies?
While we have just gone over the basic immunological principles behind mRNA vaccines, the question remains: how do these vulnerable mRNA molecules even manage to survive so they are capable of eliciting an immune response? Given the abundance of hungry RNA-degraders known as RNases roaming around in the bloodstream and the susceptibility of mRNAs as a chemical entity, a number of challenges need to be overcome for an mRNA vaccine to work. Fortunately, scientists have managed to figure out solutions to these issues.
Getting past the RNases with lipid nanoparticles (LNP)
The first challenge is to get past the hungry RNases when the mRNA vaccine is first injected into the bloodstream. To prevent mRNA degradation by ribonucleases, Pfizer-BioNtech and Moderna vaccines have lipid coats encapsulating their mRNA molecules. The lipid coat is more specifically referred to as lipid nanoparticles (LNP) and is composed of a mixture of lipids that are compatible with the membrane of our own cells. Apart from denying access of RNases to the mRNAs, these LNPs also facilitate the release of the mRNA into cells. When LNPs encounter the plasma membranes of our cells, they fuse and become part of them, consequently releasing the mRNA molecules into the cytoplasm.
Nucleoside modifications and stability elements to ensure translation
So now that we have safely guided our mRNA to the cytoplasm, how do we make sure that it is properly translated into a spike protein for our cells to recognize and remember in case of a real SARS-CoV2 attack? Translational inhibition of the mRNA is definitely another hurdle to overcome. Since single-stranded RNA viruses release their mRNA in a similar manner as the vaccine, our immune system has evolved to recognize any foreign single-stranded RNAs as a pathogen-associated molecular pattern (PAMP) and learned to inhibit the translation of these mRNA molecules. Therefore, to ensure that our vaccine mRNA gets properly translated, researchers incorporated modified nucleosides that would allow the mRNA to evade cellular immunity and increase translational efficiency. Specifically, one particular RNA nucleoside, uridine, was replaced by pseudouridines in both the Pfizer-BioNTech BNT162b2 vaccine and the Moderna mRNA-1273 vaccine. Moreover, other modifications, such as the inclusion of a regulatory region of the human alpha-globin gene known as the 5’ UTR, a 5’ cap, and an optimized poly(A) tail, were also made to increase the stability and translational efficiency of the vaccine mRNA.
What about the new SaRS-CoV-2 variants?
After some detailed discussions on the biological mechanisms behind mRNA vaccines, I hope you feel more assured about these mRNA vaccines, as I do. But what about the new mutations? Will the vaccines still be effective against these new SaRS-CoV-2 variants?
At the moment, nobody can give a definitive answer on how effective the mRNA vaccines—or any vaccine—will be against newly arising variants. Early results have revealed variations in vaccine efficacy against new variants; for example. while the Pfizer-BioNTech and Moderna vaccine may still offer decent protection against some of the UK variants, they appear less effective against the South Africa variant. However, since both vaccines are multi-epitope, it is unlikely that any particular variant will completely abolish the protective effects of the vaccines. Even if a few epitopes may be mutated in a particular variant, there are still other epitopes that will allow the virus to be neutralized to some extent. New vaccines specifically designed to target the newly arising variants are also being developed, and since the first mRNA vaccines only took 11 months to develop following the initial release of the viral sequences, these new ones are not expected to take too long.
While scientists and medical professionals are trying their best to protect against COVID-19, we must also do our part by following the COVID-19 regulations and keeping up with mask wearing, sanitizing, and social distancing. Vaccines show promise for us to win the battle against COVID-19, but it would be a mistake to underestimate our enemy.
