From Injection to Immunity: Insights on mRNA vaccine development
While mainstream media and television doctors have done a solid job explaining how the “new” technology included in your COVID-19 vaccine works, it never seems to go pass the level of spike proteins or the fact that the “m” in mRNA stands for messenger.
Macro-Level Picture
Lets start out with how the mRNA is stored within a capsule. mRNA can be thought of as an intermediary between your genes (DNA aka the blue-prints of your body) and proteins, in this case a spike protein, which is the unique virulent factor of COVID-19.
In a traditional biology class you’ll learn the transition of information goes DNA—>RNA—>Protein. Thus, the design of the Moderna and Pfizer vaccine starts at stage 2 of this process. The vaccine gives your body the mRNA to produce a unique feature of COVID, the spike protein. The hope is that your immune system will learn what the protein looks like and build unique antibodies (neutralizing assets) to kill the virus.
How does that mRNA even get to my immune system?
The mRNA sequence of the COVID-19 spike protein has been known for well over a year. Essentially vaccine designers put that sequence within a “bubble” of lipids and cholesterol. The exact makeup of these lipids, and how they may affect entry into the body or invoke a response by your cells has been studied since the 1970’s. Some of the early troubles scientists faced was the composition of the lipid nano particles. Presently, our vaccines have a lipid profile that is similar to the membranes of our own cells, reducing the likelihood of rejection. But back in the 1970’s the makeup of the “bubble” could not easily encapsulate the target of choice nor avoid rejection by our own bodies plasma membrane.
To take a step back, it would be logical to question why we don’t directly inject mRNA into our bodies. Wouldn’t this circumvent the 40+ year long endeavor to develop effective nano-particle delivery systems? The roadblock to this approach is that the plasma membrane’s of our cells are negatively charged. This makes mRNA delivery difficult because mRNA itself is negatively charged, in addition to the fact that mRNA is quickly degraded post-translation. While this quick degradation seems an unfortunate feature, it very may well quell your fears of this vaccine altering your DNA. Essentially, once your cells make the spike protein the instructions for that protein are gotten rid off.
When the vaccine is injected, the Lipid Nano-Particle (LNP) encounters an environment of nearly neutral pH. This is ideal, as the lipids are neutrally charged, and therefore we won’t expose the mRNA to the extracellular environment and thus render it incapable of getting into our cells. Yet once this complex is taken pass the most exterior barrier of the cell, the pH changes. The way the cell takes in the vaccine is a process called endocytosis. Essentially, the membrane bends inward and forms a bubble around the vaccine. The pH of this bubble, now within the cell, is much more acidic. This acidity causes the breakdown of the endocytotic vessel and the LNP surrounding the mRNA. This point alone stresses the difficulty in designing LNP. The composition must ensure that its not broken down outside the cell but CAN be broken down within the cell. At this stage, we have free mRNA within our cytosol and intracellular delivery is complete. This mRNA should travel to the protein factory of our cells, the ribosomes. Now, the mRNA can be made into the proper spike protein.
An interesting caveat is how the design of DNA and mRNA vaccines differ. DNA vaccines must reach the nucleus of the cell, requiring it to bypass the plasma membrane, leave the endocytotic vessel, and subsequently bi-pass the nuclear membrane. Yet mRNA vaccine delivery is easier, as it’s final destination is within the cytosol.
Specific Modifications included in Pfizer’s Vaccine
While the mRNA in the vaccine only encodes the S-spike protein, it still requires specialized modification. Of particular concern is the potential that unmodified mRNA would invoke a variety of dangerous immune responses, especially through Pathogen Associated Molecular Patterns (PAMP’s). Luckily, work throughout the years had yielded a direct modification that increases translation of mRNA tenfold and decreases unintentional immune activation. This modification is the replacement of a uradine with N1-methyl-pseudouridine. Uradine is a building block of mRNA, a nucleotidetriphosphate, and is simply being replaced with a less “toxic” building block. When this block is incorporated, the mRNA can silently travel through the proper pathways. Without this, a series of potent RNA receptors would potentially be activated such as Toll-Like Receptors, leading to downstream effects such as cytokine release and translation inhibition. Pfizer’s vaccine (BNT162b2) has used this modified mRNA building block, as it is the most widely used technique. So while the modification of our mRNA sounds dangerous
How does the vaccine teach immune cells and not heart cells?
The current state of technology allows for the placement of immune cell receptors on the LNP. Cells throughout your body all have receptors that allow them to process what is going on outside the cell. Effectively, the outside of the LNP has the address of the immune system on it. An easy analogy to walk through is how these receptors compare to the Postal Service. We have already discussed how the delivery of the mail (mRNA) is conducted by a specialized carrier. We don’t want our mailman to turn around at any point of resistance, say a change in pH, or else we would never get our mail. In the same way, we also don’t want our mailman to arrive to our mailbox and never let go of our mail (like never breaking down that LNP and releasing that mRNA)!
