RNA Vaccines Are Just the Start

Pfizer-BioNTech and Moderna Therapeutics developed wonderfully effective vaccines against the SARS-CoV-2 virus in 2020 based on RNA therapy. The Food and Drug Administration just approved new versions of these vaccines that are effective against the highly infectious omicron variants of the original virus.

How do these companies do this so quickly?

RNA therapy refers to the delivery of a messenger RNA molecule (mRNA), the instructions for making a medically useful protein, to a cell. RNA vaccines contain neither DNA nor any virus particles. RNA therapy is like the “Mission Impossible” letters: The instructions are given and then the message self-destructs. The vaccine delivers the message to the cytoplasm of the cell, where proteins are made, not the nucleus of the cell where DNA resides. Like most messages, the RNA does not last long. After the instructional RNA makes some protein, the RNA itself is recycled inside the cell.

For delivery, the RNA is enveloped in a fatty droplet called a lipid nanoparticle that protects the RNA and is readily taken up by cells throughout the body, including key immune system cells.  The development of lipid nanoparticles that can both protect and carry the RNA cargo took many years to perfect, just like the chemistry of the therapeutic RNA itself.

Here’s how the vaccine works. After injection, the nanoparticles for an anti-COVID-19 vaccine instruct the cells to make the virus spike protein. The immune system then responds to that spike protein to produce the antibodies. Since the spike is the part of the virus that enables the virus to enter a human cell, an antibody against the spike blocks the virus from entering and tags it for destruction. For children and adults with normal, healthy immune systems, presentation of this snippet of the virus teaches our immune systems to recognize and destroy the virus for months to years. We can get a booster if our immunity wanes.

In case a nasty SARS-2 variant like omicron emerges, Pfizer and Moderna both made new vaccines and got them approved within months. This process is fast because only the RNA instruction is modified. Everything else (nanoparticles, manufacturing, scale-up, testing and FDA review) stay the same. Vaccines directed against the omicron variants are already available. Amazing and unprecedented, really.

Are you among those who just don’t like needles? Peter Hotez, an infectious disease expert and director of the Texas Children’s Hospital Center for Vaccine Development (among other things), said that “Since May 2021 an estimated 200,000 unvaccinated Americans have died because they refused COVID-19 vaccines.” Moderna is now working on vaccine delivery by nasal sprays or even pills.

Companies like Pfizer and Moderna now appreciate the many advantages of RNA therapy compared to traditional vaccines. First, the RNA approach leads the recipient’s immune system to make antigens and elicit immune responses with exceptional biological fidelity and specificity. They also know that cocktails of different vaccines are feasible, so that one dose can treat several virus pathogens. Moderna is testing an all-in-one vaccine to treat COVID-19, seasonal flu, and respiratory syncytial virus, a common cause of respiratory tract infections that can be serious in infants or immunocompromised people. In the pipeline as well are vaccines for latent viruses such as Epstein-Barr and cytomegalovirus, and even the human immunodeficiency virus that causes AIDS.

Moderna and BioNTech are also developing RNA therapies for inherited diseases, where the gene is missing or can’t produce a needed protein. Recent research shows that an RNA for a full-length protein, not just a snippet, can be manufactured and delivered by nanoparticles to the appropriate target organ. So, mRNA treatments will soon begin clinical trials for phenylketonuria, a metabolic disorder that requires sufferers to restrict their diets for their entire lives. Already in clinical trials are RNA therapies for glycogen-storage diseases which enlarge the liver and kidneys and stunt children’s growth, and propionic and methylmalonic acidemias, two illnesses where the body cannot properly break down proteins and fats.

Anticancer RNA therapies in the form of vaccines are coming. These target proteins on the surface of a tumor that may be overexpressed, or proteins that have notorious mutations that tend to be tumor-specific. The hope is that these therapies may finally nudge a patient’s own immune system to attack a tumor by ignoring the “cloak of invisibility” that tumors exploit as they grow larger.

Vaccines produced by RNA therapy are limited only by the immune system’s own ability to fight the pathogen. Once the correct protein target from a pathogen is understood, designing the RNA cargo for a vaccine becomes simple. 

Pharmaceutical uses of RNA are in their infancy. There may be few limits to the applications of RNA therapy for human health.

Richard Gelinas, Ph.D., whose early work earned a Nobel prize, is a senior research scientist at the Institute for Systems Biology. He lives in Lakebay.