This piece was written LIVE during the University of Michigan RNA Seminar featuring Dr. Melissa Moore of Moderna Therapeutics.

Live blogger: Alyse Krausz

Editor: Emily Glass

The saying goes that when something is too good to be true, it typically is. So when the FDA authorized the use of Moderna’s COVID-19 vaccine less than a year into the SARS-CoV-2 pandemic, many people were skeptical. Is the vaccine safe? Is it effective? How was this vaccine developed so quickly when others have taken years?

It may look like all of Moderna’s COVID-19 vaccine development took place in 2020, but the technology that makes the vaccine effective has been years in the making. The Moderna and Pfizer/BioNTech vaccines are based on mRNA. These vaccines deliver mRNA inside lipid nanoparticles (similar to soap bubbles) to our body’s cells. This mRNA provides a blueprint for our cells to make the spike protein that is on the outside of the novel coronavirus. The spike protein then travels to the membrane of our cells and causes an immune response that generates antibodies. If we’re infected with SARS-CoV-2, our antibodies will bind to the spike protein and prevent the coronavirus from attaching to and infecting our cells, making us less likely to become severely ill.

Mechanism of action for the Moderna and Pfizer/BioNTech vaccines
Source: Etienne Raimondeau

Most traditional viral vaccines, such as the yearly influenza vaccine, utilize viruses that are grown in chicken eggs and then inactivated (killed) or attenuated (weakened). The process of figuring out how to grow a new virus in an egg can take months and significantly slows down development. The mRNA in the Moderna vaccine can be quickly synthesized without using the actual virus, making this technology the perfect candidate for a fast-emerging virus, such as SARS-CoV-2.

The scientists at Moderna were able to go from the sequence of the virus to having a vaccine in Phase I clinical trials (used to evaluate safety) in only 63 days. Dr. Melissa Moore, the Chief Scientific Officer of Platform Research at Moderna Therapeutics, emphasizes that Moderna did not cut corners to achieve this rapid timeline. The company did many things in parallel, but it was ultimately many years of work that came together at just the right time. “If the coronavirus had been COVID-17, we wouldn’t have been able to do it”, Moore said.

The mRNA

For the Moderna vaccine to be effective, the mRNA it delivers must be carefully engineered. The scientists at Moderna focused on optimizing three main parameters in their engineering efforts: the ability of the mRNA to be transcribed and translated accurately, the total protein generated by the mRNA, and the duration of protein expression.

The typical flow of genetic information in cells that Moderna harnessed to make their COVID-19 vaccine.
Source: Khan Academy

When generating the mRNA strands, the scientists at Moderna recognized it was imperative that translation (forming a polypeptide aka protein from an mRNA sequence) started precisely at the same place every time and could be completed without errors. Further, the mRNA strands also needed to be translated at a high rate and stay intact long enough to generate a substantial amount of protein in the desired cell type and elicit a robust immune response.

Importantly, these properties are all dependent on the coding sequence of the mRNA (the series of As, Cs, Us, and Gs). The coding sequence influences both the translation rate and how long the mRNA stays around in our cells, which in turn both influence the total spike protein produced and how long the spike protein persists in our cells.

This foundation of knowledge was in place at Moderna in November 2019 as evidenced by their paper published in PNAS explaining the importance of mRNA structure (dependent on coding sequence) on protein expression. The Moderna scientists determined that highly structured mRNA resulted in the most protein being produced. They hypothesize this may be because there are fewer ribosomes translating highly structured RNA. Ribosomes pack onto an mRNA strand during translation. If there are many ribosomes on one strand of mRNA, this can lead to collisions that result in the mRNA being degraded. If there are fewer ribosomes, then they don’t run into each other as often or at all and the mRNA does not degrade. This knowledge of how mRNA structure influences translation formed the basis for the mRNA used in the Moderna SARS-CoV-2 vaccine.

