Covid-19 and the marvel of mRNA vaccine: Know how it works

To most people in the world, we millennials in particular, before the year 2020 the idea of pandemics seemed confined to history textbooks and to Hollywood movies. None of us could have had an inkling as to the turn our lives were about to take. Our hubris was soon checked, and the limits of our public health systems and scientific understanding were brought to light. But the pandemic also showed us the extraordinary things that we can achieve, the mountains we can climb, through sheer determination and hard work. Perhaps our shortcomings were inevitable. Perhaps we need depths of failure in order to create heights of accomplishment. There is no better way to understand the story of these accomplishments than to study the science and sophistication behind our saviors - the vaccines.

Every few generations come to a discovery that changes the world. Or, perhaps, this isn’t entirely accurate. These discoveries do not change the world itself so much as the way we humans look at it; or our perspective of it. Heliocentricity. Evolution. Relativity. Then there are inventions. The best inventions are the ones that don’t exactly change our perspective of the world, but rather, our very approach to solving the world’s problems. So, the need for speedy transport was met not by building faster ships but by taking them to the sky. Come to think of it, why spend days slugging it on the high seas when the same destination can be reached in a fraction of the time, simply by changing our medium of travel? In the same vein, why spend time and resources producing better medication, waiting for people to contract diseases, and then treating them, when you can induce a milder variant of the disease and teach them to fight it for themselves? Thus came vaccines; prevention, rather than cure.

Vaccines are an invention that has possibly saved more lives than any other in history. Studying the evolution of the science of vaccines (Vaccinology) is a fascinating journey as we see its integration with parallel discoveries that science has made through the centuries. And there may be no better way to appreciate this integration than to study the working of an mRNA vaccine.

It is important to understand that the production of mRNA vaccines is a comparatively recent phenomenon. In the two centuries from the creation of the smallpox vaccine (1796) to the first instances of RNA transfection (1970s-1980s), vaccines mainly consisted of either the killed version of the pathogen that causes disease (inactivated vaccines) or, the weakened- an attenuated -a form of the pathogen (live-attenuated vaccines). The former includes the hepatitis-A and rabies vaccines while MMR, smallpox and chickenpox vaccines constitute the latter. A series of ground-breaking discoveries in the late 20^th century would lay the foundation for the production of the modern mRNA vaccines, the most famous examples of which are, of course, the Pfizer-BioNTech and Moderna vaccines for Covid-19.

Let me now revert to the topic of the integration of parallel scientific discoveries with those of vaccinology. The elucidation of the structure of Deoxyribose Nucleic Acid (DNA) in 1953 by James Watson and Francis Crick and the subsequent discovery of Messenger Ribonucleic Acid (mRNA) by Sydney Brenner and Francois Jacob in 1961 clarified for the first time the mechanisms of inheritance and the flow of hereditary information. One might wonder what the relevance of genetics is in the science of vaccinology. Vaccines, as explained earlier, mainly consisted of weakened or dead pathogens which are injected into the human body to induce an immune response and train our immune system so it can better fight off an actual infection we may acquire in the future. Why then, did we see the conversation on vaccines shift to a one on inheritance?

To understand this shift, we must first understand the working of the genetic code. Consider for a moment the better-known ‘Morse’Code. Morse code consists of a system of dots and dashes which are meant to represent letters and digits. When read in a certain order, these letters combine to form words and further sentences. For example:

.. / .-.. --- …- . / -.-- --- ..-

When translated, becomes:

I LOVE YOU

One can infer from this the symbols which correspond to particular letters. For instance, ‘I’ is represented by ‘..´, ‘O’ by ‘---’ and so forth. The genetic code is a perfect analogy. DNA is made up of smaller subunits called nucleotides. Each nucleotide is further made up of a sugar molecule, an acid moiety, and a compound called a ‘base’. We can disregard the sugar and the acid as concerns the genetic code. Only the bases hold significance in this area. There are four kinds of bases found in DNA- Adenine (A), Guanine (G), Thymine (T), and Cytosine (C). These bases are represented by the letters A, G, T, and C. The DNA code is like the Morse code, the only difference being that instead of dots and dashes, it is made up entirely of the four letters A, G, T, and C.

This code is present contiguously in our genome. However, our cells are only capable of reading this genetic code three letters at a time (a triplet code or ‘codon’). Consider the following base sequence:

AGTTCGTCAAGT

Our cells would interpret it as:

AGT   TCG   TCA   AGT

Continuing with the same metaphor, while in Morse code the dots and dashes represent letters and digits, in the genetic code, the triplets code for amino acids. As you may be aware, amino acids are small subunits that combine to form proteins. Proteins are the most essential compounds for life, they form hormones (insulin), antibodies, antigens, enzymes, receptors, etc. Each triplet code (there are 64 in all) corresponds to one out of 20 amino acids that form proteins. The same amino acid can be coded for by multiple codons and there exist additional codons for starting and stopping protein chains (recall how in Morse code too there exist codes that represent question marks, full stops, etc.). These start and stop codons, one might say, punctuate the protein chain.

However, when we transmit Morse code messages from one location to another, we convert them into forms that are easier to transport and receive, say electrical impulses, radio waves or even flashing lights. By the same principle, our cells do not read the genetic code in the form of DNA. DNA is first converted into an intermediate molecule called messenger RNA or mRNA for short. This mRNA then acts as the template for the production of proteins, a process that biologists call translation.

