mRNA vaccines became a household name in 2020 with the rollout of the first COVID-19 vaccines. Millions of people received these vaccines, and in 2023, Katalin Karikó and Drew Weissman won the Nobel Prize in Physiology or Medicine for discoveries that made them possible.

While mRNA vaccines had been in development for over a decade, the COVID-19 pandemic offered real-world proof that this approach can generate strong immunity faster than nearly any previous vaccine method. But what exactly are mRNA vaccines, how do they differ from traditional vaccines, and what other uses are scientists exploring?

To answer these questions, it helps to first understand what RNA is and how it works in a vaccine. (RNA stands for ribonucleic acid, and the “m” in mRNA means “messenger,” referring to the type of RNA that carries instructions to make proteins.)

DNA, RNA, Antigens and Vaccines

Conventional vaccines (such as those you routinely get for the flu) are made by having cells in a lab produce a protein (known as the vaccine “antigen”) in large quantities. These antigens are then painstakingly purified and formulated into a vaccine that eventually finds its way into your arm to generate life-saving immunity against a bacteria or virus. This process can be both complicated and expensive.

RNA avoids these laboratory complications by leveraging the cells in our bodies to become our own vaccine factories. Within the cells of your body, DNA is used to make RNA and RNA is used to make proteins – the building blocks of everything in your body. RNA vaccines use this process in your own cells to make the protein (antigen) of interest.

DNA Vaccines

Scientists have been exploring DNA-based vaccines for decades, but they’ve faced some big challenges. For these vaccines to work, the DNA needs to reach the nucleus of the cell — the control center where the instructions for making RNA and proteins are read. Getting there, however, isn’t easy. When these types of vaccines have been tested, most of the DNA never makes it into the nucleus, so the cell can’t produce enough of the protein (antigen) to trigger immunity.

On top of that, our cells treat DNA outside the nucleus as a warning sign of infection. When they detect it, they activate defenses that quickly destroy the DNA or even the cell itself to stop what it thinks might be an invading virus or bacteria.

RNA Vaccines

RNA vaccines avoid many of the challenges faced by DNA vaccines. They’re easy to deliver into cells and don’t need to enter the nucleus to work. The RNA is also modified to resist the cell’s natural defenses, helping it last long enough to produce the protein that trains the immune system.

Most vaccines include an antigen (the part that teaches the immune system what to attack) and an adjuvant (a substance that stimulates the immune system). Conveniently, both RNA and its delivery method naturally have adjuvant-like effects, helping the immune system wake up and respond.

Another big advantage is flexibility. RNA can be quickly updated to match changing viruses, which is why COVID vaccines could be adjusted for new strains and why RNA is being explored for seasonal flu, Zika, and Ebola.

RNA vaccines are also showing promise in cancer treatment. While effective cancer vaccines have been hard to develop, combining RNA vaccines with therapies that release the brakes on T cells (called checkpoint inhibitors) has improved outcomes, even in late-stage cancers. This represents an exciting new era in immunotherapy.

Beyond mRNA Vaccines

One of the most exciting things about RNA vaccines is that they can do much more than just teach the immune system to recognize a virus. RNA can shape how the immune system responds by engaging multiple signaling pathways, making it stronger, longer lasting, or better suited to fight different kinds of threats, from bacteria to viruses to cancer.

For example, researchers are experimenting with adding instructions to RNA vaccines that make immune-boosting molecules called cytokines. These molecules help activate immune cells and can make vaccine protection up to ten times stronger and longer lasting.

Scientists are also developing new versions of RNA that can make vaccines work more efficiently or with fewer side effects. The type used in current vaccines is called linear mRNA, which delivers its message for a short time before breaking down naturally. A newer version, called self-amplifying mRNA (SAM), can copy itself inside the cell, meaning smaller doses might be needed to get the same benefit. This could potentially reduce the short-term side effects like fever or fatigue that some people experience with RNA vaccines.

Another promising design is circular RNA (circRNA). Instead of a straight strand, the RNA is joined end-to-end to form a loop. RNA is inevitably short lived, but circRNA is more stable, allows it to keep producing protective proteins for longer, again with the potential for fewer side effects.

Beyond vaccines, RNA can also be used quiet down harmful processes in the body. Certain small pieces of RNA — i.e. antisense oligonucleotides (ASO), small interfering RNA (siRNA), and microRNA (miRNA) — can block the production of faulty or overactive proteins that cause disease. These approaches are being tested in people with conditions such as ALS (Amyotrophic lateral sclerosis), Duchenne muscular dystrophy, and spinal muscular atrophy.

Looking Ahead

Despite the misconceptions, mRNA vaccines have proven to be remarkably safe, with few, if any, long-term side effects. This technology gives scientists an incredible level of flexibility and control for manipulating the positive and negative regulators of not just immunity, but of biology more broadly. As an immunologist and vaccinologist, I can honestly say that superlatives fail me as I consider what RNA-based therapies can now make possible. It is an exciting time to be a scientist… even more an immunologist!