Example of RNA secondary structure.
Source: iGEM 2012

The Lipid Nanoparticle

Once the mRNA is engineered, it has to be delivered to our cells. The Moderna vaccine uses lipid nanoparticles (LNPs) that contain the mRNA that codes for the coronavirus spike protein along with an ionizable lipid that interacts with the mRNA, phospholipids that form the surface membrane of the nanoparticle, a sterol that enhances membrane fluidity, and a PEG lipid that prevents the lipid nanoparticles from fusing in the vaccine vial. The nanoparticles look a lot like lipid transport complexes, similar to high-density lipoprotein (HDL, “good” cholesterol) or low-density lipoprotein (LDL, “bad” cholesterol). This clever construction by Moderna allows the LNPs to utilize the natural way lipids are transported in the body. 

Moore was quick to debunk a vaccine myth: Moderna is not making artificial viruses. They are literally making lipid (aka fat) globules filled with mRNA. In April 2019, Moderna scientists published a paper in Molecular Therapy Nucleic Acids explaining how they spent years optimizing and clinically testing the mRNA-filled fat globules (LNPs) until they were ready to be used in the SARS-CoV-2 vaccine.

Scaling Up

A coronavirus vaccine is only useful if it can be deployed quickly, and this requires large amounts of vaccine to be manufactured in a short amount of time. Typically, biotech startups, such as Moderna Therapeutics, do not invest in large manufacturing facilities until they have a vaccine or drug successfully complete clinical trials. This is simply because it’s expensive to get a pharmaceutical product through clinical trials, and it can fail at any time. 

In 2016, Moderna did not follow the typical trajectory for a biotech startup and gambled $110 million on an mRNA manufacturing facility when they didn’t expect to have marketable products until 2024. This was a risk that certainly paid off as the facility was completed in 2018 and up and running in 2019, months before SARS-CoV-2.

Pandemic Preparedness

The COVID-19 pandemic isn’t the first time there has been a widespread coronavirus. There was SARS in 2003 and MERS in 2012. It was never a matter of if there would be another coronavirus outbreak but when. Preemptively, scientists were studying the spike proteins of other coronaviruses, and Moderna used this knowledge when designing their mRNA vaccine to encode the SARS-CoV-2 spike protein. 

In fact, the Executive Committee of Moderna Therapeutics was in talks with Dr. Anthony Fauci, the director of NIAID at the National Institutes of Health (NIH), and BARDA (Biomedical Advanced Research and Development Authority within the U.S. Department of Health and Human Services) to estimate how long it would take Moderna to go from a viral sequence to initiating a Phase I clinical trial for a vaccine. They were talking about conducting a dress rehearsal with MERS or another known virus, so that they could establish a timeline and be prepared when the next viral pathogen emerged. 

Unfortunately, the dress rehearsal became the performance with the emergence of SARS-CoV-2 in December 2019. When the novel coronavirus sequence was published on social media on January 11, 2020, Moderna got straight to work on a vaccine, nine days before the first COVID-19 case in the US was reported on January 20, 2020.

So how did Moderna develop the SARS-CoV-2 vaccine so quickly? Dr. Moore sums it up with, “Years of preparation and research came to fruition at just the right time!” Moderna scientists spent years studying the structure of mRNA, developing ways to deliver engineered mRNA to cells, and preparing for the next pandemic. Their hard work paid off in the development of a SARS-CoV-2 vaccine in less than a year that is safe and 94.1% effective at preventing illness. The Moderna vaccine is decidedly not too good to be true.

Dr. Melissa Moore was instrumental in developing the mRNA technology for Moderna’s COVID-19 vaccine. In fact, she’s dedicated her career to studying RNA. During her 23 years as a faculty member at Brandeis and later UMassMed, her research focused on the roles of RNA and RNA-protein (RNP) complexes in gene expression and addressed many human diseases, including cancer, neurodegeneration, and preeclampsia. She joined Moderna in 2016 to translate RNA discoveries into drugs, products, and technologies. She is currently the Chief Scientific Officer, Platform Research at Moderna Therapeutics and is responsible for leading mRNA biology, delivery, and computational science research.

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