Earlier this month the world got exciting news: the Pfizer and Moderna vaccines for Covid-19 were over 90% effective in clinical trails. This means that for every 10 people vaccinated who would have become ill, only one went on to get sick. While these are early results and the clinical trials is not yet over, 90% and over is an excellent and remarkable level of efficacy. For comparison, seasonal flu vaccines provide 60% efficacy, while the mumps vaccine provides 88%.
The way these vaccines are made is something else especially remarkable. Traditional vaccines use specific proteins generated from an extensive manufacturing process. In contrast, the two potential vaccines utilize RNA, a molecule like DNA. If approved for use, these will be the world’s first mRNA vaccines for use in humans!
Immune Response
Virus particles and microbes are everywhere. Each day, the human body is pummeled by these tiny lifeforms. Many are harmless to humans, but some can lead to mild sickness and others to death. The body has several ways of preventing this including acquiring immunity to specific tiny invaders over time. When a foreign entity, like a virus, first enters the body, antibodies in the blood stream will bind to proteins on the virus. This association allows the body to recognize the virus in the future and direct immune cells to attack.
Think of it like this: imagine being a doorman at a club and noticing a known undesired visitor by the colour of their jacket. You alert the other bouncers on your walkie-talkie and they escort the person off the premises. Here you relied on your memory of a bad person’s appearance. In a similar manner, the body relies on antibodies that will recognize a given virus.
Of course, this acquired immune response relies on surviving the first attack. As many viruses are lethal, vaccines work by causing the production of recognizer antibodies before a virus has even entered a body. Imagine recognizing the man at the club before he had ever been there. How could this be? Maybe by being warned by bouncers from other clubs that this guy is a troublemaker. This could occur by receiving a picture of someone to watch out for.
Traditional Vaccination
Classical vaccines work in two ways. They may introduce a live but weakened virus able to replicate in the body without causing disease symptoms. Or, alternatively, introduce a component of the virus which the immune system will directly recognize instead. This component is usually some kind of protein that is present on the outside of the virus’ surface. The body uses the protein to recognize the live virus when encountered. It is the picture of the unwanted guest.
How Cells Make Proteins
Proteins are large molecules within cells that carry out a diverse range of functions. They transport other molecules, carry chemical messages, provide structure, bind to other molecules to trigger changes, and much more. Basically, if anything happens in a cell, proteins are involved. Cells build proteins from smaller molecules called amino acids according to specific instructions found in DNA.
DNA is stored in a structure within cells called the nucleus. Proteins are made at another structure called the ribosome. However, DNA never leaves the nucleus. Therefore, it must be first transcribed into a similar molecule called mRNA that can leave the nucleus and travel to ribosomes.
This is a complicated process and can be compared to baking. In this analogy, the cell is a kitchen, amino acids are the ingredients and the completed protein is the cake fresh out of the oven. DNA is like a recipe. But, imagine it being like an old family recipe that is written in hard-to-read-handwriting and stuck in a thick recipe book. To make recipes easier to use when baking, they might be printed out again on a scrap piece of paper. DNA is treated similarly and transcribed. After this, mRNA also encodes instructions to make a specific protein. When the mRNA reaches the ribosome, the information is translated again, and the proper amino acids are collected and assembled, just as multiple ingredients are mixed in a bowl. Eventually, a new protein is complete.
How Scientists Make Proteins for Medical Use
Many medications are proteins, including key components of vaccines. Since they are constructed biologically within a cell and not through chemical reactions, scientists must use the same processes when making proteins for medical use. However, this is done in a controlled way. Manufacturers take carefully chosen cells and genetically engineer them to have the DNA sequences for a given protein. These cells are grown in large vats under carefully controlled environmental conditions. The cells will produce the right protein under certain circumstances, and these can then be separated out from everything else. This is a simplified description but the manufacturing process for protein viral components is complex, time-consuming, and expensive.
Alternatives for Live Viruses and Proteins: DNA Vaccines
Other vaccines, where weakened forms of a virus are injected, can bring a small risk of infection and cause some disease-like symptoms. This explains why some people who receive the flu shot feel ill the next day. This is usually little more than an inconvenience. However, another vaccine technology presents an alternative. Traditional vaccines rely on an outside-manufactured protein or a weakened live virus entering the body and triggering the body to create antibodies. As mentioned above, cells use our DNA as a recipe for making proteins. If DNA for a viral component is injected, the cell can use those instructions to make the recognizable viral protein using the cell’s own protein-making structures.