The mRNA and the DNA codes are almost identical, but, with one notable difference. The thymine (T) in DNA is replaced with a different base called Uracil (U) in mRNA. Hence, the mRNA code is composed of the 4 letters A, G, C, and U. It is this mRNA code that the cells read.

With the basics now cleared up, we can return to the topic of vaccines. There is one difference between inactivated vaccines and live attenuated vaccines that are crucial to our story. Inactivated vaccines cause only mild infections, usually accompanied by some fever and body aches when injected (as the pathogen is no longer alive).  The immunity that they provide is not very strong as a result, causing the need for multiple doses and booster shots. Since live vaccines inject weakened but nonetheless living pathogens into the host body, the microorganisms replicate and better imitate a naturally acquired infection. This helps provide strong immunity with merely one or two doses.  Of course, the symptoms experienced on vaccination may be relatively more severe.

Is it possible, then, to make a class of vaccines that provide strong immunity with relatively few doses and yet do not cause severe infection?

A virus, when it enters a host organism, uses certain proteins on its surface to bind to the membranes of the host organism’s cells. Coronavirus, recall, used spike proteins on its surface to bind to the Angiotensin Converting Enzyme-2 (ACE-2) receptors present on the cell membranes of certain cells in our lungs, heart, and gastrointestinal tract. It is important to note that while the spike protein is responsible for the entry of the virus into cells, it does not cause any disease in itself. The actual virus is responsible for that. A spike protein injected alone into an organism will not cause any infection on its own.

Additionally, viruses can be classified into two distinct camps based on whether their genetic material is in the form of DNA or RNA. RNA viruses usually present greater cause for concern. Since RNA is less stable than DNA, RNA viruses mutate faster, resulting in a greater amount of variation. Viruses such as the coronavirus and HIV carry their genetic content in the form of RNA, they do not contain DNA at all.

What is crucial is that the spike protein is, as the name suggests, a protein! This means that it will be coded for by a stretch of RNA. So, could it be possible to take the genome of the virus, isolate the part which codes for the spike protein, modify it into the form of mRNA, and inject it into a human, prompting the human cells to produce the protein, tricking them, as it were, to produce a molecule alien to them? If this could be done, the cells would produce the spike protein and the immune system of the host would immediately identify the protein as foreign, producing the necessary antibodies and thereby generating immunity. Immune cells in our body produce various different antibodies to fight off infections, however, the ones we concern ourselves with in this discussion are called ‘neutralizing antibodies’. These are essential for our body to fight off attacks by viruses. They work by binding to the spikes on the virus membranes, rendering them incapable of binding to receptors on the host cells and causing infection.  You cannot fit a key into a lock if the lock already has a key in it! Without the ability to enter cells, viruses cannot replicate and infect their hosts. The antibodies produced would remain in the recipient’s bloodstream, protecting him/her from future infection. And, since only the code for the spike protein was injected into the body, only the spike protein will be made and no infection will be caused.

This is exactly what an mRNA vaccine does. The Pfizer-BioNTech vaccine contained a stretch of mRNA that the coronaviruses use to produce their spike proteins. This mRNA enters our body cells where our cells use it to produce the spike protein, arming our immune system if, in the future, an actual virus is to enter our body. This very technique of tricking microorganisms and cells into producing a foreign protein is used in the commercial production of insulin and blood clotting factor VIII, among others. A piece of DNA that codes for insulin is injected into bacteria, the bacteria are cloned, and the insulin they produce is collected and put into vials for diabetics. Indeed, the uses of this technology range far beyond vaccines.

The sheer complexity and beauty behind this mechanism can be breathtaking at first glance. Yet, as with most emergent technologies, unnecessary misconceptions and conspiracy theories about mRNA vaccines soon arose.  One such misconception is that when the mRNA enters our cells, it is capable of tampering with our own genome. This is completely false. The mRNA stretch never enters the nuclei of the cells, where the genetic content is located.  Hence, it cannot affect our own genes in any way. Furthermore, the average lifespan of an mRNA molecule is a mere thirty minutes, with the upper limit of the lifespan being just 24 hours. Given this, all of the foreign genetic material injected into our bodies gets digested quickly, making long-term side effects unlikely. Furthermore, with the Pfizer-BioNTech vaccine in particular, we should know that rumors of it containing eggs, gelatine, electrodes, preservatives, latex, metals, and microelectronics are simply wrong. It contains as the active ingredient simply a slightly modified version of mRNA which codes for the viral spike glycoprotein of SARS-CoV-2, along with a few inactive ingredients including lipids and salts, which protect the mRNA molecules and stabilize the pH of the vaccine.

If we are to crush this pandemic as quickly as possible and prevent further infections and deaths, we need to realize the folly behind the denial of vaccine efficiency. Messenger RNA vaccines also enable mass production with great speed, prepping us for future novel pathogens and pandemics, which may inevitably arise. Increasing public awareness about their mechanism of action and also possible risk factors like myocarditis is the need of the hour.  Furthermore, technological progress is needed to help stabilise the vaccine and reduce its temperature sensitivity. Work on these fronts has already begun.

MRNA vaccines are a shining example of the heights of achievement which the human intellect and industry are capable of. Appreciating this scientific marvel, understanding it, and propagating it will go a long way in catalysing human scientific endeavors.

(Article by Vinayak Talwar, Class 12 student of Step by Step School, Noida)