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COVID-19 Vaccine: How do mRNA Vaccines Work?

February 2021

COVID-19 Vaccine vials

What is an mRNA Vaccine?

Messenger ribonucleic acid (mRNA) is genetic material that acts as instructions for cells to develop proteins. An mRNA vaccine harnesses the productive capabilities of mRNA to build up immunities by subjecting the body to proteins that will be recognizable in the future if naturally exposed to a virus.

How do mRNA Vaccines Work?

While most vaccines contain a weakened or inactive infectious pathogen, mRNA vaccines supply our cells with genetic instructions to make pathogen-specific proteins.

SARS-CoV-2, the virus responsible for COVID-19, is an mRNA virus that uses the same mechanism to reproduce within our bodies. The SARS-CoV-2 virus has unique “spike” proteins that allow the pathogens to bind to human cells and enter them.  Once the virus gains entry into the human cell, they  replicate, creating more copies of the virus to continue spreading until eradicated by the immune system.

The COVID-19 vaccines being administered by Pfizer/BioNTech and Moderna are unique, as they are the first mRNA vaccines, and as such, are dependent on mRNA to work properly. With these vaccines, synthetic mRNA attaches to cells and causes them to produce only a portion of the spike protein that is non-infectious. The virus itself is not present in either of the vaccines made by Pfizer/BioNTech or Moderna, just the necessary catalyst for the immune system to begin developing antibodies. This means an individual cannot get sick with COVID-19 as a direct result of these vaccinations.

Development

When developing an mRNA vaccine, it’s possible to encode any protein for expression. If scientists know how to artificially recreate a genetic strand related to a particular disease, they can, in theory, use an mRNA vaccine to treat it. Implementing the correct sequence is the key to treating a variety of diseases, and numerous studies are looking to leverage this technology to aid in the prevention of any number of ailments, from infections to cancer.

The first step in manufacturing this type of vaccine is to isolate functional synthetic mRNA. This can be done by in vitro transcription of a complementary DNA (cDNA) sequence. Essentially, the scientists work backwards from completed genetic material to rebuild the RNA that originally coded the DNA. With the help of certain enzymes such as RNA polymerase, the process will yield synthetic mRNA among a mixture of other nucleotides, transcripted fragments, and extracellular debris.

The next step is to remove contaminants with a combination of extraction and precipitation. Additional purification will increase protein expression and benefit downstream applications. Once the mRNA has been properly isolated and purified, it is either genetically modified to fight a specific virus, or in some cases expanded and encapsulated. If the goal is simply to elicit a particular protein, for example, there is likely no need for alterations to the cell’s genome. If the goal is to treat an existing disease, however, or to create a robust immune response without causing illness, finding and making the appropriate modifications is a critical step in functionalizing the isolated mRNA.

The COVID-19 mRNA vaccines have been artificially modified to only induce production of the harmless spike protein found on SARS-CoV-2, and not the full virus. This method of vaccine production is relatively easy compared to other, older approaches and could save time and money compared to other vaccine platforms while allowing for diverse products to be manufactured.

Immune Response

The ultimate goal of vaccination is to bolster the body’s natural immune response by training it to recognize the SARS-CoV-2 virus and prevent the host from getting COVID-19. When exposed naturally, there is a lag between the time of infection and the immune response because T cells must recognize the foreign pathogen as a threat and develop antibodies to fend it off.

Different types of T cells and B cells work together to diagnose, destroy, and remember harmful pathogens. Following exposure to a pathogen, the body will develop specialized weapons to combat it. This is why people build up immunities over time. In the case of COVID-19, the amount of time natural immunity provides protection against the disease is still unknown, as the virus  hasn’t been around long enough to answer critical questions of long-term immunity in a definitive way, although this research is ongoing. According to research from the Center for Disease Control (CDC), the length of natural immunity varies from person to person and with the emergence of new variants, there is possibly an increased potential for reinfection with a different strain. Scientists are hopeful that the mRNA vaccines will be able to address this problem.

mRNA

DNA is a double-stranded molecule found in your body’s cells that stores genetic information — specifically the instructions on how to make proteins. mRNA is a single-stranded molecule that transfers the genetic codes from the DNA to ribosomes, which actually produce the proteins. Without mRNA the human body would not be able to manufacture proteins. The ribosomes read the strand of mRNA and build a protein that will leave the cell to carry out its desired function in the body.

mRNA vaccines work in much the same way, although the genetic information doesn’t come from DNA in the nucleus, it comes from a group of scientists who have developed a code to make the exact protein they want. They send the synthetic mRNA into the body, enveloped in a defensive polymer shell that allows it to pass through the plasma membrane of cells. If there were no defensive envelope, the mRNA would be identified by the immune system and eradicated before being able to develop the desired protein.

