Why mRNA Vaccines Could Be a Game Changer

The COVID-19 pandemic has been an enormous challenge, upending our normal way of life. But one of the success stories of the pandemic has been the development of not just one, but multiple safe and effective COVID-19 vaccines in less than a year. Two of the vaccines authorized for use in the United States take advantage of a new vaccine technology that delivers mRNA to the recipient’s cells. The recipient’s cells then read the mRNA instructions to build the SARS-CoV-2 spike protein and express it on the outside of the cell for the immune system to recognize and mount an immune response against it.

More traditional vaccine platforms have relied on supplying the recipient with pre-made proteins, viral particles or bacterial cells. Generating these traditional vaccines can be expensive and resource-intensive. While the mRNA vaccines may be new to the public, they have been in development for the past decade in United States government research laboratories under the Biomedical Advanced Research Development Authority (BARDA) and the National Institute of Allergy and Infectious Diseases (NIAID). Effectively, mRNA vaccines were at the right stage of development at the right time for the COVID-19 pandemic.

mRNA: A bare-bones vaccine platform

All living cells follow what is called the "central dogma", meaning that information is processed unidirectionally from DNA to RNA to proteins. The process always proceeds in this direction and not in reverse. An exception is certain viruses like HIV that can reverse the process from RNA to DNA by virtue of a unique enzyme that it carries with it. Proteins and the unique combination of proteins a cell makes determine all sorts of things about your physical appearance, the biochemical reactions in your body, etc.

The transition between RNA and protein is called translation and this activity depends on enzymes in the cell called ribosomes. These ribosomes are located in your cells, are made of protein themselves, and build other proteins using mRNA instructions. Ribosomes read the mRNA supplied in the vaccine as readily as they read the mRNA normally generated in the cell. The cool thing about mRNA vaccines is that the mRNA molecule itself is an unstable, short-lived molecule. The vaccines deliver mRNA that lasts long enough for ribosomes to make lots of the SARS-CoV-2 spike protein, but then the mRNA falls apart within hours and its building blocks are recycled in the cell. In this sense, the mRNA vaccines were designed with safety in mind, since a molecule that falls apart rapidly is unlikely to cause long term side effects. The vaccines themselves are just a piece of mRNA surrounded by a phospholipid bilayer, similar to the membranes of our own cells. It is essentially a bare-bones vaccine platform; and as we can see in mechanics and engineering, the less complicated a design, the less chance something can go wrong.

The safety profile of the mRNA vaccines has been excellent, with millions of people vaccinated so far. Not only are they safe, but the mRNA vaccines are also incredibly effective at preventing COVID-19 disease, hospitalization and death.

An adaptable platform for personalized medicine

The bare-bones platform is helpful not only from a safety standpoint but also for rapid adaptability. Work is underway to develop a booster shot, in case any COVID-19 variant emerges for which the vaccines currently available might not provide adequate protection. It is relatively easy to make a strand of mRNA and to customize it to code whatever protein you want. Therefore, it is easy to imagine that mRNA vaccines have the potential to transform the vaccine development landscape. For parents whose children might receive multiple vaccine injections at a well-child visit, imagine a single injection that does the same job. Fewer pokes mean fewer tears. The mRNA vaccines might also mean easier development of vaccines for diseases that have proven difficult in the past. In fact, a look at Moderna’s pipeline of vaccines in development shows it is using mRNA vaccine technology to develop vaccines for Cytomegalovirus (the most advanced, in Phase II clinical trials), Zika, respiratory syncytial virus (RSV), flu, HIV and others. Cytomegalovirus is a mild infection for most people, but it can reactivate in immunocompromised persons causing a much more significant disease. RSV is another common infection that can be devastating and fatal to children in the first few years of life if they were born prematurely or are otherwise medically fragile. We have seen previous attempts at HIV vaccine development fail at various stages of clinical trials because the high mutation rate of the virus helps it to avoid the immune system. It presents a bit of a moving target for vaccine developers.

Dr Carlos del Rio is a physician and co-director of the Emory University Center for AIDS Research in Atlanta, Georgia (United States). When asked about the potential for an mRNA vaccine for HIV, he responded, “I think that the mRNA technology is great. But the challenge with HIV is not the technology for delivery of the immunogen but knowing the gene one has to include to create protective immunity.” He added, “The lack of an HIV vaccine is not because of a lack of trying or lack of resources.” With the adaptability of mRNA vaccine technology, perhaps Moderna or BioNTech will have better luck. The rapid adaptability of the mRNA vaccine technology might mean major advancements in individualized medicine. Moderna is in Phase II trials to use mRNA technology to develop individualized cancer vaccines. BioNTech is also investing big time in mRNA vaccines for various cancers including melanomas, breast and ovarian cancer, among others. This is important because so often one person’s cancer can look genetically different to another person’s cancer. Imagine treating cancer by training their immune system to attack the cancer cells only, perhaps because of a unique protein they express on their surface. It would be a fine-tuned approach with less potential for the collateral damage we observe for radiation and chemotherapy.

Storage and stability challenges

As amazing as mRNA vaccines might be, they do have one drawback. Because mRNA is an unstable molecule, it has a significant cold-chain storage requirement. This might make it a challenge to deliver these vaccines to the developing world where freezers might not be as common, but the infectious disease burden can be great. Initially, the Pfizer-BioNTech vaccine needed to be held in ultracold freezers, set to -80 °C. But recently the European Medicines Agency (EMA) announced the Pfizer-BioNTech vaccine can be held at standard refrigerator temperature for up to one month (~4 °C). This expands the potential footprint for mRNA vaccine availability. Vaccine efforts in global health have adapted for cold-chain storage in the past, but it undoubtedly adds a challenge when trying to vaccinate remote populations.

In summary, the mRNA vaccine platform has a lot of promise and potential. Assuming they continue to prove extraordinarily effective and safe as million more people are vaccinated, the mRNA vaccines might chart our path to a safer, healthier future.

About the author

Amber Schmidtke is a science communicator and medical educator who has previously worked at  the Centers for Disease Control and Prevention and the Mercer University School of Medicine. You can follow her work here.