You might think that this would be bad for the cell. That commandeering the process to make viral proteins may stop the cell from making proteins it needs to function. However, this is not the case. There are many ribosomes within a cell. Therefore, the cell produces both protein types at the same time.
RNA Vaccines
A further alternative is using mRNA to create a vaccine. In theory, since mRNA is the intermediate recipe between coded DNA and a completed protein, this technology works to make the vaccination process even more efficient within the body.
Classical vaccination works by providing the body with an antigen (i.e. the recognizable molecule) for a virus. The body generates antibodies that allow this recognizing to take place later. mRNA vaccines attack this challenge from both directions. The mRNA sequences used in the vaccine encode for the component of the virus that the body recognizes. However, in other types of mRNA vaccines, the mRNA does not code for this protein. Instead, the mRNA codes for antibody proteins that are known to be found in people with prior immunity to the virus. Therefore, the entire antibody generation process is sidestepped, and the body may recognize the virus from the get-go.
Other Benefits
In DNA vaccines, the DNA injected into the body must first be delivered into the nucleus to begin the DNA à mRNA à Protein process. Since the nucleus also contains all the cell’s DNA, there is a slight risk that the vaccine DNA may integrate into the cell DNA (this is one thing that clinical trials must show evidence against). However, since the mRNA of RNA vaccines does not enter the nucleus, there is no risk of this happening with these vaccines.
A further benefit of RNA vaccines is the straight forwardness of manufacture. Creating protein is a complicated process that requires specialized cells to generate the protein and very specialized equipment and conditions to grow them and isolate the protein. However, mRNA can be made without cells in a simple biology laboratory with a small kit of ingredients. During my MSc degree research, I made mRNA many times. All that is required is DNA to copy, and protein to prepare the DNA, and molecules to assemble the mRNA. The entire process can be completed in about two days.
Challenges
DNA and mRNA are very similar molecules. DNA consists of two stranded arranged in a twisted ladder structure. The obvious feature distinguishing RNA is that it is only one strand. These physical structures are crucial for their functions. The double-strandedness of DNA makes it very stable. It is resistant to temperature and can even be left for an extended period in a laboratory test tube or on a murder weapon at a crime scene. Alternatively, one-stranded mRNA deteriorates very quickly.
This presents several issues for the storage of mRNA vaccines. Lab-generated mRNA is very temperature-sensitive and must be kept very cold – approximately -80°C. Research lab freezers used to store mRNA do this, but this is much colder than conventional options. The Pfizer vaccine is stored at -70°C, while the Moderna vaccine is kept at -30°C for extended periods of time. This second option is more doable. Industrial freezers are built to keep temperatures below -20°C. For example, those large freezers at your local Costco can go to -40°C.
Science Finds A Way
Even with these challenges, mRNA vaccines are currently the best candidates to bring the world out of the Covid-19 pandemic. Interestingly, for many years, scientists thought RNA was a poor candidate for vaccine technology.
New mRNA disintegrates rapidly, even within the same cell it was made. To prevent this, and to help ensure proteins are made, cells rely on a few tricks. During the assembly of mRNA from DNA, the new strand undergoes specific chemical modifications. This prevents mRNA degradation when it exits the nucleus.
When lab-made mRNA is injected into a cell, it is recognized as foreign material. The body goes on the attack, just as it would with an invading virus or microbe. For many years, scientists struggled to overcome this. Some thought it was even impossible. Eventually a team of two scientists, Katalin Kariko and Drew Weissman discovered the answer. Each strand of mRNA is composed of repeating units called nucleosides. There are four types, and their order makes up the coded recipe. Kariko and Weissman discovered that chemically modified nucleosides can disguise mRNA, allowing it to enter cells successfully.
Both current candidate mRNA vaccines build off the discoveries of Kariko and Weissman. They overcame a staggering challenge, and the solution will allow for leaps forward in stem cell research, vaccines, new medication – and more. It already has. Like with this issue, the problem of storing and delivery mRNA vaccines will also be overcome. In the end, science finds a way.
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