The natural function of mRNA does the work once in a patient’s body, which means the difficult part is pinpointing the correct protein to code into it.

Protein Identification

Identifying the correct protein to code in the mRNA vaccines is a matter of observation and experimentation. By watching how the immune system naturally responds to a virus and testing which parts of that virus can be recognized, researchers can target a protein that doesn’t result in harm to the body but that can trigger an immune response, building immunity.

All known variations of the SARS-CoV-2 virus have a characteristic spike protein. The available mRNA vaccines work by teaching the immune system to recognize and attack that spike protein when it presents itself. This particular protein cannot cause harm alone, so the vaccine cannot itself cause infection by the virus. Consequently, when an individual is later exposed to the virus, the body can instantly target the spike protein and leave the rest of the pathogen unable to infect healthy cells.

New variants of the SARS-CoV-2 virus have begun mutating and are actively spreading among different countries around the world.. The current mRNA vaccines are demonstrating effectiveness against newer variants of SARS-CoV-2, which could perhaps have to do with the fact that the vaccine targets the infiltration mechanism of the virus, unlike traditional vaccines. As more is learned, researchers will be able to further customize the mRNA vaccines to increase efficacy against new strains that emerge.

mRNA Vaccines vs. Traditional Vaccines

The main differences between mRNA and traditional vaccines are the mode of delivery and pathogen presented. Both vaccine types rely on the immune system to recognize a part of a viral structure and build up antibodies for future exposure. With an mRNA vaccine, a strand of genetic material is inserted to create a harmless but recognizable protein. This protein can be dealt with quickly by the immune system, and the synthetic mRNA is destroyed by the cell’s waste management processes.

Traditional vaccines involve injecting an individual with a modified or diminished version of the virus, once again providing the immune system a chance to develop antibodies for it. Even though they’re weakened, these pathogens can still sometimes pose a threat to individuals whose immune systems aren’t functioning properly.

Along with lowering risk, mRNA vaccines can also be artificially programmed to make more than one protein. Hypothetically, a single mRNA vaccine could be administered to produce the proteins of multiple diseases at once. This technology could enable the harmless immunization from any number of ailments with only one injection, saving doctors and patients alike time and money while contributing to better health outcomes.

Drawbacks

Until the FDA granted emergency use authorization (EUA) to the COVID-19 vaccines in December 2020, no mRNA vaccines had ever been approved in the U.S. before. There are still many unanswered questions about how long the vaccine immunity will last and whether or not individuals will be able to get reinfected with the disease. Some of these answers are unknowable at this time, as the disease simply hasn’t existed long enough to track how long immunity will last, although these studies are active and ongoing.

Another issue is the fragility of mRNA molecules. The strands will fall apart if not kept frozen at cold temperatures. The Pfizer/BioNTech vaccine must be stored around minus 70 degrees Celsius to hold its structure. Moderna spent a little more time modifying their vaccine enabling it to hold form at minus 20 degrees Celsius. While the 50 degree drop makes it easier to store and transport, both vaccines are still very difficult to distribute on a wide scale because of the temperature requirement.

It’s also important to note that individuals who have received the COVID-19 vaccinations may still be capable of spreading the disease. While their immune system may be able to fight off the SARS-CoV-2 virus to prevent COVID-19, there can still be a potential buildup of pathogens in the mouth or nose to be passed along to others. However, the chances of infecting others seems to be significantly decreased, and studies into this type of transmission are underway to fully understand what role, if any, asymptomatic spread by vaccinated individuals could play in community spread. In the meantime, preventative measures like masks remain critically important.

Akadeum’s Microbubbles

While the COVID-19 mRNA vaccines are the first to be approved, the concept is not new by any means. Researchers have been contemplating and testing the use of mRNA in vaccines for quite some time for a multitude of different diseases. Evolving medical techniques in the field of immunology require scientists to study mRNA more closely than before. Akadeum Life Sciences has developed a technology that makes the gentle isolation of immune cells like T cells and B cells faster and more efficient than other traditional methods.

Cell separation techniques that rely on harsh magnetic fields or rapidly flowing fluids can cause damage to fragile cell samples – not to mention the amount of resources that must be spent on the proper personnel and equipment. Akadeum uses functionalized microbubbles to bind and float unwanted, contaminating cells to the top of a sample, leaving behind the untouched target cells for further processing. This process is called buoyancy-activated cell sorting, or BACS, and it’s designed to preserve cell health and physiology for downstream applications. BACS can be performed directly in the sample container and requires no extra equipment.

To find out more about BACS and Akadeum’s microbubbles, check out our products or contact us today.

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