The arrival of Moderna and Pfizer/BioNTech’s COVID-19 vaccines in December 2020 not only marked a turning-point in the course of the pandemic, but also an auspicious advancement in the field of biotechnology. The vaccines are the first to effectively use synthetic messenger RNA (mRNA) to help people build immunity to the SARS-CoV-2 virus; most other vaccines inoculate individuals with a weakened or inactivated form of a disease-causing pathogen. But in spite of its novelty, the technology behind mRNA vaccines required decades of persistent experimentation to develop, and future applications will only demand further refinement.
Tomás Maira-Litrán, PharmD, PhD, a researcher in the Division of Infectious Diseases, sat down with CRN to talk about the development of mRNA vaccines, their role in preventing COVID-19 and their promise for the future. An assistant professor of medicine at Harvard Medical School for more than a decade, Maira-Litrán specializes in designing vaccines for hospital-acquired infections, focusing on multi-drug resistant pathogens in particular.
What exactly is mRNA, and why is it being used in vaccines?
TML: Our cells produce mRNA by copying the molecular structure of our DNA. In all of our cells, mRNA is then used as a blueprint to produce the proteins that are essential for life. If you can inject mRNA made in a laboratory into cells, then you can have those cells produce any protein you want. With COVID-19 mRNA vaccines, we use our own cells as mini-factories to produce the spike protein, a key protein of the virus that causes COVID-19, to help the immune system learn a specific routine to respond to it.
Why have mRNA vaccines not been used until now?
TML: The concept of mRNA vaccines has been around for a while, but until about a few years ago, people thought of the idea as a dream. mRNA is very unstable, meaning it can quickly degrade and lose its function. Beyond its instability, one of the main barriers of working with mRNA is that it is very immunogenic, meaning it causes an inflammatory response. This might not only destroy the mRNA but also cause an immune response that could be hazardous to patients’ health. Researchers and funding agencies thought we would never really be able to overcome that obstacle.
One of the key breakthroughs came in the early 2000s after a decade of research, when a Hungarian-born biochemist and senior vice president at BioNTech, Katalin Karikó, PhD, succeeded in developing a slight modification to the chemical structure of the building blocks of mRNA in collaboration with her colleague at the University of Pennsylvania, Drew Weissman, MD, PhD. That modification increased the stability of the mRNA and dramatically reduced the body’s inflammatory response in reaction to it, which is critical to the success of the vaccine.
In addition, the mRNA is encapsulated in “fat bubbles” called lipid nanoparticles. The purpose of these bubbles is twofold: to protect the otherwise very unstable mRNA molecules from degradation by enzymes, and to help deliver them into the cell. We didn’t have this technology until very recently.
When a vaccine is administered, what path does the mRNA follow, from syringe to cell?
TML: The lipid nanoparticle “bubble” binds to a receptor on the cell called the LDL receptor. That receptor is found in pretty much all cells, but from what we know, it seems most likely that the mRNA is delivered locally to the site of the injection, where the immune system’s antigen-presenting cells, such as dendritic cells, internalize and process the mRNA vaccine.
Once the mRNA reaches the cell, it goes into the cytoplasm, where proteins are produced. This is different from the nucleus of the cell, where DNA lives, and there is no mechanism for the mRNA to be transferred to the nucleus. Even if the mRNA could reach the nucleus of the cell, it could not “jump” into our DNA because it would have to be converted into DNA by an enzyme we don’t have, called reverse transcriptase. Once the mRNA is in the cytoplasm of the cell, it can be read as instructions to create the spike protein on the surface of the virus. Some of the body’s B cells can then latch onto the released spike proteins and produce specific antibodies to target them, with the help of T cells in the blood stream. The mRNA vaccine molecules will eventually degrade, and the target cells will stop producing the vaccine. As a result, the mRNA vaccination does not permanently change the target “vaccinated” cells.
How long does the synthetic mRNA remain in the vaccinated cells?
TML: The half-life of the mRNA we find in our own cells is a number of hours, but the synthetic mRNA lasts for days, so that the body can build immunity by continuing to produce the spike protein. There are many different mechanisms that the cells use to degrade the mRNA molecules, which are normal mechanisms to prevent overproducing proteins. After the mRNA from the first vaccine dose is degraded, we administer a second dose. By using more than one dose, you can improve the quality of the antibody response, increasing the affinity of the antibodies or the types of antibodies we produce. Using more than one dose is common in many types of vaccination to strengthen the immune response.
Beyond COVID-19 vaccines, what are other potential applications for mRNA therapeutics? What excites you most about the future of the field?
TML: There are many other vaccines in development that use mRNA technology, including ones for Zika and rabies. You could potentially replace our current flu vaccines with mRNA vaccines, which can be synthesized in a very short amount of time. Influenza vaccines take up to nine months to prepare, and during that time the virus continues to mutate, which is one of the reasons why the vaccines aren’t always a perfect match.
Current mRNA vaccines are designed to produce proteins. We don’t have the technology yet to synthesize sugars, or polysaccharides, which are also important vaccine targets, so that is a current limitation of mRNA technologies that offers additional research opportunities.
I don’t think the scientific community truly believed in mRNA vaccines until COVID-19 came along. But now, this is a reality. Biotech companies interested in expanding the work that can be done in cancer research, the development of monoclonal antibodies and potentially more fields. I am planning to start a new project with mRNA vaccines as well: it’s still a proof-of-concept study, so I can’t discuss it yet. But this field has a lot of potential. COVID-19 turned out to be a perfect situation for mRNA vaccines to flourish, and it has opened the gates for many other mRNA vaccines and the application of mRNA technology in other fields.