So how do scientists ensure the address:
Contains the right zipcode (ie delivery to the immune system and not our heart)
Contains the right address (ie delivery to antigen presenting cells and not basophils)
Scientists design the receptors to drive accumulation in our lymph nodes, where there is a pre-existing high concentration of antigen presenting cells. You might be familiar with your lymph nodes swelling, and that being an indication of infection in your body. In theory, if we transcribe the mRNA here, the spike protein will be picked up by these cells and our immune system will quickly learn to identify and neutralize the spike protein. On the surface level, size is the most important factor in getting these LNP’s to the lymph node. If the LNP is too big, it never travels past the site where its injected. Its simply too big. If small enough, the LNP can effectively travel within the lymph node and be exposed to the right cells, and learning will hypothetically ensue. One way the design evades being attacked by the immune system is through “PEGylation”. PEG stands for polyethylene glycol, and it was first used in 1977 to deliver bovine serum into the body. Overall, PEG’s prevent the LNP from being tagged for death by the immune system and increases the time in which these particles can move in the blood.
In yet another example of how small details have drastic effects, the angle at which the needle is inserted into your arms can change how effectively the vaccine is processed within the body. When administered via intradermal injection into a section of the skin made of dense connective tissue, the vaccine comes into contact with a higher percentage of “antigen-presenting cells” than if administered subcutaneously. Antigen-presenting cells, such as macrophages and dendritic cells, are responsible for showing your immune system the protein that the mRNA encodes. In this conversation, the antigen is a foreign particle that elicits an immune reaction, such as the spike protein of the Coronavirus.
Why young people who aren’t at risk might consider getting vaccinated
When my peers who are young and metabollically healthy tell me they aren’t getting vaccinated, I often wonder how beneficial or detrimental that decision could be. On one hand, we’ve seen 99% of our friends come down with COVID-19 and barely get flu-like symptoms. Most even believe they’ve been exposed so many times at parties and events they’ve probably had it and didn’t even know it. So I truly understand where the risk curve falls for them. The disease simply hasn’t done enough damage to make a college kid bat an eye. Yet the conventional argument that you should get vaccinated to “help others” and protect yourself is falling on deaf ears. And I think it is important people who get vaccinated know why its more important than just altruism.
Yet as much as COVID-19 “blind vaccination” is overpushed, so is the idea that COVID-19 prevents no danger to young people. The CDC published data refuting the idea that young and healthy people don’t feel the effects of COVID-19. 19% of patients aged 18-34, all whom had no chronic medical conditions, failed to return to a state of normal health a week after testing positive for COVID. While COVID may not kill you, it still represents a potential prolonged illness.
While long term safety remains a valid concern, I believe the efficacy of the vaccine is without question given the current data. The data from a longitudinal study from Decemeber 2020 to March 2021 showed a 1.38 incidence rate of COVID infection for unvaccinated individuals per 1,000 people. For vaccinated people, the incidence rate was just 0.04.
The ultimate reason I got vaccinated
While the study I derive this belief from was small, I believe its strength exists in the general population as a whole. At Emory University, researchers looked at neutralizing antibody levels in 3 groups of patients. The first is those who had COVID at the time of analysis, aka infected individuals. The second is those who survived COVID, and the time of analysis is 1-3 months from infection. The final group is those who had been vaccinated. It is also important to note that the 4 columns represent the original SARS-CoV2 virus (A.1), the major circulating virus in mid 2020 (B.1), the UK variant (B.1.1.7), and the South African strain (N501Y). Neutralizing studies, like the one below, quantify the way our antibodies can block viral infection.
Heres what I see as important in this figure, and ultimately led me to get vaccinared. The high quantity of antibodies produced by vaccinated individuals is simply hard to ignore. In the figure on the far right, we see a strong clustering of data for ALL variants. I essentially view the middle chart as my antibody levels if I took my chances with the virus, while the far right represents my antibody levels if I get vaccinated. For the OG strand, the worst antibody response in a vaccinated individual was still better than the BEST antibody response in a recovered individual. In the simplest terms, you’ll have a higher quantity of antibodies if you’re vaccinated than if you took your chances with the virus. And the vaccine even prevents infection in the first place.
You’re right, as a young and healthy individual you truly won’t bear the brunt of the disease. But this vaccine has, and will continue to prove itself as a successful protective measure against COVID.
Sources:
https://pubmed.ncbi.nlm.nih.gov/33740454/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640897/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997390/#bib46
https://www.nature.com/articles/nrd.2017.243
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918810/
https://link.springer.com/chapter/10.1007/82_2020_217
https://www.trilinkbiotech.com/n1-methylpseudouridine-5-triphosphate.html
https://www.cdc.gov/mmwr/volumes/70/wr/mm7013e3.htm?s_cid=mm7013e3_w#T1_down
https://jamanetwork.com/journals/jama/fullarticle/2777898